Dima Abdulrahim, Owen Bowden-Jones - Textbook of Clinical Management of Club Drugs and Novel Psychoactive Substances - NEPTUNE Clinical Guidance-Cambridge University Press (2022)

Textbook of Clinical
Management of Club Drugs

and Novel Psychoactive
Substances
Published online by Cambridge University Press

Textbook of Clinical
Management of Club Drugs
and Novel Psychoactive
Substances
NEPTUNE Clinical Guidance
Dima Abdulrahim
Programme Manager and Principal Researcher for the NEPTUNE Project, Central and North West London NHS Foundation Trust
Owen Bowden-Jones
Consultant Addiction Psychiatrist, Central and North West London NHS Foundation Trust

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DOI: 10.1017/9781009182126
© The Royal College of Psychiatrists 2022
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every effort has been made to disguise the identities of the individuals involved.
Nevertheless, the authors, editors, and publishers can make no warranties that
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book. Readers are strongly advised to pay careful attention to information
provided by the manufacturer of any drugs or equipment that they plan to use.

Contents
Acknowledgements vi
Part I Introduction and Background 8B Amphetamine-type Stimulants: An

Overview 146
1 An Introduction to Club Drugs and Novel
Psychoactive Substances 1 9 ‘Ecstasy’: MDMA (3,4-Methylenedioxy-N-
Methylamphetamine), MDMA Analogues and
2 Psychosocial Interventions for Club Drugs and Drugs with Similar Effects 165
Novel Psychoactive Substances 22
10 Methamphetamine 202
11 Synthetic Cathinones 240
Part II Drugs with Primarily Depressant
Effects
Part IV Drugs with Primarily
3 Gamma-Hydroxybutyrate (GHB) and Gamma-
Butyrolactone (GBL) 37 Hallucinogenic Effects
4 New Benzodiazepine Novel Psychoactive 12 Hallucinogenic Drugs 267
Substances 65
5 Synthetic Opioid Novel Psychoactive Part V Synthetic Cannabinoid Receptor
Substances (Fentanyl and
Non-fentanyl) 78
Agonists
13 Synthetic Cannabinoid Receptor
6 Ketamine and Other Novel Psychoactive
Agonists 299
Substances with Dissociative Effects 101
7 Nitrous Oxide (N2O) 131
Part VI Concluding Remarks
14 Conclusion 329
Part III Drugs with Primarily Stimulant
Effects
8A Introduction to Stimulant Club Drugs and
Novel Psychoactive Substances 143
Index 330
v
Acknowledgements
The authors would like to express their gratitude to The authors would like to thank the Health
the EU Action Against Drugs and Organised Crime Foundation for supporting the development of the
(EU-ACT) (a project funded by the European Union NEPTUNE work through unrestricted educational
and implemented by FIIAPP International and Ibero- grants.
American Foundation for Administration and Public The authors would also like to thank the multi-
Policy) for an unrestricted quality improvement grant disciplinary groups of experts and experts by experience
used to produce this publication. for their invaluable support in the development of work.
The authors would like to extend particular thanks to
Paul Dargan, David Wood, Jonathan Dewhurst, Sarah
Finley, Fabrizio Schifano, Christopher Whitely, and
Luke Mitcheson.
vi
Part I Introduction and Background
Chapter
An Introduction to Club Drugs and Novel
1 Psychoactive Substances
1.1 Introduction and Background Novel psychoactive substances have been found in
most of Europe and North America, as well as
This document provides a new edition and an update
Oceania, Asia and South America, and in a number
to the 2015 NEPTUNE guidance on the clinical man-
of African countries. To some extent, however, NPS
agement of harms resulting from acute intoxication
are primarily a North American and European phe-
and from the harmful and dependent use of ‘club
nomenon. Although NPS affects all regions of the
drugs’ and ‘novel psychoactive substances’ (NPS).
world, there are diverse regional patterns, in terms
The guidance is evidence-based and is a response to
of both the type and number of NPS reported by
the gap in knowledge and experience in the management
individual countries. The NPS situation also differs
of these drugs. There is evidence that clinicians often feel
by country from one year to the next.4
poorly equipped to assess and manage the harms of NPS
and report that more education on emerging drugs and
misuse patterns is needed.1 It has also been noted that 1.2 NEPTUNE Aims and Guidance
continued education on NPS is fundamental for the
provision of improved harm reduction services, which
Development
can enhance overall care for NPS service users.2
Patterns of drug use continue to be dynamic. At 1.2.1 Objectives of NEPTUNE
the time of publication of this second edition, the This document is the 2022 update of the 2015 guid-
quantity and range of drugs available to people is ance on the harms and management of NPS and club
wider than ever. Recreational users typically use drugs, developed by NEPTUNE (Novel Psychoactive
a wide repertoire of substances: Treatment UK Network). This edition has been
• ‘Traditional’ drugs continue to be the most used funded and supported by EU-Action Against Drugs
(depending on country, but e.g. cannabis, cocaine, and Organised Crime (EU-Act).5
amphetamines). The aim of the guidance is to improve confidence,
• Novel psychoactive substances (NPS) are used competence, and skills of clinicians in the detection,
along with these traditional drugs, but have not assessment, and management of the harms associated
replaced them. with the use of NPS.
• Increase of non-medical use of prescription drugs. Specific areas addressed include:
This document focuses on the health-related harms of • Detection/identification. Recognising the
club drugs and NPS and their clinical management. significant psychological, physical, and social risks
The use of substances referred to as ‘club drugs’ which can be associated with club drugs and NPS,
has been well established for many decades. It and equipping professionals to be able to
includes illicit substances, e.g. cocaine and amphet- recognise problematic use, associated harms, and
amine, as well as NPS. dependence.
The use of NPS is a relatively more recent global • Assessment. Assessment of the problems related
phenomenon, with 120 countries and territories to the use of club drugs and NPS, including the
from all regions of the world having reported one assessment of both direct and indirect harms.
or more NPS to the United Nations Office on Drugs • Management. Clinical management of acute and
and Crime (UNODC) Early Warning Advisory on chronic harms related to the use of club drugs and
New Psychoactive Substances.3 NPS – based on the best available evidence.
1
Part I Introduction and Background
Chapter
An Introduction to Club Drugs and Novel
1 Psychoactive Substances
1.1 Introduction and Background Novel psychoactive substances have been found in
most of Europe and North America, as well as
This document provides a new edition and an update
Oceania, Asia and South America, and in a number
to the 2015 NEPTUNE guidance on the clinical man-
of African countries. To some extent, however, NPS
agement of harms resulting from acute intoxication
are primarily a North American and European phe-
and from the harmful and dependent use of ‘club
nomenon. Although NPS affects all regions of the
drugs’ and ‘novel psychoactive substances’ (NPS).
world, there are diverse regional patterns, in terms
The guidance is evidence-based and is a response to
of both the type and number of NPS reported by
the gap in knowledge and experience in the management
individual countries. The NPS situation also differs
of these drugs. There is evidence that clinicians often feel
by country from one year to the next.4
poorly equipped to assess and manage the harms of NPS
and report that more education on emerging drugs and
misuse patterns is needed.1 It has also been noted that 1.2 NEPTUNE Aims and Guidance
continued education on NPS is fundamental for the
provision of improved harm reduction services, which
Development
can enhance overall care for NPS service users.2
Patterns of drug use continue to be dynamic. At 1.2.1 Objectives of NEPTUNE
the time of publication of this second edition, the This document is the 2022 update of the 2015 guid-
quantity and range of drugs available to people is ance on the harms and management of NPS and club
wider than ever. Recreational users typically use drugs, developed by NEPTUNE (Novel Psychoactive
a wide repertoire of substances: Treatment UK Network). This edition has been
• ‘Traditional’ drugs continue to be the most used funded and supported by EU-Action Against Drugs
(depending on country, but e.g. cannabis, cocaine, and Organised Crime (EU-Act).5
amphetamines). The aim of the guidance is to improve confidence,
• Novel psychoactive substances (NPS) are used competence, and skills of clinicians in the detection,
along with these traditional drugs, but have not assessment, and management of the harms associated
replaced them. with the use of NPS.
• Increase of non-medical use of prescription drugs. Specific areas addressed include:
This document focuses on the health-related harms of • Detection/identification. Recognising the
club drugs and NPS and their clinical management. significant psychological, physical, and social risks
The use of substances referred to as ‘club drugs’ which can be associated with club drugs and NPS,
has been well established for many decades. It and equipping professionals to be able to
includes illicit substances, e.g. cocaine and amphet- recognise problematic use, associated harms, and
amine, as well as NPS. dependence.
The use of NPS is a relatively more recent global • Assessment. Assessment of the problems related
phenomenon, with 120 countries and territories to the use of club drugs and NPS, including the
from all regions of the world having reported one assessment of both direct and indirect harms.
or more NPS to the United Nations Office on Drugs • Management. Clinical management of acute and
and Crime (UNODC) Early Warning Advisory on chronic harms related to the use of club drugs and
New Psychoactive Substances.3 NPS – based on the best available evidence.
1
https://doi.org/10.1017/9781009182126.001 Published online by Cambridge University Press
An Introduction to Club Drugs and Novel Psychoactive Substances
• Harmr eduction. Interventions aimed at preventing • New populations in treatment (including new
morbidity and mortality among individuals patterns of drug use and contexts of harm);
presenting to clinical settings, including measures to • New harms (some club drugs are associated
reduce the harms of club drugs and NPS for with harms not previously linked to illicit
individuals and communities and to help patients drug use, e.g. ketamine-related ulcerative
achieve and sustain recovery and well-being. cystitis);
This document provides guidance, not guidelines. The • New manifestation of drug-related harms which
implementation of NEPTUNE at national levels must are familiar to clinicians (e.g. dependence and
take place within the principles of national and inter- withdrawal associated with gamma-
national guidelines, national and local protocols, as hydroxybutyrate (GHB).
well as the international standards and broad principles NEPTUNE therefore aims to improve clinicians’
for the treatment of substance misuse disorders.6,7 knowledge of the specific issues relating to NPS and
The implementation of NEPTUNE learning into to support evidence-based practice at local levels. It
clinical practice must adapt the learning to take into also aims to help improve clinicians’ confidence in
account factors specific to the region, country or sector working with patients who use NPS, by providing
where they are implemented. This includes the needs, the following:
priorities, legislation, policies, systems of healthcare • ‘Technical’ knowledge (what the drugs are and
delivery and resources of the various countries. how they work);
Adaptation should be carried out without undermining • ‘Cultural’ knowledge (who is using them, and how);
the validity of the evidence-based training. Local and
• ‘Clinical’ knowledge (how to clinically manage
national protocols, including prescribing protocols,
both acute and chronic presentations).
should be used.
For up-to-date information, it is also recom-
mended that clinicians contact the Poisons Centres 1.3 Target Audience for the Guidance
in their region, where available. These are specialised
units that advise on, and assist with, the prevention, 1.3.1 Primary Audience
diagnosis, and management of poisoning. Their struc-
This guidance is aimed primarily at a clinical audience
ture and function varies around the world; however,
and most specifically clinicians who manage physical and
at a minimum, a poisons centre is an information
mental health problems associated with harmful or/and
service. Some centres may also include a toxicology
dependent drug use and ensuing acute or chronic
laboratory and/or a clinical treatment unit.8
problems.
These will include clinicians working in spe-
1.2.2 Why Produce Guidance on Club cialist drug treatment and recovery services, as
Drugs and Novel Psychoactive Substances? well as in emergency departments. The document
The underlying principles of good clinical practice in is also relevant to professionals working with
relation to the users of club drugs and NPS are the same populations at risk of drug-related harms and
as for harmful and dependent drug misuse in general. associated poorer treatment outcomes, such as
Clinicians’ existing experience of the treatment of mental health services, prison health services, pri-
other commonly used drugs (such as heroin, alcohol mary care, sexual health services, HIV treatment,
or cannabis for example) is very relevant to the treat- hepatology and others.
ment of club drugs and NPS.
However, good assessment and management of the 1.3.2 Other Audiences
harms of club drugs and NPS must also consider the Although not directly aimed at them, this docu-
particular challenges posed by novel drugs and address ment is also a resource for funders/commissioners
them directly. These include challenges posed by: and policy-makers in developing local, national or
• New drugs (rapidly changing profile and ever- regional services. It also provides patients and
increasing numbers of substances, with poorly carers with information on what interventions
understood harms); should be available.
2
1.4 The Process of Developing the Guidance
1.4 The Process of Developing base on NPS remains relatively small, albeit exp-
anding.10
the Guidance In particular, studies on the toxicity and manage-
ment of the harms of NPS and risks associated with
1.4.1 Method for the Literature Review long-term use and dependence liability are few, partly
This document is based on a comprehensive review of because most NPS have limited or no medical use, and
the English language literature on the harms and the partly because some of these substances have only
clinical management of a range of club drugs and recently emerged.
NPS, using systematic methods. A multi-disciplinary Overall, a review of the evidence shows that there
group of people were involved in developing the continues to be limited robust evidence, in particular
NEPTUNE framework and the guidance document from meta-analyses or high-quality randomised con-
was independently peer reviewed. trolled trials, and even controlled and semi-
The first edition of this guidance was published in experimental studies are few. The bulk of the research
March 2015.This edition also includes a review of the available provides what is referred to as emerging
research literature published until 2021. research evidence, as it is based principally on non-
For the review of the evidence, studies were iden- experimental descriptive studies, consisting mainly of
tified using electronic searches of Medline, Medline case reports and series and a small number of pro-
Plus, the Cochrane Library, CINAHL, Current spective observational studies, retrospective cohort
Content, Embase, PUBMED, PsychINFO, Google studies and analysis of patient records.
Scholar and the Science Citation Index. In addition, This document therefore does not give definitive
bibliographies of articles were screened for additional answers on the clinical management of NPS, but broad
relevant studies. guidance based on the current best available evidence.
The outputs of searches were considered against
sets of inclusion and exclusion criteria. The citations 1.4.2 Substances and Drug Groups
produced by these searches were then screened via
their abstract. Those considered relevant were identi- Covered by This Guidance
fied and subjected to critical assessment.
The critical assessment of the evidence was based 1.4.2.1 Classifying Novel Psychoactive Substances
on the framework developed by the British Just over psychoactive drugs (NPS) have been
Association for Psychopharmacology for the develop- reported for the first time in the last decade or so.
ment of guidelines for the management of substance Because of the very large number of NPS that have
misuse.9 This classifies the strength of evidence as been detected and those that will emerge in the future,
follows: it is not possible to cover them all in any detail within
• Strong research evidence (e.g. Cochrane reviews, the confines of this work. Nor is it realistic for clin-
meta-analyses, high-quality randomised icians to remember information on all NPS.
controlled trials); In order to deal with these large numbers of NPS
• Research evidence (e.g. controlled studies or semi-
and to future-proof this guidance, a two-pronged
experimental studies); approach has been adopted.
• Emerging research evidence (e.g. descriptive or Categorising Groups of Novel Psychoactive Substances
comparative studies, correlation studies,
In order to understand the harms of NPS and how to
evaluations or surveys and non-analytic studies,
manage them, it is useful to be able to classify them
e.g. case reports, case series);
into different categories. Classification of NPS could
• Expert panel evidence/consensus;
be achieved using a variety of approaches, including
• Expert by experience evidence (service users/ chemical structure or pharmacological effect.
patients); However, a useful method of categorising NPS is
• Lack of evidence (no evidence, for or against); according to their primary psychoactive, physical and
• Conflicting evidence. psychiatric effects and to use categories that clinicians
The 2021 update of the 2015 NEPTUNE guidance working with the effects of substance misuse are
document continues to suggest that the evidence already familiar with (see Figure 1.1).
3
Primarily STIMULANT
Cathinones piperazines Primarily DEPRESSANTS
Phenethylamines (including GHB/GBL
amphetamines, methamphetamine, Ketamine
mephedrone, MDMA, 2C series, Methoxetamine
D series, benzodifurans, Nitrous oxide
PMMA, PMA)
Primarily HALLUCINOGENS
(Agonists at 5H2A receptor) SYNTHETIC CANNABONOID
Tryptamines DMT, psilocybin, RECEPTOR AGONISTS
AMT LSD phenethylamines CB1 and CB2 receptor agonists
NBOMe, 2CB including JWH and CP
Salvia divinorum (classical, non-classical and hybrid)
Amanita mushrooms
Figure 1.1 Categorising substances by their primary psychoactive effects
A drug’s primary effects will provide a conceptual to those associated with the controlled drugs they
framework for NPS, which will help clinicians navi- have been manufactured to mimic.
gate the hundreds of new substances detected in The proximal mechanisms of most of these effects
recent years, while allowing them to draw on their (as far as they are known) are shown in Table 1.1.
existing experience of substance misuse.
This classifies NPS and club drugs into the following 1.4.2.2 Focus on Particular Substances
groups: The second prong of our approach is to focus in more
• Primarily stimulants detail on some commonly used NPS drugs (as well as
• Primarily depressants their derivatives and related compounds) and those
• Primarily hallucinogens that potentially cause most harm.
• Synthetic Cannabinoid Receptor Agonists Where a particular NPS is not discussed in this
(SCRAs) are put in a category of their own and document, clinicians can refer to the broad groups
are classified as a fourth separate category, as to which it belongs and can extrapolate informa-
they do not fit easily into the other groups. tion on the management of its acute and chronic
This is because they are such a chemically and harms, while taking into account potential differ-
pharmacologically diverse group that their ences in potency, toxicity, half-life and length of
specific harms and clinical management also effect.
varies widely.
Although these classifications provide a useful frame- 1.5 Background: What Are Club Drugs
work for this guidance, it is important to note that and Novel Psychoactive Substances?
they are not rigid categories. In reality, many drugs
have a combination of effects, often dose-related, e.g.
a primarily depressant drug can have stimulant effects 1.5.1 What Is a Club Drug?
at low doses. In addition, people will sometimes use ‘Club drugs’ is a short-hand term used for conveni-
NPS as part of a wider repertoire of illegal drugs and ence to refer to a group of psychoactive substances
alcohol. The co-ingestion of more than one drug is typically used in dance venues, house parties, music
common. festivals and sometimes in a sexual context. The term
Most NPS are designed to provide legal alterna- therefore describes a diverse group of substances with
tives to controlled substances, and have harms similar different actions.
4
1.5 Background: What Are Club Drugs and Novel Psychoactive Substances?
Table 1.1 Proximal mechanisms of drug effects
Drug Primary (proximal) target Brain effect

Alcohol Agonist at GABA and antagonist at Increases GABA; blocks NMDA glutamate
glutamate receptors receptors
Benzodiazepines Agonists at benzodiazepine site on GABA-A Increase GABA
receptor
GHB GHB and GABA-B receptor agonist Mimics GABA; inhibits dopamine release
Ketamine NMDA glutamate receptor antagonist Blocks glutamate
Khat (natural cathinone) Releases ephedrine, a dopamine releaser Mild increase in noradrenaline and dopamine
Mephedrone (synthetic Releases dopamine and blocks reuptake
cathinone)
Natural cannabis Cannabis CB1 receptor agonist Stimulates endo-cannabinoid signalling,
leading to a change in cortical and memory
function
Cocaine Blocks dopamine reuptake site Greatly increases dopamine
Amphetamines Release dopamine and block reuptake Greatly increase dopamine and noradrenaline
(dexamphetamine and
methyl)
MDMA Blocks serotonin and dopamine reuptake Increases serotonin and dopamine functioning
Hallucinogens Agonists at serotonin 5-HT2A receptors Change across-cortex signalling
Opioids Agonists at endorphin receptors Produce euphoria, reduce pain
Agonist = drug that activates or stimulates a receptor; Antagonist = drug that blocks a receptor.
1.5.2 What Is a Novel Psychoactive aware of the legal framework surrounding illicit sub-
stances and are continuously replacing controlled
Substance? compounds with an array of compounds, which are
The term ‘novel psychoactive substance’ (NPS) has modified to avoid legal control. Given the very
been used to describe a diverse group of sub- numerous possibilities for altering the structure of
stances that rapidly emerged from the early to chemicals, the list of substances produced is likely to
mid-2000s.11 grow continuously.12 New substances are produced
The UNODC defines NPS as ‘substances of abuse, very quickly to replace those that are placed under
either in a pure form or a preparation, that are not legal control by various states.13
controlled by the 1961 Single Convention on Narcotic As the number of NPS grew rapidly, by 2013 the
Drugs or the 1971 Convention on Psychotropic number of NPS already exceeded the number of
Substances, but which may pose a public health psychoactive substances controlled at the inter-
threat’. national level.14 By December 2021, a total of 1,124
Most NPS are thought to be manufactured to mimic unique new substances have been reported to the
the effects of controlled drugs. NPS were developed UNODC Early Warning Advisory (EWA) on NPS
initially as ‘legal’ replacements to established controlled by Governments, laboratories and partner organisa-
drugs such as cannabis, heroin, cocaine and MDMA. tions. These can be grouped as follows: stimulants
They are sold openly, in some countries at least, as well 36%, SCRAs 29%, classic hallucinogens 15%, opioids
as on the Internet in branded products advertised as 9%, dissociatives 3%, sedatives/hypnotics 3% and not
‘legal highs’ or ‘research chemicals’ or as ‘food supple- yet assigned 5%.15,16
ments’, in attempts to make these substances attractive to In Europe, 830 new psychoactive substances were
users. being monitored by the end of 2020 by the European
Many hundreds of NPS have been reported for the Monitoring Centre for Drugs and Drug Addiction
first time in the last decade. There is no doubt that the (EMCDDA), 46 of which were detected for the first
producers of novel NPS and ‘legal highs’ are well time in Europe in 2020.17
5
Not all NPS detected continue to be available over under international control. These control measures
time, as some appear for the first time and then have to be implemented into the national legal frame-
disappear from the market. The World Drug work of each country.28
Reports suggest that the overall number of NPS pre- Other NPS continue to be outside International
sent on the market has stabilised at approximately 500 Drug Control Conventions. However, their legal sta-
substances per year over the period 2015–2019. tus differs widely from country to country. To date,
In terms of the use of NPS and despite the con- approximately 60 countries have implemented legal
tinuing increase in the emergence of new NPS, one responses to control NPS by amending existing legis-
study suggested that a core group of over 80 NPS have lation or through innovative legal instruments.
become established as recreational drugs, supple- Some countries have adopted controls on entire
menting traditional drugs that are misused and substance groups of NPS using a so-called generic
becoming part of the repertoire of substances avail- approach, or have introduced analogue legislation
able for consumption.18 that invokes the principal of ‘chemical similarity’ to
Currently, most NPS are stimulants, followed by an already controlled substance to control substances
synthetic cannabinoid receptor agonists and a smaller not explicitly mentioned in the legislation.29
number of hallucinogenics and opioids.19,20 It has These controls have limited the open sale of these
been noted that the increase in the number of opioid products. They may also have played a role in redu-
NPS and benzodiazepine NPS potentially signals that cing the number of NPS detected for the first time.
new psychoactive substances are increasingly more However, challenges remain.
targeted at the long-term and more problematic
drug users.21 1.5.4 Development and Spread of Large
Novel psychoactive substances are generally pro-
duced in bulk quantities by chemical and pharma- Numbers of Novel Psychoactive Substances
ceutical companies often in China or India, or in Although the number of NPS has been growing at
clandestine laboratories in Europe. They are then a very fast pace, it has been noted that this yearly
shipped to Europe, where they are processed into increase appears to be slowing down in recent years.
products, packaged and marketed.22 In Europe, it has been reported that the number of
It has been argued that these substances are not new substances identified for the first time each year
‘legal’ but are instead ‘not prohibited’. Their non- peaked in 2014–2015, but has since stabilised at levels
controlled status does not reflect their safety, but comparable to 2011–2012.30
rather the lack of regulation over their production, The causes of this are unclear, however may reflect
distribution and use.23,24 Many are untested and have the results of sustained efforts to control new sub-
unknown psychological and toxicological effects.25,26 stances in Europe and legislation in some countries.
Not all NPS are ‘novel’. ‘New’ does not always This may have resulted in reducing the incentive for
mean a new invention but could refer to substances producers to keep ahead of legal controls and develop
that have recently been made available for recre- new compounds. In addition, control measures and
ational use, e.g. mephedrone was reportedly first syn- law enforcement operations in China targeting
thesised in 1929, but emerged as a recreational laboratories producing NPS may also have played
substance of misuse as late as 2007.27 Other ‘new’ a role.31,32
substances were synthesised and patented in the Nonetheless, and despite reduction in yearly num-
1970s or earlier, but recently their chemistry has ber of NPS detected, challenges continue and new
been modified slightly to produce psychoactive effects ones emerge. NPS continue to appear at the rate of
similar to those of well-established illicit substances. one per week. There is also no evidence that the
overall availability of NPS has reduced and the drugs
1.5.3 Changes in Legal Control of Novel may still be available more covertly on the illicit
market.33
Psychoactive Substances Some NPS are also now well-established in the
The legal position of some NPS has changed over drugs market, most particularly SCRAs and synthetic
time. At the international level, up to March 2019, cathinones.34 There is also some evidence the tighten-
the Commission on Narcotic Drugs placed 48 NPS ing of regulation may have sometimes led to the
6
1.6 Club Drug and Novel Psychoactive Substance Use
decrease in the number of people using NPS, but users the specific types of NPS being consumed. Benshop
instead switched to other types of drugs.35 et al.’s (2020) exploratory and confirmatory factor
There are also changes in the type of substances analysis identified five factors across a number of
being detected for the first time globally, with new countries: coping, enhancement, social, conformity
substances increasingly targeted at long-term and and expansion motives. Overall, marginalised users
more problematic drug users, particularly NPS scored higher on coping and conformity motives.
synthetic opioids and benzodiazepines.36,37,38,39,40 Nightlife groups showed higher endorsement of social
Problematic NPS use is also increasingly found in motive, whereas online community users showed
some vulnerable groups in Europe, e.g. people who higher scores on expansion motives. Various types
inject drugs and homeless people, and has been asso- of NPS were also associated with different motives.
ciated with increased levels of physical and mental Motives for use of the specific substances are also
health problems.41 discussed in the relevant sections throughout this
chapter.48,49,50,51,52,53,54
Some NPS, e.g. mephedrone, are also used for
1.6 Club Drug and Novel Psychoactive sexual enhancement, including by gay and bisexual
Substance Use men who use it in the context of ‘chemsex’.55
1.6.1 Overall Drug Use 1.6.3 Population Groups Most Likely

Novel psychoactive substances have not replaced to Use Novel Psychoactive Substances
traditional illicit drugs, but exist alongside them. There is evidence that levels of NPS- and drug use are
Data from European countries on NPS are avail- higher among particular populations. These are the
able from half the countries, but are often not com- following:
parable. Existing information suggests that use of NPS
is overall low in comparison to traditional illicit club 1.6.3.1 Young People
drugs. NPS nonetheless are consumed and are more The use of club drugs and NPS occurs in nearly all age
likely to be used by some population sub-groups. groups, but studies have also shown that young people
are more likely to use them than older people and that
1.6.2 Club Drug Users and Contexts of Use they are mainly used by young males.56,57,58
In general, clubbing and club drug use, as part of
Different people will use substances for different reasons
a socially active lifestyle, has been associated with
and each chapter in this text will look at the subjective
elevated sexual health risks59 and a history of promis-
effects of a substance desired by people who use it.
cuous sexual activity.60
There is some research that has looked at why
people use NPS specifically, which includes the fact
1.6.3.2 Poly-drug Use
that users turn to NPS as a substitute to traditional
drugs when these are prohibited or when there is The users of club drugs and NPS will typically use
reduced supply or perceived drop in quality.42 a wide repertoire of substances. The co-ingestion of
There is also evidence that the motives for using more than one substance (simultaneous use), includ-
NPS are curiosity, enhancement of social situations, ing alcohol, increases the risk of adverse effects,61 as is
the enjoyable effects, a desire to ‘get high’, and a belief discussed in greater detail in later chapters of this text.
that NPS are safer and more convenient.43,44,45,46 In comparison to other drug users, NPS users have
Novel psychoactive substances were also used higher levels of poly-drug use, and a history of over-
because they were seen as facilitating a novel and dose on any drug in the past year.62
exciting adventure, as promoting self-exploration
and personal growth, functioning as coping agents, 1.6.3.3 ‘Clubbers’ and People Who Frequent Night-
enhancing abilities and performance, fostering social Time Economy Leisure Venues
bonding and belonging, and acting as a means for Studies have consistently shown that drug use is more
recreation and pleasure.47 commonly reported in surveys carried out in nightlife
It has been argued that the motives for NPS use settings (like clubs, bars or music festivals) than
may be associated with both the groups of users and among the general population.63 There is evidence
7
that people who use the night-time economy, and 1.6.3.5 Problem Drug Users
dance clubs or nightclubs in particular, are more likely As mentioned previously, NPS are increasingly tar-
to use club drugs than the general population.64,65 geted at established long-term drug users, such as
Young adults attending nightlife events in pubs and people dependent on opioids or benzodiazepines. In
discos are also more prone to poly-substance use, addition, in some European countries, stimulant NPS
mainly combining NPS with alcohol and cocaine.66 and most particularly synthetic cathinones are one of
There is also some evidence that the use of club drugs the main substances injected by problem drug users.
and NPS is higher among people who attend electronic This will be discussed in further detail below.
dance music parties at nightclubs, festivals and ‘raves’
than those who do not.67,68,69,70,71,72 1.6.3.6 Homeless Populations and Prison Inmates
Other targeted surveys have also shown variations In some countries, synthetic cannabinoid receptor
by user of different types of venues in the night-time agonists (SCRAs), in particular, have been associated
economy, e.g. those attending nightclubs reporting with homeless people and with prison populations.
significantly higher levels of drug use than bar/pub This will be discussed in further detail in the following.
attenders.73
There is some evidence that increased levels of 1.6.3.7 ‘Psychonauts’
drug use were associated with a higher frequency of ‘Psychonaut’ is a term given to a group of people who
visits to pubs, bars and nightclubs. E.g., in the UK, use have been described as having a relatively good under-
of any Class A drug (including MDMA and cocaine) standing of how NPS work, based on them experi-
in the last year was around 11 times higher among menting with a wide variety of traditional and new
those who had visited a nightclub at least four times in substances. Psychonauts will document their experi-
the past month (22.4%) compared with those who had ence. NPS are typically consumed in a familiar and
not visited a nightclub (2.1%).74 relatively controlled environment, with dosages often
carefully measured and timed. Their experiences are
1.6.3.4 Lesbian, Gay, Bisexual and Transgender often made available to other psychonauts through
Populations (LGBT+) online fora.99
There is evidence that levels of club drug use among Internet sites and moderated discussion fora and
men who have sex with men (MSM) and among les- blogs are used to share information about newer com-
bian, gay, bisexual and transexual (LGBT) people, are pounds, feedback on the effects of drugs and harm
higher than in the general population.75,76,77,78,79,80,81 reduction advice developed through experience.100
Club drugs have been described as a popular aspect of The Internet and sites such as Drugs Forum,
socialisation.82 Bluelight and Erowid, provide platforms for sharing
There are concerns over associations between club experience and information.101 These user sites have
drug and NPS use and high-risk sexual behaviours also provided researchers with some understanding of
among a minority of MSM. This includes concern these drugs in instances where scientific evidence was
over ‘chemsex’, a term used to describe sex between not available and it is suggested that they are a good
men that occurs under the influence of drugs imme- source of information for researchers for the better
diately preceding and/or during the sexual understanding of NPS.102
session,83,84 with methamphetamine, GHB/GBL and
mephedrone the drugs most often reported. 1.6.4 New Markets and User
A combination of factors, including high-risk
sexual practices and injecting drug use, have Communication about Drugs
been described as ‘a perfect storm for transmission ‘Traditional’ methods remain the most common ways
of both HIV and hepatitis C (HCV), as well as to acquire drugs (dealers, friends, family), both classic
a catalogue of ensuing mental health problems’.85 drugs and NPS. However, the Internet now occupies
Whereas not all individuals involved in ‘chemsex’ a growing role in the sale of drugs, with significant
practice engage in high-risk behaviours, ‘chemsex’ drug sales on the darknet and the potential to grow.
has been associated with risk and adverse Novel psychoactive substances can sometimes be
effects.86,87,88,89,90,91,92,93,94,95,96,97,98 bought on the ‘clearnet’ (a part of the Internet
8
1.7 Brief Overview of the Effects and Harms of Club Drugs
accessible to standard search engines) or from the ‘dark structure, pharmacological activity or psycho-
web’ (a part of the Internet only accessible through logical effects.53,54,115,116
specialist anonymising web browsers), with the ‘dark-
net’ also selling controlled substances.103,104,105,106,107 It 1.7.2 Toxicity and Other Acute Harms
has been reported that when compared with current The harms associated with club drugs and NPS can, as
estimates of the annual retail value of the overall EU with ‘traditional’ drugs including alcohol, be ranked
drug market, sales volumes on darknet markets are based on the relative harms.117
currently modest, but growing.108 ‘Toxicity’ generally refers to the extent to which
For a growing number of people, the Internet is a substance causes functional or systemic damage to
now the first place they look when searching for a living organism.118,119
recreational drugs and their related information, Our knowledge of the effects and toxicity of many
especially when faced with the rapid and baffling NPS remains limited, as it is often mainly based on user
proliferation of NPS.109 A study carried out in the reports and clinical intoxication cases, with very limited
Netherlands has shown that online customers are pharmacological and toxicological data available.120
sometimes willing to pay more for the convenience There is nonetheless enough evidence to show that
of purchasing drugs online.110 club drugs and NPS are associated with a range of
The Internet has also had an impact on drug use harms.121 The growing market for new substances has
patterns and behaviours. A UNODC 2020 publication been linked to an increase in the number of serious
has reported that more than a quarter of people who adverse events – particularly non-fatal and fatal
started using drugs before they began buying drugs on poisonings.122,123,124
the darknet, then consumed a wider range of drugs, There are wide variations in the toxicity of the
and approximately 10% reported that that they con- various club drugs and NPS, including their single-
sumed a different class of drugs.111 dose lethal toxicity.125 An index for fatal toxicity has
Especially when not controlled, NPS have been been developed, showing differences between the
marketed as ‘plant food’, ‘bath salts’, ‘research chem- various NPS and demonstrating that GHB/GBL,
icals’, ‘incense’ or ‘herbal highs’ and are typically AMT, synthetic cannabinoid receptor agonists
labelled as ‘not for human consumption’.112,113 (SCRAs) and benzofurans had a higher fatal toxicity
There is also some evidence that NPS, as well as than other NPS.126 In recent years, benzodiazepine
traditional drugs, are sometimes acquired through NPS have also been linked with fatalities, such as the
social media. The most commonly used technology case of etizolam and other ‘street’ benzodiazepines.127
to acquire drugs is that of mobile phones. Phone- Similarly, new opioids including fentanyl NPS have
based drug delivery services, sometimes known as been associated with high levels of acute toxicity.
‘ring and bring drug phone lines’ or ‘dial-a-drug’ are The harm associated with any drug of potential
increasingly common. This is true for NPS as well as misuse may include: the physical and mental health
traditional illicit substances, and the European market harms to the individual user caused by the drug;
for cocaine has been described as undergoing overdose; the dependence-inducing potential of the
a process of ‘Uberisation’, where more sellers provide drug; and the effects of drug use on families, commu-
‘fast delivery anywhere at any time’.114 nities and society.128 All aspects need to be considered
when assessing the impact of a drug.
1.7 Brief Overview of the Effects In addition, individuals vary greatly with respect
to metabolism and vulnerability to physical and men-
and Harms of Club Drugs tal health problems. A number of other factors are
also linked to acute toxicity:
1.7.1 How Drugs Work • The consumption of more than one substance will
Most NPS are designed to provide legal alternatives to increase the chances of acute toxicity, particularly
controlled substances, and have effects similar to when drugs with similar physiological effects are
those associated with the controlled drugs they have combined (e.g. sedatives such as GHB and alcohol,
been manufactured to mimic. or stimulants such as cocaine and amphetamine).
As mentioned previously, drugs can be classi- • The risk of overdose is increased by repeated
fied in various ways – according to chemical administration of the drug.
9
• The safety ratio of drugs does not reflect the • Poly-drug use continues to be a factor and an
metabolic or functional tolerance that a user may important consideration in NPS fatalities.
have developed. • Benzodiazepine-type NPS feature highly in cases
• Non-drug variables can alter toxic reactions of driving under the influence of drugs.134
significantly (e.g. the psychological effects of the Some NPS have also been shown to have a liability to
environment, diet, stress, expectation etc.).58,129 produce dependence and some have been associated
• The mode of administration, with injecting not with a withdrawal syndrome, which can be severe, for
only exposing the user to the risk of bacterial example in the case of GHB/GBL.
infections but also increasing the risk of overdose
and dependence.130
• Drug purity and adulterants can affect toxicity.
1.7.3 Particular Challenges of Novel
Club drugs and NPS pose a particular challenge to Psychoactive Substances
clinicians and constitute a public health challenge for
the following reasons:131 1.7.3.1 Unpredictability of Novel Psychoactive
• these substances are not approved for human Substances: Products Which Are Not What They Claim
consumption; to Be
• they are associated with a number of unknown The non-regulated production techniques involved in
adverse effects; manufacturing NPS create large variation in dosage,
• insufficient information is available in peer- potency or even the content of an NPS product, mak-
reviewed scientific journals on harms; ing it difficult to predict effects on users. There are, of
• they appear in increasingly sophisticated (i.e. non- course, no regulations concerning content, potency,
powder) forms and remain unregulated; point of sale and purchase age135, and even branded
• they are often synthesised in underground products that look the same and have similar lists of
laboratories by modifying the molecular structure chemical content, may in fact be very different.
of controlled drugs, raising concerns over the Although unpredictability of the content of
presence of contaminating agents; a product was also a factor with traditional substances
• they are largely available online to everyone, ‘just to an extent, it is argued that what is distinctive about
a click away’. NPS is that this is significantly more so than with
traditional drugs.136
Whereas all users of club drugs face the risk of acute People using NPS often have poor knowledge of
toxicity, the harms caused by club drugs encompass what they are consuming. The reasons for this
a wide range of different patterns. Club drugs are asso- include:
ciated with harmful use, which can be physical harms
(e.g. ketamine can lead to ulcerative cystitis) or mental • Research has shown that there is significant
(e.g. psychosis associated with synthetic cannabinoids). variation in the content of ‘legal high’ products
Although still limited, we have an increasing bought over the Internet.137,138,139,140,141,142
understanding of the harms associated with NPS • NPS preparations and products sold for
through animal and human studies.132 recreational purposes can include a combination
Recently, information has been provided through of different NPS and/or traditional drugs.
the Tox-Portal, an online tool developed in collabor- Products can contain a mixture of two or three
ation with The International Association of Forensic different active compounds (including controlled
Toxicologists (TIAFT) that collects data on toxicology compounds).143 This can increase the risk of
and harm related to the use of NPS at a global level.133 adverse effects, as well as potentially altering
This has shown the following: clinical presentations.
• synthetic cannabinoids, synthetic opioids and For example, the analysis of samples seen by the
synthetic stimulants account for the majority of NPS Home Office Forensic Early Warning System
reported to the UNODC EWA Toxicology Portal. (FEWS) – 2016/2017 showed that 35% of the sam-
• Synthetic cannabinoids in particular remain ples analysed contained a mixture of two or more
harmful, persistent and prevalent. substances .144
10
1.7 Brief Overview of the Effects and Harms of Club Drugs
• Branded products of the same name can contain collected appeared to change over time from poorly
different active compounds, depending on time, elaborated forms such as powder, to tablets, which
place and batch purchased.145,146,147,148,149,150 One become the most common form.166
study found that six out of seven products Importantly, new formulations of various NPS
analysed did not contain the advertised active have become available over time. They are often
ingredients but, rather, some controlled more potent than earlier forms and may be associated
traditional drugs.151 with greater harms. For example,
• Research to shed light on the purity and price of 10 • Four generations of synthetic cannabinoid
NPS in the European Union (France, United receptor agonists ((SCRA). Newer generations
Kingdom (UK), the Netherlands, Czech Republic appear to be associated with severe adverse
and Poland) investigated the products in each of reactions, such as catatonia, serious toxicity and
these countries purchased from different death. (For more information see Chapter 13)
webshops. The study found that a considerable • New generation synthetic cathinones. E.g.
proportion of NPS were mislabelled by the compounds such as α-PVP and MDPHP (also
webshops. In most instances, highly similar NPS known as ‘monkey dust’) are associated with more
analogues were sold instead of the specific severe effects than previous cathinones. (For more
compounds advertised. However, in some cases, information see Chapter 11)
the contents were entirely different to those • Hallucinogens. For example, 25B-NBOMe is
advertised, the consequences of which could cause a highly potent 2C-B derivative even at
serious harm. For instance, α-PVP is a much more microgram-level doses. (For more information see
potent stimulant than 4-FA and it was present in Chapter 14.)
one sample advertised as 4-FA.152
• In some cases, studies have shown that NPS 1.7.3.3 Limited Drug Testing
analogues similar to more commonly used One of the attractions of NPS to people who use them
substances were sold instead of the specific is the limited ability of standard drug tests to identify
compounds advertised.153 Sometimes much them. This may lead the user to feel that they can use
stronger substances were used than the one NPS without risk of detection by occupational ser-
advertised. For example, NPS drugs with vices or law enforcement.
hallucinogenic effects such as 25I-NBOMe have This, however, can pose challenges to clinicians.
been sold as LSD to users who were not aware that There are currently very limited accurate clinic-based
they have consumed other substances, with testing devices for most of the NPS, despite continued
a considerably higher dose than equivalent doses developments in the area of chemical standards, ana-
of LSD.154 lytical capability and forensic detection of
• Similarly, NPS are sometimes substituted in compounds.
place of traditional drugs or other NPS and It has been argued that although toxicological
consumed by users who are not aware of the screening tests are not routinely used in most hos-
substitution. In some cases, much more potent pitals across Europe, they can be helpful, mostly in
substitutions are made. Later chapters will look cases of use of unknown agents and unclear clinical
for example at substitution of MDMA by PMA/ presentations, provided that the results are rapidly
PMMA, LSD by 25I-NBOMe,155,156,157,158 or available and interpreted correctly.167
fentanyl substituted for, or used to adulterate, In addition, not all laboratories have the capacity
heroin.159,160,161,162,163,164,165 As will be discussed to detect the more uncommon substances. Reference
later, this can be associated with severe harm standards are essential for forensic and toxicological
and overdose. investigations for new psychoactive substances; how-
ever, these are not available in many laboratories.168
1.7.3.2 New Generations of Substances and Novel The diagnosis of acute toxicity associated with
Psychoactive Substances Over the Years NPS will in most cases be made by clinical assessment.
The ‘market’ for club drugs and NPS appears to have As rapid urine or serum field tests are not commonly
gradually become more sophisticated. For example, available, analytical assessment should not be con-
a Spanish study of 2C-B reported that samples sidered a component of routine diagnosis of NPS.
11
Assessment should be based on the recognition of the 9% of presentations over the four-year period, with
clinical toxidrome associated with the NPS used and significant geographical variation in the involvement
the potentially harmful modes of use, with other of NPS in presentations.180
causes of presentation excluded. Data on deaths associated with club drugs and
NPS also remain limited, and it has been argued that
the absence of European forensic toxicology guide-
1.8 Response to Club Drug and Novel lines for drug-related death investigations is a barrier
Psychoactive Substance Use to improving monitoring and practice in this area.181
However, there is evidence that NPS, including
1.8.1 Novel Psychoactive Substance and synthetic opioids, synthetic cannabinoid receptor
agonists and synthetic cathinones continue to be asso-
Drug-Related Presentations to Hospital ciated with acute intoxications and deaths. As with all
Emergency Departments drug-related deaths, fatalities often involve the use of
Accurate data on emergency hospital admissions more than one substance (poly-drug use).182
resulting from club drug and NPS use in the UK Emergency medicine physicians and other clin-
were difficult to obtain for a variety of reasons, not icians should seek advice on the diagnosis, treatment
least because ICD-10 codes did not include specific and care of patients who may have been poisoned with
codes for NPS169,170,171 and because coding is gener- a club drug or an NPS, including from national or
ally based on clinical condition at presentation.172 regional poisons information services. Interventions
More recently, the new classification of substance provided must be based on local, national and inter-
use disorders and problems in ICD-11 includes national protocols and guidelines.
a range of diagnostic categories that cover a broad
spectrum of health conditions reflecting different 1.8.2 Sexual Health Services
levels and patterns of substance use.173 ICD-11 also The association between substance misuse, including
covers some NPS and club drugs, for example syn- alcohol use, and high-risk sexual behaviours is well
thetic cathinones,174 SCRAs175 and MDMA.176 established, although evidence of a causal relationship
It has been suggested that these changes may in is limited.
part help with some of the coding issues, enabling There is also some evidence from some countries
better understanding of the burden of healthcare util- that the prevalence of drug use is higher among the
isation related to the use of a wider range of patients of sexual health services than the general
substances.177 However, in clinical practice, clinicians population and most particularly patients who identify
may not record drug-related codes, but codes based as men who have sex with men (MSM). For example,
on clinical presentation. In addition, the rapidly one study of patients at a London sexual health clinic
emerging number of NPS means that some may not reported significantly higher rates of past month drug
codeable under existing ICD-10 and even ICD-11 use than in the general adult population in England
codes. and Wales. This was particularly so among MSM.183
Data on acute drug-related hospital presentations Patients of sexual health services who misuse alco-
associated with NPS continue to be limited,178 but hol and drugs have also been identified as higher-risk
have been improving. Interventions have taken place groups for poor sexual health outcomes. Substance
in Europe for a number of years now, including the misuse interventions in these settings have been
European Drug Emergencies Network (Euro-Den), in recommended.184,185,186,187
order to address this current paucity of reliable It has therefore been argued that sexual health
data.179 services may provide opportunistic encounters to
Euro-Den data from 31 sentinel sites in 21 coun- identify patterns of recreational drug use, explore
tries reported that there were 23,947 acute drug tox- motivations for use and implement strategies to
icity presentations reported by the Euro-DEN Plus reduce harms related to drug use.188,189,190,191 It has
centres over the four-year period between been suggested that patient assessment in sexual
January 2014 and December 2017. These represented health services should include a history of alcohol
a median of 0.3% of all emergency presentations to the and recreational drug use.192 Integrated services
sentinel hospitals. Amongst those, NPS were seen in have also been suggested.193
12
1.9 Reducing Drug-Related Harms
Table 1.2 The role of particular settings and the aims of interventions provided
Detection Assessment Brief Complex Complex

intervention intervention intervention
(acute) (chronic)
Primary care ✓ ✓ ✓
Emergency ✓ ✓ ✓ ✓
department
Sexual health ✓ ✓ ✓
Substance misuse ✓ ✓ ✓ Some ✓
treatment
1.8.3 Substance Misuse Treatment Building on these principles, at a practical level, drug
treatment services and systems can consider the fol-
Services lowing to improve their understanding:
International Standards for Treatment of Drug Use • Amending data recording tools to ensure NPS use
Disorders have been developed by the UNODC- and associated adverse health effects are accurately
WHO, and provide the rules and minimum require- recorded
ments for clinical practice and the generally accepted • Engaging in research to build the evidence base for
principles of patient management in any healthcare treatment interventions
system.194
A set of best practice principles that should under-
lay drug dependence treatment has been identified 1.8.4 Overview of the Interventions
and defined by the United Nations Office for Drugs for the Screening, Identification
and Crime (UNODC) and the World Health
Organization (WHO), and are listed in Box 1.1.195 and Management of Drug Harms
in the Target Settings
Box 1.1 Outline of the Key Principles and The different target organisations (treatment settings)
Standards for the Treatment of Drug Use
of the NEPTUNE guidance have different roles in the
Disorders
detection, identification and management of chronic
• Principle 1: Availability and accessibility of drug harms and/or dependence resulting from the use of
dependence treatment club drugs and NPS. This is determined by the com-
• Principle 2: Screening, assessment, diagnosis and petence of clinicians to deliver substance misuse treat-
treatment planning ment and particular pharmacological, psychosocial
• Principle 3: Evidence-informed drug dependence and recovery interventions.
treatment Table 1.2 provides a summary of the role of each
• Principle 4: Drug dependence treatment, human of the target settings and the aims of the interven-
rights, and patient dignity tions provided in terms of the screening, identifica-
• Principle 5: Targeting special subgroups and tion, assessment and management of the harms
conditions linked to the use of club drugs. Further information
• Principle 6: Addiction treatment and the criminal on the level of intervention needed is also presented
justice system in Chapter 2.
• Principle 7: Community involvement, participation
and patient orientation 1.9 Reducing Drug-Related Harms
• Principle 8: Clinical governance of drug The reduction of the harms associated with the use
dependence treatment services of club drugs and NPS are to a very large extent
• Principle 9: Treatment systems: policy based on the same principles that must be adopted
development, strategic planning and for the reduction of harms associated with trad-
coordination of services itional drugs.
13
A number of measures are adopted by users or the pharmacological management of substance abuse, harmful
recommended by professionals, including regulating use, addiction and comorbidity: recommendations from BAP.
J Psychopharmacol 2012;26(7):899–952. https://doi.org/10
the quantity of drugs used, spacing out doses within .1177/0269881112444324
a session of substance use, and not combining mul-
10. See e.g. Santos-Toscano R, Guirguis A, Davidson D. How
tiple stimulants or depressants.196,197,198,199
preclinical studies have influenced novel psychoactive
A study has shown that polysubstance-using festi- substance legislation in the UK and Europe. Br J Clin
val attendees who frequently adopt dosing-related Pharmacol, Special Issue: New Psychoactive Substances
harm reduction strategies frequently experience less 2020;86(3):452–481.
drug-related harm. However, whereas many users will 11. Peacock A, Bruno R, Gisev N, et al. New psychoactive
adopt harm reduction strategies frequently, others substances: challenges for drug surveillance, control, and
will rarely carry out protective strategies, suggesting public health responses. Lancet 2019;394:1668–1684.
that there is still a need to encourage use of these 12. United Nations Office on Drugs and Crime (UNODC). The
strategies among this population.200 Challenge of New Psychoactive Substances. Global SMART
Programme 2013.
13. United Nations Office on Drugs and Crime (UNODC). Global
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21
Chapter
Psychosocial Interventions for Club Drugs
2 and Novel Psychoactive Substances
2.1 Introduction Box 2.1 European Monitoring Centre for Drugs

There is a large body of evidence on the effectiveness and Drug Addiction (EMCDDA): Key Principles
of psychosocial interventions (PSIs) for the manage- for Health and Social Responses to Drug
ment of substance misuse problems, including Problems12
national guidelines. It is therefore possible to make
According to the EMCDDA, the key principles for
specific and robust recommendations. health and social responses to drug problems in
Effective treatment for all substance misuse prob- Europe should be the following:
lems includes PSIs. These in fact are the primary form
• Be respectful of human rights, including:
of treatment intervention for the misuse of, and depend-
o The right to the enjoyment of the highest
ence on, the majority of substances, as only a small attainable standard of physical and mental
number of substances of misuse have recognised health;
pharmacological interventions, such as opiate substitutes o The right of the drug user to give informed
for opiate dependence.1 Where pharmacological inter- consent to treatment;
ventions do have a role, for instance in opioid depend- • Respect ethical principles, including informed
ence, PSIs are generally associated with enhanced consent, confidentiality and equity of access;
treatment outcomes.2 PSIs are important in helping • Promote service user and peer involvement in service
people prepare for planned, medically assisted detoxifi- design and delivery;
cation and are essential following detoxification, to sus- • Take a public health approach;
tain positive changes.
• Be based on an assessment of needs and tailored to
Psychological interventions for substance misuse the specific requirements of the target population;
problems focus on supporting behaviour change to
• Respond to cultural and social characteristics,
achieve desired outcomes. PSIs may aim to support including gender issues and health inequalities; and
people to achieve abstinence from use of specific or
• Be properly designed and based on evidence, duly
multiple substances, or a reduction in use to a less harm- monitored and evaluated.
ful level or in a less harmful manner. Psychological
interventions are also used to help with co-occurring
psychological, social or physical problems, again with
the aim of contributing to sustained change in substance 2.2 Psychosocial Interventions
misuse.
There is evidence for the effectiveness of PSIs includ- for Novel Psychoactive Substances
ing brief interventions, motivational interviewing, self- Very limited research has so far been published relating
help groups, behavioural couples therapy, contingency specifically to PSIs for the treatment of NPS. Where this
management, CBT-based relapse prevention, commu- exists, it has been summarised in the relevant chapters
nity reinforcement approaches, social behaviour net- in this publication. It is argued that the large number of
work therapy, family therapy and psychodynamic NPS, their diversity and the speed at which they appear,
therapy.3,4,5,6,7,8,9,10 However, in what Orford terms the is challenging both for monitoring and developing
‘outcome equivalence paradox’, no single approach is effective and timely responses.
regarded as universally superior.11 See Box 2.1 for the Many NPS are stimulant in nature and this chap-
key principles for health and social responses to drug ter therefore draws heavily on research for the treat-
problems in Europe, according to the EMCDDA. ment of stimulant misuse and also draws on the
22
2.4 Identification of Novel Psychoactive Substance Use and Its Severity
broader literature on PSIs for health behaviour However, evidence supporting a strong association
change in general.6 Reference is also made to com- between exposure to childhood adversity and early life
monly accepted good practice for effective psycho- trauma and opioid dependence, polydrug use, poor
logical interventions in general. retention in treatment,16,17,18,19,20,21,22,23 and drug use
Patterns of NPS use show a close parallel to recog- and imprisonment, suggests that this must be con-
nised patterns of alcohol use. The most common pattern sidered in interventions for club drugs and NPS.24,25,26
is infrequent, non-dependent use, with lower risk of Suggestions have been made on
severity and likelihood of harm. A much smaller pro- how trauma-informed interventions should be
portion of users engage in entrenched dependent use developed.27,28,29,30,31,32,33,34
with the potential for more significant associated harm.
The chapter therefore also draws on the much more 2.3 Stepped Care
extensive literature on PSIs for alcohol problems.7 Psychosocial interventions for substance use are com-
Recent developments in the NPS market, such as monly provided following a stepped care model
opioid and benzodiazepine NPS and potent synthetic (Figure 2.1).35,36
cannabinoid receptor agonists (SCRAs), appear to be Within stepped care models, psychological and
targeted primarily at the long-term and more prob- social interventions are grouped according to the
lematic drug users.13 This means that existing recom- level of specific psychological and social treatment
mendations and guidelines for relevant interventions competences required to deliver them effectively. It
in these groups of users must be considered. is therefore common to refer to ‘lower-intensity PSIs’
Specialist treatment for problems caused by new and and ‘higher-intensity PSIs’.
emerging substances is not well developed in most The main principles of a stepped care approach
countries. It has been noted that many of the health are as follows:
and social responses to new substances in Europe and • The least intrusive intervention needed to achieve
elsewhere are adaptations of programmes for ‘estab- a required outcome is delivered first.
lished’ or ‘traditional’ drugs. Existing interventions • If an intervention does not achieve the desired
often target particular groups. These vary by country outcome, service users should be offered the
but include: recreational stimulant users, psychonauts, option of being ‘stepped up’ to a more intensive
men who have sex with men, people avoiding drug tests, intervention.
and high-risk drug users. Specific guidance on respond-
• Where a higher level of intensity of treatment is no
ing to the use of these substances in prisons and custo-
longer required, ‘stepping down’ to a less intensive
dial settings is also being developed in some countries.14
option should be offered.
In developing club drug and NPS-specific interven-
• Service users should have access to all levels of
tions, adjustments to existing protocols need to take
treatment within a treatment system.
account of specific drug effects, socio-cultural charac-
• Service users should have direct access to the
teristics of risk groups (e.g. party-goers, men who have
intensity of intervention likely to be required to
sex with men) or particular risk behaviours (e.g. high
achieve their desired outcomes, and not
injecting frequency). Multi-disciplinary responses and
unnecessarily proceed through lower levels in
collaborations between health providers in different
a stepwise order.
settings (e.g. sexual health clinics, custodial settings
and drug treatment centres) are needed to reduce
these harms. Cultural competence, or an understand- 2.4 Identification of Novel
ing of how cultural issues influence patterns of drug use
and associated harms is needed within services, in
Psychoactive Substance Use
order to enhance service engagement and uptake.14 and Its Severity
As the relationship between trauma and substance The clinical identification of individuals experiencing
use is becoming increasingly established, the need for NPS harmful use or dependence, particularly those less
trauma-informed interventions has been identified to severely affected, is not always easy when regular use
facilitate long-term recovery from both addiction and may be linked to lifestyle. Determining the need for
trauma.15 The link between the harmful use of NPS and specific psychosocial interventions to address behaviour
club drugs and trauma has not been investigated. change will also be influenced by a wide range of factors.
23
Psychosocial Interventions for Club Drugs and Novel Psychoactive Substances
Many people make substantial changes to their sub- a ‘recovery capital’ model, rather than a deficits-based
stance misuse without formal treatment.11 approach37. A recovery capital model looks at the
Substance use or intoxication is not in itself an strengths and needs a service user has over a range of
indication for treatment. Unlike the several robust domains beyond substance use. More resources across
screening tools for alcohol use, there are no recognised the domains would suggest greater likelihood of posi-
screening tools specifically developed for NPS use and tive outcomes, and fewer resources suggest an indica-
there is no routine screening for NPS use in general tion for broader and more intensive interventions.
health care settings. However, any contact with a health Four types of recovery capital are identified:38
professional where NPS and club drug use is identified • Human capital – e.g. skills, employment, mental
can be an opportunity to offer non-judgmental health and physical health;
advice on safety and, potentially, change.
• Physical capital – e.g. tangible resources, housing,
Self-report, incidental or opportunistic enquiry
money;
may reveal NPS use and risk but no evidence of
• Cultural capital – e.g. values, beliefs;
harm or need for a treatment intervention. This pro-
vides a potentially useful opportunity to offer infor- • Social capital – e.g. relationships with others.
mation and brief advice or to signpost to sources of Those who have more strengths and resources (recov-
further information. Other individuals will provide ery capital) may be more likely to achieve their desired
clearer evidence of at least some degree of problematic outcomes with little or no professional input.39
use. Many such problematic users will be able to Indicators for more intensive interventions include:
change their risky behaviour without assistance and longer problem duration, injecting drug use, sub-
will not require professional help. Some of these prob- stance dependence, unsuccessful independent
lematic users will however benefit from brief advice attempts to change, multiple substance misuse prob-
and information in addition to the offer of referral to lems, multiple co-occurring problems, fewer individ-
formal treatment services. When information and ual strengths and less access to resources. An
brief advice is used in this way to help address prob- additional consideration is that people may have sub-
lem use, it forms part of the stepped care ‘treatment’ stantial substance misuse problems but at the present
pathway shown in Figure 2.1. time are only ready or able to access and engage with
Addressing substance misuse problems emphasises less intensive interventions (e.g. needle exchange
approaches based on strengths and needs, for example interventions for injecting drug use).
Identification of
problematic
NPS use
Higher severity
Lower severity
and dependence
Lower-intensity PSI Higher-intensity PSI

Residential
Brief advice and information Structured drug treatment and treatment
and brief intervention formal psychological therapy
Mutual aid
Figure 2.1 Stepped care PSI for problematic NPS use
24
2.5 Settings for the Delivery of Psychosocial Interventions
The intensity of the PSI should be more dir- interaction with a service user, the offer of brief
ectly related to the severity of the substance misuse advice and information may be helpful. Such non-
problem than to the severity of the health and drug treatment settings include primary care, emer-
other consequences of the substance use. For gency departments, primary and secondary care
example, someone experiencing an extreme med- mental health services, sexual health clinics and
ical consequence of one-off use of a substance may HIV services, in addition to other services where
be able to make desired changes without formal people may present with acute problems related to
treatment. NPS use.
It seems likely that most NPS use is infrequent, There are a number of non-drug treatment clinical
largely remains within the control of the individual services that work with service user groups with
and is associated with a low risk of harm.40 a higher prevalence of NPS use, and these services
Nonetheless, some NPS are injected and the majority should consider developing the relevant skills and
of NPS are associated with reported incidents of competences to offer brief interventions (BIs) and
serious acute and chronic harms. The repeated use referral pathways for additional support if needed.
of some NPS can lead to dependence and for some, Primary care is the obvious example, but there is
such as GHB/GBL, acute withdrawal can be evidence that NPS use has a higher prevalence in
a medical emergency. people attending sexual health services41 and HIV
Box 2.2 lists the recommended pragmatic indica- treatment services.42 These services (and others with
tors for a referral to drug treatment services, which service users with known higher prevalence rates of
will include PSIs. NPS use) have an appropriate opportunity actively to
ask about NPS use as part of their normal clinical
2.5 Settings for the Delivery assessment process.
Numerous studies report people living with HIV
of Psychosocial Interventions have a higher prevalence of NPS use (as will be dis-
The intensity of the psychosocial intervention cussed later) and there are concerns about the add-
(PSI) delivered will vary across the settings in itional health and viral transmission risks NPS use
which they are offered. Some PSIs require add- may pose. People living with diagnosed HIV typically
itional or specialist competences to deliver them, have frequent medical review appointments at HIV
whereas mutual aid, for instance, is a peer-led treatment services. These service contacts provide
intervention and so is not dependent on particular a valuable opportunity for appropriate questions on
settings for its delivery (and therefore is not dis- NPS use (asked routinely or targeted as appropriate),
cussed further in this sub-section). and the offer of brief advice, information and, if suit-
able, brief interventions.
2.5.1 Settings for Lower-Intensity Because of high levels of presentations related
to substance use, some emergency departments
Psychosocial Interventions (EDs) may employ staff with skills to provide
In non-drug treatment settings, where NPS use, or brief interventions. Similarly, because there are
problematic use, has been identified during a clinical high levels of substance misuse among people
accessing mental health services,43 these services
often have staff with additional competences
Box 2.2 Indicators for a Referral to Drug (‘dual-diagnosis workers’) to provide higher-
Treatment Services and Psychosocial intensity drug interventions in combination with
Interventions mental health interventions.
• Current injecting of any substance;

• Self-report 2 of inability to make changes to NPS
2.5.2 Settings for Higher-Intensity
use when attempted; Psychosocial Interventions
• Repeated presentation(s) with drug-related harm Higher-intensity PSIs, structured drug treatment and
(psychological, social or physical); formal psychological therapy are likely to be delivered
• Self-identification of needing specialist help or in community or residential drug treatment services.
request for referral to drug treatment services.
25
There may be benefits in locating the delivery of Table 2.1 Minimum recommended levels of psychosocial
interventions in health settings dealing with NPS use
higher-intensity PSIs in specific non-drug services
where presentation with problematic NPS use is fre- Setting Minimum level of PSI
quent and associated with other health or social prob- Primary care/general Availability of brief advice
lems. This may encourage engagement in drug practice
treatment by minimising any perceived stigma Emergency department Availability of brief advice
involved in attending drug treatment services. There and
may also be merit in developing specialist hybrid ser- Sexual health services Availability of brief advice
vices for specific populations with co-occurring needs. and information plus brief
intervention
For example, innovative services where drug treatment
and psychological therapy are provided in settings such HIV services Availability of brief advice
and information plus brief
as sexual health services with a high level of presenta- intervention
tion of co-occurring sexual health problems, problem- Mental health services Availability of brief advice
atic NPS use and in some cases psychological problems. (including primary and and information plus brief
These differing levels of intensity of interventions secondary care intervention
psychological therapy provide structured
will be reflected in the increasingly specialised com- services)
petences that the health professionals delivering them
Drug treatment services Availability of brief advice
will have. All levels of intervention must be delivered and information, brief
within an appropriate governance framework with intervention, structured drug
more intensive PSIs requiring specific supervision.4 treatment, formal
psychological therapy,
A stepped care model of interventions for NPS use facilitated access to mutual
should be available to service users across a treatment aid. Access to assessment for
system, with referral pathways between the various residential drug treatment
services where service users are likely to present. It is
recommended that the settings listed in Table 2.1 offer
a minimum level of PSI. Each intervention is be in the lower severity range. Provision of brief advice,
described in greater detail in the following. information and brief interventions is also commonly
All non-drug treatment services should offer refer- recommended for risky drinking and alcohol
ral to drug treatment services, as indicated in Box 2.2. problems.4,7,44
Lower-intensity PSIs (brief advice and informa-
2.6 Lower-Intensity Psychosocial tion, and brief interventions) may be carried out by
Interventions health professionals outside of the substance misuse
treatment field who have identified problematic sub-
Lower-intensity PSIs can be divided into two main inter-
stance use in the course of a consultation for another
ventions: provision of brief advice and information; and
problem or after routine or opportunistic screening.
provision of brief interventions. The published evidence
Lower-intensity PSIs may take no longer than a few
that underlies this for drug users mainly relates to the
minutes, perhaps forming part of a wider conversa-
provision of brief interventions. However, recommend-
tion about a health problem. Typically, lower-
ing the provision of brief advice and information is
intensity PSIs for substance use involve:
a considered and pragmatic approach that takes account
of wider evidence on brief advice and is based on what is • Identification of substance use (and any related
considered a minimum approach to addressing the basic problems);
health needs of NPS users attending non-drug treatment • Personalised feedback;
services. Brief interventions, derived mainly from the • The offer of information on how changes might be
principles of motivational interviewing, have been made if the service user decides to take up the advice.
recommended. They are also opportunistic interventions The information may include a short information
used in non-drug treatment settings with people who leaflet or reference to reliable Internet resources.
have little or no contact with drug treatment services. Lower-intensity PSIs can be effective at reducing
Winstock and Mitcheson recommend brief interven- the risks and harms associated with substance use.3
tions for the majority of NPS users, whose use would The user’s desired outcome may be a reduction in
26
2.7 Higher-Intensity Psychosocial Interventions
drug-related harms rather than drug abstinence. Box 2.3 FRAMES: A Framework for Brief
Lower-intensity PSIs are more likely to be effective Interventions
when users perceive they have a problem (or reason
to change) and believe that they can make a change. Identification of NPS use (and any related problems)
All health professionals should already have the followed by:
competences required to deliver brief advice and • F Feedback on personal risk – from screening,
information. Clinicians can adopt a key element of medical tests or clinical interviews, give
motivational interviewing, which has a very strong personalised feedback on the person’s current and
evidence base for its effectiveness as a substance use likely substance-related problems
intervention, known as the ‘elicit, provide, elicit’ strat- • R Responsibility and choice – emphasise the
egy (see Figure 2.2).45 service user’s responsibility for and choice in
Brief interventions offer structured advice on behav- making any changes
iour change in the context of a warm, reflective, • A Advice to change – give clear advice to change
empathic and collaborative approach by the practitioner. substance use
While this is likely to require no more than the compe- • M Menu of options – offer a variety of strategies or
tences expected of any healthcare professional, options
a commonly used structure for brief interventions across • E Empathy – a warm, reflective and understanding
the substance misuse field is FRAMES (see Box 2.3).46 style of delivering brief intervention is more
effective
Recommendations from alcohol treatment suggest
that simple brief interventions can be enhanced by • S Self-efficacy and optimism – build confidence by
affirming what the service user has already done
including goal-setting (e.g. start date and daily or weekly
or some aspect of strength
limits of use), written self-help materials for the service
user to take away (this may contain more detailed infor-
mation on consequences of substance use and tips on
cutting down) and arrangements for follow-up An example of a brief intervention based on the
monitoring.47 FRAMES model is given in Box 2.4.
The World Health Organization has developed
a manual on brief interventions in substance misuse 2.7 Higher-Intensity Psychosocial
for primary care.48 The manual draws on components Interventions
of motivational interviewing and the FRAMES model.
Although the manual was not developed for, or tested
with, NPS specifically, it does cover a range of sub- 2.7.1 Structured Drug Treatment
stances, including amphetamine-type stimulants. The Structured drug treatment comprises two or more
manual provides clear information on how to deliver treatment sessions, each lasting half an hour or
brief interventions. longer, applying a single or range of psychosocial
• Ask permission to give information

Elicit
• Check if interested in possible information
• Provide relevant information in

Provide
a neutral manner
• Elicit service user’s view or interest in

Elicit
the information provided
Figure 2.2 A proposed framework for brief advice and information
27
Box 2.4 Example of a Brief Intervention Based on the FRAMES Model

HEALTH WORKER (HW): Good news. All of the tests have come back and they are all normal. That means that you are
medically fit to be discharged. Before you go, I wonder if you have a few minutes to think about how to avoid
something like this from happening again? (Asking permission)
SERVICE USER (SU): Yes, okay, if you like.
HW: You mentioned to me earlier you were using 2C-B pretty much every weekend of late? Did I get that right?
(Brief history)
SU: Yeah, every weekend for a couple of months now, more often than it used to be.
HW: What would a typical weekend be like? (Open-ended question/brief history)
SU: Well, no weekend is the same. It depends on who I’m with and where we are going.
HW: Well, maybe you could tell me about this weekend. (Open-ended question)
SU: This weekend was a pretty big one: it was my friend’s birthday. We were partying then clubbing, then we
hooked up with a few other friends and went on to another club.
HW: So you came here to A&E early this morning, Sunday. When did you start?
SU: Early Saturday night, at a friend’s place. We had a few drinks then a line or two of cocaine, then just before we all
left for the club, we all took 2C-B. I guess before we left I’d had more than usual, but I had decided to wait
a couple of hours before taking anything more because I knew it was going to be a long night.
HW: You were thinking ahead, pacing yourself. Good for you. (Affirmation)
SU: Then at the club we were having a great time and someone offered me another 2C-B, which hit me quite hard.
We were there until about 3am, although things were getting a bit hard to remember by then. I think there were
more shots of vodka, but I’m not sure. We left there and went on to another club with these people we met in the
first club. They were all really into their 2C-B and had really good quality 2C-B with them. We started taking their
2C-B as we had run out. In the second club things got really messy. I started tripping out. I had never had this with
2C-B before, but I think I had taken too much and that it was much stronger than I was used to. My heart started
racing and I was panicking like mad. I went to sit outside with a friend and told him not to let me drink or use any
more drugs that night because I had had enough.
HW: So you realized you had taken too much and decided to stop at that point. (Affirmation)
SU: I thought things would just settle but they got worse and worse. I’m really confused about what happened next
but I remember the ambulance crew arriving and my friends looking really scared.
HW: So, from what you’ve said, it sounds like your use of 2C-B has been pretty regular over the last few months and
may be increasing. This weekend was a big one, as you say. It’s likely that you took more and stronger 2C-B than
usual and also mixed it with cocaine and alcohol which led to you feeling really ill. It’s good someone called an
ambulance to get you here. (Feedback)Would you be interested to hear about the kinds of problems we see with
2C-B use? (Asking permission)
SU: Well, I thought I was pretty clued up, but maybe I should do a bit more research.
HW: 2C-B is a drug causing stimulating and hallucinogenic effects. The dose in a tablet can vary greatly between batches,
or even from one tablet to another. If you take too much 2C-B it can lead to severe and frightening hallucinations,
confusion and vomiting. This risk increases greatly if you mix 2C-B with other stimulant drugs, such as cocaine,
because when combined, they can cause the brain to be flooded with too much serotonin, a stimulating chemical
messenger, which can make you really unwell. Mixing with alcohol can also increase the harms from 2C-B. (Feedback)
It’s of course up to you what you do with this kind of information, I’m just letting you know how your current
pattern of 2C-B use might be linked to some health risks or problems that could develop. (Responsibility)
SU: I knew a fair bit of that, but some of it, like getting too much serotonin, would concern me. I need to think about
how I mix more carefully, because I don’t want to end up back here.
HW: Planning what you are going to use on a night out and not mixing too much drugs and alcohol at the same time
is a really sensible approach. (Advice)
28
2.7 Higher-Intensity Psychosocial Interventions
Box 2.4 (cont.)
In terms of being safer, stopping using 2C-B would be the safest option. If that doesn’t feel like something you
could do just now, not mixing with alcohol or other drugs would make problems like the ones that brought you
here less likely. If you do continue use, using less and knowing how much you’re using would help. Some people
take a very small test dose of 2C-B to judge how strong it is, before deciding how much of the tablet they need for
the desired effect without taking too much. It’s good that you use with friends and you take care of each other if
needed. (Menu of options)
SU: I’m not sure stopping taking it is what I want to do right now, but I’d already been a bit concerned about using so often.
HW: You could try having some weekends not using? It sounds like that’s something you’ve managed before. (Self-
efficacy)
SU: Yes, I’ve got friends who don’t use, but I’ve not been spending much time with them lately, which isn’t what I want.
HW: Is there anything more you’d like me to help with? I have the details of a website that has the information I just
spoke about if you’d like it? I’ll leave you this card with the details of a local service just in case you want some
more expert help. I’ve heard good things about them.
approaches, commonly including motivational inter- given the multi-dimensional nature of stimulant
viewing. Structured drug treatment may range from dependence. They further argued that for sustained
an extended form of brief intervention, sometimes outcomes, treatment needs to support service users to
known as extended brief intervention, to a more make effective changes to their lives, including abstin-
ongoing, regular set of treatment sessions. ence from stimulant use, the ability to work and the
Structured drug treatment of any duration includes ability to maintain successful relationships. A focus on
the setting and evaluation of specific goal(s) relating narrow, short-term goals such as reductions in amount
to a change in substance use. or frequency of use is of little benefit in achieving
Structured drug treatment should follow from sustained change.9 The intervention will draw on evi-
a more comprehensive assessment of needs and dence-based psychosocial approaches and is likely to
resources that has led to intervention based on a care include motivational interviewing.8
plan.49 More advanced competences, of accreditation As a minimum, structured drug treatment should
standard, in these approaches will be required for effect- include: goal setting and planning, feedback and moni-
ive delivery, along with supervision and an appropriate toring, and developing social support.6 The largest
governance framework. Structured drug treatment may amount of reported evidence for structured drug treat-
be delivered as individual psychological therapy or as ment is for cognitive behavioural therapy (CBT), contin-
group-based interventions. There is evidence that the gency management (CM) and the community
outcomes of drug treatment (all drug treatment, not reinforcement approach (CRA) as mentioned earlier.9
only PSIs) can be enhanced with the use of mapping Specific competences to deliver such interventions,
tools.50 Mapping tools are not in themselves supervision and an appropriate governance framework
a psychosocial intervention but an approach that can are required.
enhance the effective delivery of treatment. Mapping
tools employ a structure known as ‘node link mapping’
to visually convey key elements for a structured conver-
2.7.2 Formal Psychological Treatment
sation derived from evidence-based PSIs.51 The most More intensive treatment and formal psychological
relevant research findings relate to PSIs for various treatment is likely to be effective for people with higher-
forms of stimulant use. Knapp et al., in a Cochrane severity and dependent use. Formal psychological treat-
review, reported that interventions based on cognitive ment is particularly relevant where a service user has
behavioural therapy and contingency management a co-occurring common mental health problem3 or
approaches appear to be effective.52 Knapp et al. argued other psychological problems. Formal psychological
that a comprehensive treatment package drawing on treatment usually consists of a planned, time-limited
these three models may be required for better outcomes, series of sessions. The intervention will be grounded in
29
a psychological formulation, derived from a process of • Suggests how the service user’s difficulties may
assessment and evaluated using formal or informal out- relate to one another, by drawing on psychological
come measures. The competences required to deliver theories and principles;
this intensity of intervention will be more advanced – of • Aims to explain, on the basis of psychological
professional registration standard – and a governance theory, the development and maintenance of the
and supervision structure will be needed.53 service user’s difficulties, at this time and in these
Formal psychological treatment may be delivered situations;
as individual therapy or as a group-based interven- • Indicates a plan of intervention which is based in
tion. It is likely to draw on one or more of the evi- the psychological processes and principles
dence-based psychological therapy models listed identified;
below and may be combined with other evidence- • Is open to revision and reformulation.
based interventions for psychological problems. A distinguishing characteristic of psychological formu-
The aims of formal psychological treatment are likely lation is its multiple-model perspective – it integrates
to be a combination of changes: to the substance use, to theory and evidence from a range of psychological
the psychological problems, but also in related domains models as well as biological, social/societal and cultural
(e.g. health, social functioning, criminal justice). domains.
There are high levels of co-occurring mental health The incorporation of this multiple-model perspec-
problems in drug treatment populations32, and it can be tive may have particular value in working with service
assumed this will be similar for dependent users of NPS. users from marginalised and stigmatised populations,
Some NPS users may have other co-occurring as it explicitly incorporates culture-specific issues.
psychological difficulties; for example, there are For example, a recent report54 describes the asso-
reports of problematic NPS use associated with psy- ciation of NPS use and sexual behaviours, often
cho-sexual problems. referred to as ‘chemsex’. As detailed in Part III of
Treatment services need to be able to screen, assess this publication, contemporary research has high-
and provide treatment for these co-occurring difficulties. lighted the frequent use of NPS by men who have
Whilst some3 recommend CBT to treat co- sex with men (MSM) in the context of sex.
occurring mental health problems, the complexity of A proportion of this behaviour has also been linked
the presenting psychological difficulties may limit the to drug-related and sex-related harms. Sex under the
impact of these approaches. Other approaches may be influence or intoxication of substances with the
required for psycho-sexual problems. potential for associated harm is by no means a new
For patients with complex needs, formal phenomenon, however.
psychological treatment may be complemented by Bourne et al.55 suggest some NPS offer a specific
a formulation-based approach.40 range of psychological and physical sex-enhancing
A psychological formulation is a hypothesis about effects. Where problematic sex and NPS use have
a person’s difficulties and integrates a broad range of over time become powerfully associated for an indi-
biopsychosocial causal factors which link theory with vidual, a combined approach to treatment is likely to
practice to guide the intervention. It is individually be required. By identifying motivations, meanings and
determined and may draw upon a range of psycho- values associated with sexualised drug use, individual-
logical models to achieve an effective treatment plan. ised for that service user, a psychological formulation
A psychological formulation can integrate both can be developed, leading to proposed psychological
the substance use behaviour and the co-occurring interventions. A small number of studies in the US
mental distress in a way that seeks to reveal the func- have looked at the impact of psychological interven-
tion of the substance use for the service user. It can tions on condom-less sex among methamphetamine-
also include consideration of other psychological and using MSM. Combined cognitive behavioural and
behavioural factors, such as sexual behaviour. contingency management (CM) interventions have
A formulation-based approach can incorporate shown a positive impact on changing drug use and
personal meaning and be constructed collaboratively sexual behaviours among this population.55,56
with service users and their care teams. Working with the same population, however,
Some key features of a formulation are that it: Rajasingham et al.57 suggest that CM fails to address
• Summarises the service user’s core problems; service users’ mental health needs or to develop
30
2.10 Models for Specific Psychosocial Approaches
post-intervention relapse prevention plans. A review of Broadly, the indications for residential treatment
three randomised controlled trials (RCTs) examining the are:
outcomes of CBT interventions and HIV risk behaviours • Multiple co-existing psychological, physical and/
among substance-misusing MSM found that while CBT or social problems;
did reduce unprotected anal intercourse in this group, it • Poly-drug dependence;
was unclear whether CBT was more effective than less • Optimised community treatment has not been
intensive interventions or mere assessment.58 effective;
It is good practice that higher-intensity PSIs • The service user has a treatment goal of long-term
(structured drug treatment and/or formal psycho- abstinence.3
logical therapy) are offered to service users where
It is good practice that service users with significant
medically assisted detoxification is part of the recom-
physical, psychological and/or social problems associ-
mended treatment. Unless detoxification is under-
taken as an emergency, higher-intensity PSIs, ated with NPS dependence (or use of high severity),
including motivational interviewing, should be who are aiming for long-term abstinence and who
offered before detoxification. Following detoxifica- have been unable to achieve this in effective commu-
nity treatment (or who would be highly unlikely to be
tion, it is essential that higher-intensity PSIs, typic-
able to do so), have access to residential treatment,
ally including a relapse prevention model, are
including, where necessary, prior medically assisted
offered. Service users completing detoxification
detoxification. On successful completion of residen-
may also benefit from formal psychological therapy
tial treatment, relapse prevention support should be
for any co-occurring psychological problems such as
common mental health problems or psycho-sexual offered to help service users maintain changes. Service
problems. users who leave residential treatment before its com-
pletion should be promptly offered support to min-
imise any return to substance use and the risk of
2.8 Residential Psychosocial overdose.
Treatment
Residential treatment is defined by the controlled 2.9 Mutual Aid
environment where treatment takes place. It generally There is a long tradition of mutual aid in the sub-
involves one or more evidence-based high-intensity stance misuse field. Perhaps the best-known are
psychological interventions and requires the same Alcoholics Anonymous (AA) and Narcotics
level of competence and governance as the higher- Anonymous (NA), sometimes known as 12-step
intensity PSIs described in Section 2.7. Residential groups. More recently, other forms of mutual aid
treatment may be preceded by medically assisted have been developed, including SMART groups
detoxification for safe withdrawal from specific where the approach is derived from CBT. There is
substances. a strong evidence base for the outcomes from mutual
Service users live within the treatment service (or aid (the research has primarily been with 12-step
very nearby) for the duration of the treatment. groups).59
Residential treatment is considered a more intense Mutual aid is not a professionally delivered treat-
form of treatment, often requiring several hours ment. There is, though, evidence of the benefit of
per day of treatment engagement over a minimum health professionals proactively supporting service
period of typically 12 weeks. The location of the treat- users’ engagement with mutual aid, often referred to
ment service is generally a distance away from the as facilitating access to mutual aid (FAMA).3,7,60
service user’s usual home. Residential treatment is rec-
ognised as an important option; however, there is debate 2.10 Models for Specific Psychosocial
around the precise indications for its use and the evi-
dence base is currently far from clear. Almost without Approaches
exception, the explicit aim of residential treatment is Higher-intensity PSIs for the treatment of substance
long-term or lifetime abstinence from all substances. misuse problems, in the form of structured drug
Residential treatment is therefore not appropriate for treatment, formal psychological therapy and many
people who are not prepared for this treatment aim. of the approaches used in residential treatment, are
31
derived from specific psychological therapy models. Inevitably, innovative developments may take time
The main evidence-based models are described only to be included in high-level meta-analyses. It is worth
briefly here, but references are given to sources of noting the current attention to what are often referred to
more detailed information and to treatment as ‘third-wave CBT models’. These contemporary devel-
manuals. opments include mindfulness-based interventions
(MBIs), acceptance and commitment therapy (ACT)
2.10.1 Motivational Interviewing and dialectical behaviour therapy (DBT). In
Ambivalence about changing substance use behaviour a systematic review of evidence, Chiesa and Serretti
is common, even for people actively seeking treat- report that MBIs can reduce the use of a range of
ment. Motivational interviewing as an approach offers substances, including stimulant drugs.68 Zgierska and
a framework for helping people resolve ambivalence Marcus69 note that the combined findings of early stud-
to changes in their substance use. Motivational inter- ies of MBIs suggest these may be efficacious for sub-
viewing and its more manualised variant motivational stance misuse problems. Of note, Smout et al.70
enhancement therapy (MET) have a robust evidence conducted a preliminary RCT of ACT for metham-
base across a wide range of substances.3,4,7 The use of phetamine use disorders. While it had no advantage
motivational interviewing is likely to be a part of brief over CBT, Smout et al. described it as a viable interven-
interventions and the early part of structured tion for this population. Zgierska and Marcus noted the
treatment.61 strength of positive evidence for MBIs with common
mental health problems and concluded that they are
2.10.2 Network and Environmental therefore of value for service users with co-occurring
substance misuse and mental health problems.54
Therapies
Network and environmental therapies are a range of
psychological approaches which seek to utilise social
2.10.4 Contingency Management
contextual reinforcers to promote and sustain change Contingency management has a strong evidence base
in substance use. This often involves enlisting the sup- from numerous research trials, carried out primarily
port of (non-using) partners, families or peers. in the US, focusing on stimulant use. CM is used to
Behavioural couples therapy (BCT) has been shown to reduce substance use by the provision of tangible
be effective in the treatment of drug misuse3,7 including (often monetary or material) rewards for the achieve-
lesbian and gay people.62 Similarly, studies have shown ment of verifiable behavioural goals, such as negative
the positive impact of network and environmental biological drug screen tests.13
therapies,3,7 social behaviour network therapy (SBNT),
the community reinforcement approach (CRA) and 2.10.5 Social Re-integration
behavioural couples therapy (BCT).63,64,65
Psychological interventions must often be accompan-
ied by those that focus on social re-integration. It is well
2.10.3 CBT-Based Relapse Prevention recognised that social exclusion is experienced by many
Relapse prevention (RP) is a commonly used psycho- high-risk drug and chronic users, and that interven-
logical approach in substance misuse treatment66, and is tions addressing these issues, with a focus on the social
recommended for the treatment of alcohol problems.3,7 re-integration of drug users, including improving
It has been argued that CBT focused on drug mis- a person’s ability to gain and maintain employment,
use only is not recommended.3 RP aims to help people may be needed. Interventions include vocational train-
make and sustain changes to substance misuse through ing programmes and housing support.71 It is widely
the identification of thinking and behavioural patterns recognised that social support is important in achiev-
that typically precede an individual’s substance use. RP ing positive outcomes for drug problems.6
is considered particularly relevant in helping people
sustain changes to substance misuse once they have
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e288. https://doi.org/10.1136/bmj.e288 /09595230801919494
41. Hunter LJ, Dargan PI, Benzie A, White JA, Wood DM. 56. Reback CJ, Larkins S, Shoptaw S. Changes in the meaning of
Recreational drug use in men who have sex with men (MSM) sexual risk behaviors among gay and bisexual male
attending UK sexual health services is significantly higher than methamphetamine abusers before and after drug treatment.
in non-MSM. Postgrad Med J 2014;90(1061):133–138. https:// AIDS Behav 2004;8(1):87–9
doi.org/10.1136/postgradmedj-2012-131428
57. Rajasingham R, Mimiaga MJ, White JM, Pinkston MM,
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Clin Infect Dis 2006;42(10):1463–1469. treatment outcome studies among HIV-infected men who have
sex with men who abuse crystal methamphetamine. AIDS
43. Weaver T, Madden P, Charles V, et al. Comorbidity of
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substance misuse and mental illness in community mental
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Alcoholism and Drug Abuse. Guilford, 2006. (2):271–277.
35
Part II Drugs with Primarily Depressant Effects
Chapter
Gamma-Hydroxybutyrate (GHB)
3 and Gamma-Butyrolactone (GBL)
3.1 Introduction 3.4 Brief Summary of Pharmacology

This chapter discusses gamma-hydroxybutyrate (GHB) GHB acts primarily as a CNS depressant, but at
and its precursor gamma-butyrolactone (GBL). Other low doses can also produce euphoric effects and
precursors of GHB are 1,4-butanediol (1,4-BD) and effects that appear to be like those of stimulants.
gamma-valerolactone (GVL). GHB is both a metabolite and a precursor of the
In some European countries such as the UK, it is inhibitory neurotransmitter gamma-aminobutyric
GBL rather than GHB that is mainly used for recre- acid (GABA)4 and acts as a neuromodulator in
ational purposes. However, it seems that elsewhere too, the GABA system, acting on both GABA-B and
GBL appears to be replacing GHB, in part because of its its own so-called GHB receptors. GBL and 1,4-BD
lower cost and the fact that it is easier to obtain.1 There are converted into GHB after they are absorbed.5
are also a small number of reports on acute toxicity A number of studies have looked at GHB pharma-
linked to 1,4-butanediol.2,3 cokinetics in healthy volunteers.6,7,8,9,10 GHB is
absorbed rapidly, is extensively metabolised to carbon
dioxide and rapidly eliminated,11 mainly through the
3.2 Legal Status lungs (less than 5% is excreted in the urine as GHB,
GHB was placed in Schedule IV of the 1971 Convention although this may be greater in overdose). It has
on Psychotropic Substances of the UN Commission on a half-life of only 20–30 minutes.12
Narcotic Drugs. It was classified as a controlled The effects of GHB usually occur 15–20 minutes
substance in the US in 2000 (Schedule I) and in EU after ingestion and can last for up to 3–4 hours,13 with
nations in 2001 (Schedule III or IV). peak effects at 30–60 minutes after ingestion.12 It is
GBL and 1,4-butanediol are available for legitimate undetectable in urine after approximately 12 hours.14
use in industry, but some countries in Europe (Italy, GBL is a precursor of GHB and is non-
Latvia and Sweden) now control one or both pre- enzymatically converted in the body into GHB. GBL
cursors under drug control or equivalent legislation. is absorbed more rapidly than GHB and potentially
has a faster onset of action. Its duration of action may
3.3 Quality of the Research Evidence also be longer.14 Some users report that GBL is more
The international evidence on the management of the potent than GHB.
acute and chronic harms related to the use of GHB In contrast, larger doses of GHV may be needed to
and GBL is emerging. A small number of randomised produce GHB-like effects and therefore GHV toxicity
control trials have been conducted, but the evidence may pose a greater public health concern than GHB.15
mainly consists of case reports and series together 1,4-BD is another precursor to GHB; it is
with a small number of prospective observational converted in the liver through a two-step conversion,
studies, retrospective cohort studies and analysis of via hepatic alcohol dehydrogenase to gamma-
patient records. hydroxybutyraldehyde followed by metabolism into
Despite these limitations, data/evidence from GHB via hepatic acetaldehyde dehydrogenase.16,17
these sources is relatively consistent. Animal studies have shown that both ethanol and
37
Part II Drugs with Primarily Depressant Effects
Chapter
Gamma-Hydroxybutyrate (GHB)
3 and Gamma-Butyrolactone (GBL)
3.1 Introduction 3.4 Brief Summary of Pharmacology

This chapter discusses gamma-hydroxybutyrate (GHB) GHB acts primarily as a CNS depressant, but at
and its precursor gamma-butyrolactone (GBL). Other low doses can also produce euphoric effects and
precursors of GHB are 1,4-butanediol (1,4-BD) and effects that appear to be like those of stimulants.
gamma-valerolactone (GVL). GHB is both a metabolite and a precursor of the
In some European countries such as the UK, it is inhibitory neurotransmitter gamma-aminobutyric
GBL rather than GHB that is mainly used for recre- acid (GABA)4 and acts as a neuromodulator in
ational purposes. However, it seems that elsewhere too, the GABA system, acting on both GABA-B and
GBL appears to be replacing GHB, in part because of its its own so-called GHB receptors. GBL and 1,4-BD
lower cost and the fact that it is easier to obtain.1 There are converted into GHB after they are absorbed.5
are also a small number of reports on acute toxicity A number of studies have looked at GHB pharma-
linked to 1,4-butanediol.2,3 cokinetics in healthy volunteers.6,7,8,9,10 GHB is
absorbed rapidly, is extensively metabolised to carbon
dioxide and rapidly eliminated,11 mainly through the
3.2 Legal Status lungs (less than 5% is excreted in the urine as GHB,
GHB was placed in Schedule IV of the 1971 Convention although this may be greater in overdose). It has
on Psychotropic Substances of the UN Commission on a half-life of only 20–30 minutes.12
Narcotic Drugs. It was classified as a controlled The effects of GHB usually occur 15–20 minutes
substance in the US in 2000 (Schedule I) and in EU after ingestion and can last for up to 3–4 hours,13 with
nations in 2001 (Schedule III or IV). peak effects at 30–60 minutes after ingestion.12 It is
GBL and 1,4-butanediol are available for legitimate undetectable in urine after approximately 12 hours.14
use in industry, but some countries in Europe (Italy, GBL is a precursor of GHB and is non-
Latvia and Sweden) now control one or both pre- enzymatically converted in the body into GHB. GBL
cursors under drug control or equivalent legislation. is absorbed more rapidly than GHB and potentially
has a faster onset of action. Its duration of action may
3.3 Quality of the Research Evidence also be longer.14 Some users report that GBL is more
The international evidence on the management of the potent than GHB.
acute and chronic harms related to the use of GHB In contrast, larger doses of GHV may be needed to
and GBL is emerging. A small number of randomised produce GHB-like effects and therefore GHV toxicity
control trials have been conducted, but the evidence may pose a greater public health concern than GHB.15
mainly consists of case reports and series together 1,4-BD is another precursor to GHB; it is
with a small number of prospective observational converted in the liver through a two-step conversion,
studies, retrospective cohort studies and analysis of via hepatic alcohol dehydrogenase to gamma-
patient records. hydroxybutyraldehyde followed by metabolism into
Despite these limitations, data/evidence from GHB via hepatic acetaldehyde dehydrogenase.16,17
these sources is relatively consistent. Animal studies have shown that both ethanol and
37
Gamma-Hydroxybutyrate (GHB) and Gamma-Butyrolactone (GBL)
fomepizole competitively block the metabolism of included with any drugs screen that is done in these
1,4-BD to GHB.18,19 cases.31
GHB (and therefore GBL and 1,4-BD) has a steep There is also some evidence from a study from
dose–response curve and narrow therapeutic threshold, Hungary that GHB can also be implicated in drug-
whereby even a small increase in dose can cause serious facilitated acquisitive crimes.32
toxic effects, such as impaired consciousness and coma. GBL and 1,4-BD are used extensively by the chem-
This steep dose–response relationship differentiates ical industry as precursors for the synthesis of plastics
GHB/GBL from other drugs. It can readily cross both and industrial solvents. They are found in floor-
the placenta and the blood–brain barrier, leading to cleaning products, nail polish (previously nail polish
profound CNS and respiratory depression.12,13 removers) and superglue removers.
Daily use of GHB/GBL can lead to dependence
and the possibility of withdrawal syndrome on cessa- 3.6 Prevalence and Patterns of Use
tion of use, which can be severe, with agitation and
At population levels, the use of GHB/GBL is relatively
delirium. Acute GHB/GBL toxicity and acute with-
low. However, the health costs of GHB/GBL misuse
drawal can be life threatening.
are relatively high compared with other drugs,33
Gamma-hydroxyvaleric (GHV) is a 4-methyl-
because of its intrinsic toxicity, high dependence
substituted analogue of GHB and a direct GABA
liability and potentially life-threatening withdrawal
receptor agonist. Gamma-valerolactone (GVL) is
syndrome, as discussed in Section 3.12.2.
a precursor of GHV. Larger doses of GHV may be
Although its use is limited in comparison to other
needed to produce GHB-like effects and therefore
drugs used for recreational purposes, the use of GHB and
GHV toxicity may pose a public health concern.20
GBL has increased in the last decade in some European
Countries, Australia and the US.34,35,36 Nonetheless,
3.5 Clinical and Other Uses national estimates, where they exist, of the prevalence
Clinical uses of GHB have included alcohol and opiate of GHB in adult and school populations remain low. For
detoxification regimens, anti-craving medication after example, in their 2017 survey, Norway reported preva-
alcohol detoxification,13 and one study has looked at lence of GHB use at 0.1% for adults (age 16–64 years).37
detoxification from illicit GHB by titration and taper- In Europe in 2017, seizures of GHB or GBL were
ing of pharmaceutical GHB.21 reported by 14 EU countries as well as Norway and
GHB is used as an anaesthetic agent in some Turkey, with Norway accounting for over a quarter of
European countries, although this latter use is now the total number of seizures. Seizures amounted to
declining. The sodium salt of GHB, sodium oxybate almost 127 kilograms and 1,300 litres of the drug.
(Xyrem SPC), is approved for the treatment of narco- Belgium seized almost half of the total quantity, mainly
lepsy with problematic catalepsy in specialist sleep as GBL.38
centres in the US and Europe. A recent systematic review There is evidence that GHB/GBL users are most
and meta-analysis of its effectiveness has been likely to be male.39 The use of GHB appears to be
conducted.22 concentrated among some sub-groups, often in spe-
GHB was sold in US health food stores for weight cific contexts. In the UK, mainland Europe, the US,
control and sedation, until over-the-counter sales were Australia and elsewhere, GHB/GBL use is popular
banned in 1990 following reports of acute among some gay men and other men who have sex
intoxication.23 It has also been sold for its antidepres- with men; it is often one of the drugs used in
sant and anxiolytic effects and for its cholesterol- ‘chemsex’.30,40,41,42,43,44,45,46,47,48 For example, an
lowering effects. It has also been used in bodybuilding, Australian study reported that 5.4% of gay and bisex-
as it has been thought to release growth hormone; ual men had used GHB in the past 6 months.49
however, its anabolic effects are unproven.24 However, although it seems that rates of use
GHB has been implicated as a facilitator in ‘date among women are much lower than men, and in
rape’ and sexual assaults, but it is not the only sub- particular men who have sex with men, there are
stance implicated.25,26,27 Nonetheless, it has been reports of women using GHB/GBL.50
argued that it is important to consider GHB and its Due to its pro-sexual effects and muscle relaxant
precursors with any cases of sexual assault and non- properties, GHB/GBL is often used by men who have
consensual sex,28,29,30 and GHB/GBL should be sex with men in a sexual context.50 GHB is one of the
38
3.8 Desired and Unwanted Effects of GHB/GBL
drugs commonly implicated in ‘chemsex’ and it has lipophilic than GHB; hence, typical ingested dosages
been associated with high-risk sexual behaviours. of GBL are lower than those of GHB.58,59
Drug surveys have also consistently found higher GHB/GBL dose is often measured by users in
GHB use rates in people socialising on the gay club imprecise ‘capfuls’, teaspoons, eye droppers or vials.
scene, primarily gay males, but also other LGBT This imprecise dose measurement is one of the main
people, as well as by heterosexual people.50 suggested causes of the acute GHB/GBL-related
GHB/GBL use has been associated with ‘clubbing’ harms, as users risk overdose because of its steep
and visiting the night time economy.50,51 A number of dose–response curve, which is discussed in greater
European surveys conducted in dance music venues and detail in this chapter.
other targeted settings suggest that the lifetime preva- Recreational users will typically use small doses
lence of use of GHB/GBL ranges from 3% to 19%.30 frequently, in the context of binges, or sometimes at
The demographic and socio-economic profile of night to assist with sleep. Dependent users will ingest
people who use GHB/GBL shows conflicting results, GHB/GBL frequently and at regular intervals over
possibly differing by country. Data from Australia and prolonged periods. They will generally use multiple
the UK suggest that GHB/GBL users tend to be well- daily doses, including at night.50 The mean frequency
educated and well-functioning people.36,52 Conversely, of dosing in cases of dependence was reported by
a study in the Netherlands showed that heavy, high-risk McDonough et al. to be every 4.4 hours,60 although
GHB consumption is primarily found among what the case reports and series show a wide range, from hourly
study describes as ‘poorly educated young adolescents in to daily.51,61,62
economically less privileged provincial communities’.53 There is evidence that GHB/GBL is often used as
part of a wider poly-drug repertoire (see Section 3.10.2).
An Internet survey of 189 GHB/GBL users reported that
3.7 Routes of Ingestion a third had taken GHB/GBL during the last month and
and Frequency of Dosing that two-thirds reported mixing GHB/GBL with other
The routes of administration of GHB/GBL include: drugs.35
• Oral use (this route is the most common, when it is GHB/GBL is reportedly co-ingested with other
typically diluted in a beverage); drugs, including cannabis, ecstasy, stimulants and
• Insufflation (snorting); sildenafil (Viagra).36,37 Polydrug use increases the
risk of acute toxicity, most significantly when another
• Injection (although this is rare);
CNS depressant has been consumed.
• Mucosal (e.g. previously from absorption of nail
polish removal pads).
GHB/GBL used for recreational purposes is most
3.8 Desired and Unwanted Effects
usually sold in the form of a liquid formulation, often of GHB/GBL
in bottles or vials. Its taste is described as unpleasant GHB/GBL affects people in different ways and
and salty and it is therefore typically diluted in a euphoric dose for one person may be a sedative
a beverage. It is more rarely used as a powder, usually dose for another.63 GHB/GBL tends to produce
GHB sodium salt (capsules or loose) or a waxy sub- euphoric and pleasurable effects64 without hangover
stance to which water can be added.30 The ‘irritant’ or other subacute adverse effects, which helped popu-
nature of GHB/GBL has been described, with a case larise it as a ‘club drug’.5 The desired effects of GHB/
report of a user syringing the liquid into capsules to GBL include euphoria, relaxation, increased sociabil-
make it easier to swallow.54 ity and confidence, social and sexual disinhibition,
GBL for recreational use is usually bought from enhanced libido, increased sexual arousal and
street dealers or via the Internet in amounts ranging enhancement of sexual encounters, with effects
from 125 ml to 10 litres. Usually, 1 ml of liquid being dose dependent.12,30,65,66,67
contains 1 g of GHB, although purity and concentra- The use of GHB/GBL for its stimulant, dissociative
tion may vary.30,55,56,57 Miotto et al. suggest that single and sedating effects has also been reported.50,68,69 In
doses of GHB can range from 0.5 g to 5 g and those addition, some individuals use GHB/GBL after using
who develop tolerance and dependence will use in the other drugs (generally stimulants), to help ‘come
range of more than 25 g per day.50 GBL is far more down’36 or to enhance and modify the effects of
39
drugs.50 GHB/GBL is also used as self-medication for been implicated in cases of sexual assault and victims
sleep problems and anxiety. There are reports of of acquisitive crime.81
people using GHB/GBL in the hope that it will
improve cognitive ability, reduce the effects of ageing, 3.9 Mortality
reduce depression and anxiety, or make them feel
Acute GHB/GBL toxicity and a severe withdrawal
more energised.70
syndrome have been associated with profound CNS
There are a number of unwanted effects associated
and respiratory depression and death.82,83,84,85,86
with GHB/GBL. GHB/GBL use is often associated
Studies have shown that the co-use of alcohol and
with ‘blackout’ and loss of consciousness. This can
other drugs, especially CNS depressants, was impli-
be a risk factor for users for becoming involved in
cated in many GHB-related deaths.87,88
unwanted sexual activity or enduring sexual or
A study of 74 Australian cases in which GHB
acquisitive crimes.71
contributed to death found that typical cases were
Concerns have also been voiced about the potential
young males who swallowed GHB and used it with
role of GHB/GBL in reducing safe sex practices because
other substances, most commonly at home. Other
of its links to disinhibition and unconsciousness.72,73
substances were also found in 92.2% of cases, most
GHB is associated with high-risk sexual behaviour and
commonly psychostimulants (64.1%), hypnoseda-
thus with an increased risk of sexually transmitted infec-
tives (28.2%) and alcohol (20.3%). Resuscitation
tions. Studies have shown that GHB/GBL use is associ-
was attempted in 20.3% of cases. Acute pneumonia
ated with increased sexual risk, with HIV-positive men
(36.7%) and aspiration of vomitus (30.6%) were
more likely to use GHB/GBL and more likely to use it in
common. The study shows that acute drug toxicity
a sexual context40,74,75 than those not known to be
was the most common cause of death, but there was
infected.76
a substantial minority due to trauma or suicide.89
A study based on data from 16,065 UK-based
It has been suggested that the rise in the number of
respondents to the European MSM Internet Survey
deaths reported in some countries may be associated
(2010), showed that men who have sex with men who
with increased participation in ‘chemsex’.90 A study of
reported using methamphetamine and GHB/GBL in
death of LGBT people associated with the use of GHB/
the previous year had 1.92- and 2.23-fold higher odds
GBL based on data from the UK’s National
of gonorrhoea, respectively, over the same period
Programme on Substance Abuse Deaths database
after adjusting for age, recruitment website, HIV sta-
has suggested that typical victims were: male (100%);
tus, residence and use of other ‘chemsex’ drugs.
white (67%), young (mean age 34 years); employed
Another study showed that multi-partner encounters
(90%) and with a drug misuse history (81%). Most
and condom-unprotected anal intercourse have been
deaths were accidental (67%) or related to recreational
associated with GHB use in the previous 6 months.77
drug use (19%), the remaining were (potential) sui-
The role of ‘chemsex’ in problematic GHB use has
cides. GHB/GBL alone was implicated in 10% of fatal-
been observed with recommendations for the need for
ities, with others involving the additional use of at
public health providers to engage with novel psycho-
least one other substance.91
active substance use and the health and well-being
effects of ‘chemsex’ and the provision of sensitive,
culturally competent interventions.78 It has been sug- 3.10 Acute Harms
gested that the routine screening for sexualised drug
use in men who have sex with men should be imple- 3.10.1 Acute GHB/GBL Toxicity
mented so that healthcare professionals can provide As mentioned above, GHB/GBL affects people in dif-
better-informed and higher-quality health care to this ferent ways and a euphoric dose for one person could
population.79 Models for the joining up of sexual be a sedative dose for another.58 The adverse effects of
health and drug services to better meet client needs GHB/GBL happen at a variety of doses, indicating the
have also been proposed.80 variable individual responses to the drug92 and are
The effects of the drugs, which include drowsiness, also influenced by the dose ingested, individual vari-
reduced consciousness and coma, make individuals ation and other substances ingested. Clinical effects
vulnerable to sexual assault, rape and administration are potentiated by ethanol, benzodiazepines, anti-
of further substances. GHB and related products have psychotics and other CNS depressants, including
40
3.10 Acute Harms
some co-ingested recreational drugs.93 In addition to The usual clinical course after overdose – if other
the GHB-related adverse effects, the adulterant com- CNS depressants (including alcohol) have not been
pounds may also have serious toxic effects.30 used – is rapid, spontaneous awakening from drug-
There are potential acute harms relating to any use induced loss of consciousness or coma and uneventful
of GHB/GBL. All GHB/GBL users risk acute toxicity recovery.109
and overdose; tolerance is not fully protective of over- Temporary GHB-induced coma generally lasts
dose and people dependent on GHB/GBL are also at between 1 and 4 hours, but could be much briefer. It
risk of acute toxicity.94 often reaches the most severe classification on the
In terms of acute single-dose systemic toxicity, Glasgow Coma Scale,110,111,112 but it has been noted
GHB/GBL appears to be a physiologically toxic club that often no side effects are apparent after sudden
drug, with overdoses typically occurring as awakening from this coma. CNS depression usually
a consequence of using repeatedly over a short period, persists for 1–3 hours, with patients typically, but not
or when GHB/GBL is used in combination with other always, making a full recovery within 4–8
CNS depressants, such as alcohol or benzodiazepines.13 hours.82,113,114,115 Thus, patients with acute intoxica-
The hazard profile of GHB has been described as less tion typically develop signs of intoxication rapidly but
favourable than that of many other psychoactive sub- then improve quickly.
stances. One study concluded that GHB is the most Overdoses are common among all users – depend-
physiologically hazardous drug, partly because of the ent users as well as inexperienced, intermittent and
narrow safe dosage range95 and because its effects vary regular users. Tolerance and dependence do not pro-
between individuals and whether other substances tect against overdose.36
have also been used. The imprecise dosing of illicit In an Australian study of 76 GHB users, half
GHB or GBL can be associated with acute harms and reported a history of overdose during which they
overdose.85 had lost consciousness.36 In another study, 66%
The effects of GHB are dose-dependent, as sum- reported some degree of loss of consciousness.50
marised in a recent review (Table 3.2).8 Similarly, a study of 505 consecutive GHB cases in
Loss of consciousness and coma associated with emergency departments in Barcelona showed that the
GHB/GBL intoxication is common and recurrent motive for seeking medical treatment in all cases was
coma is a common experience of people who use reduced consciousness.60
this drug even recreationally.101 Unconsciousness or As with alcohol, and unlike with benzodiazepines,
reduced consciousness are the most common symp- there is no antagonist or antidote. Because of GHB’s
toms of GHB overdose.102,103 However, it seems that short elimination half-life, people can progress from
despite the fact that regular GHB users may experi- deep coma to wakefulness over about 30 minutes. A 30-
ence GHB-induced coma repeatedly, many still con- month review of an Australian emergency department
sider its use to be safe.104,105,106,107 reported that if ventilation was not required, the great
This is sometimes referred to by users as ‘black- majority improved rapidly and were discharged
outs’, with one study showing that 14% of participants straight from the emergency department, without
experienced blackouts ‘nearly always’ or ‘always’, and a need for further medical treatment.116,117 A study of
24% experienced blackouts in at least half of their presentation to hospital associated with GHB intoxica-
GHB-using episodes.108 tions, for example, reported sudden recovery in one
third of the cases presenting to hospital with impaired
consciousness, and the majority of the patients were
Table 3.1 Dose-dependent effects of GHB discharged home directly from the emergency depart-
ment, despite the characterisation of their intoxication
Dose Effects as ‘severe’ at the time of presentation.118
Below Mild clinical effects: short term anterograde In European cities, accidental GHB/GBL over-
10 mg/kg amnesia, hypotonia and euphoria96 doses in night clubs account for a substantial propor-
20–30 mg/ Drowsiness, sleep and myoclonus can tion of drug-related emergencies that require
kg happen86,97
ambulance, emergency or hospital services.30
50 mg/kg May cause coma.98,99,100 May lead to the
and over onset ofcoma, bradycardia and/or
A study of GHB/GBL overdose in Norway based
respiratory depression and death86,88,90 on ambulance records suggested that patients were
41
male, in their mid-20s, and found unconscious at the • Severe effects include coma, convulsions,
scene. The temporal patterns suggest party use, being bradycardia, ECG abnormalities (e.g. U waves), in
most frequent during late-night and weekends.119 The rare cases hypertension after intravenous use,
GHB/GBL victims are younger than opioid overdose Cheyne–Stokes respiration and respiratory
victims, and are hospitalised more often.120 depression leading to respiratory arrest. Metabolic
acidosis has been reported.
3.10.1.1 The Features of Acute GHB/GBL Toxicity GHB/GBL produces CNS and respiratory depression
Overall, the reported effects of acute GHB/GBL toxicity of relatively short duration. Laboratory investiga-
are summarised as follows (see also Boxes 3.1, 3.2 and tions may also indicate hypernatraemia, hypokal-
3.3): aemia, hyperglycaemia and metabolic acidosis.
• Mild/moderate effects include nausea, High anion gap metabolic acidosis (HAGMA) has
hypersalivation, vomiting, diarrhoea, drowsiness, been associated with GHB/GBL and 1,4-BD
headache, ataxia, dizziness, confusion, amnesia, intoxication.121,122
urinary incontinence, tremor, myoclonus, Psychotic episodes may occur. It has also been
hypotonia, agitation, euphoria and hypothermia. suggested that GHB/GBL intoxication should be
Box 3.1 Reported Neurological and Psychiatric Effects
Effects are dose-related. Patients may therefore present with CNS symptoms ranging from sudden drowsiness
through to unresponsive coma, depending on dose.60,82–84,97,98,100,101,123–134
• Amnesia135,136
• Ataxia61,63,88,98,113,119,120, 137–171
• Hypotonia88,108,116,121,172
• Disorientation60,98,120,126,151
• Hyporeflexia133,142,148,152
• Dizziness61,110,119,134,135,136,153
• Tremor88,122
• Confusion110,120,121,135,136
• Myoclonus82,88,89,97,119,132,173,174,175
• Hallucination125,126,135,136
• Somnolence120,124,132,154
• Agitation,63 bizarre behaviour and combativeness, either at presentation or when
waking60,63,86,87,97,98,100,108,110,113,117,118,119,120,122,123,126,127,130,134,135,136,138,140,143,148,150,152,156,157
• Slurred speech122,125,126
• Miosis60,110
• Dysarthria60,119
• Confusion110,126,108
• Mydriasis (wide pupils)60,110,114,122,127,128,132,134,135
• Headache60,127
• Horizontal and vertical gaze nystagmus121,122,125,126,127
• Reduced coordination122,135
• Pupils may be sluggish and non-reactive108,114,136,149
• Euphoria
• Convulsions (seizures or seizure-like activity) have been
reported,50,88,97,98,100,101,107,110,111,114,116,120,129,131,135,136,139,150,155,156 but most studies have shown them to be
uncommon. They may occur secondary to hypoxia or due to other substances used12
• Less common neurological effects include bruxism,140 vertigo,88 delusion,152 extrapyramidal side effects,125
dystonia125 and athetoid posturing140
42
3.10 Acute Harms
Box 3.2 Cardiovascular Effects
• Bradycardia60,88,97,98,107,110,114,118,119,120,122,126,131,134,135,137,138,140,142,144,148,149,150,151,154,156,157
• Mild bradycardia without haemodynamic compromise is the most common cardiovascular effect and has been
noted in recreational drug users82
• Chest tightness60,136
• Tachycardia and hypertension60,98,100,114,119,120,121,123,135,148
• Hypotension60,88,100,110,116,119,126,131,140,143,144,149,154,176 is rare when GHB/GBL is used on its own; generally, it
occurs only when GHB/GBL is co-ingested with other substances 54,68
• ECG abnormalities occur occasionally100
Box 3.3 Central Nervous System and Respiratory Effects
• Dose-related respiratory depression 87,88,97,98,107,110,113,114,117,119,120,123,130,134,135,149

Respiratory failure is normally the cause of death from GHB/GBL
• Tachypnoea100
• Bradypnea60,100,101,108,119,126,133,134,140,142,143,146,149
• Pneumothorax151
• Periodic (Cheyne–Stokes) respirations156,177,178
• Cyanosis108,114
• Pulmonary aspiration98,108,109,110,112,115,149
• Pulmonary oedema119,130,147,179,180
• Apnoea and respiratory failure82,84,135
considered a differential diagnosis for patients pre- score ≤8, which is the usual cut-off for intubation.107
senting to an emergency department with acute A case series of 88 patients presenting to medical ser-
agitation.63 vices after taking GHB reported a GCS score of 3 and
Reported features of GHB/GBL intoxication are 33% had a score of 4–8.82
listed in Boxes 3.1 and 3.2. It is important to note that Acute GHB/GBL toxicity can cause amnesia, which
other additional symptoms or features may occur due increases the risk of relapse because users do not remem-
to co-use of alcohol (ethanol) or other drugs. ber the experience of acute intoxication and overdose.181
The CNS symptoms of acute toxicity can vary, As mentioned above, GHB can cause profound uncon-
depending on ingested dose, from sudden drowsiness sciousness and the steep dose–response curve puts the
to unresponsiveness and profound coma. CNS depres- user at risk of death. The co-ingestion of alcohol is
sion typically persists for 1–3 hours, with patients mak- a significant added risk factor, but GHB/GBL intoxica-
ing a complete recovery typically within 4–8 hours. tion alone can cause death.5 Other reported effects of
Coma accounts for a significant proportion of GHB/GBL use include one observational case report of
GHB-/GBL-related presentations to emergency acute central serous chorioretinopathy.182
departments, with a reported range of 16–33%.110 For
example, a third of cases in a Swiss study110 presented Vomiting
to hospital with coma, 28% of cases of a US study82 and Vomiting during acute intoxication is common. The
16% of cases in a study conducted in Spain.97 In a case London-based study mentioned above reported that
series of presentations to a London emergency depart- vomiting occurred in 17% of presentations,107 while
ment, approximately 16% of cases had severe coma at Garrison et al. reported vomiting in 22% of
presentation, with a score on the Glasgow Coma Scale presentations.183 Other studies have reported higher
(GCS) of 3. In this study, 47% of patients had a GCS rates including vomiting in 30% of the presentations
43
to a US emergency department study82 and in more A double-blind, placebo-controlled, cross-over vol-

than half of cases of GHB/GBL overdose in an unteer study that investigated the potential for tox-
Australian study.36 Vomiting in individuals with icity associated with GHB alone compared with GHB
reduced consciousness (especially when the GCS and alcohol co-ingestion showed that GHB plus
score is less than 8 out of 15) is believed to increase ethanol was associated with more adverse effects, in
the risk of aspiration due to the lack of protective particular hypotension and hypoxia; there were no
airway reflexes.184 Indeed, aspiration in patients differences in GHB/GBL concentrations between the
intoxicated with GHB/GBL needs to be considered groups.187
a significant risk, particularly in those with reduced Co-ingestion of GHB/GBL and alcohol has been
consciousness. Local clinical protocols should include associated with increased agitation110 and aggressive
steps to assess and reduce the likelihood of vomiting behaviour. Patients who used alcohol were also more
and subsequent aspiration. likely to vomit.110 There is evidence that when GHB/
Seizures or seizure-like activity are associated with GBL is taken in combination with other drugs
GHB/GBL consumption and have been widely (including alcohol or stimulants), the duration and
reported,50,97,100,107,110,114,129,135,155,185 especially when depth of coma is greater than when it is consumed
intoxication is severe. Studies suggest however that alone, and recovery times are longer.60,110,188
seizures are uncommon,12 although it has been argued
that it is difficult to determine the true frequency of 3.10.2.1 GHB and HIV Antiretroviral Therapy (ART)
‘seizures’, as GHB and its analogues have been shown There is evidence that men who have sex with men
to cause myoclonic jerks, which – in pre-hospital who are living with HIV are one of the population
settings in particular – may be misinterpreted as groups likely to use GHB/GBL.189 Many will be
a seizure.168 receiving antiretroviral therapy (ART).
Hypothermia is usually not severe, but can be While clearance of GHB from the systemic circula-
common. For example, in a series of 88 cases of tion occurs rapidly by oxidation to succinic acid,190,191
GHB/GBL overdose, 55% were assessed to have an animal data suggest that GHB is also a substrate of first-
initial temperature of 36°C or less and 25% an initial pass metabolism (which may involve the enzymes
temperature of 35°C or less.82 CYP2D6 and CYP3A4). Therefore, co-administration
Bradycardia is also common. In the same case of GHB with CYP2D6 inhibitors (i.e. cobicistat) or
series of 88 GHB overdose patients, over one-third CYP3A4 inhibitors (i.e. ritonavir, cobicistat) may lead
(36%) developed bradycardia, although only one case to raised systemic exposures of GHB and increased
was severe enough to require atropine.82 toxicity. It has been recommended that GHB/GBL
should be used with caution by people receiving ART
3.10.1.2 Acute Withdrawal with predisposing seizure disorders or with opportun-
People who use at least daily may commonly develop istic infections that may lower seizure threshold (i.e.
tolerance and dependence. Withdrawal syndrome fol- toxoplasmosis, cryptococcal meningitis), as GHB/GBL
lowing abstinence or dose reduction after prolonged may precipitate seizure-like activity.
use can be severe and must be treated as a medical There is a case study of a patient taking saquinavir/
emergency. For more details on withdrawal see ritonavir and experiencing extreme sedation, myoclo-
Section 3.12.2. nus and bradycardia after taking a small dose of GHB.
These severe manifestations of GHB toxicity were
3.10.2 Poly-drug Use and Drug thought to be due to CYP isoenzyme inhibition with
resultant drug accumulation.192
Interactions GHB/GBL use may cause severe nausea, vomiting
The co-ingestion of alcohol (ethanol) and/or other and gastrointestinal tract irritation, and adversely
recreational drugs may contribute to some of the affect absorption of ART.193 There are also concerns
other clinical features seen in patients presenting about compliance with HIV medication while intoxi-
with GHB/GBL and or GHB/GBL toxicity.186 cated, especially during prolonged binges, which may
A number of authors have suggested that GHB complicate ART and affect adherence.177
users who co-ingest alcohol are more likely to It has also been noted that the co-administration of
develop severe complications related to GHB use. EVG/COBI (Elvitegravir; Cobicistat) may potentially
44
3.11 Clinical Management of Acute Toxicity
increase concentration of phencyclidine (PCD) or There is consistency in the evidence reviewed that the
methamphetamine, cocaine, GABA-mimetics (e.g. lor- treatment of GHB/GBL acute toxicity should consist of
azepam, midazolam, triazolam, alprazolam and GHB). symptom-directed supportive care with an emphasis
EVG/COBI via inhibition of P-gp could potentially on respiratory support.201 Wood et al. suggest that the
increase the effects of opiates in the CNS.194,195 duration of reduced consciousness (particularly non-
responsive coma) is generally short-lived, with the
3.11 Clinical Management of Acute majority of patients recovering fully within 2–3 hours
of the onset of coma.168
Toxicity The protection of airways and proper airway man-
agement is recommended because vomiting is
3.11.1 Identification and Assessment common.98,117,151,162,202
Diagnosis of acute GHB/GBL toxicity should be made It has been argued that routine intubation of
on clinical assessment. Urine and serum tests are not patients with acute GHB/GBL toxicity is not recom-
routinely available196 in frontline clinical settings so mended unless patients exhibit vomiting, seizures or
analytical assessment should not be considered other clinical indications for intubation.168 Clinical
a component of routine diagnosis. It has been sug- consensus suggests that there does not appear to be
gested that the diagnosis of acute GHB/GBL toxicity a need to intubate purely on the basis of GCS score, as
be based on the recognition of the clinical toxidrome in other medical presentations and trauma. On the
associated with the overdose of GHB/GBL.168 other hand, others have recommended that if the
Standard medical assessment is always indicated, so patients are unconscious then intubation should be
that other causes of the presentation can be excluded. considered for the first few hours of recovery.203
Problems relating to the identification of GHB/GBL Reports in the literature indicate that intubation is
intoxication are linked to the similarities in clinical fea- needed in 3–13% of cases.82,97,100,110,204 One study
tures to alcohol, opiate and/or benzodiazepine found a greater requirement for mechanical ventilation
intoxication,12,197,198 or similarities to other clinical for patients who had ingested GHB/GBL with other
presentations, such as hypoglycaemia. Given the simi- drugs or alcohol, as the duration and depth of coma
larity to acute opioid toxicity, it is recommended that were greater than when GHB/GBL was taken alone.60
where there is clinical uncertainty, it may be worth In addition, is it recommended that in cases of
considering a trial of the opioid antagonist naloxone, GHB overdose, clinicians should monitor vital signs
although it is not effective in managing acute GHB/GBL and cardiac rhythm and check the capillary blood
intoxication.199 sugar. A 12-lead ECG should be performed in all
Diagnosis is also complicated by frequency of patients who require assessment and it is recom-
other co-intoxicants200 and by the diversity of clin- mended that 12-lead ECGs are repeated, especially
ical presentation.63 Some or all of the clinical fea- in symptomatic patients or in those who have co-
tures of acute GHB/GBL toxicity may be ‘masked’ ingested other sustained release preparations.
by other co-ingested substances (e.g. an individual Clinicians should also check cardiac rhythm, QRS
may present with drowsiness and normal heart rate duration and QT interval. It is also recommended
due to co-ingestion of GHB/GBL and a stimulant that clinicians check U&Es and creatinine, blood glu-
such as cocaine or amphetamine). cose and CK in all patients who require assessment. It
is also recommended that clinicians consider arterial
blood gas analysis in patients who have a reduced level
3.11.2 Clinical Management of Overdose of consciousness (e.g. GCS less than 8; AVPU scale
and Acute Toxicity P or U) or have reduced oxygen saturation on pulse
oximetry.205
For up-to-date guidance on the management of GHB/
Symptom-directed supportive care might include
GBL acute toxicity, it is recommended that information the management of seizures, bradycardia, hypotension,
be sought from national or regional poisons hypertension, metabolic acidosis, hyperthermia, rhabdo-
information services. myolysis, agitation and delirium.206 Cardiovascular
Clinicians should also consult their local or symptoms resulting from overdosing with GHB don’t
national guidelines and protocols. normally require invasive therapy.207
45
It has been recommended that all patients who longer for those with severely reduced consciousness,
require assessment should be observed for at least 4 typically resulting from poly-substance use.60,100 They
hours after exposure. Asymptomatic patients can then also show a rapid rate of discharge from hospital, 60,100
be considered for discharge with advice to return if although people presenting to hospital with a low
symptoms develop.208 GCS may have a longer recovery period.107
Expert consensus has highlighted the need to fully A retrospective study of patients presenting to
investigate unconscious patients, particularly when a large London inner-city emergency department
the diagnosis is unclear. CT scanning may be indicted, with acute poisoning with self-reported GHB/GBL tox-
particularly when convulsions occur, although there is icity reported on the disposition of patients with acute
no robust evidence on the routine use of CT scanning GHB/GBL intoxication. The majority (92.2%) were
specifically for GHB/GBL overdoses. discharged directly or self-discharged from the depart-
Some patients may have a fluctuating course on ment or required only a short period of observation in
recovery, where they have periods of agitation alongside the emergency department observation ward. Fewer
periods of drowsiness or coma. These patients can some- than 1 in 10 (7.8%) required admission to hospital.
times be difficult to manage, since they require appro- Among those, the majority were admitted to critical
priate sedation for their periods of agitation, which may care facilities, usually because of significant neuro-
worsen the degree of sedation when it occurs. Should logical or respiratory compromise and the need for
this occur, there may be a need for appropriate respira- airway protection and intubation. The study also
tory support until the patient has fully recovered. looked at length of stay and reported an overall median
Dependent users may begin to go into withdrawal on stay of 2.8 hours: discharged or self-discharged directly
recovery from the overdose – see Section 3.12.2. from the emergency department 2.4 hours (range 1.7–
Gastric decontamination (e.g. activated charcoal) 3); admitted to the emergency department observation
is not recommended, as its effects are uncertain. There ward 5.6 hours (range 3.6–8.6); admitted to general
are no antidotes for GHB/GBL poisoning.12 medical ward 15.6 hours; admitted to a critical care
A study has suggested that treatment with inhibitors facility 18.7 hours (range 10.1–39.2).107
of monocarboxylate transporter 1 (MCT1) (a trans- As amnesia is a direct effect of GHB/GBL, patients
porter that mediates many of the processes involved in may recover with no recall of GHB/GBL intoxication or
the absorption, distribution, including brain uptake and overdose.50 In a study of 42 users, 13% had amnesia
elimination of GHB/GBL), has been shown to prevent during GHB use and 45% after GBL use.50 It has been
GHB-induced respiratory depression by increasing the noted that because they do not remember their experi-
renal clearance of GHB. Overall, this study indicates ence of overdose, people may put themselves at risk of
that inhibition of MCT1 is an effective treatment of overdosing in another GHB use episode or may delay
GHB/GBL overdose.209 treatment.165
Outside clinical settings, in night clubs for
example, harm reduction information should stress
the need to put people in the recovery position and
3.11.4 Acute Withdrawal Following
call for an ambulance. GHB/GBL users should simi- Detoxification
larly be told to put people with signs of acute intoxi- In GBL-/GHB-dependent people, rapid improvement
cation in the recovery position (see also Section 3.15 ). from acute toxicity may be followed by deterioration
as withdrawal symptoms develop (for details on with-
3.11.3 Treatment Outcome drawal see Section 3.12.2). Withdrawal symptoms
Patients with GHB/GBL acute toxicity will typically may manifest quickly, or up to 24–48 hours later,
develop symptoms quickly, but will generally also and the potential for delayed onset of withdrawal
improve rapidly. Even in more severe cases, patients symptoms in those with GHB/GBL dependence
will usually make a full recovery, provided they are must be considered in the management of acute
hospitalised and receive appropriate supportive toxicity.211 A vital part of discharge instructions
care.12,210 from hospital to GHB-/GBL-dependent patients,
Studies have shown that patients will regain a GCS their friends and carers after recovery from overdose,
score of 15 in a short time after presentation (a is to inform them about the potential for withdrawal
median of 76 minutes in one study), albeit this is symptoms to occur after discharge.196
46
3.12 Harms Associated with Chronic Use
In the majority of published cases of GHB/GBL GHB/GBL withdrawal can appear clinically simi-
withdrawal, detoxification was unplanned and started lar to withdrawal from opioids, benzodiazepines and
after the patient presented in crisis, usually to an alcohol,12 and problems relating to the identification
emergency department.55 Acute withdrawal is poten- of GHB/GBL intoxication and withdrawal are linked
tially life threatening and it is recommended that to the similarities in clinical features.182 Symptoms
cases are considered a medical emergency. It is also are often more prolonged than in alcohol withdrawal
recommended that all dependent users of GHB/GBL (up to 2 weeks, occasionally longer) and are typically
are advised not to stop use abruptly or to attempt self- more resistant to treatment with benzodiazepines.
detoxification. Medical assistance should always be GHB/GBL withdrawal can also have similarities to
sought. clinical presentations such as hypoglycaemia or sym-
pathomimetic toxicity, typically associated with
3.12 Harms Associated with Chronic stimulant use.
Use 3.12.2.1 Predictors of Withdrawal
Dependent users will develop withdrawal symptoms
3.12.1 Dependence on reduction or cessation of use, which can be severe
The regular, prolonged use of GHB/GBL and its ana- and life threatening.55,213,214,215 GHB/GBL with-
logues can lead to physiological dependence.12 Its drawal symptoms occur on a spectrum that varies in
typical features include difficulty controlling the clinical severity.
amount used, neglect of other activities and with- Withdrawal symptoms have typically been
drawal symptoms, which in the case of GHB/GBL observed after prolonged use of high doses of GHB
can be severe. but can be seen after as little as 2–3 months of use,55 or
Part of the dependence syndrome is tolerance, in even a shorter time after high-frequency use.
which larger doses are needed over time to produce the There is increasing evidence that daily use of GHB/
same psychoactive effects. Long-term users therefore GBL is a predictor of withdrawal.55 People who con-
typically use higher doses than naïve users.30 Users sume GHB doses at short intervals (e.g. every 2–3
have reported taking larger doses in order to achieve hours) appear to have the highest risk of severe with-
previous effects or use just ‘to normalise’ themselves drawal symptoms when stopping GHB use. It is sug-
rather than to experience acute intoxication.56 Cross- gested that GHB users who consume the drug at
tolerance between GHB/GBL and alcohol may exist. regular intervals during the day and night (every 1–3
At a social level, dependence has been described by hours) appear to be particularly at risk to develop
patients to be the opposite to why they chose to use dependence.216 Less-frequent users may experience
GHB/GBL in the first place: rather than enhancing mild withdrawal symptoms upon cessation.217
sociability, GHB/GBL dependence leads to introver- In their review, McDonough et al. report
sion, lack of motivation and failing to maintain contact a minimum daily dose associated with withdrawal is
with family and non-using friends; other concerns approximately 18 g for GHB and 10 g for GBL,55 but it
included absenteeism and loss of employment.47 is possible that it occurs at lower daily doses.
3.12.2.2 Onset and Duration of Withdrawal Syndrome

3.12.2 The GHB/GBL Withdrawal One distinctive feature of GHB/GBL dependence is
Syndrome the quick onset of withdrawal symptoms. These can
The potential of GHB/GBL to produce dependence is occur 30 minutes after the last dose, but more typic-
well recognised. Dependent users will consume GHB/ ally after a few hours. GHB/GBL withdrawal symp-
GBL at regular intervals during the day and at night, toms have been reported to last from 48 hours to 21
sometimes as often as every 1–3 hours,13 in order to days,12,55 with one review reporting a mean of 9
avoid withdrawal. days.55 Longer term withdrawal symptoms tend to
Abrupt decrease or discontinuation of heavy GHB include psychiatric symptoms such as delirium,
use may result in a severe and life-threatening with- psychosis or depression.218,219,220
drawal syndrome, characterised by autonomic Wood et al. report that in their clinical experience,
instability, delirium and aggression.212 50% of those who present to hospital with acute GHB/
47
GBL withdrawal will require barbiturates and admis- It is not possible to determine accurately how
sion to intensive care, as they typically present with common these symptoms are. A review of 36 emer-
delirium.221 gency department presentations reported that the
early symptoms of withdrawal were tremor (67%),
3.12.2.3 Individual Variations and Unpredictability hallucinations (63%), tachycardia (63%), insomnia
of the Withdrawal Syndrome (58%), seizures (7%) and rhabdomyolysis (7%).200
Although there are similarities between cases of GHB/ McDonough et al. in their review reported that an
GBL withdrawal reported in the literature, there are eight-hourly dosing was the minimum frequency
also wide variations in both the withdrawal symptoms associated with withdrawal delirium.55 There are indi-
and the clinical responses between patients.222 cations that heavy, frequent users are most likely to
Withdrawal symptoms can be self-limiting in some progress to severe delirium. It has been proposed that
patients, but others can present with more severe withdrawal in cases of co-dependence on GHB/GBL
withdrawal that can progress rapidly and require and another CNS depressant (opiates or other seda-
acute medical intervention. tives) or CNS stimulant are likely to be more severe,
but such cases have not been widely described in the
3.12.2.4 GHB/GBL Withdrawal Symptoms literature.55 Seizures associated with GHB/GBL with-
The symptoms of GHB/GBL withdrawal seem to drawal appear to be less common than with alcohol
vary between people, and may depend on the amount and are reported in fewer than 10% of cases.
and duration of use of GHB. Withdrawal symptoms The early symptoms of GHB/GBL withdrawal typ-
typically start a few hours after the last GHB ically include insomnia, tremor, confusion, nausea and
ingestion.223 vomiting. Over the next 12–48 hours, tachycardia,
Withdrawal symptoms reported in the literature hypertension, agitation, seizures and/or myoclonic
are summarised in Box 3.4. jerks and hallucinations may develop.
Box 3.4 GHB Withdrawal Symptoms

Commonly Reported Symptoms
• Hallucinations – visual and auditory13,23,57,198,200,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238
• Anxiety23,37,50,56,57,90,198,208,209,215,239,240,241
• Tremors37,52,56,57,90,182,207–210,213,215,216,218–223
• Paranoia13,23,56,57,198,212–215,218,221
• Tachycardia23,50,57,198,200,207–210,212,215–218,222,223
• Insomnia23,37,52,57,90,207,208,210,212,215,217,221
• Hypertension57,198,207,208,217,218,223
• Disorientation23,198,200,208,209,212,215,217,221
• Sweating52,56,57,198,207,208,210,213–216,218,222
• Confusion23,198,182,208,212,215,219
• Agitation50,198,182,200,212,214,216,217,219,242
• Aggression/combativeness56,198,209,211,218
Other Reported Symptoms

• Depression52,57,215
• Tachypnoea213
• Miosis212
• Nausea and vomiting198,222
• Nystagmus23,216,221,223
• Diarrhoea198,224
• Cardiac palpitations51,219,223
48
3.13 Harms from Chronic Use
• Abdominal pain (less common)223

• Dyspnoea219
• Myoclonic jerks168
Severe Withdrawal
• Delirium37,50,57,182,200,207,216,217,219
• Seizures56,182,198,200,212 – may become life-threatening
• Psychosis109,210,212,215,218,219,220
• Withdrawal mimicking schizophrenia243
• Rhabdomyolysis200,208,220
Medical complications reported during withdrawal include sepsis, myoglobinuria, Wernicke’s encephalopathy
without alcohol dependence, catatonic stupor and mutism have also been reported244
Life-threatening complications include seizures, bradycardia, cardiac arrest and renal failure245,246
It has been suggested that although GHB/GBL including psychiatric (and cognitive), physical and
withdrawal syndrome does not always follow teratogenicity-related harms. This includes the rec-
a predictable pattern, it can be broadly divided into ommendation by Miotto et al. to study the possibility
three phases247: of persistent problems with memory acquisition as
• The first stage, which typically lasts 1–3 hours, is a result of GHB/GBL use.254
characterised by severe craving, profuse Among men who have sex with men in particular,
sweating – mostly of the palms and feet, GHB/GBL is often used in a sexual context and in
tachycardia, irritability, anxiety and nausea. a context of potential high-risk sexual behaviour.
• The second stage, lasting for up to 3 days, is Studies have shown that GHB/GBL use is associated
characterised by psychiatric symptoms such as with increased sexual risk and potential transmission
confusion, delirium, and visual, auditory and of HIV, as well as other sexually transmitted and
tactile hallucinations. The physical symptoms blood-borne infections255,256,257
include autonomic dysregulation (e.g. raised
blood pressure) and motor symptoms, which can 3.13.1 Clinical Management
include muscle spasms, convulsions, choreatic
movements of extremities and restlessness of the of Dependence
tongue.248,249,250
• The last phase can last for days to months. It is
3.13.1.1 Identification and Assessment of GHB/GBL
characterised by dysphoria, anxiety, lethargy and Dependence and Withdrawal
apathy, lack of concentration, sleep problems and Signs suggesting GHB/GBL dependence include:
loss of libido. Over the longer term, symptoms of • Multiple daily dosing;
withdrawal may include persisting depression, • Waking at night to dose;
apathetic state and cognitive problems including • Using other drugs to prevent withdrawal
memory problems.251,252,253 symptoms overnight;
• Withdrawal symptoms on days when not using or
3.13 Harms from Chronic Use after periods of reduction or cessation;
GBL has been described as a mild skin irritant and • Not able to go a day without use.
a strong mucous membrane irritant. It can penetrate There are no validated GHB/GBL withdrawal scales.
the epidermis and cause rashes and eczema.5 In the absence of a specific scale, it may be reasonable
Little is known about the long-term harms of to use alcohol or benzodiazepine withdrawal scales.
GHB/GBL that are secondary to acute harms or However, in cases of emergency acute withdrawal,
dependence. It is recommended that more research many would recommend focusing treatment on the
be carried out on the long-term effects of GHB/GBL, basis of symptomatic control, since non-GHB-specific
49
scales do not always pick up the degree of neuro- the National Poisons Information Service suggests in
psychiatric symptoms, which could lead to inappro- excess of 100 mg in divided doses of 10–20 mg at 2–4
priate clinical management and subsequent escalation hourly intervals263 in severe cases or when treatment
of withdrawal symptoms including delirium. is delayed. Some studies have suggested that for the
In specialist drug treatment clinical practice, the treatment of severe withdrawal, high dosages of up to
Clinical Institute Withdrawal Assessment of Alcohol 300 mg diazepam or 130–200 mg lorazepam may be
Scale (CIWA-Ar) has been used,258 as well as the necessary.264,265,266,267,268,269
Alcohol Withdrawal Scale (AWS). Other scales used Combined evidence suggests that benzodiazepines
include the Subjective Withdrawal Scale, where staff are the first line of treatment, but adjuncts may be
record standard observations, such as heart rate and helpful to control symptoms,208 especially where there
blood pressure.259 is benzodiazepine-resistance or poor response.
There are no validated tools for the identification Baclofen and barbiturates have been described
of or screening for harmful GHB/GBL use in non- as second-line adjuncts.55,57,86,198,168,200 The use of
drug specific settings. Winstock and Mitcheson have a combination of diazepam and baclofen has been
provided helpful guidance for addressing substance used successfully in clinical practice, as part of medically
misuse issues in general practice.260 assisted detoxification37,270 and to prevent relapse.271
One study has suggested 10 mg of baclofen three
3.13.1.2 Psychosocial and Pharmacological Support times a day as an adjunct to benzodiazepine
Chapter 2 discusses in general terms the psychosocial prescribing, with the addition of a two-day preload
interventions for the use of club drugs. These are applic- of baclofen 10 mg three times a day in elective
able to the management of the chronic harms of GHB detoxifications.272
use, as well as aftercare and support, and so are not The use of Baclofen on its own has also been
discussed further here. The pharmacological interven- suggested,273,274 as baclofen might be an adequate sub-
tions are discussed below. GHB treatment should be stitute for GHB due to its high-affinity for the GABA-B
based on a bio-psycho-social model as discussed below. receptor. Baclofen’s GABA-B agonism is similar to
GHB,14,15 but with a longer half-life (T = 2–6 h).275
3.13.2 Clinical Management Detoxification by titration and tapering (DeTiTap)
with pharmaceutical GHB in an open-label consecutive
of Withdrawal case series of 23 GHB-dependent patients was shown to
GHB detoxification can be challenging for frontline be feasible, effective and safe. However, the high
clinicians because of the rapid onset and potentially relapse rates warrant further investigation.276,277
life-threatening symptoms that can occur during There is limited evidence that patients receiving
withdrawal. It has been argued that the focus of baclofen after detoxification showed reduced relapse
the treatment should be to prevent complications rates compared with patients receiving treatment as
such as delirium, psychosis, extreme anxiety and usual.278,279,280 However, one study has suggested that
hypertension.261 baclofen 45–60 mg/day for 3 months might be effect-
The research evidence on the management of ive in preventing relapse and increasing treatment
GHB/GBL withdrawal is still emerging and it is there- adherence in patients with GHB use disorder.281 The
fore not possible to draw robust recommendations. use of baclofen up to 60 mg daily in patients with GHB
It is, though, consistently suggested that symp- use disorder appears safe, when prescribed according
tomatic treatment is indicated for GHB/GBL with- to the protocol. Mild tiredness, sleepiness and
drawal syndrome. The review of the evidence shows depressed feelings were reported in the baclofen
that benzodiazepines are most typically used for this group as the most relevant side effects. Future studies
purpose.23,198,208,212,213,217,222,224 There is one case with longer follow-up and a randomised double-blind
report, which shows the challenges associated with design should be conducted to confirm these findings
detoxification during pregnancy.262 before recommendations for clinical practice can be
There are no consistently recommended benzodi- made.282,283
azepine titration regimens in the literature, with stud- There is some evidence that patients receiving
ies recommending a wide range of intervals of dosing baclofen after detoxification showed reduced relapse
and of benzodiazepine doses. In the UK, Toxbase of rates compared with patients receiving treatment as
50
3.13 Harms from Chronic Use
usual. Studies have shown the potential effectiveness been used to manage acute withdrawal are listed in
of baclofen in preventing relapse in patients with Box 3.5.
GHB dependence after detoxification. However, It is worth noting that some individuals self-medicate
more research is needed. with baclofen, ethanol or benzodiazepines to prevent
Baclofen may play a role in relapse prevention, as GHB/GBL withdrawal. There is some evidence from
shown in a case series of GHB-dependent patients. Internet fora that baclofen is consumed without medical
However, controlled studies on the effectiveness of supervision by GHB/GBL users to treat GHB
baclofen to prevent relapse in GHB-dependent patients withdrawal.289 Clinicians must be aware of the risks of
are still limited.284 patients taking baclofen in addition to GHB/GBL, as the
A wide range of medications have been used and combination can lead to respiratory distress and
described as potentially helpful in GHB/GBL with- coma.290 Self-detoxification from GHB/GBL can be dan-
drawal management. However, supporting evidence gerous and should be avoided, as withdrawal symptoms
for any of these medications is mainly based on can be severe and potentially life threatening. GHB/GBL
a small number of case reports and case series. The users who wish to stop should be encouraged to seek
decision on which additional agent to use depends on medical assistance. If they want to reduce GHB/GBL use
the clinical presentation. Antipsychotics should be used on their own, they should do so in very small increments
with caution due to the risk of neuroleptic malignant and with the support of health professionals.
syndrome and the lowering of the seizure threshold. Consumption diaries are suggested as a useful tool to
Medications reported by the literature and which have assist in gradual withdrawal.
Box 3.5 Medications Used to Manage Acute GHB/GBL Withdrawal
Benzodiazepines are safe and effective in managing most cases

Diazepam198,196,224,285
Baclofen37,182,215
Barbiturates57,90,216,218,220
Barbiturates can be used in benzodiazepine refractory cases55
Carbamazepine215
Gabapentin215
Chloral hydrate210,215
Clonidine51,215
Paroxetine51
Beta blockers51,286
Bromocriptine200
Trazadone57,209,215
Propofol64,119,220
Antipsychotics23,198,209,210,212,214,218,219,220,221,225
• Antipsychotics, including haloperidol, should be administered with caution.210,216,219,287 Typical antipsychotics
should be avoided due to the risk of developing NMS type syndromes.215
• It is suggested that intramuscular typical antipsychotics in GHB withdrawal should be used with caution.220
Antipsychotics are not indicated unless delirium is present.226
Also reported:
Lorazepam and/or droperiol for the management of agitation.63
Olanzapine 160 and Pentobarbital have been reported in an inpatient setting.57
Propranolol51 and pharmaceutical GHB.51
Some argue that a serious withdrawal syndrome can be prevented by titration tapering with pharmaceutical
GHB. This alternative to benzodiazepines was shown to be effective and safe, especially in patients who have
developed resistance to benzodiazepines.288
51
Attempts at self-detoxification from GHB/GBL Some have recommended that GHB/GBL with-
can be ineffective. In one study of 56 GHB/GBL drawal symptoms in the context of a planned, medically
users recruited via the Internet, respondents had assisted detoxification should be monitored in an inten-
unsuccessfully attempted to cease using GHB/GBL sive care unit (ICU) along with continuous monitoring
on average 4.07 times. Only 30% had been previously of vital parameters because of the severity of associated
treated for GHB/GBL misuse by health services.65 symptoms.12,306,307 Others have described successful
outpatient detoxification.37 There have been some
3.13.3 Medically Assisted Elective attempts to identify the parameters and to develop
algorithms for the management of GHB/GBL detoxifi-
or Planned Withdrawal and Detoxification cation in specialist drug treatment or acute centres on
It has been argued that it is best if medically assisted an inpatient or outpatient basis,55 as well as to define the
GHB/GBL detoxification is carried out on an elective medication and monitoring required.37,55
basis,37 planned in advance so that withdrawal symp- An algorithm was developed based on a study of
toms can be identified and treated early. Most patients the bio-psychosocial state of 20 vignette patients,
presenting to emergency services symptomatically fol- whereby addiction physicians and psychiatrists estab-
lowing enforced abstinence have presented with more lished the criteria and conditions recommended for
severe symptoms and increased risk of delirium.57 An the indication of an outpatient GHB detoxification.
elective approach to detoxification also enables plan- Criteria for identification of the setting included
ning of post-withdrawal support and recovery. intensity of addiction in terms of daily dose and fre-
There is limited evidence on the provision of quency of dosing as well as the complexity of any
elective medically assisted withdrawal of GHB/GBL, comorbid psychiatric disorders. The importance of
as most case reports and series are concerned a stable support system for the person undergoing
with unplanned withdrawal in acute medical detoxification was emphasised.308
settings.37,291,292,293,294,295 However, where elective Rosenberg et al. suggest that all cases of GHB
withdrawal has taken place, the management of with- withdrawal delirium be considered medical emergen-
drawal in most cases is by titration with high doses of cies and be managed in critical care settings, rather
benzodiazepines and successive tapering off.296 than psychiatric settings. The involvement of both
For planned detoxification and based on existing disciplines, however, may be required.220
evidence, Kamal et al. (2017)297 suggested an algo-
rithm for the treatment of GHB withdrawal, using
benzodiazepines as follows:298,299 3.13.4 Treatment Outcome: Aftercare
• For patients using less than 30–32 g of GHB in 24 and Supporting Recovery
hours, daily doses of diazepam up to 20–60 mg Epidemiological data from the Netherlands show that
could be administered.300 GHB patients stay longer in inpatient care and show
• When 30–32 g or more of GHB is used in 24 hours, high relapse rates (60% within 3 months after detoxi-
daily doses of diazepam from 80 to 150 mg daily fication) compared with other substance-dependent
may be needed.301 patients.309 There is some evidence that heavier GHB/
• Stabilisation for 2–3 days followed by tapering GBL use predicted poor treatment retention.310
diazepam by 5–10 mg per day over 7–21 days has A Dutch study compared patients with GHB
been suggested.302,303 dependence with those dependent on other drugs
• The presence of symptoms of delirium might and behavioural addictions. It found that of all
require higher dosages of diazepam, and it has patients in addiction care, GHB-dependent patients
been suggested that benzodiazepine resistance showed the highest treatment intensity, as indicated
may require administration of oral long-acting by high admission rates, long admissions and high
phenobarbital after 24 hours.304,305 number of treatment contacts. In addition, GHB-
There is no consensus on what the best clinical setting dependent patients had the highest risk of re-
for elective detoxification from GHB/GBL should be. enrolment into a new treatment episode in addiction
Intensive care, hospital inpatient basis or in out- care. In addition, duration of admission was higher in
patient specialist drug treatment centres have all GHB-dependent patients as compared with other
been suggested. patients, as well as high re-enrolment rates.311
52
3.15 Harm Reduction
A number of studies have examined the high

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64
Chapter
New Benzodiazepine Novel Psychoactive
4 Substances
4.1 Introduction controlled under the Misuse of Drugs Act by the

listing of individual substances – rather than by the
Benzodiazepine misuse is a worldwide public health
use of a generic definition. In contrast, the German
concern that is associated with a number of concern-
generic definition was designed to ensure all estab-
ing consequences.1 Whereas in the past, the misuse of
lished and novel analogues of this drug group were
benzodiazepines was linked to the diversion of medi-
brought within the scope of their Narcotics Act.
cinal benzodiazepines, currently synthetic processes
Their generic definition is based on the use of
for benzodiazepine manufacture are freely available,
a series of structural diagrams of 16 different benzo-
and many illicitly manufactured benzodiazepines
diazepine cores, together with a defined range of
have been reported in recent years.
modifications, coupled with a limit on the molecular
Over the last decade, a number of new benzodi-
weight of the materials controlled.5
azepines have been developed and marketed, typically
Etizolam has been listed as an NPS by the World
in clandestine laboratories in ways very similar to
Health Organization (WHO) since 2015.6 Etizolam,
other novel psychoactive substances (NPS). Like
as well as alprazolam, triazolam and flualprazolam,
other NPS, these new benzodiazepines can evade
are in Schedule IV of the 1971 Convention on
drug misuse legislation, at least initially.2 In Europe
Psychotropic Substances.
today, new benzodiazepines, often sold at a very low
price, have appeared on illicit drug markets in some
countries and have been associated with harm, includ- 4.4 Quality of Research Evidence
ing an increased risk of overdose. The use of these There is a wide body of evidence on the efficacy of
NPS by high-risk drug users and other marginalised medically prescribed benzodiazepines as well as the
and vulnerable populations also appears to have harms associated with their use.
increased.3 This chapter focuses on the non-medical use of
Benzodiazepine NPS are sold in their own right. benzodiazepines, where the evidence is much more
They are also used to make fake versions of medicinal limited. In particular, information on the new benzo-
benzodiazepines, which are also sold on the illicit diazepines, their pharmacology, pharmacokinetics,
drug market or Internet. A small number of new adverse effects and their management is sparse.
benzodiazepines may be sourced from companies in
some countries such as India for example, typically as 4.5 Brief Summary of Pharmacology
finished medicinal products.4 Benzodiazepines in general increase the binding of γ-
aminobutyric acid (GABA) primarily at the GABAA-
4.2 Street Names receptor, and to a lesser extent at the GABAB-receptor,
Various names for many drugs exist, depending on which causes a sedative-hypnotic effect. They are pre-
location and substance. For example, phenazepan is scribed on a short-term basis for their anxiolytic, anti-
sometimes known as Bonzai or Bonzai Supersleep. epileptic, muscle relaxant and hypnotic effects. They
are also used as premedication for anaesthesia and as
adjuncts for withdrawal from alcohol and other
4.3 Legal Status substances.
There are some differences in the way that different The chemical structure and pharmacokinetics of
European countries control benzodiazepine NPS. benzodiazepines vary widely. There are differences in
For example, in the UK, benzodiazepines are their lipid solubility, and this affects how they are
65
New Benzodiazepine Novel Psychoactive Substances
processed in the body, including the duration of their international drug control laws. By June 2019, the
psychoactive effects.7 Benzodiazepines can be cat- EMCDDA was monitoring 28 new (NPS) benzodi-
egorised based upon their elimination half-life as:8,9 azepines – 23 of which were first detected in Europe
• Short acting, with half-lives of less than 6 hours in the last 5 years (European Drug Report 2019). As
(e.g. midazolam, triazolam); with opioid NPS discussed in Chapter 5, the appear-
• Intermediate acting, 6–24 hours (e.g. temazepam, ance and increase in the number of benzodiazepine
alprazolam); NPS has been seen as potentially signalling that new
• Long acting with half-lives of over 24 hours psychoactive substances are increasingly more tar-
(e.g. diazepam). geted at long-term and more problematic drug users.15
The first illicit benzodiazepines identified in
Europe to the EMCDDA were phenazepam (fenaze-
4.6 Novel Psychoactive Substances pam), nimetazepam and etizolam.16 Today, the most
or Designer Benzodiazepines common are phenazepam, etizolam, diclazepam, flu-
bromazolam and pyrazolam.17 The most seized new
In recent years, a number of NPS benzodiazepines,
benzodiazepines reported in the EU, Norway and
sometimes referred to as ‘designer’ benzodiazepines,
Turkey, are etizolam, clonazolam/clonitrazolam, nor-
are emerging as recreational drugs.10 A market for
fludiazepam, diclazepam and phenazepam.18 At the
non-controlled benzodiazepine-type substances,
time of writing, these and a large number of other
used alone or in combination with controlled benzo-
benzodiazepine NPS have been detected, with more
diazepines, is emerging in some Western countries.11
likely to emerge in the future.19,20,21,22
Overall, as with other NPS, there is a range of
Like pharmaceutical benzodiazepines, they have
possible modifications which are applicable to several
different core structures which are structurally
different benzodiazepine core structures, so there is
related to different benzodiazepines. Many benzodi-
a potential for the development of families of novel,
azepine NPS are particularly potent, even at a small
closely related benzodiazepine NPS. This position is
dose. For example, flualprazolam is structurally
similar to that of the synthetic cannabinoids.12
related to alprazolam (Xanax), but more potent.
The majority of benzodiazepine-type NPS are not
Norfludiazepam is structurally related to diazepam
registered as medications and have not undergone
and 4-chlorodiazepam and can be used in the syn-
clinical trials.13 Most have been synthesised as poten-
thesis of midazolam. Fluclotizolam is structurally
tial drug candidates by pharmaceutical companies,
related to brotizolam and etizolam, and claims have
but were not subsequently marketed as medication.
been made that it has an approximately three-fold
They have not been approved for medicinal use in any
higher potency and a shorter half-life compared to
country and are sold on the Internet, generally as
etizolam.23
‘research chemicals’.
There are also differences between the various
It is also possible to purchase benzodiazepine NPS
benzodiazepine NPS in their half-life and duration
on the illicit market or online. Benzodiazepines such
of effects. For example, flubromazepam has a half-
as etizolam or phenazepam, which are licensed in
life of 106 hours, longer than other benzodiazepines
a small number of countries only, appear to be
in therapeutic use such as diazepam (20–100 hours)
increasingly used recreationally, particularly in
and other NPS-benzodiazepines such as phenazepam
Europe where they have been classed as NPS.14
(60 hours).24 Some consumers have suggested that
Most benzodiazepine NPS are sourced from China
flubromazepam has a greater ‘euphoric’ effect and
as bulk powders. In Europe, they are processed into
has resulted in prolonged fatigue over days.24
tablets and other products and sold as legal replace-
ments for commonly prescribed benzodiazepine
medicines, such as alprazolam and diazepam. They 4.7 Modes of Use
are also used to make fake versions of these medicines, NPS benzodiazepines are sold as tablets, capsules,
which are then sold on the illicit drug market. blotters in various doses (similar to LSD) and as
According to the 2019 European Drug Report, pure powders25 and pellets.26 They have also been
over the last few years there has been an increase in reported as liquid.27
the number, type and availability of the new benzodi- The forms in which benzodiazepine NPS are sold,
azepine class, which are not controlled under together with the high potency of some products, can
66
4.9 Desired Effects
make it difficult for users to measure doses accurately. The effects of benzodiazepines are alcohol-like
Tablets can vary greatly in the content of active ingre- and they can be used instead of alcohol; more com-
dient, leading to the risk of unintended overdose (see monly they are used with alcohol to potentiate its
Section 4.11 for details). effects.35
A number of EU countries have expressed concern
regarding the availability on the Internet of extremely
4.8 Prevalence and Patterns of Use cheap, often counterfeit, illicit benzodiazepines, lead-
In Europe, the 2019 European Drug Report suggested ing to the increased use of these drugs by vulnerable
that there seemed to be an increase of reports to the teenagers, often in combination with alcohol.36
EU Early Warning System for benzodiazepine NPS. A number of other factors have been identified.
Similarly, although police seizures of NPS are typic- For example, a study of 333 posts on discussion
ally dominated by synthetic cannabinoids and cath- groups and forums has shown that people misused
inones, the quantity of benzodiazepines seized in NPS benzodiazepine for the following reasons: anxio-
Europe appears to have increased.28 lysis, tapering benzodiazepines/ management of
The World Drug Report 2018 reported that the benzodiazepine withdrawal, sedation/sleep aid, man-
non-medical use of the common sedative/hypnotic agement of stimulant withdrawal, euphoria, ability to
benzodiazepines and similar substances was one of function during use and muscle relaxation. Other
the main drug use problems in some 60 countries.29 minor reasons for use reported included use to com-
The 2019 report stated that in 2017, 40 Member States bat alcohol withdrawal, opioid withdrawal, calm
ranked the non-medical use of sedatives and tranquil- a ‘trip’, increased sociability, unavailability of pre-
lisers among the three most commonly used sub- ferred benzodiazepine supply, low cost, combat vaso-
stances in their countries, while the non-medical use constriction, chronic pain and solubility.37
of benzodiazepines was ranked number one within Benzodiazepines are often used in the context of
the broader category of sedatives and tranquillisers.30 polydrug use. They are used with other sedatives to
It has also been noted that recent signs suggest that potentiate their effects, or to reduce the ‘come down’
use of these substances might be growing among young after stimulant use. They are also sometimes used by
people, and this is an area requiring further investiga- injection to produce heroin-like effects, and benzo-
tion, policy consideration and prevention efforts.31 diazepines such as alprazolam (‘Xanax’) are some-
Overall, there is significant emerging evidence times found mixed into heroin as ‘extenders’.38
indicating that the misuse of benzodiazepines is Benzodiazepines have limited potential as euphori-
associated with a range of poor outcomes, includ- ants when administered alone, but euphoric effects
ing increased risk of mortality, HIV/HCV high- appear to be enhanced when taken in combination
risk behaviours, poor self-reported quality of life, with opioids.39
criminality, and continued substance use during In comparison to the general population, there is
treatment.32 evidence to suggest that the misuse of benzodiazep-
In the UK, population level data from the Office of ines is more common among people with psychiatric
National Statistics for the year ending in March 2020 or physical comorbidity and people with substance
reported that 0.5% of the adult population (16–59 misuse disorder. People from low socio-economic
years) have used ‘tranquillisers’ in the past year. backgrounds are also more likely to misuse benzodi-
Within the 16-to-25-year age group, this rises to azepines as well as young people in general.
0.8% (tranquillisers can either be classified as Class In the US for example, research has shown that
B (such as barbiturates) or Class C (such as young people and young adults under 25 years of age
benzodiazepines).33 are one of the population groups most likely to misuse
tranquillisers/sedatives40 In Europe, the increasing
4.9 Desired Effects use and availability of sedative drugs amongst young
There are many reasons why people chose to misuse people has been identified as an area of particular
benzodiazepine, including NPS benzodiazepines. concern, requiring further investigation, policy con-
Reports from users on Internet forums suggest that sideration and prevention efforts.
the effects of benzodiazepine NPS resemble those of There is some evidence to suggest that rates of
prescription benzodiazepines.34 non-medical use of benzodiazepines appears to be
67
relatively high among people who use the night time protocols are available on the management of over-
economy and ‘clubbers’ in particular, in comparison dose, as well as the management of the adverse effects
to the general population. A study found that the use of long-term and frequent use, including dependence
of benzodiazepines is prevalent in the club scene and and withdrawal.59,60,61,62,63,64
the authors have argued that benzodiazepine depend- The effects of benzodiazepines are dose-
ence appears to be more prevalent in this sample than dependent and include drowsiness, lethargy, fatigue,
in other populations described in the literature.41 excessive sedation, stupor and ‘hangover effects’.
Among young people, factors associated with ele- Benzodiazepines have effects on memory, concentra-
vated levels of use are similar to those associated with tion and attention, which put people at risk of acci-
illicit drugs, including clubbing and high frequency of dents. The use of benzodiazepines is also linked to
using the night-time economy. Some studies have also nystagmus, hypotonia and ataxia. It can be associated
shown that gay clubbers and other young men who with decreased libido and erectile dysfunction.
have sex with men who attend nightlife venues misuse Symptoms of benzodiazepine toxicity may range
tranquillisers regularly.42 Young polydrug users also from mild drowsiness to a coma-like state, which is
misuse benzodiazepine and this sometimes occurs in more likely to occur in cases of polydrug use.
the context of ‘coming down’ from club drugs and Similarly, hypotension, bradycardia and respiratory
countering the effects of stimulants used.43,44 depression may occur occasionally, but tend to be
The misuse of benzodiazepines is also common more severe if benzodiazepines are taken with other
among opiate users, including among people in opioid- CNS depressants, including alcohol.
substitution treatment (OST) programmes. It is also Studies show a dose–response relationship
a strong predictor of a more severe polysubstance use between benzodiazepines and all-cause mortality.65
problem, including more harmful patterns of use of Life-threatening respiratory depression can occur
benzodiazepines.45 Benzodiazepines are commonly with large oral ingestions with or without co-
implicated in opioid-related mortality. Overdoses asso- ingestants.66 However, the co-ingestion of alcohol
ciated with the ingestion of benzodiazepines are more and other central nervous system depressants potenti-
likely to occur with concomitant use of opioids.46 ates the effects of benzodiazepines and can increase
There is a strong association between benzodiazep- toxicity67,68 and the likelihood of adverse effects,
ine use and suicidal ideation in opioid use disorders.47,48 including the potential of respiratory depression and
Benzodiazepine misuse among opiate substitute airway compromise. Severe effects in overdose also
treatment (OST) clients presents a serious public include rhabdomyolysis and hypothermia.
health risk as these individuals are at increased risk
of overdose49 and multiple drug overdoses.50,51 4.11 Risks of Untested
Amongst this group, benzodiazepine use is also
associated with a number of other adverse outcomes,52 Benzodiazepine Novel Psychoactive
which include: Substances and Counterfeit
• People who are prescribed opioids and Medications
benzodiazepines were found to take higher opioid
The evidence of adverse effects of benzodiazepine
doses and for longer periods;53
NPS is limited, and little is known about their effects.
• Reduced likelihood of opioid abstinence;54
However, it can be assumed that they will be broadly
• Reduced retention in treatment and early similar to those of currently available pharmaceutical
withdrawal from treatment;55,56 benzodiazepines and will require similar clinical
• Increased use of other psychoactive drugs and management.
greater levels of anxiety and depression;57 Nonetheless, the limited evidence on benzodi-
• Increased injecting-related risks;58 azepine NPS also suggests that clinicians may need
• Participation in criminal activities.58 to consider issues particular to NPS. In fact, it has
been argued that given the limited information on
their pharmacology, toxicity, variations in dosage,
4.10 Benzodiazepine Acute Harms onset of effects, combination of substances, potency
The potential harms associated with pharmaceutical and general patient or individual variability, the con-
benzodiazepines are well known. Guidance and comitant use of these substances with other drugs in
68
4.12 High-risk Sexual Behaviours
particular entails several and unpredictable risks.69 analyses of police seizures suggests that branded
The fact that some of them are extremely powerful, benzodiazepines such as ‘Valium’ and ‘Xanax’ often
including at lower dosages, must be considered. contain other benzodiazepines instead of, or as well
In general, the reported adverse effects of benzo- as, the product they are claimed to be. For example,
diazepine NPS are typical for a sedative-hypnotic tox- out of the 712 samples submitted to WEDINOS81 in
idrome, but have also included atypical symptoms in 2020/2021 with purchase intent stated as diazepam,
some cases, such as agitation, hyperthermia and 22 other substances, either in isolation or combin-
tachycardia.70 A review of the adverse effects of ation, were identified. Of the 320 samples submitted
designer benzodiazepines reported fatigue, impair- as alprazolam, 16 other substances, either in isola-
ment of thinking, confusion, dizziness, drowsiness, tion or combination, were identified; 58% of samples
lethargy, amnesia, blurred vision, slurred speech, pal- submitted as alprazolam were found to contain other
pitations and muscle weakness, as well as auditory and substances. The most common substitute was
visual hallucinations, delirium, seizures, deep sleep flualprazolam.
and coma at high doses.71 The dose of benzodiazepine in the product can
Some benzodiazepine NPS have either a higher also be variable and unpredictable. For example,
potency and/or longer duration of action than trad- ’Xanax’ (alprazolam) sold in the UK is mainly
itional benzodiazepines, which in turn may lead to counterfeit82 and analysis reveals that the majority of
increased sedation and/or amnesia. pills contain alprazolam, but concentration varies
Some of these benzodiazepine NPS are highly widely, with some which are much stronger than the
potent, with the potential of producing harm at low dose indicates on the tablet or packaging.85
dose. For example, etizolam is six to ten times more Cases of hospital presentations and overdose related
potent than diazepam. Similarly, due to their high to the use of benzodiazepine NPS have been reported.
potency, compounds like clonazolam or flubromazo- They include presentations involving toxicity from
lam can cause strong sedation and amnesia at oral diclazepam83 and the STRIDA project has also reported
doses as low as 0.5 mg.72 There is emerging evidence on hospital presentations involving etizolam, metizo-
of severe intoxication following the use of flubroma- lam, estazolam, pyrazolam, flubromazepam, nifoxipam,
zolam, resulting in prolonged, severe symptoms diclazepam, meclonazepam, bromazepam, flubromazo-
including prolonged bradycardia,73 hypotension, lam, deschloroetizolam, clonazolam, 3-hydroxyphena-
rhabdomyolysis and coma.73 zepam, ketazolam and phenazepam. Most cases
It has also been shown that the slow elimination of reported by the study (89%) also involved other drugs.
some benzodiazepine NPS, such as flunitrazolam, CNS depression was the most prominent clinical
causes their accumulation in lipid-based tissues, sign, a minority of patients were observed in the
which can lead to a delayed overdose in case of intensive care unit, and they responded positively to
repeated consumption.74 flumazenil treatment.84
Benzodiazepine NPS can pose a risk of severe life- There is evidence from some countries that deaths
threatening intoxication,75,76,77,78,79,80 not only where a benzodiazepine was implicated have
because of the risks of the benzodiazepine itself but increased over the past decade, consistent with an
because other factors can also increase the risk. As increased role of illicitly manufactured benzodiazep-
mentioned earlier, dosing for example, poses a risk to ines. In Scotland for example, ‘street’ or unlicensed
people who use benzodiazepine NPS, as it is difficult benzodiazepines were involved in 85% of the 792
for users to accurately measure doses, particularly deaths in 2018 where a benzodiazepine was impli-
when consumed as a powder. cated, while medicinal ‘prescribed’ benzodiazepines
Tablets can also vary greatly in the content of were reported in only 30%.85
active ingredients, leading to the risk of unintended
overdose. There is also unpredictability in what
a product manufactured in a clandestine laboratory 4.12 High-Risk Sexual Behaviours
contains. As people are buying benzodiazepines There is a link between the use of sedatives and hyp-
from the illicit ‘street’ market or the Internet, they notics (including benzodiazepines) and high-risk sex-
face the risk of using unknown substances and doses. ual behaviours. A study of non-medical prescription
In the UK, it has been reported that laboratory drug use in five European countries mentioned earlier
69
also reported that sexual health risk factors were asso- 4.14 Management of Acute Toxicity
ciated with an increased likelihood of past-year non-
medical prescription drug use.86
US studies also suggest that polysubstance use, 4.14.1 Testing
particularly when it involves prescription drug use, Whereas rapid bedside testing may not be available to
may be associated with high-risk sexual behaviours detect benzodiazepine NPS, it is possible to detect these
in young people. This was found among young newer benzodiazepines with traditional forensic toxi-
people within a study, for example, reporting signifi- cology laboratory tools and it is important to include
cant relationships between prescription drug misuse these benzodiazepines in the confirmation tests.94
and sexual risk behaviours among adolescents and Treatment for acute benzodiazepine toxicity must
young adults (ages 14–20), with each class of drug be based on local and national protocols and clinical
(i.e. sedatives, stimulants, opioids/pain relievers) guidance. Management is mainly supportive care and
being positively associated with sexual risk may include endotracheal intubation to provide
behaviours.87 definitive airway management.
Other research showed that students with lifetime Flumazenil treatment can be used for the manage-
prescription medication misuse were more likely to ment of benzodiazepine intoxication primarily to
report past-3-month sexual risk behaviours.90,88 reverse the sedative effect of benzodiazepines and
Similarly, in a study among US college students, pre- prevent respiratory depression. However, there are
scription medication misusers were significantly more potential adverse effects associated with its use.95
likely than others to report having multiple sexual There are reports of the effectiveness of flumazenil
partners, unprotected sex, sex after ‘having too for NPS benzodiazepines.96
much to drink’ and sex after using drugs.91
Clayton et al.’s 89 data from cross-sectional surveys
conducted among nationally representative samples of
4.15 Chronic Harms
students also showed that non-medical use of prescrip- Regular and long-term benzodiazepine use has been
tion drugs is associated with sexual behaviours that put linked to impaired cognitive functioning97,98 and an
high school students at risk for sexually transmitted increased risk of accidental falls.99,100
infections.92 People who use benzodiazepines regularly are at
Non-medical use of prescription drugs (NMUPD) risk of developing dependence, including withdrawal
was associated with having sexual intercourse, being symptoms and tolerance. Symptom rebound (i.e.
currently sexually active having ≥4 lifetime sexual part- recurrence of the original disorder, most commonly
ners, drinking alcohol or using drugs before last sexual a sleep disorder) after discontinuation has been
intercourse and not using a condom at last sexual inter- described.101,102,103,104,105,106,107,108 It has been sug-
course. The authors also reported that as the frequency gested that dependence develops in approximately
of NMUPD increased, the association between NMUPD half of patients who use benzodiazepines for longer
and each of the sexual risk behaviours increased in than 1 month.109
strength, suggesting a dose–response relationship.92
4.16 Dependence and Withdrawal
4.13 Aggressive Behaviours People who become dependent on benzodiazepines
Benzodiazepines in general can cause aggressive behav- and stop using the drug abruptly may experience with-
ioural reactions. There is evidence that alprazolam is of drawal symptoms, which can begin as early as a few
particular concern, especially when used with hours after the drug was last taken. It has been sug-
alcohol.90,91 It is possible that this also applies to benzo- gested that dependence develops in approximately half
diazepine NPS which are structurally related to alprazo- of patients who use benzodiazepines for longer than 1
lam, including flualprazolam, flunitrazolam and month.109 Symptoms of withdrawal after long-term
clobromazolam.92 benzodiazepine use usually develop faster with shorter
As well as being self-administered, benzodi- acting agents than with longer-acting agents.110
azepines have potential for use in drug-facilitated Benzodiazepine withdrawal symptoms include:
crimes, particularly as some are known to cause • Increased anxiety
amnesia.93 • Nervousness
70
4.18 Treatment of Dependence/Withdrawal
• Sleep disorders There is also evidence that benzodiazepines have

• Inner restlessness direct depressive effects,116,117 which may be particu-
• Depressive symptoms larly harmful to individuals with bipolar disorder.
• Irritability There is an association between benzodiazepine
• Psychosis-like conditions, delirium use and dependence and suicide ideation.118
• Depersonalisation and derealisation Benzodiazepine intoxication, high-dose prescription
• Confusion of benzodiazepines and a diagnosis of depression are
also considered significant risk factors in reported and
• Trembling
completed suicides.119
• Sweating
• Nausea and vomiting
• Motor agitation 4.18 Treatment of Dependence/
• Dyspnea Withdrawal
• Increased heart rate For treatment of benzodiazepine dependence and for
• Elevated blood pressure benzodiazepine detoxification, clinicians must fellow
• Headaches local protocols and national guidelines and reduction
• Muscle tension regimens.
• Increased risk of seizures Specific information on the management of depend-
• Impairment of voluntary movements ence and detoxification associated with benzodiazepine
• Cognitive impairments NPS and clandestinely manufactured benzodiazepines
• Impairment of memory is not available, although it is likely to be broadly similar
• Pronounced perceptual impairments to that of pharmaceutical benzodiazepines.
• Hyperacusis Some recommend to first convert sedative-
• Photophobia hypnotics into an appropriate dose of diazepam or
similar benzodiazepines. This is particularly indicated
• Hypersomnia
if the patient is dependent on short-acting, potent
• Dysesthesia, kinaesthetic disorders, muscle
benzodiazepines or on preparations that do not easily
twitching and fasciculation110
allow for small reductions in dose.120
Seizures are associated with benzodiazepine, especially if Clinicians should follow national recommenda-
it is discontinued abruptly. It can be assumed that this is tions on reduction regimens, but keep in mind that
also true for benzodiazepine NPS. Severe withdrawal an optimal speed or duration of dose reduction is not
symptoms include paranoid thoughts, hallucinations, known.121 It has been recommended that the medical
depersonalisation and withdrawal delirium.110 People management of benzodiazepine NPS withdrawal
dependent on benzodiazepines should not attempt to should be individually tailored to the patient. It usually
stop taking them on their own and instead seek medical involves prescribing a longer-acting benzodiazepine,
support. Withdrawal symptoms from these drugs can be prescribing on a slow dose taper, maintaining the
severe and can be potentially life-threatening. dose if symptoms become uncomfortable or increasing
The chronic use of benzodiazepine NPS may also the dose if symptoms become intolerable. Additional
lead to the development of tolerance and dependence.111 prescribing for symptomatic relief may be needed.122
Withdrawal symptoms, such as anxiety, panic attacks, For people with long-term benzodiazepine depend-
restlessness, insomnia, seizures and life-threatening con- ence, the period needed for complete withdrawal may
vulsions, may follow the abrupt cessation of chronic vary from several months to a year or more.123
benzodiazepine NPS use.112,113 No medication is approved for the treatment of
benzodiazepine-use disorders and dependence and
4.17 Mental Health Co-morbidity there is a paucity of evidence for effective interven-
Bipolar disorder patients with regular use of benzodi- tions to support withdrawal. A recent review failed to
azepines show higher levels of treatment resistance to identify evidence of sufficient quality to support any
mood stabilisers.114 They are also at greater risk of pharmacological interventions.124
both manic and depressive relapses that is independ- It is argued that concomitant psychopharma-
ent of the effects of comorbid anxiety and insomnia.115 cotherapy for benzodiazepine withdrawal should be
71
symptom-oriented and pragmatic. Reduction regimens

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Chapter
Synthetic Opioid Novel Psychoactive
5 Substances (Fentanyl and Non-fentanyl)
5.1 Introduction NPS. The appearance and increase in the number of

these opioid NPS has been seen as potentially signalling
New synthetic opioids are an increasing risk for public
that new psychoactive substances are increasingly more
health across the world. These drugs can be divided
targeted at the long-term and more problematic drug
into two categories, pharmaceutical and non-
users.5
pharmaceutical fentanyls, as well as non-fentanyl opi-
These substances have also been described as
oid novel psychoactive substances (NPS). These NPS
a global public health threat,6 with implications for
are easily available on the Internet and are character-
clinical practice.7 The World Drug Report suggests
ised by low price, purity, legality and lack of detection
that this increase in the number of opioid NPS, as well
in laboratory tests. However, most have not been
as the increase of benzodiazepine NPS for example,
approved or are not recommended for human use.1
potentially signals that new psychoactive substances
In North America in particular, a crisis linked to
are increasingly more targeted at the long-term and
the misuse of opioids has been observed for a number
more problematic drug users.8
of years and has been associated with very high levels
In Europe, a large-scale recent study showed that
of mortality. The origins of the crisis are to some
non-medical prescription high-potency opioid use is
extent associated over-prescription, and unauthorised
a public health concern in Europe.9
distribution or the diversion of opioid medications.2
The 2019 European Drugs Report showed that since
Only a relatively limited number of people have
2009, 49 opioid NPS have been detected on Europe’s
required specialised drug treatment for addiction to
drug market – including 11 reported for the first time in
opioid pain medication in Europe, in contrast to other
2018. Of the 49 opioid NPS, 34 were fentanyl derivatives
countries, such as the US for example. However,
(six of which were reported for the first time in 2018),
under-reporting cannot be dismissed and it is possible
but a small number of other types of opioids (such as
that the real level of dependence on opioid medication
U-47,700 and U-51,754) were also reported.10
is under-estimated.
At a global level, the number of new psychoactive
There is evidence of some misuse of opioid medi-
substances reported that are opioids have been rising at
cation. For example, in a survey of young people in
an unprecedented rate and consists mainly of fentanyl
European schools, 4% of students aged 15–16 years
analogues. Numbers rose from just one substance in
reported lifetime use of painkillers to get high.3 Data
2009, to 15 in 2015 and 46 in 2017. Although, the
from the European Early Warning System has also
number of opioid NPS is still small, they now form
been reporting a rise in the number of deaths related
a greater proportion of NPS in general. Opioid NPS
to synthetic opioids and an increasing number of new
accounted for just 2% of the number of NPS identified
synthetic opioids are being reported, including new
in 2014, but by 2018 that figure had risen to 9%.11
fentanyls.4
This chapter focuses on the misuse of fentanyl,
In recent years, opioids with structures distinct from
fentanyl analogues and other non-fentanyl opioid
those used therapeutically have been emerging, in par-
NPS and does not address issues pertaining to their
ticular fentanyl derivatives and other substances that are
use in legitimate therapeutic and clinical contexts.
linked with significant risk of acute toxicity and over-
dose. Although the number of novel synthetic opioid
analogues detected is small in comparison with other 5.2 Legal Status
types of NPS, such as stimulants, the largest percentage Fentanyl and its pharmaceutical analogues are Schedule
increase in recent years has been observed in opioid I substances according to the United Nations Single
78
5.4 New Fentanyl Analogues
Convention on Narcotic Drugs 1961, amended in 1972 veterinary practice, for example carfentanil for large
(substances that are highly addictive and liable to animals. However, these drugs also have euphoric
abuse). Some non-pharmaceutical analogues are effects and most have the potential for misuse.15
Schedule I–IV substances, while new compounds are In recent years, a number of opioid NPS have been
being progressively incorporated into the lists. reported to the EU Early Warning System on new
psychoactive substances and adverse effects associated
5.3 Quality of the Research Evidence with their use have been reported. They include car-
fentanyl, which is intended only for veterinary use on
Although there is a large body of evidence relating to
large animals, is not approved for medical use in
pharmaceutical opioids including fentanyl and its ana-
humans and is estimated to be about 10,000 times
logues, the evidence on the novel fentanyls and other
more potent than morphine.13,16,17
opioid NPS, their harms and clinical management, is
Other new fentanyl derivatives sold on the illicit
currently limited and cannot be considered as robust.
market include analogues that have been redis-
Nonetheless, the research findings are broadly consist-
covered by the manufacturers from studies described
ent and this document provides clinically relevant infor-
in the scientific literature but never developed into
mation based on the best evidence currently available. In
pharmaceutical products. New fentanyls also include
addition, it is expected that the harms associated with
newly designed fentanyl analogues made by new
opioid NPS and their management are broadly the same
modifications of the fentanyl chemical structure, to
as other opioids.
avoid legal control, as with other NPS (see Box 5.1).
The harms of new fentanyls and other opioid NPS
They are produced in clandestine laboratories and
will be discussed in greater detail in this chapter. New
are sometimes referred to as non-pharmaceutical
fentanyls in particular are associated with severe
fentanyls (NPF) or even ‘research chemicals’. It has
adverse effects resulting from their strong potency in
been argued that as a result of the low cost of clan-
comparison to morphine and the length of the effects
destine laboratory production and enormous profit
of some. They are often used in combination with
potential, opioid NPS and fentanyls in particular are
other drugs which can result in toxicity, including
establishing a strong position on the illegal drug
respiratory depression. They are also associated with
market as stand-alone products, adulterants in her-
dependence and a withdrawal syndrome.
oin, or constituents of counterfeit prescription
medications.18
5.4 New Fentanyl Analogues
5.4.1 Brief Summary of Pharmacology Box 5.1 Examples of Non-pharmaceutical
Fentanyl (N-[1-(2-phenylethyl)-4-piperidinyl]-N-phe- Fentanyl Analogues
nylpropanamide) is a potent opioid used in human
and veterinary medicine. It has analgesic and sedative Alpha-methyl-fentanyl, 3-methylfentanyl,
effects and is widely used in the management of severe acetylfentanyl, butyrylfentanyl, betahydroxy-
pain and in anaesthesia.12 Fentanyl is a full agonist at the thio-fentanyl, 4-fluorobuyrylfentanyl,
μ-opioid receptor. It is at least 80 times more potent than furanylfentanyl, ocfentanil, acrylyolfentanyl,
morphine13,14 and when misused is associated with 4-methoxibutyrylfentanyl, tetrahydr ofuranfentanyl,
beta-hydroxytihiofentanyl, para-fluoro-isobutyryl
a risk of acute toxicity.
fentanyl, cyclopentyfentanyl,
Licensed fentanyl and fentanyl analogues are used in
4-fluoroisobutyrylfentanyl, and
human medicine for pain relief and used regularly in 4-chloroisobutyrylfentanyl, 3-fluorofentanyl,
hospitals, especially in intensive care units and operating 4-fluorobutyrfentanyl, 4-methoxybutyrfentanyl,
theatres, for anaesthesia and post-operative pain con- acetylfentanyl, acrylfentanyl, beta-hydroxy-
trol. They are also used to provide sedation and pain thiofentanyl, butyrfentanyl, despropionylfentanyl,
relief for medical procedures such as fracture manipula- despropionyl-2-fluorofentanyl, furanylfentanyl,
tion. Some are also used by pre-hospital teams, emer- isobutyrfentanyl, (iso)butyr-F-fentanyl N-benzyl
gency departments and in primary care, for example, by analog, methoxyacetylfentanyl, ocfentanil,
patients receiving palliative care at home. Some fenta- parafluoroisobutyrfentanyl,
nyls are not licensed for human use but may be used in tetrahydrofuranylfentanyl, and valerylfentanyl.
79
Synthetic Opioid Novel Psychoactive Substances (Fentanyl and Non-fentanyl)
Published data on the pharmacology of most Our knowledge of novel non-pharmaceutical ana-
fentanyl NPS are limited mainly to in vitro and logues is limited, and these drugs may differ in their
in vivo animal studies. These data suggest that they potency, efficacy and duration of action.24,25
are selective and potent µ-opioid receptor agonists There are differences between the various fenta-
with a pharmacology that is broadly comparable to nyls. Butyrylfentanyl, for example, is a potent, short-
fentanyl (e.g. furanylfentanyl) and include: acting synthetic opioid analgesic, around one-quarter
• Furanylfentanyl, or N-phenyl- of the potency of fentanyl. On the other hand, some
N-[1-(2-phenylethyl)piperidin-4-yl]furan- fentanyl analogues are more potent than fentanyl and
2-carboxamide; some fentanyl analogues have a longer duration of
• Acryloylfentanyl, or N-(1phenethylpiperidin- action.26
4-yl)-N-phenylacrylamide; These new fentanyls have been associated with
• Acrylofentanyl, or N-(1-phenethylpiperidin-4-yl)- significant morbidity and mortality, including from
N-phenylacrylamide; illicitly manufactured fentanyls and fentanyl
• Para-fluoroisobutyrfentanyl;
analogues.27,28
• 4-fluorobutyrfentanyl;
• Methoxyacetylfentanyl2-methoxy-N-phenyl- 5.5 Mode and Patterns of Use
N-[1-(2-phenylethyl)piperidin-4-yl]acetamide of Fentanyl Novel Psychoactive
(methoxyacetylfentanyl)
• (cyclopropylfentanyl);
Substances
• 4-fluoroisobutrylfentanyl,
Clandestinely manufactured fentanyl and/or its ana-
tetrahydrofuranylfentanyl and carfentanil. logues are sold in solid or liquid forms,13 including
powders, pills, capsules, patches, lozenges and liquid,
Fentanyl has a rapid onset of action, almost and on blotting paper. Although less common, fura-
immediate, following intravenous administration, nylfentanyl has also been seized in Europe as a green
but its maximal analgesic and respiratory depres- ‘herbal’ material, as well as being sold as e-liquids for
sant effect may not be noted for several minutes. vaping in electronic cigarettes.29,30,31
Following intramuscular administration, the Fentanyl and its analogues may be consumed by
onset of action is from 7 to 8 minutes and the several routes, including injecting (intravenous or
duration of action is 1–2 hours. The duration of intramuscular), orally, trans-dermally, by smoking,32
action of fentanyl, when administered intraven- intra-nasally or sublingually through a spray or
ously, is 30–60 minutes,19,20 much shorter than vaporisation.31 Also worth noting are new forms of
with heroin (4–5 hours). This may lead to fre- pharmaceutical fentanyl, for example oromucosal
quent redosing.21 administration as ‘lollipops’. One concern noted in
Overall, reasons for the potency of fentanyl the EMCDDA European Drug Report 2017 was the
include its high lipophilicity (which allows it easily appearance on the market of nasal sprays containing
to cross the blood–brain barrier) and high receptor non-pharmaceutical fentanyls, such as acryloylfenta-
affinity, with high selectivity and specificity for the μ- nyl and furanylfentanyl.33
opioid receptor over other opioid receptor subtypes.22 The prevalence of use of fentanyl and NPS fen-
In terms of toxicity, as potent agonists of the µ-opioid tanyl varies significantly between European countries.
receptor, fentanyls are associated with a number of In Estonia, for example, the majority of treatment
acute physiological effects, including respiratory entrants reporting an opioid as their primary drug
depression. were using fentanyl34 and an endemic problem with
Fentanyl analogues developed by pharmaceutical fentanyl has existed since the early 2000s, with high
companies, but not sold, have properties similar to rates of overdose in comparison with other EU coun-
fentanyl. Non-pharmaceutical analogues have higher tries. Fentanyl and 3-methylfentanyl have also been
potencies than morphine, for example butyryl-fentanyl marketed in 2010–2012 as replacements for heroin in
(1.5–7), acetylfentanyl and 4-fluorobutyrfentanyl (15.7), EU countries affected by heroin shortages (e.g.
alpha-metylfentanyl (56.9), octafentanil (90), 3-methyl- Bulgaria, Slovakia). Fentanyl and its analogues have
fentanyl (48.5–569) and beta-hydroxy-3-methylfentanyl also been reported in other European countries, for
(6,300).23 example in Germany, Finland and the UK, where
80
5.7 Acute Harms of Fentanyls
fentanyl-related deaths have been mentioned,35 as they had used a fentanyl (initially believing that they
well as in Sweden, Hungary, Belgium, Switzerland were administering heroin) described the effects of
and Poland.36,37 In Estonia, the majority of treatment fentanyls as stronger and qualitatively different from
entrants reporting an opioid as their primary drug those of heroin,49 or describe the experience as like
were using fentanyl.38 taking heroin but more intense.50,51,52
Fentanyl, fentanyl analogues and other new syn-
thetic opioids are often also sold on the illicit market 5.7 Acute Harms of Fentanyls
as heroin (or mixed with heroin) to people who
The reported acute harms associated with the use of
believe they are receiving heroin. There are in add-
fentanyls are summarised in Table 5.1.
ition reports from elsewhere in the world that they are
Intoxication associated with opioid NPS is charac-
also sold as, or mixed with, other illicit drugs and
terised by a reduced level of consciousness, which can
counterfeit medicines.34 International evidence sug-
range from drowsiness to stupor, and resembles that
gests that fentanyl products have also been found in
produced by more classic opioid agents.53
products sold as cocaine or crack cocaine, ‘black tar’
The adverse effects of fentanyls are dose-
heroin and MDMA.13,39 Furthermore, there are
dependent and are similar to those of other opioids.
reports of individuals purchasing prescription medi-
They include pruritus (itchy skin), constipation and
cation, such as oxycodone40 and alprazolam,41,42 on
delirium.54 Adverse effects of fentanyl also include
the Internet only to be sold counterfeit products that
constipation, nausea, vomiting, itching, cough sup-
contain new fentanyls.43,44
pression, nasal burn or nasal drip after insufflation,
a bitter taste after oral ingestion, anxiety, agitation,
5.6 Desired Effects of Fentanyls sweating, disorientation, orthostatic (or postural)
All the fentanyl class drugs are associated with hypotension and urinary urgency or retention, brady-
a feeling of warmth and euphoria. These effects can cardia and hypothermia. Other adverse effects linked
be more intense, but last a shorter time that those of to the use of fentanyls include dysphoria, depression,
morphine and diamorphine.45 The effects of fentanyls paranoia and hallucinations.48,55,56
that are desired by those who use them outside med- The health risks associated with the use of fentanyl
ical supervision are similar to those of other opioids and its analogues are linked to the very high potency
and include analgesia, anxiolysis, euphoria, drowsi- of the substances, leading to a high risk of overdose
ness and feelings of relaxation, with some suggestion and respiratory depression.57,58,59
that the latter are less pronounced than with heroin The misuse of fentanyls is associated with a high
and morphine.46,47 risk of acute toxicity, or ability to cause harm through
There are reports of heroin users being suspicious a single or short-term exposure to the drug. For fen-
that they had unknowingly consumed a new synthetic tanyl, the estimated lethal dose in humans could be as
opioid or fentanyl, as their experience of the drug low as 2 mg by intravenous injection. The features of
effect was different from normal.48 Some research opioid overdose include reduced level of conscious-
suggests that users who were initially unaware that ness, miosis and respiratory depression associated
Table 5.1 Fentanyl toxicity
Fentanyl toxicity Fentanyl severe toxicity Differences between heroin

and fentanyl overdoses
• Miosis (pinpoint pupils) • Respiratory and central nervous • In comparison with heroin, intoxication
• Nausea, vomiting system depression with fentanyl and analogues presents with:
• Anxiety, agitation • Decreased consciousness • Increased risk of overdose
• Euphoria, dysphoria • Apnoea • More rapid onset of overdose
• Depression • Can lead to deep coma, convulsions • More rapid progression of signs and
• Paranoia and respiratory arrest. symptoms
• Hallucinations • Sudden-onset chest wall rigidity
may be associated with increased
risk of mortality
81
with loss of respiratory reflexes and risk of aspiration. substance.54 This can result in a user inadvertently
These may rapidly lead to respiratory arrest and death consuming a significantly more potent and more
in the absence of appropriate medical treatment.60 unpredictable substance than intended.13,44
Respiratory depression is associated with In addition to the risks associated with the potency
increasing doses and may occur with fentanyl more of fentanyl and its analogues, fentanyl products sold
quickly after overdose than with heroin, reducing the online and on the black market pose a threat to public
window of opportunity for effective treatment with health, because of variable components and erratic
naloxone.61 adulteration13,22 or because the potency of the sub-
Fentanyl causes dose-dependent respiratory stance is unpredictable.56
depression, which has been reported by one study to The risk of overdose is increased by unsafe
be maximal 25 minutes after a single intravenous dose methods of preparation and administration (espe-
and to last as long as 2–3 hours.56 Fentanyls can also cially intravenous injection), imprecise measuring
be linked to apnoea, severe bradycardia, asystole, con- by users, drug potency and users mostly being
vulsions, respiratory arrest, deep coma and death.62 unaware of what they are consuming.13 The
Fentanyl toxicity has been associated with chest EMCCDA has reported concerns over the apparent
wall rigidity, particularly when injected.47,48,56,57,63–66 popularity of selling ready-to-use or using home-
Fentanyl-induced respiratory muscle rigidity made nasal sprays containing solutions for the
(FIRMR), can cause increased stiffness of the chest administration of fentanyls, including cyclopropyl-
wall (also known as ‘wooden chest’) and laryngos- fentanyl. These typically contain milligram amounts
pasm (vocal cord closure), further restricting breath- of dissolved substance, but the dosage is imprecise
ing. This effect of fentanyls is distinct from the and may lead to solutions with higher (or lower)
respiratory depression caused by opioids and can concentrations.80
occur rapidly after intravenous fentanyl use and We do not know much about the adverse effects of
occasionally after modest doses.67,68,69 There are the various fentanyl NPS; information, especially in
suggestions that sudden-onset chest wall rigidity is humans, is currently very limited, however it is
a significant factor in deaths from intravenous fen- expected that they are similar to the harms of fentanyl.
tanyl use.70 There are differences between the various fentanyl
Atypical characteristics in overdoses with fentanyl NPS, as well as differences between the latter and
and analogues have been described to include: fentanyl. As shown in Box 5.2, some NPS are less
• Immediate blue discolouration of the lips, potent than fentanyl while others appear to be more
gurgling sounds with breathing, foaming at the potent.
mouth, confusion, stiffening of the body or In addition, it has been argued that the pro-
seizure-like activity, and confusion or strange longation of effects (for some opioid NPS), and
affect before unresponsiveness;71,72,73,74,75 their frequent use in combination with other
• Lung damage (including alveolar haemorrhage, drugs increases the risk of serious drug inter-
haemoptysis and acute lung injury, with the NPS actions which can result in toxicity (e.g. respira-
butyrfentanyl);76 tory depression) and opioid withdrawal symptoms
• Toxic leukoencephalopathy characterised by (in the case of previously developed opioid
cerebellar white matter;77 tolerance).81
• Syncope and chest pain mimicking acute coronary
There is evidence from Europe that fentanyl
syndrome;78 NPS have been associated with overdose and
deaths. For example, cases of acute intoxication
• Unusual amnestic syndrome associated with
suspected to be due to furanylfentanyl reported
combined fentanyl and cocaine use that included
in Europe showed clinical features generally
acute, complete and bilateral hippocampal lesions
consistent with opioid-like toxicity and included
on magnetic resonance imaging.79
life-threatening effects and death.40,41 There are
One of the risks of overdose is directly related to the similar reports regarding acute toxicity and deaths
fact that a substantial number of people who had used linked to acryloylfentanyl and methoxyacetylfenta-
fentanyl or its analogue NPS did not know that they nyl, including considerable risk of acute toxicity
had done so when they consumed the drug, but through respiratory depression.42,82
thought they were using heroin or another
82
5.7 Acute Harms of Fentanyls
Box 5.2 Example of Fentanyl Novel Psychoactive Substances
Acetylfentanyl
Acetylfentanyl is a common novel opioid, with reported deaths from drug toxicity in several European countries and
across much of the US. Acetylfentanyl is 5–15 times more potent than heroin, 16 times more potent than morphine,
but its potency is one third that of fentanyl.96 It has been reported that the range between the therapeutic dose as
a medication dose and the lethal dose of acetylfentanyl when it is misused is narrower than that of morphine and
fentanyl, which increases the risk of a fatal overdose.97 Acetylfentanyl has been associated with deaths that have
occurred when used by insufflation as well as intravenously and orally. Almost all cases are fatalities from poly-drug
use or use of multiple drugs.98
Furanylfentanyl
Furanylfentanyl is more potent than morphine but approximately five times less potent than fentanyl. Deaths
associated with it have been reported in Canada, Sweden and the US.98
Acrylfentanyl also known as acryloylfentanyl is slightly more potent than fentanyl in displacing labelled
naloxone from the mu-opioid receptor. Deaths have been reported and have included evidence of nasal insufflation
of both sprays and crushed tablets.98
Butyrylfentanyl: Also Known as Butyrfentanyl
Butyrylfentanyl is a potent short-acting synthetic opioid analgesic, around one-quarter of the potency of fentanyl,
but approximately seven times more potent than morphine
Butyrylfentanyl has no current legitimate clinical use. It appears to be in the form of powder, tablets, capsules,
blotters, liquids or in injectable formulas. It could be administered orally, nasally (using sprays), by snorting, smoking
or by intravenous injection. Butyrylfentanyl has been associated with deaths in Europe and the US.99,100
4-Fluorobutyrylfentanyl
It is usually in the form of powder or a nasal spray, liquids, tablets or capsules. It is used orally, nasally (with sprays),
by snorting, smoking, by intravenous injection rectally or by heating the drug and inhaling the vapour. It is available
on the Internet added to heroin, often without the user’s knowledge. Fatalities have been reported.101
Ocfentanil
This opioid is about twice as potent as fentanyl, with reported cases of associated deaths when no other drugs were
apparently involved.101
Methylfentanyls
3-Methylfentanyl is approximately 7,000 times more potent than morphine and has been associated with morbidity
and mortality for many years, but first reported in the US in the 1980s. More recently, deaths have been reported in
Finland102 and later in an epidemic in Estonia.103,104,105
Carfentanyl
Carfentanyl is an analogue of fentanyl, and is one of the most potent opioids known and used commercially.
Carfentanyl has been approved for use in veterinary medicine as a general anaesthetic agent or as a tranquillising
agent for large-animal use only.
Carfentanyl is 10,000 times more potent than morphine and 100 times more potent than fentanyl,106 with
activity in humans starting at about 1 microgram. There have been cases of carfentanyl laced with or disguised as
heroin, leading to a number of deaths.107
The non-medical use of fentanyl has been implicated by increases in the numbers of deaths involving fentanyl,
in a significant and increasing number of deaths in which are likely due to illicitly manufactured fentanyl.92
several countries, including some European countries, Deaths related to opioid NPS, including fentanyls,
Australia and Japan.47,83,84,85,86 In Canada and the US, have been reported in Europe, albeit at a significantly
the problem of opioid-related overdose death has been lower rate. Nonetheless deaths were reported where
particularly severe for a number of years.87,88,89,90,91 In fentanyl NPS were implicated including acryloylfenta-
the US, it has been suggested that the increases in the nyl, furanylfentanyl methoxyacetylfentanyl and
numbers of deaths involving opioid NPS are being driven cyclopropylfentanyl.93,94
83
It has been reported by the EMCDDA that highly heroin, whereby deaths are most likely to be associ-
potent opioid NPS, and the fentanyl derivatives in ated with intravenous injecting.
particular, appear to be playing an increasing role in
drug overdose in Europe.95 Deaths related to 5.9 Poly-drug Use
a number of fentanyls and analogues have been As with other opioids, the combined use of fentanyl
reported in Sweden and other Nordic countries as with other CNS and respiratory depressants, such as
well as a small number in the US.96 Deaths where alcohol or benzodiazepines, is linked to increased
other fentanyl NPS were implicated include acetyl- toxicity. Studies have recommended the ongoing
fentanyl, acrylfentanyl, butr(yl)fentanyl, carfentanil, need for targeted messages on risks of synthetic opi-
2- and 4-fluorofentanyls, 4-fluorobutyrfentanyl, oids alone, as well as their use in combination with
4-fluoroisobutyrfentanyl, furanylfentanyl, a- and alcohol and other CNS depressants.116
3-methylfentanyls, 4-methoxyfentanyl, ocfentanil96 In general, the use of opioids with other CNS
and 4-methoxybutyrfentanyl.96 depressants, such as alcohol or benzodiazepines,
increases CNS depression which can lead to respira-
5.8 Differences between Heroin tory distress, coma and death.
A new trend which has also been reported is fen-
and Fentanyl Acute Toxicity tanyl that is added to cocaine for the purpose of
The high potency of fentanyls, as well as their rapid ‘speedballing’, to combine the rush of the stimulant
onset of action, contributes to making them particu- (cocaine) with a drug that depresses the CNS (fen-
larly dangerous in comparison with heroin when used tanyl), thus helping to ease the after effects. People
in a non-medical setting.15,108,109 A report from who use drugs may also be inadvertently exposed to
a drug consumption room in Australia found that, fentanyl or other opioid NPS when they are unknow-
under medical surveillance, the risk of overdose when ingly taking cocaine or other drugs that are laced with
injecting fentanyl was two times higher than when them. In this case, a drug interaction can also occur
injecting heroin, and eight times higher than and the user can have unexpected adverse effects.117
when injecting other prescription opioids.110 Like other opioids, opioid NPS including fentanyls
Fentanyl overdose can begin suddenly, rapidly will interact with other illicit substances, as well as
progress to death and manifest atypical physical medication.118 Amphetamines in combination with opi-
symptoms. In comparison with heroin overdose, ates enhance the sense of euphoria.119 Dexamphetamine
where death typically does not occur until at least and methylphenidate increase the analgesic effects of
20–30 minutes after use,111 fentanyl can be associated morphine and other opioids and reduce their sedative
with potentially lethal respiratory depression within 2 and respiratory depressant effects.120,121 Combinations
minutes.22,43,112 involving amphetamine-like substances with certain opi-
Fatalities associated with fentanyl often also involve oids may increase the risk of serotonin syndrome
the concurrent use of other substances, such as cocaine through effects on the serotonin transporter or serotonin
and heroin.113,107,110 The use of fentanyl (and ana- receptors (tramadol and fentanyl most frequently
logues) at the same time as other CNS depressants implicated).122
(e.g. alcohol, benzodiazepine, pregabalin, gabapentin) The use of fentanyl in combination with inhibitors
can have serious adverse effects; poly-drug use has been of the isoenzymes CYP450 3A4 and CYP450 3A5 may
reported to be common among fentanyl-related fatal- result in increased plasma concentration of fentanyl
ities in Europe31 and elsewhere.114 (and probably new analogues), thus increasing the
Injecting is the most commonly reported route of risk of poisoning, including potentially fatal respira-
administration of fentanyl in fatal overdoses, but tory depression. Inhibitors include ritonavir, clari-
deaths linked with other modes of use of fentanyl thromycin, erythromycin, fluconazole, indinavir,
have also been reported. For example, a study looking itraconazole, ketoconazole, nefazodone, saquinavir,
at fentanyl-related deaths in the US from July to verapamil and grapefruit juice.31
December 2016 reported that one in five deaths There is limited evidence that use of fentanyl with
involving fentanyl or fentanyl analogues had evidence serotoninergic agents (prescribed medication includ-
of insufflation, smoking or ingestion and no evidence ing SSRIs, SNRIs or MAOIs, or illicit substances, such
of injecting.115 This is an important distinction from as MDMA) may be associated with serotonin
84
5.12 Clinical Settings
syndrome.123 It is not known if this association is also overdose in 2014.127 As shown in Table 5.2 below, the
seen with fentanyl derivatives.31 use of naloxone for opioid overdose is recommended.
Buprenorphine is predicted to increase the risk of This is also recommended by the EMCDDA.128,129
precipitated opioid withdrawal when given with Naloxone plays an important role in preventing
fentanyl.124 deaths associated with opioids, including fentanyl.
Naloxone reverses the features of opioid toxicity,
improving the level of consciousness and respiratory
5.10 Lack of Testing rate. Naloxone is very effective provided it can be
Analytical methods for detecting fentanyl and other administered in adequate doses before irreversible
opioid NPS use are very limited at present and it is effects occur, such as brain damage resulting from
unlikely that onsite testing is currently available in lack of oxygen delivery.130
hospital laboratories. There are clear distinctions between the responses to
Standard immunoassay screening tests in the clin- opioid overdose carried out in community settings and
ical setting do not detect synthetic opioids. More com- responses in hospital or other acute medical settings. At
plex methods are required, such as gas chromatography a global level, access to naloxone is generally limited to
mass spectrometry or liquid chromatography mass health professionals and it is a prescription medicine in
spectrometry. Testing is complicated by the fact that almost all countries, although there has been an increase
tests for fentanyl may not detect all analogues. in recent years of ‘take home’ naloxone schemes.
5.11 Management of Acute Toxicity 5.12 Clinical Settings

The evidence on the management of acute adverse effects Clinicians should refer to their national and local
associated specifically with the misuse of fentanyl and its protocols and guidelines on naloxone regimens and
analogue NPS and overdose is limited, but emerging.22 administration.
However, they are broadly similar to other fentanyls and WHO guidelines131 make recommendations on the
opioids, with effects potentially reversed by naloxone.125 use of naloxone for the management of opioid overdose.
There are several documents and guidance issues They recommend using a dose of 0.4 mg naloxone and
by international organisations aimed at addressing repeating the dose if necessary, and suggest monitoring
the prevention of drug-related deaths126 and the prin- the person for 4 hours after resuscitation. These guide-
ciples they suggest should inform clinical practice. lines also state that long-acting-opioid overdose may
The World Health Organization (WHO) published need to be managed in hospital, with assisted ventilation
guidelines for the community management of opioid and/or naloxone infusion.
Table 5.2 World Health Organization recommendations
Recommendation Strength Quality

of of
recommendation evidence
People likely to witness an opioid overdose should have access to naloxone and be Strong Very low
instructed in its administration to enable them to use it for emergency management of
suspected opioid overdose
Naloxone is effective when delivered by intravenous, intramuscular, subcutaneous and Conditional Very low
intranasal routes of administration. Persons using naloxone should select a route of
administration based on the formulation available, their skills in administration, the setting
and local context
In suspected opioid overdose, first responders should focus on airway management, Strong Very low
assisting ventilation and administering naloxone
After successful resuscitation following the administration of naloxone, the level of Strong Very low
consciousness and breathing of the affected person should be closely monitored until full
recovery has been achieved
Source: WHO, 2014
85
It has been suggested that naloxone regimens reverse respiratory depression and can be lifesaving,
developed for the reversal of heroin overdose are but giving too much can lead to an acute withdrawal
likely to be effective for the majority of cases of fen- syndrome. It has been noted that the naloxone
tanyl toxicity, however, the total dose may be too low, administration regimen must be based on an appro-
and the rate of administration too slow for the most priate and flexible strategy which balances the risk of
severe cases.132 The dose of naloxone required in an delayed reversal of respiratory depression with that
emergency is dependent upon many factors. Some of causing acute withdrawal from excessive naloxone
patients with fentanyl overdose have required rela- use.139
tively high doses of naloxone, with up to 2.4 mg However, some people argue for the use of high doses
being reported.133 of naloxone, despite the risk of acute withdrawal.140 For
There are a number of naloxone regimens. In the example, Moss et al. (2019) have argued that the benefit
UK for example, current recommended naloxone of adequately reversing opioid toxicity outweighs the risk
dosing in the UK for acute treatment of adults with of opioid withdrawal syndrome.140
heroin overdose by healthcare professionals is an ini- It has been argued opioid NPS, including fenta-
tial injection of 0.4 mg. If this is ineffective, a further nyls, do not require hospital clinical staff to change
injection should be administered after 1 minute; this their approach to the management of acute opioid
can be repeated after another minute if needed (total toxicity and overdose.141 It has been suggested that
dose 2.0 mg). If that is ineffective, a further dose of initial care of the opioid-intoxicated patient should
2.0 mg is advised.134 This regimen allows the admin- focus on protecting the airway and maintaining
istration of up to 4 mg naloxone within 3 minutes for breathing and circulation, as in any emergency.
those patients who need a high dose.135 A rapid dose External stimulation should be attempted in all
titration is also appropriate for those exposed to patients, and an external ventilatory support mask
highly potent analogues such as carfentanil.136 device should be provided for those with profound
Naloxone, however, is not effective for treating hypoventilation.148
fentanyl-induced respiratory muscle rigidity • Anticipatory titration of naloxone with the goal of
(FIRMR) or laryngospasm triggered by fentanyls, restoring ventilatory drive remains the mainstay
where the use of a muscle relaxant, endotracheal for patients who do not respond in a sustained
intubation and mechanical ventilation are fashion to the above.148 Overdoses can be reversed
required.137 Other potential challenges include the through the use of naloxone as in the case of other
fact that some fentanyl analogues have a prolonged opioids, together with appropriate supportive
duration of effect, whereas naloxone has a relatively care.142
short half-life. Initially effective treatment may be • It has been proposed that clinical suspicion may be
followed by a relapse of the symptoms of opioid over- sufficient to carry out empirical treatment with
dose, especially if a longer-acting fentanyl has been naloxone, considering that there are no significant
used. This necessitates longer medical observation.137 side-effects to its use in such circumstances.149
There are reports of multiple doses of naloxone • Potent, faster-acting synthetic opioids, such as
sometimes being required.71 Because the length of fentanyls, make it more difficult to balance the
time is shorter between substance use and potentially need for an effective opioid antidote with the risks
life-threatening respiratory depression with fentanyl of precipitated withdrawal.143
than with heroin, the reversal of the fentanyl overdose
may be less likely than with heroin, as the naloxone
can be administered late. There have been reports of 5.12.1 Administering Naloxone
unsuccessful attempts to revive with naloxone despite in Community Settings
administration of multiple or escalating doses. It is acknowledged that overdoses are often witnessed
Despite the standard resuscitation procedures indi- by a family member, friend or peer and that increased
cating the potential need to administer repeat doses of access to naloxone for people likely to witness an
naloxone, the clinical outcome of fentanyl poisoning overdose could significantly reduce the high numbers
may vary from case to case.138 of opioid overdose deaths.144 There is evidence on the
There are other challenges. The prompt adminis- effectiveness of training family members or peers in
tration of naloxone in an emergency situation can how to administer the drug.145
86
5.13 Chronic Harms and Dependence
‘Take-home’ naloxone (THN) programmes are some naloxone programmes providing more than
now increasingly available in Europe. They aim to the standard two doses of naloxone, and others have
make naloxone more readily available in places begun utilising higher-dose devices.22 More research
where overdoses might occur and to expand the avail- is needed to assess whether the approach will prove to
ability of naloxone to opioid-using peers, family be effective.
members and other trained laypeople. THN pro- Other interventions to prevent fentanyl-related
grammes can also target other potential first harm include the use of fentanyl test strips as an
responders to an overdose, such as healthcare pro- opioid overdose prevention strategy by allowing
viders, staff in homeless shelters and police and prison users to test if fentanyl analogues are mixed with
officers. As part of these programmes, trainees learn heroin and often sold to unwitting consumers.150,151
how to correctly recognise and respond to an over- A study has demonstrated that devices for fentanyl
dose, including administration of naloxone, before drug checking are valid.152
the arrival of emergency medical help.146
It has been argued that the same principles of 5.13 Chronic Harms and Dependence
response with THN initiatives apply to the prevention
Despite limited evidence, it is assumed that fentanyls,
of deaths from fentanyl overdose as with other opioids,
including the novel analogues, have a high potential
although early administration of naloxone is likely
crucial.147
A number of naloxone products for THN are
dispensed in different European countries, including Box 5.3 Overdose Management: Fentanyl
injectable formulation (including ampoules and pre- in Comparison with Heroin Overdose
filled syringes) and nasal sprays. In the case of sus-
pected fentanyl overdose, it is suggested that training The broad principles of management apply to all
for THN should emphasise: opioids, with the following to be taken into account
where fentanyl is suspected:
• The importance of calling ambulance or
emergency services promptly and transfer to • Where the use of fentanyls is suspected, there is
a need to call emergency services and transfer to
hospital, especially in cases where naloxone is not
hospital, especially in cases where naloxone is not
available in the community, or if there is need for
available in the community, or if there is need for
prolonged naloxone administration, which may be prolonged naloxone administration.
the case for fentanyl overdose.
• A more rapid escalation of additional doses of
• It has also been suggested that more advanced naloxone may be needed in comparison with
resuscitation skills (such as chest compressions heroin or other opioids.
and automatic defibrillators) may need to be more • Overall, higher doses of naloxone may be needed
widely incorporated into community emergency for fentanyl patients than for heroin patients.
response training to tackle fentanyl overdose, and • A longer period of clinical observation is advised
is vital if responsiveness to naloxone for fentanyl patients than for heroin patients.
administration is inadequate or delayed.33 • In cases of heroin overdose, some have suggested
However, there is growing evidence that higher doses that patients with heroin-induced respiratory
or multiple administrations of naloxone are required depression can be safely discharged from hospital
to fully reverse the toxicity of illicitly manufactured after a one-hour observation period.153 Armenian
fentanyl analogues. Recently, the US Food and Drug et al. argued that this is not recommended for
Administration approved THN kits with opioid NPS, including fentanyls, which may
require larger and repeated doses of naloxone and
a concentrated naloxone dose that produce high bio-
require a longer period of observation because
availability. However, their accessibility to the general
symptoms may recur when the naloxone wears
public is limited.148 There are also some reports that off.23
small-scale interventions targeted at fentanyl have
• They also recommend that due to the extremely
been developed based on the assumption that take- high potency and lack of human pharmacokinetic
home naloxone kits provided to users of opioid NPS and clinical overdose knowledge of carfentanyl,
may require higher doses of naloxone than those that all carfentanyl cases be monitored for 24
provided to heroin users.149 There are reports of hours in the hospital setting.23
87
for harmful use and a high dependence liability that is bacterial infections and vein damage, with one study
similar to, or greater than morphine. showing how fentanyl injecting-related harms are
Increasing numbers of people are entering drug exacerbated by the use of lemon juice or vinegar,
treatment for fentanyl-related harmful or dependent which can cause vein damage when injected.163
use. In the US, where there is currently a significantly There have been suggestions that fentanyl-specific
higher level of fentanyl use than in the UK, a study of harm-reduction information be developed. It has
people entering drug treatment reported that fentanyl been suggested that ‘an increase in fentanyl-related
misuse increased modestly from 2012 to 2016. overdoses and deaths suggests that information about
However, it also showed that whereas the misuse of how to reduce harms associated with injecting fen-
branded fentanyl products remained stable, the mis- tanyl is lacking’. In their study of the non-medical use
use of ‘unknown’ fentanyls, presumed to be non- of fentanyl patches, users reported lack of knowledge
pharmaceutical fentanyl, increased significantly.154 of the drug they were using, including exactly what it
In Estonia, data from specialised drug treatment was, how to extract it and how to measure the dose.
centres indicate that opioid NPS (mainly non- Peer networks were identified as the key source of
pharmaceutical fentanyl or 3 methylfentanyl) were information in drug-using practices, but information
the most commonly reported primary substances for shared was poor, even dangerous.163
first-time clients entering treatment in 2015. In more
recent years, fentanyl has become the main injected
opioid substance in that country.155
5.16 Management of Fentanyl
Fentanyls are associated with tolerance and with- and Other Opioid Novel Psychoactive
drawal symptoms. Reports from users suggest the Substances Dependence
development of tolerance, withdrawal-like symptoms
There is little published information on the manage-
and physiological dependence similar to those with
ment of dependence and withdrawal specifically for
other opioids.156,157 Characteristic withdrawal symp-
fentanyl misuse or its analogues. Methadone and
toms include sweating, anxiety, diarrhoea, bone pain,
buprenorphine are listed by the World Health
abdominal cramps and shivers or ‘goose flesh’.47,48
Organization (WHO) as essential medicines for the
pharmacological treatment for opioid use disorders to
5.14 Other Long-term Effects reduce cravings and withdrawal symptoms.
There is some limited evidence that the long-term use Methadone has been used in cases of fentanyl depend-
of fentanyl has also been associated with: hyperalgesia ence. In Estonia, where the most commonly reported
(opioid-induced abnormal pain sensitivity, also called primary substances for first-time clients entering
paradoxical hyperalgesia);158 gastrointestinal treatment in 2015 were fentanyls, most clients
disturbance; immunological dysfunction;166 hormo-
159
received opioid substitution therapy (OST) and
nal disruption;166 muscle rigidity and myoclonus.166 methadone in particular. As with any effective treat-
Among older people in particular, long-term use of ment of dependence, pharmacology should be com-
fentanyl is linked to raised risk of fracture and acute plemented by psycho-social interventions.
myocardial infarction160 and generally increased The management of dependence associated with
mortality.161 fentanyl and analogues is similar to that of other opioids
and requires a bio-psycho-social response. It is some-
5.15 Public Health Risks: Injecting times appropriate to stabilise opioid-dependent patients
on to a prescribed opioid in the context of care-planned
and Other High-Risk Drug-Using treatment and support. While the evidence base is
Behaviours limited for fentanyl and analogue NPS, buprenorphine
It has been argued that fentanyl and its analogues pose or methadone are often used and there is a good body of
distinct risks for the transmission of blood-borne vir- evidence to support pharmacological interventions for
uses such as hepatitis C and HIV.162 There is also some relapse prevention or craving management for opiates,
evidence that use is associated with high-risk behav- although evidence on NPS opioids is limited.
iours. Users of illicit fentanyl in Toronto, for example, Pharmacological interventions and substitute pre-
reported engaging in practices that exposed them to scribing must involve a psycho-social component to
blood-borne viruses.169 It has also been associated with help support an individual’s recovery. As with all drug
88
5.21 Unwanted and Adverse Effects of Intoxication
treatment, a psycho-social response is also required as opioid receptor agonist; AH-7921 is an agonist of µ
part of the treatment plan, including assessment of co- and κ receptors; and MT-45 is an agonist of µ-, κ-
occurring physical, mental and social morbidity. and δ-opioid receptors.). However, some opioid NPS
have different mechanisms of action. U-50488 is
mainly a κ-opioid receptor agonist that has been
5.17 Other Novel Synthetic Opioids studied in animal models as an analgesic, antitussive,
(Non-fentanyl) diuretic, and anticonvulsant. Its side effects include
In addition to fentanyl and its analogues, in the dysphoria and hallucinations, and it has been
past years more than a dozen additional opioid reported to present µ-opioid receptor antagonist
NPS have entered the illicit opioid market. These effects. U-51754 is not as selective for k-opioid
were all first synthesised in the 1970s163 by receptor.167
pharmaceutical companies, but never progressed The pharmacology, availability and modes of use
to clinical trials or were never used in pharmaceut- of these three substances are outlined in Table 5.3.
ical or medicinal products. Some have been redis-
covered by traffickers from research published 5.19 Availability and Mode of Use
between the 1960s and 1990s, when they were Opioid NPS are generally found on websites selling
described in the scientific literature but never so-called ‘research chemicals’. They are usually con-
developed into pharmaceutical products. sumed orally, but can also be used by inhalation/
Newly marketed opioid NPS have appeared vaporising, nasal insufflation, sub-lingually, intraven-
with structures distinct from those used in medical ous injection or rectal administration and are sold as
practice. Examples include, but are not limited to, a powder, tablets and capsules.176,177,178 See Box 5.4.
AH-7921 (a benzamide), U-47700 (a compound Opioid NPS are marketed as stand-alone products but
closely related to AH-7921) and MT-45 (a pipera- are also found as adulterants in heroin and in coun-
zine), U448800, U-77891, U-50488, U-51754, and terfeit opioid medications.179
O-desmethyltramadol.164 See Box 5.4.
5.20 Desired Effects
5.18 Pharmacology Based on user reports, the effects of opioid NPS
Opioid NPS have lower potencies than fentanyl, but appear to resemble those of classical opioids
are more potent than morphine.166 including mild euphoria and relaxation.184,185
Most opioid NPS have mechanisms of action and Some users report self-medicating to relieve pain,
effects similar to established opioids, with their main others to alleviate withdrawal symptoms due to
effects mediated through activation of µ-opioid cessation of other opioids. It has also been noted
receptors (for example, U-47700 is a potent µ- that the effects are not only the general and
expected opioid effects, but some opioid NPS also
show other unanticipated effects including
Box 5.4 Chemical Structures of Opioid Novel increased energy, reduced inhibition and
Psychoactive Substances a facilitation of social situations.186 In one study,
people who used opioid NPS reported ‘pleasure and
Opioid NPS have different chemical structures. For
enjoyment’, ‘coping with life challenges’ and
example:
addictive character of these substances.187
• AH-7921 is 3,4-dichloro-N-(1-(dimethylamino) The effects desired by users are listed in Table 5.5.
cyclohexylmethyl)benzamide;
• U-47700 is trans-3,4-dichloro-
N-(2-(dimethylamino)cyclohexyl)-
5.21 Unwanted and Adverse Effects
N-methylbenzamide; of Intoxication
• MT-45 is 1-cyclohexyl-4-(1,2-diphenylethyl) AH-7921, U-47700 and MT-45 have broadly similar
piperazine; profiles of unwanted and adverse effects, as shown in
• U-448800, and U77891 are benzamides; Table 5.6. Signs of intoxication include196:
• U-50488 and U-51754 are acetamides.165
89
Table 5.3 Non-fentanyl opioid novel psychoactive substances: brief pharmacology
Pharmacology
AH-7921 U-47700 MT-45
AH-7921 is an opioid analgesic patented U-47700 is an opioid analgesic and is MT-45, also known as IC-6, was
by Allen and Hanburys Ltd in 1976 but structurally related to AH-7921. Although developed in the 1970s as an alternative
has never been used in a pharmaceutical U-47700 exhibits some k-opioid receptor to morphine for analgesia. It is an N,N-di-
or medicinal product. Thought to be agonism, it has far more activity at the µ- substituted 4-(1,2-diphenylethyl)
a morphine-like analgesic acting mainly opioid receptors.49 It is a selective µ- piperazine chemically unrelated to other
as a µ-opioid receptor agonist. Human opioid receptor agonist, and in animal opioid agonists. The pharmacology of
data are mostly not available, but animal models has been demonstrated to have MT-45 is complex and involves opioid
studies have shown that AH-7921 is ~7.5 times the potency of and non-opioid receptors that have not
approximately as potent as morphine morphine.171,172,173 According to user been fully characterised; however, it has
with regard to respiratory depression, reports, U-47700 acts longer than AH- been demonstrated in animal studies to
antinociception, sedation and miosis 792126 have approximately the same potency as
(decrease in pupil diameter), decrease in morphine.174 It appears that MT-45 has
body temperature and inhibition of gut a slow onset of action, greater than 1–2
propulsion168,169,170 hours when taken orally, which may
increase the risk of toxic overdose from
redosing before peak effect is reached175
Table 5.4 Availability and Mode of Use
AH-7921 U-47700 MT-45

AH-7921 has been available in Europe In the recreational drug market, U-47700 MT-45 is typically sold on the Internet or
since mid-2012 via websites selling is sometimes referred to as ‘pink’, illicit market as a dihydrochloride salt.
‘research chemicals’. AH-7921 is sold as because it can be slightly pink in colour. Typical routes of administration include
a free base and as a hydrochloride salt in The drug is also known as ‘U4’.182 It is oral, insufflation, intravenous and
a white/off-white powder form,180 but taken orally, nasally, rectally, by smoking, intramuscular. Rectal use has also been
has also been detected in Japan as a co- intravenous injection or by combinations reported.57 It has been found mixed
ingredient in synthetic cannabinoid and of these routes26 with other drugs, including synthetic
cathinones.181 AH-7921 is usually cannabinoids and synthetic
consumed orally but can also be used by cathinones183
inhalation/vaporising, nasal insufflation,
sub-lingually, intravenous injection or
rectal administration and is sold as
a powder, tablet or capsule
• Miosis (pinpoint pupils), with the exception of the depression of the level of consciousness can lead to
MT-45, which has only a small miotic effect deep coma, convulsions and respiratory arrest.
• Nausea, vomiting
• Anxiety, agitation 5.22 Management of Acute
• Euphoria, dysphoria
• Depression
Intoxication and Overdose
Opioid NPS are currently not tested as a routine part
• Paranoia
of most forensic drug screening. However, it has
• Hallucinations
been argued that the clinical approach in managing
These opioid NPS have a broadly similar, or opioid toxicity and overdose should not change and
higher potential to morphine in inducing analgesia; should include the management of airways and the
acute harms include respiratory depression, hypo- administration of naloxone to reverse the
thermia and dependence liability.194,195,196,197,198 overdose.209
Severe opioid toxicity produces depression of the AH-7921, U-47700 and MT-45 require similar
respiratory and central nervous systems. If untreated, management of acute intoxication and overdose to
90
5.22 Management of Acute Intoxication and Overdose
Table 5.5 Desired effects of three novel synthetic opioids
AH-7921 U-47700 MT-45

Much of what we know about its effects comes Based on animal models, it is Effects similar to other
from reports of people who have used it. expected that U-47700 produces opioids57
Based on this, the effects of AH-7921 appear effects similar to those of other
to resemble those of classic opioids potent opioid agonists, including
Experience with AH-7921 was described as analgesia, sedation, euphoria.192 It
predictable and repetitive. Effects reported has been suggested that U-47700
by users include nausea and vertigo, ‘opiate induces significant euphoria, which
glow’, alertness, occasional itching, nausea is short-lived and causes an urge to
and tremors188 keep ‘redosing’193
AH-7921 produces relaxation, euphoria,
a physical anaesthetic effect, mental
relaxation and pleasant mood lift.189 An
interesting finding reported by one study
was that the users of AH-7921 (as well as of
MT-45) report experiences of increased
energy190
There are reports of its use as self-medication to
relieve pain or to alleviate withdrawal
symptoms due to cessation of the use of
other opioids197
The dissociative effects of AH-7921 were also
reported191
Table 5.6 Unwanted and adverse effects of intoxication of three novel synthetic opioids
All opioid NPS are associated with respiratory depression. Other adverse effects and acute harms include the following:
AH-7921 U-47700 MT45

A study found that morphine has Based on animal models, it is MT-45 has only a small miotic effect
a twofold greater safety margin than expected that U-47700 (restriction of pupils or pinned pupils),202
AH-7921, which suggests readier produces effects similar to in contrast to other commonly used
appearance of toxic effects after AH- those of other potent opioid opioid drugs
7921 use199,200 agonists including Although MT-45 is structurally unrelated to
The side-effects range from milder constipation, itching and morphine, it has analgesic and CNS
symptoms (e.g. stomach upsets, light respiratory depression41,199 depressant properties similar to those of
headache) to more severe conditions morphine, including respiratory
(e.g. anxiety and panic)197 depression.203 Some animal studies
Other reported adverse effects include suggest a higher toxicity than
abdominal pain, constipation, reduced morphine210
mobility, light-headedness, headache, Drug users also report some dissociative-like
urinary retention, visual impairment, symptoms.181 Other reported unwanted
pain in the mouth effects include nausea, itching, bilateral
Unwanted adverse effects also include hearing loss and possible withdrawal
vertigo induced by movement.196 Users symptoms
also reported itching as one of the side- A unique feature of MT-45 toxicity is its
effects of AH-7921 use, as well as other association with ototoxicity – that is, it is
forms of skin irritation. There are also linked with hearing loss, with a reported
reports of numbing of different parts of case of bilateral hearing loss lasting for 2
the body197 weeks57,182
Temperature change, tremors, numbness, MT-45 has been associated with bilateral
blister, seizures, hypertension and hearing loss, hair depigmentation and
tachycardia and respiratory depression loss, folliculitis, dermatitis, dry eyes,
have also been reported201 liver enzyme alteration and
leukonychia striata on the nails.
Cataracts have also been
observed204,205,206,207
Other symptoms including dry and scaly skin,
angular cheilitis, cracks on the fingers and
under the feet, redness and moist
91
Table 5.6 (cont.)
AH-7921 U-47700 MT45

maceration of the groin and armpits, and
total alopecia, as well as loss of taste, smell
and chills almost constantly, elevated levels
of the enzymes aspartate transaminase
(AST) and alanine transaminase (ALT),
sudden hearing loss and deafness, irritated
and dry eyes, culminating in loss of vision
and almost blindness, imposing the need
for cataract surgery performed on both
eyes208
Deaths
Overall, it seems that lethal doses for opioid NPS are often variable and deaths associated with these compounds seem to occur at both
low and high concentrations, probably due to different levels of tolerance and individual differences. In most cases, opioid NPS
associated with death also involves other drugs as well209
AH-7921 has been associated with fatal Deaths reported199,200,216,217 Deaths reported in Europe and
overdoses, including a small number elsewhere57,199,218,219,220,221,222,223,224,225
of deaths in the UK187,210,211,212,213,214
Deaths associated with AH-7921 seem to
occur both at low and high
concentrations, possibly a result of
different levels of tolerance to the
drug215
As with other overdose deaths, poly-drug
use has been involved in many AH-7921
deaths,175,196 but AH-7921 use alone
has also been reported222
those required for other opioids (see Section 5.11). It 5.24 Managing Dependence
has been suggested that emergency responders may
The management of dependence will be the same as
have difficulty in identifying MT-45 overdose because
for other opioids and opioid NPS, including fentanyl.
the drug produces a small miotic effect (restriction of
See Section 5.16.
pupils) and this is important for clinical staff to be
aware of.209
As opioid NPS have various potencies, receptor
affinities and street concentrations, it has been argued
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100
Chapter
Ketamine and Other Novel Psychoactive
6 Substances with Dissociative Effects
6.1 ‘Dissociative’ Drugs ‘alteration in one’s experience and awareness of the

self, leading to feelings of being unreal or detached
Dissociative drugs distort perceptions of sight and
from one’s own body’, and de-realisation, where indi-
sound and produce feelings of detachment (or dis-
viduals ‘feel that the world around them has suddenly
sociation) from the environment and self. Among the
become unreal’.2,3
dissociative drugs, ketamine and phencyclidine (PCP)
Ketamine hydrochloride is one of the dissociative
are the drugs most commonly used for recreational
drugs most commonly used for recreational purposes.
purposes.
At a global level, 96% of all ketamine quantities seized
In the last decade, a new generation of synthetic
worldwide between 2013 and 2017 were reported by
dissociative drugs appeared on the market, including
authorities in Asia, mostly in East and South-East
methoxethamine (MXE), methoxphenidine, dipheni-
Asia. However, ketamine trafficking appears to be
dine and phencyclidine derivatives (e.g. 4-MeOPCP),
spreading to other regions, including Europe, the
which have rapidly spread, initially as legal replace-
Americas and Oceania.4 In 2017, a total of 17
ments for the banned ketamine and PCP.
European countries reported police seizures of the
Ketamine is widely used in human and veterinary
drug. In the same year, last year prevalence of keta-
medicine and there is now increasing interest in its role
mine use among young adults (16–34 years) was esti-
in treatment-resistant depression, as discussed in this
mated at 0.6 % in Denmark and 1.7 % in the UK.5
chapter. However, ketamine and then its novel ana-
In addition to the recreational use of ketamine, the
logues have also been used for recreational purposes
use of the novel psychoactive substance (NPS) analogues
and have been regarded as novel psychoactive sub-
of ketamine and PCP has also been reported. As with
stances, in order to differentiate it from controlled
other NPS, the control of one substance leads to the
substances.1 This document discusses the non-medical
development of others. For example, methoxetamine
use of ketamine and its analogues and not its therapeutic
((RS)-2-(ethylamino)-2-(3- methoxyphenyl) cyclohexa-
role used in a controlled clinical setting.
none) 2-(3-methoxyphenyl)-2-(ethylamino) cyclohexa-
Ketamine is a derivative of phencyclidine (PCP).
none (methoxetamine) was one of the first to be
Both these substances and their analogues are dis-
detected, but this gave rise to methoxphenidine (MXP)
sociative drugs and have been placed in this present
which was one of several NMDA antagonists marketed
text in the ‘depressant’ category for convenience and
to replace methoxetamine (MXE) when this was
because they are predominantly sedative drugs.
controlled.6
Ketamine, however, has a complex neuro-chemical
As with other NPS, new compounds have been
profile, reflecting its actions as a psycho-stimulant,
developed to replace those which become controlled.
dissociative, anaesthetic and analgesic substance,
For example, methoxetamine was introduced as an
with amnestic properties.
alternative to ketamine, to be followed by methoxphe-
Ketamine can also distort perceptions of sight and
nidine (MXP), which was one of several NMDA ant-
sound and create feelings of detachment from the self
agonists marketed in 2013 to replace the compound
and the environment. It can also be associated with
methoxetamine (MXE) which became a controlled
hallucinogenic effects.
substance.
Drugs with dissociative effects act primarily as
Similarly, substituted analogues to ketamine, dex-
non-competitive antagonists at glutamate receptors
tromethorphan (DXM), and phencyclidine (PCP)
of the N-methyl-D-aspartate (NMDA). One of their
3-methoxy-PCP (3-MeO-PCP), 4-MeO-PCP (also
prominent effects is depersonalisation, or an
101
Ketamine and Other Novel Psychoactive Substances with Dissociative Effects
known as ‘methoxydine’), diphenidine, and methox- NMDA receptors.14,15 Ketamine also acts at dopa-
phenidine (MXP, 2-MeO-diphenidine) have emerged mine D2 and 5-HT2A receptors and the activation
on the NPS market as legal alternatives to the classical of 5-HT2A receptors is thought to be related to per-
banned dissociatives.7,8,9,10,11,12,13,14,15,16,17,18 ceptual disorders and hallucinations. Ketamine also
shows affinity for mu, delta, and sigma opioid recep-
6.2 Street Names tors and affects monoamine transporters.21
Like phencyclidine (PCP), ketamine stimulates the
Street names of illicit ketamine will differ between
vital functions of heartbeat and respiration, though it
countries and languages. They include, but are not
is less toxic and shorter acting than PCP.22 The term
limited to: K, Ket, Special K, Kit-Kat, Cat Valium,
‘dissociative’ suggests that sensory loss and analgesia,
Super K and Vitamin K.
as well as amnesia, are not accompanied by actual loss
Street names for methoxetamine include: M-ket,
of consciousness.23
K-max, Mexxy, MXE powder, Special M and METH-O.
As a dissociative anaesthetic, ketamine has the
capacity to induce narcosis and narcosis-like states
6.3 Legal Status in which consciousness appears to be separated from
Ketamine has been widely used in human and veter- the body.14 Its use can lead to a trance-like cataleptic
inary medicine and is listed as an essential medicine state, unconsciousness, amnesia and deep analgesia,
by the World Health Organization (WHO).19 but with intact ocular, laryngeal and pharyngeal
Because of the spread of its non-medical use and of reflexes.15 Ketamine impairs psychomotor perform-
counterfeit manufacturing, ketamine is a Schedule III ance in a dose-dependent fashion.
substance.20 Ketamine has a plasma half-life of 2–4 hours.24
Methoxetamine (MXE) is controlled in Schedule Peak plasma concentrations are reached within
II of the 1971 Convention, but derivatives such as a minute when ketamine is injected intravenously,
3-MeO-PCE and 4-MeO-PCP are not under inter- 5–15 minutes when injected intramuscularly or
national control. snorted, and 4–6 hours when taken orally.16,17
Enzyme kinetic studies have shown that for keta-
6.4 Quality of the Research Evidence mine the initial metabolic steps in humans (N-de-
In comparison with other club drugs and NPS, the ethylation) are catalysed by CYP2B6 and CYP3A4.
international evidence on the management of the Therefore, caution should be addressed when co-
acute and chronic harms related to the use of keta- administered orally with CYP3A4 and CYP2B6
mine in a clinical context is relatively wide and inhibitors (such as ritonavir and cobicistat).18,25
includes studies of healthy volunteers and animal Methoxetamine, which is 2-(3-methoxyphenyl)-
studies. In contrast, the evidence on the harms associ- 2-(ethylamino)cyclohexanone, is an analogue of keta-
ated with the misuse of ketamine and use in mine. It has and can be classified as a dissociative
a recreational context is more limited and less robust. drug.26 Its analogues are 1-[1-(3-methoxyphenyl)
The evidence regarding ketamine analogues is cyclohexyl]-piperidine (methoxyphencyclidine;
very limited. 3-MeO-PCP) and N-ethyl-1- phenylcyclohexylamine
(eticyclidine).
Methoxetamine was detected on drug markets
6.5 Brief Summary of Pharmacology in 2010 and was synthesised as a close structural
Ketamine is a predominantly sedative drug, but its analogue of ketamine in order to elude the classi-
complex neurochemical profile reflects its actions as fication of ketamine while retaining its psycho-
a dissociative, anaesthetic, psychostimulant and anal- active properties.27 Because of its structural
gesic substance.21 similarities to PCP and ketamine, it has been
Ketamine is a non-competitive N-methyl- assumed that the effects of methoxetamine are
D-aspartate (NMDA) receptor antagonist that acts as
broadly similar.28
a dissociative anaesthetic with analgesic and amnestic Methoxetamine is both a dopamine reuptake
properties. Ketamine is a derivative of phencyclidine inhibitor and an NMDA receptor blocker; its affinity
(PCP) and is, as are its analogues, an arylcyclohexyla- for the NMDA receptor is comparable to or higher
mine. This is a miscellaneous group of dissociative than that of ketamine. In addition, methoxetamine (in
anesthetic-type substances, acting by antagonism on
102
6.8 Ketamine Use and High-Risk Sexual and Injecting Behaviours
addition to PCP and its analogues) has affinity for the duration of action.61 It has also been argued that as an
serotonin transporters.29 analogue of ketamine, it could be of pharmaceutical
Methoxetamine has more potency and higher opi- interest for treatment-resistant depression if it were to
oid receptor affinity than phencyclidine and weaker show rapid antidepressant properties similar to those of
analgesic and anaesthetic effects, but longer duration ketamine.62,63,64 There is limited evidence that metham-
of action, than ketamine.30,31,32,33 phetamine analogues (N-ethylnorketamine hydrochlor-
Methoxetamine has been marketed to drug users as ide (NENK), 2-MeO-N-ethylketamine hydrochloride
much more powerful and as having longer-lasting (2-MeO-NEK), and 4-MeO-N-ethylketamine hydro-
effects than ketamine. The psychoactive effects should chloride (4-MeO-NEK)) elicit rapid antidepressant
be anticipated to last longer than would be expected for effects via activation of AMPA and 5-HT2 receptors.65
ketamine.28
It was originally claimed that methoxetamine is 6.7 Prevalence and Patterns of Use
a ‘bladder-friendly’ alternative to ketamine, and some
The recreational use of ketamine has been character-
users believed that methoxetamine was less damaging
ised by the EMCDDA as having ‘potential for more
to their kidneys as well as their bladder than
widespread diffusion’.66 The Global Drug Survey 2019
ketamine.34,35,36,37 However, there is now evidence
reported that darknet purchases of ketamine have
that this is not the case. Studies indicate that high-
increased over the last 5 years.67
dose, chronic administration of methoxetamine
The recreational use of ketamine has been reported
induces urinary toxicity that is comparable to that
among subgroups of drug users in Europe for the last
induced by ketamine.38
two decades. However, national estimates, where they
exist, show that the prevalence of its use in adult and
6.6 Medical Uses of Ketamine school populations remains low. In 2017, last year
Ketamine is used as an anaesthetic and a powerful prevalence of ketamine use among young adults (16–
analgesic, particularly in paediatric, emergency medi- 34) was estimated at 0.6% in Denmark and 1.7% in the
cine and veterinary medicine, and is considered as UK.68
a safe battlefield anaesthetic due to its pharmaco- There is some evidence that initiation in ketamine
logical profile. It also has a medical role in the man- use may take place at a slightly older age than for other
agement of pain in both humans and animals, substances, and that it is possible more experienced
including as an analgesic in chronic cancer pain (pal- users add ketamine to their poly-use repertoire.69
liative care) and non-cancer pain.39,40 Research carried out in the US, England and
Ketamine has also been used for the treatment of Australia suggests that ketamine users tend to be
substance misuse disorders, including alcohol, cocaine, white, male, urban and under 30 years old.70,71,72,73
cannabis, and opioid use and there is limited evidence Ketamine used for recreational purposes is typ-
that that ketamine may facilitate abstinence across mul- ically made in clandestine laboratories, but can
tiple substances.41 More recently, a number of studies also be diverted from licit channels.74,75 It is usu-
have investigated the role of ketamine in treatment- ally sold as ketamine, but in countries such as
resistant depression and major depressive disorders, Indonesia and Thailand, ketamine may also be
whereby positive and encouraging outcomes have been sold to unwitting users as ‘ecstasy’ or metham-
reported.42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58 phetamine tablets.76
Nonetheless, concerns have been voiced over the Ketamine is typically used intra-nasally, by insuf-
medical use of ketamine for chronic conditions flation. It is rarely injected. A study conducted in
because of its toxic effects, especially associated with Scotland, for example, found that ketamine was
very high doses for prolonged periods of time. injected by only 0.9% of users.77
Recommendations for adequate monitoring of
patients have been made.59,60 6.8 Ketamine Use and High-Risk
There are currently no clinical or non-clinical
legitimate uses of methoxetamine. Some have argued Sexual and Injecting Behaviours
however that because of its similarity to ketamine, Like other club drugs, ketamine is used as part of
methoxetamine may have some analgesic or anti- a socially active lifestyle and is associated with elevated,
nociceptive properties, with enhanced potency and even pronounced, sexual health risks.78
103
Ketamine is associated with an increased incidence Illicit ketamine for recreational use is often sold as
of unsafe sex among gay men.79,80,81,82 A US study of a powder of fine crystal and is crushed for insufflation.
gay and bisexual men attending ‘circuit parties’ in It is usually white or transparent but can also be off-
three cities found that over 60% had used ketamine white or brown. In some countries such as the UK for
at parties in the past year and unsafe sexual behaviour example, doses for recreational use are often meas-
was associated with frequent ketamine use.81 ured as the quantity of powder that fits on the tip of
There have also been reported cases of sexual a domestic key, a method therefore known as ‘keying’.
dysfunction associated with ketamine abuse.83,84 Ketamine is sometimes sold in tablet form (in
As mentioned above, ketamine is rarely injected which form it is on occasion falsely sold to users as
(typically being taken intra-nasally) but some use by ecstasy). Ketamine is sometimes dissolved for inject-
injection has been reported. Laukenau et al. studied ing and then has a faster and more potent effect.
young ketamine injectors in US cities and described Ketamine is rarely taken orally, as it will then be
two types of ketamine injectors with different demo- metabolised into norketamine, which produces
graphic profiles: experienced injecting drug users a sedative effect rather than the desired effect. It can
(IDUs), who injected a number of drugs and who also be smoked, used rectally90,91 or swallowed in
tended to be homeless youth and homeless a wrap of paper.
travellers;85,86 and new IDUs, who initiated injecting The onset of the effects of ketamine is likely to
with ketamine and tended to have stable housing and occur approximately 5 minutes (but up to 30
who associated with others who used ketamine.86 minutes) after insufflation, the most common
There is also some anecdotal evidence which sug- form of use. Effects occur in a matter of seconds
gests that it is possible that a minority of older inject- or minutes after injection, smoking and smoke
ing opiate drug users also inject ketamine86,87 and that inhalation. This rapid onset of effect is thought to
ketamine is sometimes injected.88,89 increase its potential for misuse. The effects them-
In interviews with ketamine injectors, subjects selves are generally short-lived, typically lasting 1–4
reported the advantages of injecting over snorting: hours,92 depending on dose, tolerance, individual
sniffing aggravated the nasal passage and injecting pro- factors and other drugs ingested. This short dur-
duced what was referred to as a ‘cleaner’ high. Those ation of effect may promote bingeing; ketamine
who developed tolerance from sniffing found that users in a session will typically self-administer
injecting was a more potent and reliable mode of several doses in order to maintain psychotropic
ingestion.86 Most reported that the main reason for effects over time,93 until supplies are exhausted.94,95
injecting was to achieve the ‘k-hole’ (where the user On the other hand, the short duration of effects may
experiences feelings of detachment and perceptions also increase its appeal over longer-lasting
appear divorced from reality), which was more reliably hallucinogens.69
achieved and intensely experienced by injecting.86 A typical recreational dose is approximately 10–
Among those who injected ketamine only, a study 25% of the effective general anaesthetic dose.15 Single
has shown intramuscular injecting was more com- doses for intranasal use vary widely.15,95,96 The small
mon than intravenous injecting. Injecting ketamine number of specialist treatment services offering spe-
was shown to be associated with high-risk behaviours. cific treatment to ketamine users report that most of
Multiple injections were typical, for example eight to their patients use ketamine most days or every day
ten injections over several hours.86 and use up to several grams per day.40 The highest
dose noted in a series of 60 patients attending three
6.9 Routes of Ingestion, Dosing clinical urology centres for a ketamine-related uro-
logical syndrome was 20 grams per day.97
and Frequency of Dosing
6.9.2 Methoxetamine
6.9.1 Ketamine Methoxetamine is generally sold as a white crystal pow-
Illicit ketamine is mainly in powder form, typically der, but can be found in tablet form. It is generally used
sold in gram doses. It is less frequently available as by insufflation, but can be used rectally, by sublingual
a liquid, in which form it is possibly diverted from application and by injection (intramuscular mainly, but
pharmaceutical supplies. also intravenous).28,98 It is also used orally, usually
104
6.10 Desired Effects for Recreational Use
swallowed in a cigarette paper, or as tablets. The range associated with the use of dissociative drugs, as well
of doses reported is 20–100 mg for oral administration as a higher endorsement of the coping motive.108
and 10–50 mg for intramuscular injection.23,28,98 According to Teltzrow et al., ketamine has charac-
The onset of the effects of methoxetamine have teristic subjective effects which differ according to
been described to start 10–20 minutes after individual and setting of use.109
ingestion,98 but can be delayed by 30–90 minutes Overall, however, it can produce a range of experi-
after insufflation.23 ences, depending on dose110:
One of the most significant differences between • At low doses, ketamine produces distortion of
ketamine and methoxetamine appears to be the much time and space, visual and auditory hallucinations
slower onset of action of the latter (up to 90 and mild dissociative effects.111 It also has
minutes).99,100,101 It is suspected to sometimes lead to stimulant-type properties.112
repeated dosing and to inadvertent excessive dosing by • At high doses, it produces more severe
people who think that their drug has had no effect.102 dissociation, known by some users as the ‘K-hole’,
This may lead to unintentional overdose103 as users may where the user experiences feelings of intense
ingest a second dose thinking that the first dose was detachment and perceptions appear completely
inadequate. Compulsive re-dosing has also been divorced from reality.111 With higher doses of
described.92 The effects after intramuscular injection ketamine, dissociative and hallucinogenic effects
are faster, with onset after approximately 5 minutes.92 become the primary experience and the effect of
The effects of methoxetamine last for approxi- the environment diminishes. Auditory
mately 1–7 hours, depending on the route of hallucinations are fairly rare following ketamine
administration.104 Drug user websites investigated use and have been reported much less
by Corazza et al. stated that the duration of action of consistently.113
methoxetamine ranges from 5 to 7 hours when insuf-
Ketamine has been described as able to induce
flated, less (approximately 1 hour) when administered
a ‘raft’ of intense experiences, including some that
by intramuscular injection.64
can be characterised as positive and negative psych-
Powders and tablets sold as methoxetamine have
otic-like features.114 It is dissociative inasmuch as it
been found typically to include a range of other com-
causes users to feel both sedated and separate from
pounds and adulterants, including mephedrone, caf-
their bodies.86
feine and cocaine.105
The combination of effects of ketamine has been
Newer analogues of ketamine and PCP, such as
described by some as ‘alcohol-like intoxication,
dextromethorphan (DXM), 3-methoxy-PCP (3-MeO-
cocaine-like stimulation, opiate-like calming, and
PCP), 4-MeO-PCP, the methoxylated analogues of
cannabis-like imagery’.115 Moore et al. referred to
PCP 3- and 4-MeO-PCP, 1,2-diarylethylamines,
the ‘playful’ effect of ketamine, in that it leads to
have also been sold as ‘legal highs’ in a number of
improved moods and a child-like state. The intensity
different forms including powders and tablets.106
of ketamine was also emphasised.69 Its effects include
euphoria, depersonalisation and derealisation, feel-
6.10 Desired Effects for Recreational ings of universal empathy and experiencing synaes-
Use thesia (combinations of sense experiences such as
sound and colour).116
Ketamine users also report that it enhances cre-
6.10.1 Ketamine ativity and that it is used to manage the ‘come-down’
The mind-altering effects of ketamine make it attract- from other drugs, such as stimulants.
ive to some drug users, along with its lack of hangover, Ketamine users often experience floating sensa-
short duration and relatively low cost. One of the tions, sensory distortions and transcendental phe-
earliest studies on the recreational use of ketamine nomena, such as mystical insight, spiritual trips,
found that users perceived it as a safe and potent revelations or alternative realities.111 Ketamine is
hallucinogen with short duration of action and an sought by some because it induces a ‘separate reality’,
equal balance of positive and negative effects.107 ‘near death’, ‘lack of fear of death’ and out-of-body
It has been argued by Benschop et al. (2000), that experiences.117 States similar to those reported as
the expansion and coping motives were also near-death experiences have been described and
105
include altered perceptions of time, a strong sense of distorted sense of reality, vivid hallucinations, dereal-
detachment from the physical body and a sense of isation, introspection, brief antidepressant effects,
peace and joy.118 feelings of peacefulness and calmness, and spiritual
There are individual variations in motivations to and transcendental experiences.123 Other desired
use ketamine, as well as in what constitutes desired or effects include euphoria, feelings of peacefulness,
unwanted effects. These have been described by increased empathy and social interaction and a sense
a study as revolving around axes of sociability and of going deeper inside the self.124 It is also associated
intensity, with control over effect being an important with sensory deprivation and dissociation from the
concept. The voluntary versus involuntary entry into physical body, which are all features of a ‘near-death
the K-hole69 is a salient example: for some it is too experience’ and part of the desired effects of
intense; for others it is a desired journey or place. methoxetamine.125,126 It has been reported that
Interviews with users suggest that the dose is a key a sense of empowerment occurs in the afterglow
point of control, which users associate with the possi- experience.127
bility of negative or positive consequences of keta- The effects of methoxetamine are linked to mode
mine use. of ingestion. Typically, it works as a short-acting
It has been reported that some users ‘test’ doses of mood enhancer, with powerful visual hallucinogenic
ketamine to assess the strength of batches69 and then and dissociative properties. The desired effects
adjust doses for desired effects. Self-administration of include euphoria, empathy, ‘cosiness’, intensification
titrated ketamine is attempted by users to achieve the of sensory experiences, especially while listening to
desired amount of dissociative sensation, hallucin- music, a mild to strong sense of dissociation, distor-
ation and transcendental experience.107 tion of the sense of reality, vivid hallucinations, intro-
In addition to dose used, the frequency of use and spection and brief antidepressant effects.23 An
past exposure have been self-reported as influencing ‘M-hole’ has been described by users, typically refer-
the experience. In a study of recreational users, 58% ring to a subjective state of dissociation, which mimics
interviewed said they had experienced the K-hole and the out-of-body experiences of near-death
that this was related to increased exposure to the drug experiences,118,128 and is often accompanied by feel-
(more than 20 times).71 ings of derealisation, depersonalisation and disorien-
Ketamine is also used for self-medication for tation, as well as vivid hallucinations.
depression and studies are currently being con- There are also user reports that at high doses
ducted to examine its antidepressant action. There (>40 mg), methoxetamine can produce a wide range
is also anecdotal evidence that it is also used as self- of unwanted effects including out-of-body or near-
medication for sleep and anxiety. Anecdotal death experience, reduced ability to concentrate and
evidence also suggests that it is commonly used by focus, psychomotor agitation, intense dissociative
men who have sex with men for some forms of anal and hallucinogenic experiences, paranoia, anxiety
sex because of its anaesthetic and muscle-relaxing and distortions in the perception of time, distance,
effects. proportion and body image.129,130,131
6.10.2 Methoxetamine 6.11 Acute Ketamine Toxicity

Reports from users suggest that methoxetamine pro- In comparison with other drugs, ketamine in itself has
duces ketamine-like effects, but is more powerful and a wide margin of safety,132 but the use of illicit keta-
longer-lasting than ketamine (but less so than mine is not risk-free and ketamine is often co-ingested
PCP).23,28,119,120 Methoxetamine is linked to with other substances, which increases both its asso-
increased psychological effects (both desired and ciated harms and those of other substances. It also
adverse) and increased toxicity compared with gives rise to a greater risk of accidents (see
ketamine.121 Section 6.11.3) and chronic use can lead to urological
Methoxetamine produced dissociative and stimu- problems, which can be severe (see Section 6.14.4).
lant wave outcome often lasting for days.122 Effects Nevertheless, ketamine is characterised by its
described by users include euphoria, enhanced ability to cause unconsciousness, amnesia and anal-
empathy and social interaction, pleasant intensifica- gesia, while sparing airway reflexes and maintaining
tion of sensory experiences (especially music), haemodynamic stability.15 Coughing and swallowing
106
6.11 Acute Ketamine Toxicity
reflexes are maintained with minor suppression of the Box 6.1 Analogues and Derivatives
gag reflex, even when a user is very intoxicated, thus of Ketamine and Phencyclidine
reducing the potential risk for users, if ketamine is
used on its own.132 Ketamine is the most commonly used drug with
The Morgan and Curran review suggests a lack of dissociative effects, followed to some extent by
severe acute physical health consequences, with no methoxetamine.
adverse outcome reported from large overdose, There are nonetheless a number of other NPS
arylcyclohexylamine substances that have been
where no other substances are co-ingested.132
notified to the Early Warning System in Europe. Like
The main features of acute intoxication associated
ketamine and its analogues, they are NMDA receptor
with ketamine are related to its psychoactive, dissocia- antagonists. NPS with dissociative effects include:
tive and hallucinogenic properties. In humans, a single
• 2-methoxyketamine
dose of ketamine induces dose-dependent impairments
• N-ethylnorketamine
in working and episodic memory, which can have
a profound effect on the user’s ability to function.133 • 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)
Ketamine is associated with direct neurotoxicity and can • 4-MeO-PCP
cause acute neuropsychiatric effects, such as agitation or • cyclohexanamine
ketamine-related psychotic states. Often clinical features • 1-[1-(3-methoxyphenyl) cyclohexyl]piperidine
when people present to hospital are related to physical • 4-methoxyphencyclidine (4-MeO-PCP)
harm (e.g. agitation or accidents), and behaviours • 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine
resulting from dissociative effects. -N-ethyl norketamine
However, systemic toxicity with cardiovascular
• N-ethylketamine
effects can occur and can be severe. Ketamine is
• tiletamine
a mild respiratory depressant, but its effects with
• dextromethorphan
clinical dose on the cardiovascular system are min-
imal and unusual for respiratory effects to occur. • N-ethyl norketamine
However, with recreational doses, especially higher • diphenidine (1-(1,2-diphenylethyl)piperidine)
doses, ketamine may increase heart rate, cardiac out- • methoxphenidine (MXP, 2-MeO-diphenidine)
put, and blood pressure,132,134 with a study reporting • 2-oxo-PCE
that tachycardia is the most common reason for pres- • 2-(3-methoxyphenyl)-2-(propylamino)
entation to emergency departments by recreational cyclohexan-1-one (methoxpropamine)
ketamine users.135 It has been suggested that the
stimulating effects of ketamine on the cardiovascular
system may have implications for recreational users (45%), abdominal pain (21%), lower urinary tract
with pre-existing cardiac issues or hypertension.136 symptoms (12%) and dizziness (12%). The most com-
This will present a risk for people with hypertension mon physical symptoms included high blood pressure
or severe cardiac disease, and people at risk of stroke (40%), tachycardia (39%), abdominal tenderness
and raised intracranial pressure. Risks are increased (18%) and chest discomfort and palpitations (11%).
with co-ingestion of stimulants132 and should be However, no patient had serious cardiovascular com-
emphasised in harm reduction messages (Section 6.16). plications (e.g. myocardial infarction or significant
arrhythmias).
6.11.1 Features of Acute Ketamine In that study, 46% of patients had a period of altered
consciousness at some point after ketamine ingestion.
Toxicity137 This effect of ketamine was short-live; however, only
The reported acute effects of ketamine use are sum- 14% of the patients had a score on the Glasgow Coma
marised in Box 6.1. Scale of less than 15 when examined in hospital. Among
Case reports provide some insight into how com- patients who had blood tests performed, leukocytosis (in
mon these ketamine-related effects are. In a study by 36%) and a raised creatinine kinase level (in 32%) were
Ng et al.138 which reviewed 233 cases of presentations the most common abnormalities, whereas 16% had
to an emergency department, the most common pre- abnormal liver function test results and 3% had abnor-
senting symptoms were: impaired consciousness mal renal function test results. Most of the patients were
107
Box 6.2 The Reported Acute Effects of Ketamine Use

Dermatological
Transient rash, predominantly in face and neck
Gastrointestinal
Nausea
Vomiting
Neurobehavioural Effects/Psychiatric Effects107,133,139

Hallucinations (visual and auditory)
Slurred speech
Dizziness
Numbness
Confusion
Blurred vision
Insomnia
Decreased sexual motivation
Cognitive impairment
Aggression
Paranoia and display of dissociative-type symptoms
Ataxia
Dystonia
Agitation (agitated patients are at risk of other effects including hyperthermia, rhabdomyolysis, self-injury,
enhanced perception, depersonalisation, movement disorders and confusion)
Paralysis and muscle rigidity
Ketamine-related psychotic states (typically short-lived with complete resolution).114,140 Among patients with
schizophrenia stabilised on an antipsychotic, however, ketamine can cause a relapse of psychotic symptoms,141
which are idiosyncratic to those each individual exhibited during the acute phase of their illness142,143
Delirium
Polyneuropathy
Seizures
Convulsions
Cardiovascular and Respiratory144,145,146

Self-resolving sinus tachycardia (most commonly reported)
Hypertension (common)
Chest pain
Palpitation
Transient major Brugada ECG patterns (one case report)
Raised intracranial pressure
Pulmonary oedema
Respiratory depression
Cardiac and respiratory arrest
Increased muscle tone and activity may produce hyperpyrexia
108
6.11 Acute Ketamine Toxicity
managed solely in the emergency department (72%) and Box 6.3 3- and/or 4-MeO-PCP
85% had no or only minor complaints.138
It has been reported by the STRIDA Project that the
6.11.2 Methoxetamine adverse effects noted in acute intoxications
involving 3- and/or 4-MeOPCP resembled those of
The effects of methoxetamine are dose dependent and classical dissociatives such as PCP, ketamine and
include mild euphoria, depersonalisation, de-realisation methoxetamine.160
hallucinations, disorientation, confusion, vertigo, drow- 3-MeO-PCP is expected to elicit effects similar to
siness, incoordination/falls, slurred speech, anxiety, other NMDA antagonists,161,162,163 but half-life was
reduced ability to focus and concentrate, analgesia, approximately 11 hours.164 Activity is reported to
numbness, anxiety, impaired motor coordination, agita- begin at doses as low as 5 mg.165,166,167
tion, aggression, loss of consciousness, amnesia and As with PCP, low doses are associated with
catatonia. anxiety, muscle tremors, drowsiness and
Unwanted effects include vomiting, diarrhoea, hallucinations and higher doses have the potential to
cause violent behaviour, tachycardia, hyperthermia,
insomnia, agitation, sweating, catatonia and hypertonia.
suicidal impulses, seizure or coma. At higher doses,
They also include dysphoria, psychomotor agitation,
individuals may also experience pulmonary aspiration
vertical nystagmus, labile mood and dissociative confu- or cardiovascular collapse, as with PCP.168,169,170
sion, including partial amnesia to the preceding The most common features of acute toxicity
events.147 have been reported to be tachycardia and
Methoxetamine seems to have more severe side- hypertension followed by an altered mental
effects than ketamine.92 It has been argued that the status.171,172 Delayed verbal responses to questions
acute methoxetamine toxidrome can be roughly div- and ataxia have also been reported.173
ided into three types of symptoms: dissociative/deliri- A study presents two cases of intoxication due to
ous, sympathomimetic and cerebellar.148 consumption of 3-MeO-PCP and alcohol, respiratory
Initial presentations to hospital generally acidosis, right anisocoria with mydriatic pupils and
hypothermia. The patients were intubated for 7–
involve loss of consciousness, incoordination with
8 hours. Almost 24 hours after hospitalisation, they
falls, agitation and aggression, and audio-visual
were still in a delirious and agitated status.174
hallucinations and delusions. It has been suggested
that it was common at initial presentation for men-
tal status to fluctuate between comatose, confusion,
and agitation and aggression.148 People have pre- also been associated with pyrexia, tachypnea, ele-
sented at hospital with methoxetamine intoxication vated creatine kinase, tremor, as well as depressive
with impaired consciousness and coma.149 thoughts and suicide attempts.28,157,158,159
Methoxetamine can cause rapid onset of neuro-
logical impairment, characterised by acute cerebel- 6.11.3 Acute Withdrawal
lar toxicity.149 Reversible cerebellar impairment has For withdrawal see Section 6.13.2.
also been reported,150 but recovery could extend
over several days.149 Cerebellar ataxia, incoordin- 6.11.4 Poly-drug Use: Complicating
ation, dysarthria and tremor have been
reported.28,149,151,152 There are also cases reporting Factors for Acute Toxicity
truncal ataxia, dysarthria and nystagmus (horizon- Acute ketamine toxicity, or toxicity associated with
tal, vertical and rotary).153 all arylcyclohexylamines, is often complicated by
Although there is limited research, cognitive poly-drug use, which is common. In one study of
impairment has also been reported,105and there are attenders at an emergency department, 89% of
a small number of cases of acute methoxetamine self-reported ketamine users stated that they had
causing cerebellar toxicity154 and cases of dissociation used another drug and/or alcohol.144 It is therefore
and catatonia.155 recommended that when people present with acute
Methoxetamine has greater effects than ketamine toxicity after ketamine use, clinicians consider the
in terms of hypertension and other stimulant-like possible impact of other drugs ingested.15 Poly-
effects, including agitation, tachycardia, hypertension drug use has also been implicated in death (see
and cerebellar features, such as ataxia.105,153,156 It has Section 6.10).
109
Box 6.4 Methoxphenidine and Diphenidine Box 6.5 2-oxo-PCE
Methoxphenidine (2-MXP; (±)-1-[1-(2-methoxyphenyl)- 2-oxo-PCE is another ketamine analogue. Its adverse

2-phnylethyl] piperidine; 2-Meo-diphenidine) 2-MXP, is effects are similar to those of ketamine, but are
a structural analogue of diephenidine and was potentially more toxic, which led to it being
introduced in the market as the replacement to described as ‘a dangerous emerging
methoxetamine (MXE). Anecdotal reports suggest arylcyclohexylamine analogue’.187 A report of
2-MXP has greater oral potency and effects reported a cluster of 56 cases of 2-oxo-PCE-associated acute
online by users suggest that it may have a dopamine poisoning between October and November 2017
reuptake inhibitor action.175 showed that the main clinical symptoms associated
The Swedish STRIDA study investigated cases of with sole 2-oxo-PCE use include impaired
diphenidine (n=14) and methoxphenidine176 (n=3) consciousness (84%), confusion (60%), abnormal
toxicity, which were reported to involve high levels of behaviour (44%), hypertension (80%) and
polyuse. The adverse effects noted in analytically tachycardia (40%). Convulsion (16%) was also
confirmed cases were similar to those reported for observed relatively frequently.188
other dissociative substances such as ketamine and
methoxetamine, a fact also noted by other
studies.177,178
Symptoms of toxicity reported commonly respiratory depression. Concurrent use of diazepam
include hypertension (76%), tachycardia (47%), or other benzodiazepines will increase plasma levels
anxiety (65%), and altered mental state (65%) and reduce the clearance rate of ketamine.190
including confusion, disorientation, dissociation, A retrospective study of all Australian cases in
and/or hallucinations. Just under half of cases (n=8) which self-administered ketamine was a mechanism
displayed severe intoxication. However, the high contributory to death in 2000–2019 reported that
proportion of polysubstance use might have played other drugs were detected in 95.5% of cases. The
a role in the intoxication and clinical features in some
study reported that pulmonary oedema was present
cases.179 Other studies and case reports have
in 82.2% of cases that underwent autopsy and pneu-
mentioned the same symptoms180,181,182,183
Other features of methoxphenidine described in monia in 26.7%.191
case reports also include symptoms such as, It has also been noted that deaths from ketamine
echolalia, confusion, agitation, opisthotonus, alone could have been associated with the increased
nystagmus and amnesia were consistent with likelihood of accidents caused by the drug’s dissocia-
phencyclidine-induced adverse effects.184 A case of tive effects.128 The effects of ketamine, notably
severe rhabdomyolysis and acute kidney injury a reduced awareness of risk, a reduced perception of
associated with methoxphenidine has also been pain, a lack of coordination, a temporary paralysis and
published.185 According to online drug users, it can an inability to speak, would put users at significant
induce dissociation, visual effects and seems to be risk of injury or accidents. Although some argued that
associated with seizures at heavy dosages.186
the highest risk of mortality from ketamine is through
accidental death when intoxicated,91,192 but evidence
to support this is limited at present and more research
6.11.5 Mortality is needed.82
In terms of recreational use, fatalities solely linked to
ketamine toxicity are relatively uncommon, but can
happen. Ketamine-related deaths have been reported
6.11.5.1 Methoxetamine and Other
in adults using high doses189 after intravenous doses Dissociative Novel Psychoactive Substances
of 500–1,000 mg.74,75 Fatal and non-fatal intoxication associated with meth-
Deaths where ketamine is implicated, typically – oxetamine has been reported.193 This was often asso-
but not always – involve the co-consumption of ciated with hyperthermia and/or the presence of other
another additional substance, suggesting the particu- drugs.92,194
lar risk is posed by poly-drug use and drug inter- There are also reported deaths associated with 2-
action. For example, the use of ketamine with other Methoxydiphenidine (2-MXP)195,196 and 2-Methoxy
CNS depressants (e.g. alcohol) can potentiate CNS diphenidine.197,198 There are also reports of fatal
depression and/or increase the risk of developing and non-fatal acute intoxication associated
110
6.12 Management of Acute Harms
with 3-MeO-PCP.199,200,201 Also, case reports202 Even in the case of more toxic drugs, such as
associated with 4-methoxyphencyclidine 2-oxo-PCE, most patients will not require intensive
(4-MeO-PCP).203,204,205,206 care. For example, in a cluster of 56 cases, only three
patients required intensive care.208
6.12 Management of Acute Harms Although randomised controlled trials and other
robust studies are not available, there is consistency in
case reports and series that patients are best managed
6.12.1 Identification and Assessment with:
of Acute Toxicity • Standard supportive care, with special attention to
Diagnosis of acute ketamine, or other arylcyclo- cardiac and respiratory functions, as the effects of
hexylamine intoxication in an emergency depart- the drug are usually short-lived;15,145,209
ment setting should be made on clinical • Benzodiazepines may be required;
assessment and the recognition of the clinical • Consideration of other causes for clinical
effects of ketamine, also taking into account the presentation, for example co-ingestion of other
common co-ingestion of a number of substances, psychoactive drugs, head injury, hypoglycaemia
including alcohol. etc.
A case series of US emergency department pres- • Removal of the person from auditory and visual
entations suggested that the diagnosis of ketamine stimulation until symptoms resolve has been
should be considered when people (especially young recommended. A quiet environment, with
people) present with agitation, tachycardia and either minimal external stimuli, may prevent excessive
visual hallucinations or nystagmus, although the agitation.15
absence of the latter two findings does not rule out Observation of the patient until vital signs and mental
the possibility of ketamine misuse. The authors also state have normalised is also recommended. If symp-
recommend that if symptoms are not improving, they toms fail to improve within an hour of presentation,
should investigate other drugs co-ingested or another the diagnosis and the management should be
differential diagnosis.145 reviewed.15,145 Profoundly obtunded (altered level of
Because the onset of the effects of ketamine is consciousness) patients may require airway support,
rapid and effects are generally short-lived, people intravenous fluids and titrated benzodiazepine ther-
will typically develop adverse effects in the setting apy if they are agitated, hyperthermic or show overt
where the drug was ingested, and symptoms may sympathomimetic signs.138
resolve before they reach hospital. Indeed, some A study of presentations at a Hong Kong emer-
night clubs provide a room or area where unwell gency department138 reported that most of the
users of club drugs are initially assessed and managed patients (197/233; 85%) developed no or only
prior to transfer to hospital, if required.207 minor complications. The majority (168/233;
This is not the case for all arylcyclohexylamine. 72%) were safely managed in the emergency
The effects of other ketamine and PCP NPS analogues department with supportive measures, including
can last longer, as mentioned previously. intravenous fluid and benzodiazepines for agita-
tion. The five patients requiring management in
6.12.2 Clinical Management of Acute an intensive care setting had all co-ingested other
Toxicity drugs that could have contributed to their clinical
status.138
No antidote exists for ketamine overdose. The effects
As for ketamine, in the management of acute
of ketamine are not reversed by naloxone and no
methoxetamine intoxication, observation and symp-
other agents are available to reverse the effect in
tom-directed supportive care28 are recommended;
humans.24Activated charcoal is not necessary after
cardiovascular and respiratory support is sometimes
ketamine acute intoxication, unless there is evidence
needed. In case reports, spontaneous recovery was
that a co-ingestant may be contributing to the
observed, but the duration of recovery may extend to
patient’s symptoms or, in the case of a large ingestion,
several days, as for example in a case whereby the
if the patient presents very early. Most patients will
patient’s features of cerebellar toxicity persisted for
improve rapidly following acute ketamine toxicity.15
3–4 days before gradual recovery.210
111
As there are at present no specific management whilst three patients required intensive care. All
recommendations for acute methoxetamine toxicity patients were described as having recovered
and in light of the similarities with PCP and ketamine uneventfully.217 For all these substances, there are
both in terms of pharmacology and clinical presenta- however some cases of fatalities associated with
tion, Craig et al. (2014) suggested that it would be acute toxicity as discussed previously.
reasonable to treat methoxetamine toxicity similarly
to ketamine.211 For up-to-date guidance on the management of
Case reports show that oral benzodiazepines acute toxicity induced by ketamine, its analogues and
are commonly prescribed. Other symptomatic pre- other dissociatives, readers must consult their local or
scribing has also been described, such as anti- national guidelines and treatment protocols.
emetics for nausea and vomiting, and intravenous Information should also be sought from the local
fluids to prevent or manage rhabdomyolysis, for or regional National Poisons Information Services. It is
example.212,213 recommended that relevant clinicians and
Low-dose benzodiazepines appear to have been departments are registered to receive these facilities.
sufficient in many cases of methoxetamine acute
intoxication, depending on presentation. For
example, in addition to observation in hospital, one 6.13 Harms Associated with Chronic
report described patients being prescribed a dose of
5 mg of oral diazepam, but another needing 5 mg Ketamine Use
intramuscular of midazolam, to manage agitation, The frequent and long-term recreational use of keta-
confusion and physiological features.214 mine and its analogues has been shown to be associ-
Spontaneous recovery was reported, and many ated with a number of adverse effects including:
patients will recover quickly within 24 hours.
However, not all will do so. The duration of recovery 6.13.1 Ketamine Dependence
may extend to several days, as shown for example in There is evidence that the administration of NMDA
a case report describing a patient with features of receptor agonists, such as ketamine, increases the
cerebellar toxicity which persisted for 3–4 days before release of dopamine in the nucleus accumbens,
gradual recovery.215 which is typically associated with addiction
Based on the analysis of cases of suspected NPS liability.218 There are case reports of ketamine
intoxication originating from the emergency dependence,110,219,220,221 but a lack of large studies,
department or intensive care unit from July 2013 so the incidence is not known.
to March 2015, the STRIA project in Sweden iden- Frequent ketamine use has been associated with
tified nine patients who tested positive for 3-MeO- tolerance. Animal studies222,223 and human studies
PCP, 4-MeO-PCP or both. It reported that the (children undergoing anaesthesia224) have shown
adverse effects noted in acute intoxications involv- a rapid development of tolerance with repeated keta-
ing 3- and/or 4-MeOPCP resembled those of clas- mine dosing. A study of Australian recreational keta-
sical dissociatives such as PCP and ketamine. mine users found that 22% reported physical
Management of toxicity was based on observation tolerance to ketamine.71 Frequent users of recre-
and standard supportive therapy. In addition, ational ketamine report escalating dose, with one
pharmacological treatment with sedatives was case report of a 600% increase from dose at first
reported in 29 (49%) cases. Medical records showed use95and another reported a 760% increase from the
benzodiazepine (primarily diazepam and/or mida- initiation dose.225 Also of concern among frequent
zolam) in 26 (44%), propofol in 13 (22%) and halo- users are the compulsive patterns of behaviour: binge-
peridol in 5 (8%) medical records. Length of stay in ing or using without stopping until supplies run
hospital ranged between 1 and 9 days (mean and out.227
median of 2) days, but most patients (85%) stayed Ketamine is associated with craving and a study
for 1 or 2 days.216 has shown a high prevalence of depression in patients
Similarly, a report of a cluster of 56 cases of 2-oxo- with ketamine dependence, particularly those with
PCE-associated acute poisoning reported that the higher levels of cravings. The authors suggest that
management of acute toxicity was mainly supportive, clients presenting with greater cravings and more
112
6.13 Harms Associated with Chronic Ketamine Use
depression might require a longer duration of with- shaking, sweating, palpitations, tiredness, low appe-
drawal treatment.226 tite and low mood.116
Even less is known about dependence to methox-
6.13.1.1 Methoxetamine etamine and other dissociatives. There are nonethe-
Although this has not been thoroughly investigated, less reports from people who use it that symptoms
there are suggestions that methoxetamine has an following intoxication include low mood, cognitive
abuse liability and addictive effects.227,228 impairment and insomnia. Craving and tolerance
Corazza et al. investigated through their analysis are reported.233
of drug user websites the effects of chronic methox-
etamine use. Withdrawal symptoms were described 6.13.3 Other Harms of Chronic Use
and included low mood and depressive thoughts, cog-
nitive impairment for many hours, as well as insom- of Ketamine
nia and suicide attempts.23
6.13.3.1 Ketamine-Induced Damage to the Urinary
6.13.2 Ketamine Withdrawal Tract
There is conflicting evidence on the existence of Ketamine use is associated with damage to the urinary
a specific ketamine withdrawal syndrome following system, which can be in the form of severe and in
cessation of ketamine use, but a specific ketamine some cases irreversible bladder damage. This has been
withdrawal syndrome has not yet been described.132 referred to as ketamine-induced ulcerative cystitis,132
In a study of 30 daily users, 28 reported having although some have argued that it would be more
tried to stop taking ketamine but failing; all reported appropriate and concise to describe it as ketamine-
ketamine cravings as the reason for failure. The study induced uropathy.234 The mechanism of damage from
also found that 12 of the 30 daily users reported ketamine is not yet clear but the effects, which are not
withdrawal symptoms – anxiety, shaking, sweating specific to the bladder, are most likely to result from
and palpitations.95 Other studies also reported crav- direct toxicity of ketamine or its metabolites. Damage
ing and somatic and psychological symptoms (e.g. can affect the entire urinary tract.97
anxiety) of ketamine withdrawal.116,229,230 The urological syndrome associated with ketamine
Clinical experience suggests that ketamine with- use can lead to severe clinical symptoms:97a small, very
drawal does exist. Although ketamine rarely produces painful bladder, dysuria, painful haematuria, urge
serious withdrawal symptoms, the marked drug toler- incontinence, frequent and urgent urination, nocturia,
ance and psychological dependence might contribute obstruction of the upper urinary tract, papillary
to difficulty in abstaining.231 It has been argued that in necrosis and hepatic dysfunction.97,236,235,236,237
cases of sustained and heavy use, the existence of Auxiliary examination showed cases of patients
a ketamine withdrawal syndrome must be with symptoms including the following: sterile pyuria,
considered.116 contracted bladder (involving chronic inflammation
Although ketamine has a short half-life, metab- with ulceration), erythematous swelling, necrotic
olites are present for some hours and may be mucosa, thin epithelium with neutrophilic and lym-
responsible for continuing symptoms.116 In add- phoplasma cell infiltration in bladder mucosa, colla-
ition, it has also been argued the symptoms of gen and adipose tissue and bladder wall fibrosis with
acute withdrawal may be short-lived and therefore or without vesico-ureteric reflux and involvement of
not identified.232 the upper urinary tract.236 It has also been reported
Nonetheless, case reports have described somatic that high dosage and prolonged exposure to ketamine
and psychological aspects of anxiety as withdrawal and its metabolites results in inflammatory changes,
symptoms.116,231,232 One case report mentioned with- with microvascular damage, ischaemia and
drawal symptoms such as ‘chills’, autonomic arousal, fibrosis.17,238 End-stage renal disease from upper
lacrimation, restlessness, nightmares and psycho- tract obstruction is another potentially severe harm
logical craving, with further ketamine use to relieve which can affect chronic ketamine users.239
these symptoms.232Another described in detail the Cystoscopic inspection of the bladder also often
effects of discontinuation of use on one patient, shows a denuded urothelium, which, in the most
which included craving and drug hunting, anxiety, severe cases, may slough off as intact sheets of cells.
113
There are reports of young patients at an end-stage of and urological symptoms need to have their kidneys
the disease process who required cystectomy (bladder imaged to rule out ureteric strictures.
removal) and reconstruction,97 with a serious impact A study has shown that ketamine bladder problems
on life expectancy. have a considerable impact on those affected. In addition
An analysis of the experiences of people with keta- to pain and physical effects more generally, it is common
mine bladder problems has shown that initial symp- that ketamine bladder problems cause feelings such
toms are normalised due to their progressive nature as embarrassment, uncertainty, anxiety, guilt, self-
and because they are common amongst other keta- loathing and depression. It has also been suggested that
mine users. It is argued that this results in delayed the emotional impact is perhaps further compounded by
help seeking, exacerbates disease progression and fur- participants’ relatively young age and the perceived self-
ther complicates patient management.240 inflicted nature of their condition. The study also shows
It has been reported that 20–30% of ketamine users that advanced symptoms appear to result in behaviour
suffer from lower urinary tract symptoms.227,237 modification, such as staying close to a toilet, and that
A study assessing the prevalence of urinary symptoms this can contribute to social isolation.243
in a large cohort of non-treatment-seeking ketamine Methoxetamine was marketed as a more ‘bladder
users found that harms to the urinary tract are dose- friendly’ drug than ketamine. However, there is emer-
related and are particularly common among regular ging evidence from an animal study that exposure to
and dependent users. Urinary symptoms are associated methoxetamine can induce changes in the kidney and
with an increased frequency of use and increased bladder after daily use, suggesting that chronic use of
amount used per session.40 However, the duration methoxetamine in humans may be associated with
and/or amount of ketamine used to induce lower urin- similar lower urinary tract symptoms, as those
ary tract symptoms is not known. described for chronic ketamine use.244
The time of onset of lower urinary tract symptoms A cross-sectional, anonymous online survey in the
following ketamine misuse varies from a few days to US and UK investigated the prevalence of urinary
a few years following the onset of use, with the severity symptoms in a group of methoxetamine users who
being in part determined by the chronicity of use. Up had also used ketamine at least once in their lifetime.
to 100% of those using more than 5 grams per day Approximately one-quarter of methoxetamine users
report urinary symptoms.241 Because of the severe questioned reported urinary symptoms; however,
bladder pain, users frequently self-medicate for severe previous ketamine use cannot be ruled out as the
pain with ketamine, as the only effective means of pain cause of the symptoms.245
relief they know, thus perpetuating the damage to
their urinary tract.97 6.13.3.2 Gastrointestinal Toxicity
Studies of patients in chronic pain and palliative The use of ketamine has also been linked to gastro-
care receiving pharmacological ketamine suggest intestinal toxicity.246 The intense abdominal pain
individual variations, with some individuals more associated with ketamine use is referred to by users
susceptible than others to ketamine-related urological in some countries as ‘K-cramps’.227
damage.97 Some series have reported a slight male The Ng study of presentations to emergency
predominance, but this is statistically insignificant departments reported that 21% of ketamine patients
and not universally reported.242 At the present time, presented with abdominal pain and 15% had abnormal
it would seem that ketamine-induced vesicopathy liver function.138 More recently, a cross-sectional study
does not exhibit any gender bias.237 of 611 consecutive patients who were seeking treatment
There is also a link between chronic ketamine use and for ketamine uropathy found that 27.5% (n=168) of
kidney dysfunction. Hydronephrosis secondary to sten- these patients reported the presence of upper gastro-
osis of the ureter seems to be an emerging health problem intestinal symptoms. The mean duration of ketamine
associated with frequent and high-dose ketamine use.132 use before symptom presentation was 5.0 ± 3.1 years.
Chu et al.237 reported in their study of ketamine-induced In this study, the presenting symptoms included
ulcerative cystitis that 51% of patients presented with epigastric pain (n=155, 25.4%), recurrent vomiting
unilateral or bilateral hydronephrosis. Four patients (n=48, 7.9%), anaemia (n=36, 5.9%) and gastrointestinal
also showed papillary necrosis and this led to renal failure bleeding (n=20, 3.3%).247 Interestingly, the study found
in one. Patients presenting with a history of ketamine use that uropathy symptoms were preceded by upper
114
6.13 Harms Associated with Chronic Ketamine Use
gastrointestinal symptoms for 4.4 ± 3.0 years in the impairment. However, there is evidence that frequent
majority (n=41, 83.9%) of patients. Other independent ketamine users do have profound impairments of
factors associated with upper gastrointestinal toxicity their short-term and long-term memory, although
were older age, current use and longer duration of many studies have been cross-sectional and hence
ketamine use.248 unable to address causation.132
Little is currently known about ketamine-induced Neuropsychological harms appear to be related to
abdominal pain. A small number of case frequency and quantity of dosing. Cognitive impairment
reports238,249,250 have described colic-like, upper gastric and long-term psychological effects can result from pro-
pain in young ketamine users who also presented with longed use.277 Ketamine is associated with direct neuro-
abnormal liver function. CT scans showed dilation of toxicity and can cause acute neuropsychiatric effects.
the common bile duct, mimicking cholecystitis. One longitudinal study showed that frequent ketamine
It has been suggested that ketamine may adversely use impaired visual recognition and spatial working
affect the liver by direct toxicity to parenchymal cells, memory; the degree of impairment was correlated with
resulting in bile duct damage.251 Impairment of the changes in the level of ketamine use over 12 months.194
smooth muscle of the sphincter of Oddi may also be Acute and acute-on-chronic use has been associated with
responsible for bile duct dilation.138,238,251,252 A study impaired information handling within working memory
has shown that the degree of dilation of the common and episodic memory, as well as deficits in semantic
bile duct was positively correlated with duration of keta- processing,133,278 with men more affected than
mine use.253 women.279
These symptoms appear to resolve once the A case control study found that frequent ketamine
patient stops using ketamine and cessation of keta- use is associated with impairment of working mem-
mine use potentially reverses the bile duct and liver ory, episodic memory, executive function and psycho-
injury in these patients.254,255 However, in one case logical wellbeing.280 One-year follow-up with the
study, a person had a dilated common bile duct that same group showed the frequent users on increasing
regressed with abstinence but recurred following doses were more likely to have cognitive deficits,
a return to ketamine use.251 especially with spatial working memory and pattern
recognition memory tasks, with both short-term and
6.13.3.3 Diabetic Ketoacidosis long-term memory affected.279
Ketamine can precipitate diabetic ketoacidosis (DKA) One study has shown that delusional thinking was
in type 1 diabetes. The metabolic acidosis can be positively correlated with the amount used by frequent
severe and has, in some cases, been associated with users and persisted despite abstinence.282 A dose-
rhabdomyolysis.256–275 dependent relationship was found at one-year follow-
up, with frequent users more delusional than infrequent,
6.13.3.4 Drug Interaction abstinent and non-users.279
The use of ketamine raises general issues of adherence Taking ketamine regularly has detrimental effects
to antiretroviral regimens. As a substrate of the on memory function which last beyond the acute
CYP450 system (specifically 3A4), ketamine may effects of the drug. Research suggests frequent use of
interact with certain antiretroviral medications, par- ketamine produces long-lasting impairments in epi-
ticularly the protease inhibitors with CYP450 inhibi- sodic memory and aspects of retrieval from semantic
tive properties.276 memory, which goes beyond ingestion.93
Also, its cardiovascular effects may be deleterious A three-year longitudinal study of people who had
among any patients with underlying heart disease or ceased or reduced ketamine use reported that some
lipid abnormalities. may continue to experience drug-related symptoms
three years later. This is particularly in relation to
6.13.3.5 Neurobehavioural, Psychiatric impairment of episodic memory which was still pre-
and Psychological Effects sent three years later and possibly also attentional
Cognitive Impairment and Memory Impairment functioning. Schizotypal symptoms and perceptual
Overall, studies have shown that infrequent ketamine distortion may also continue after ketamine
users do not appear to experience long-term cognitive cessation.281
115
Research on infrequent users (defined as taking Neurological Effects

ketamine more than once a month but less than three Animal studies have shown that ketamine is directly
times per week) and daily ketamine users found that neurotoxic. Abnormalities were also found in keta-
scores on measures for delusion, dissociation and mine-dependent patients in bilateral frontal
schizotypy were higher in the daily users.70,279 Morgan (including corpus callosum and anterior cingulate
et al. found that daily ketamine users had patterns of cortex) and left temporoparietal white matter.
symptoms similar to individuals in the prodromal phase A recent human study of 41 ketamine-dependent
of schizophrenia.279 Long-term ketamine users have users and 44 drug-free volunteers showed bilateral
more pronounced and persistent neuropsychiatric degeneration of frontal and left temporoparietal
symptoms, generally characterised as schizophrenia- white matter in ketamine users.309 The study also
like symptoms. However, there is no evidence of clinic- reported that fractional anisotropy values nega-
ally significant positive or negative psychotic symptoms tively correlated with the total lifetime ketamine
among infrequent users.282 There is also little evidence consumption.311
of a link between chronic heavy use of ketamine and A case report has also demonstrated a reduction
diagnosis of a psychotic disorder.132 of frontal grey matter volume in ketamine-
dependent patients. This reduction was correlated
Depression with duration of ketamine use; reduction in the left
There is some evidence that ketamine may be of superior frontal gyrus correlated with estimated total
therapeutic use for the management of treatment- lifetime consumption.310
resistant depression,56,57,283 as well as post-traumatic
stress disorder.284–305 A large clinical trial testing the Social Harms
efficacy of intravenous ketamine in mood disorders A study of 100 recreational users of ketamine found
reported that it was associated with a rapid and large that while one in five stated that they had ever experi-
antidepressant effect at 24 hours, significantly super- enced severe side-effects, more than one third (38%)
ior to midazolam. Ketamine appears to possess rapid reported having to deal with someone else who had
antidepressant effects independent of its transient suffered badly following ketamine use. The most
psychoactive effects.306 commonly reported problems were in the areas of
In contrast, the frequent use of recreational keta- employment (20%), relationships (5%), financial
mine or ketamine used outside medical supervision is (5%) and legal (1%).71The authors suggest that the
typified by increased dissociative and depressive problems were likely linked to the neurochemical
symptoms,279,307 as well as subtle visual anomalies.223 consequences of ketamine use and the toxicity that
Morgan et al.’s longitudinal study279found increased might result.71
levels of depression in both daily users and ex-ketamine
users over the course of one year, but not among infre-
quent users. However, the depression was not at clinical
6.14 Management of Harms Related
levels and the increase was not correlated with changes in to Chronic Ketamine Use
ketamine use.132
It is possible that rates of depression are higher 6.14.1 Identification and Assessment
among people who are getting treatment for ketamine
The first step for the identification of ketamine use
use disorders. A study of case records of 129 patients
and harms by specialist treatment services is to
classified as dependent on ketamine and receiving
include questions relating to ketamine in routine care.
treatment at three substance use clinics in
The modification of existing assessment instru-
Hong Kong between January 2008 and August 2012
ments and data collection tools is indicated.
found a high frequency of psychosis and/or depression
Assessment of ketamine use is similar to assess-
in patients with chronic ketamine use. In this study,
ment for other drug use, with the addition of screen-
substance-induced psychotic disorder accounted for
ing questions on urological and gastrointestinal
31.8% followed by depressive disorder (27.9%). The
symptoms and questions on the direct consequences
authors reported that depressive symptoms can either
of dissociation (e.g. cognitive impairment, sexual
be premorbid or secondary to substance use.308
behaviours).
116
6.14 Management of Harms Related to Chronic Ketamine Use
6.14.2 Psychosocial and Pharmacological There is also a case report of withdrawal symp-
toms which responded well to naltrexone.313 There
Support are a very small number of case reports that mention
anti-psychotics and anti-depressants. For example,
6.14.2.1 Psychological Support one case report mentioned that Paliperidone
Information on psychosocial support is presented in Palmitate may be useful in drug dose-reduction and
Chapter 2 and is relevant for ketamine users. maintaining abstinence.314 Another report described
A small number of ketamine-specific studies have what is called a significant reduction in craving and
also been conducted. Copeland et al. suggest that the ketamine use after taking lamotrigine.315
harms that require further investigation are the asso- A case report has shown a patient with a history of
ciation of ketamine use with unsafe sex and injecting alcohol and ketamine dependence experiencing keta-
behaviours and its neurotoxic effects. They also argue mine-like dissociative symptoms after alcohol con-
that effective brief and early interventions are needed sumption in the context of ketamine abstinence. It
for those who are at risk of harm because of ketamine has been suggested that high dose alcohol may directly
intoxication and/or excessive and regular consump- produce ‘K-hole experiences’ or perhaps trigger con-
tion. Interventions should address ketamine use ditioned ketamine-like experiences in a patient who
in situations where there is a heightened risk of acci- had been abstinent from ketamine for at least 1 year
dental death because cognition is impaired.24 and was admitted for alcohol withdrawal
Critchlow described the treatment of a person treatment.316
with dependence on ketamine that involved three
motivational interviewing sessions in the first 6.14.2.3 Aftercare and Support
instance.116 Maxwell suggests an abstinence-oriented Chapter 2 presents information on aftercare. A few
approach be used for ketamine, similar to that used ketamine-specific studies have been conducted, with
for psychostimulants.311 They suggest following the some suggesting that ketamine users’ ability and will-
model used for cocaine and amphetamine depend- ingness to abstain from using the drug may be low,
ence, with abstinence from all drugs from day 1. even when (and perhaps because) experiencing signifi-
This may require the therapist to avoid being confron- cant urological problems. Chu et al. showed that 9 out
tational to prevent treatment drop-out; relapse pre- of 24 ketamine users with bladder problems were able
vention is also indicated.94 to abstain from the drug and complete the Pelvic Pain
and Urgency/Frequency questionnaire.237Another
6.14.2.2 Pharmacological Interventions study found that only 3 out of 10 patients stayed
for Dependence and Withdrawal ketamine free for more than one year.233
Ketamine withdrawal is described in Section 6.13.2.
A case report describes medically assisted detoxi- 6.14.3 Management of Urinary Tract
fication carried out in conjunction with three sessions
of motivational interviewing. Detoxification was car-
Problems
ried out using a reducing regimen of diazepam over 3 Within substance misuse treatment centres, it is
days. The regimen was successful and eliminated the recommended that patients with a ketamine use his-
majority of withdrawal symptoms.116 tory and with recurrent urological problems, or
Others have also suggested that, in cases of sustained patients with unexplained urinary symptoms, are
heavy use and where acute withdrawal syndrome is assessed by a urologist to exclude other causes and
a possibility, a benzodiazepine detoxification regimen evaluate any damage. Any other patients with unex-
modified from alcohol detoxification regimens may plained symptoms should be screened for ketamine
lessen the symptoms arising from discontinuation.312 use.97Appropriate support to stop ketamine use must
It has been suggested that symptomatic manage- be available, as well as advice regarding appropriate
ment of withdrawal is indicated in some cases, with medical pain relief.
low-dose benzodiazepine as a starting point. There are It has been argued that many health care profes-
no studies to support the use of other pharmaceutical sionals, including psychiatrists, are still unaware of
agents, so any prescribing must be based on clinical the ‘devastating potential of ketamine’ for the urinary
assessment. tract317 and should be alerted to this problem.318 The
117
authors also recommend that ketamine use should be some symptoms and include cystoplasty, distention,
considered by other clinicians. Specifically, gastro- partial cystectomy, opiates, pregabalin, duloxetine,
enterologists should consider ketamine use in tricyclic antidepressants, anticholinergics and anti-
a setting of biliary ectasia without an obstructive inflammatory drugs.325
cause. They also suggest that ketamine should be Urinary tract reconstruction in patients with
considered by urologists and nephrologists in patients severe morbidity has been described as a major under-
with a history of drug abuse and lower urinary tract taking with a high risk of perioperative morbidity.326
symptoms in the absence of another aetiology.319 A study suggests that people with a history of keta-
The most effective treatment for ketamine-related mine use appeared to have a significantly higher rate
urological problems is cessation of use and it is essential of postoperative complications when compared with
that use of ketamine is stopped upon recognition of patients who underwent reconstructive surgery for
symptoms. Strategies are limited when use other benign disease (congenital anomalies, neuro-
continues.320 If drug cessation is achieved, the syndrome genic disease, intractable incontinence and interstitial
may be partially or completely reversed, but if ketamine cystitis/bladder pain syndrome (IC/BPS)).327
use persists, so do symptoms. In a few patients, however, A strategy for the treatment of ketamine-related
symptoms persist despite stopping drug use.321,322 urological problems has been suggested by Wood
Patients should also be referred to specialist drug et al.97 Central to this is the requirement for patients
services.97 A survey of UK urologists suggested that to stop their ketamine use. However, this may be com-
approximately one third of urological problems plicated by a need for pain control in those with ulcera-
resolved after drug cessation, one-third remained tive cystitis. This will require the treating team to
static and one-third progressed.322 develop an alternative pain management plan with the
There is limited literature to support how to man- patient. There may also be a lack of motivation to
age patients with ketamine-related uropathy. It is sug- abstain and non-compliance with urological investiga-
gested that most patients are managed conservatively, tion and treatment appointments.97
or with minimally invasive surgical intervention. Winstock et al. recommended a multidisciplinary
Early stages of the urological syndrome may present approach promoting harm reduction, cessation and
in casual or weekend users as episodes of cystitis, which early referral, to avoid progression to severe and irre-
can be treated empirically97 (based on practical experi- versible urological pathologies.324 Similarly, Wood et al.
ence and observation). More frequent users may have suggested a need for liaison between specialist drug
irreversible damage and scarring. The most affected services and local urology services.324 Some drug agen-
patients may require major surgery, in the form of cies have developed proactive models.97 However, this is
cystectomy and bladder reconstruction.97 Urinary tract not always possible, as patients can see urology depart-
reconstruction is reserved for those with refractory ments outside their residential area. In this case, support
symptoms, contracted bladders or upper tract is best organised by the general medical practitioner.97
compromise.323 It has been suggested that healthcare profes-
Where ketamine is identified as a factor, it has sionals can successfully engage young people during
been recommended that renal function be assessed; their stay in hospital for ketamine-related urological
a CT urogram can also be an important investigation problems to participate in a package of psychosocial
to reveal the extent of the disease. A urine culture is interventions, motivational interviewing and life-
mandatory. A routine evaluation of the upper tracts style re-design.328
with a CT urogram can rule out ureteric stricture and In all cases, appropriate support to stop ketamine
cystoscopy can be used to assess bladder capacity.97 In use must be available, as well as advice regarding
patients with normal renal function and with an ultra- appropriate medical pain relief.
sound that shows no hydronephrosis, a CT scan may
not be necessary.324 6.15 Public Health and Public Safety
Treatment for urinary tract symptoms is either
symptomatic (analgesia, urinary diversion) or the
treatment of complications (e.g. percutaneous 6.15.1 Viral and Bacterial Infections
nephrostomy insertion).322 Surgical and pharmaco- Studies have reported that ketamine injecting is asso-
logical approaches have been tried in order to relieve ciated with high-risk behaviours like the sharing of
118
6.16 Harm Reduction
injecting equipment and paraphernalia,329,330 poly- • Users who develop tolerance and who find
drug use331,332 and multiple injections. Ketamine themselves needing to use increasingly higher doses,
injecting puts the user at risk of viral and bacterial and who are using more frequently than intended,
infections and hence the potential risk of their trans- should be advised to monitor their intake. Diaries
mission to others. and electronic tools can be very useful.
• Advice should be given to users that those acutely
6.15.2 Accidents and Assaults intoxicated should not be left alone in case of
accidents and should have someone with them
Ketamine impairs psychomotor functioning dose-
who has not used the substance.132
dependently and higher doses increase the risk of
accidents.332,333 Ketamine use has been associated • Users should be made aware of the potential
with driving accidents in Hong Kong: 9% of fatal neurological and cognitive changes following
drug- and alcohol-related single-car collisions in frequent use of ketamine, which can result in poor
Hong King during 1996–2000 involved ketamine.334 performance at school, college or work.132
Driving accidents associated with methoxetamine • Ketamine users who feel depressed and anxious
have been reported.335 when stopping or reducing ketamine should be
Ketamine use can place the user at risk of sexual encouraged to seek professional help to manage
assault, although studies have suggested that ketamine their symptoms during a gradual reduction or
is not implicated in drug-facilitated assault.336,337 detoxification.
• Users should be made aware that the anaesthetic
topical effects of ketamine mean that they may not
6.16 Harm Reduction feel pain from tissue trauma and extra caution
It has been recommended that all ketamine users are must be exercised with any sexual activity which
given the standard harm reduction advice, which risks tissue damage.
includes not using the drug when alone, avoiding
• Daily use of ketamine should be avoided, due to
poly-use and co-ingestion of other substances, includ-
the urological risks.
ing alcohol, and information on a safe environment
• Ketamine users with urological problems
and safer injecting techniques.24,93
should be strongly encouraged to cease using
The following more specific harm reduction
the drug.
advice should be given to ketamine users:
Advice should be given to users with urological prob-
• Users should be advised to measure dose carefully
lems not to deliberately dehydrate and to seek medical
and start with a small test dose. They should also
help and referral to a specialist to reduce the risk of
be advised to measure intervals between doses
permanent harm. Corazza et al. in their analysis of
accurately.
Internet sites found that users themselves suggested
• People who use or suspect that they are using
that dosages should increase only gradually. Users
methoxetamine should be aware that it has much
recommended that doses of 50 mg should not be
slower onset of action of the latter (up to 90
exceeded on the first occasion of use, or when the
minutes). Repeated dosing and inadvertent excessive
drug was taken orally. The websites also advised
dosing may result in unintentional overdose.
users not to use methoxetamine with alcohol, tetra-
• The use of ketamine with other drugs, including hydrocannabinol, selective serotonin reuptake inhibi-
alcohol, should be avoided.24 tors or monoamine oxidase inhibitors. Users were
• Users should minimise the risk of accidental advised to try a test dose of a few milligrams and to
injury by ensuring that intoxicated friends are wait 2 hours before re-dosing.
always accompanied by others who are not.132
The dissociative effect of ketamine puts users at
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298. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an
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300. Schwartz J, Murrough JW, Iosifescu DV. Ketamine for
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305. SchakJennifer KM, Van de Voort L, Johnson EK, et al.
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130
Chapter
Nitrous Oxide (N2O)
7
7.1 Quality of the Research Evidence 7.3 Clinical and Other Legitimate
The evidence on the management of the acute and Uses of Nitrous Oxide
chronic harms associated with the recreational use of
Nitrous oxide was first synthesised by the English
nitrous oxide (N2O) is limited and consists mainly of
chemist and philosopher Joseph Priestley in 1772. It
case reports, with occasional experimental studies
has been used as a medical anaesthetic for over 150
into acute effects. There are few findings on acute
years and continues to be widely used for medical,
harms and interventions relating to the use of the
dental and veterinary purposes. It is also used for
drug, but consistent findings on the chronic effects analgesia and can help relieve anxiety.8 It is used in
of prolonged nitrous oxide use.
various settings, including ambulances, emergency
departments, relief for women in labour and in den-
7.2 Brief Summary of Pharmacology tistry, where its short duration of action is an
Nitrous oxide is a gas whose pharmacology is not advantage.9,10 Nitrous oxide has been shown to ameli-
well studied and existing evidence is not conclu- orate craving and withdrawal symptoms from alcohol,
sive. It has been suggested, however, that opioid opioid, nicotine, cocaine and cannabis.11,12,13,14,15,16
receptors may be responsible for its analgesic Concerns have however been raised about use of
properties1 and a study has shown that naloxone nitrous oxide in anaesthesia, because of the potential
inhibits its analgesic effects.2 Furthermore, nitrous adverse effects and hazards posed to both clinicians
oxide may act as an N-methyl-D-aspartate through unintended occupational exposure and
(NMDA) antagonist, similar in nature to ketamine, patients, specifically by its haematological, neuro-
another anaesthetic (see Chapter 4).3 Nitrous oxide logical, myocardial and immunological effects, and
works primarily via the opiate system, mediating because it can lead to postoperative nausea and vomit-
the release of beta-endorphins and directly binding ing and expansion of air-filled spaces.17
to mu, delta and kappa opiate receptors.4 Nitrous Outside of human and animal medical applications,
oxide is used clinically as an anaesthetic gas with nitrous oxide is used as a fuel additive, as an oxidising
pain-relieving properties. agent to increase the power of cars, as a component of
Nitrous oxide is a ‘dissociative’ drug. Although rocket fuel, as an aerosol dispersant and in the catering
the effects of the drug on the brain are not fully industry in the dispensing of whipped cream.
understood, its dissociative effects are probably The latter forms the basis of its sale for recre-
caused by preventing the normal action of the ational use on websites, where users purchase it in
NMDA receptor. the form of small canisters or larger tanks, which are
When inhaled, nitrous oxide is rapidly absorbed via labelled with ‘approved for food use’.18
pulmonary circulation.5 Due to high lipid solubility, it
passes easily through the blood–brain barrier and has 7.4 Prevalence and Patterns of Use
a rapid onset of action; it is cleared from the body within
The use of nitrous oxide for recreational purposes is
a few hours.6 The use of nitrous oxide leads to vitamin
not new, as ‘laughing gas parties’ were popular in the
B12 depletion, which is believed to be due to its effect on
UK in Victorian times, mostly in the context of variety
cobalt in vitamin B12, whereby the vitamin is converted performances in music halls, theatres and carnivals.
from an active, monovalent form to an inactive, bivalent
More recently, the Global Drug Survey 2018,
form.7
which reported data from 123,814 people from more
131
Nitrous Oxide (N2O)
than 30 countries, showed that nitrous oxide was the tanks of nitrous oxide intended to boost horsepower
tenth most used drug in the last 12 months (excluding of gasoline engines in cars can contain harmful con-
tobacco and alcohol).19 There are wide differences in taminants like sulphur dioxide.
the prevalence of use of nitrous oxide by country, with Nitrous oxide is rarely the only drug used by
Germany being the country with lowest lifetime people who have taken it; instead it tends to be
prevalence, (reported ≈11% lifetime nitrous oxide used as part of a wide repertoire of substances, or
use, 3.5 times lower than in the UK, where over one polydrug use.22,23 It has been suggested that typic-
third (≈38%) of participants reported lifetime).20 ally, the recreational use of nitrous oxide is moder-
Nonetheless, and despite varying rates of use, the ate, with approximately 80% of users having less
recreational use of nitrous oxide has been reported than 10 episodes per year.24 It seems that people
in many parts of the world, including China.21 using nitrous oxide will usually take fewer than 10
balloons of nitrous oxide per episode,25 with some
7.5 Routes of Ingestion case studies showing even smaller amounts, with an
average number of fewer than five per session.26
and Frequency of Dosing For example, a survey of students in Auckland
Nitrous oxide is a colourless gas that is slightly sweet found that recreational use typically amounted
smelling and tasting. between two to five containers in a session.27
Nitrous oxide is typically inhaled, commonly via However, not all use is ‘moderate’, as other studies
balloons, from small steel cartridges or cylinders report a range of 10–100 cylinders used in one
(sometimes called ‘bulbs’ or ‘chargers’). Cartridges session.28,29,30,31,32,33,34,35,36,37,38,39
contain highly pressurised nitrous oxide that are Recreational users will typically inhale a number
available from catering suppliers and used for of small, imprecise doses from small containers and
whipped cream. They vary by brand, but are approxi- consequently it may be difficult to assess the quantity
mately 6 cm long, 1.8 cm wide and have a wall of nitrous oxide consumed. An experimental study
approximately 2 mm thick to withstand the pressure testing the effects of nitrous oxide in 12 volunteers
of the gas. Most contain approximately 8 g of nitrous found that the primary effects were found only at the
oxide under pressure and are non-refillable. inhalation of 20% to 40% concentrations.40 At the
These cartridges are supplied with a dispenser into inhalation of 40% nitrous oxide (the highest concen-
which, when fitted, they release their compressed gas. tration tested), subjects were confused, sedated, high,
If the dispenser is not filled with cream, the nozzle dysphoric and stimulated, but fatigue and depression
simply releases the gas only. A balloon can be placed were observed once the effects had worn off.
over the nozzle to capture the nitrous oxide. As nitrous oxide is used as an anaesthetic, official
Alternatively, the cartridges can be opened with the advice has been issued on the short-term occupational
‘cracker’ on the cream dispenser and the nitrous oxide exposure limit, to avoid harms. The advice on this
again released into a balloon, from which it then can ranges from 25 parts per million (ppm) to 100 ppm,41
be inhaled. Both cartridges and crackers can be and may provide an indication of the level at which
obtained from online suppliers. They are generally harms can occur in recreational users. The harms
low cost. resulting from nitrous oxide are largely determined
The quality (purity) of the nitrous oxide depends by its mode of use rather than its direct physiological
on its source. Products intended for food use are of effects. Inhalation through balloons or canisters is
higher quality, especially if they originate from the relatively safe, whereas the use of airtight bags,
EU. Products for industrial use may be adulterated or masks or respirators carries a high risk of
impure. asphyxiation.42
Nitrous oxide is also available in much larger gas
cylinders intended for medical or industrial use. The 7.6 Desired Effects of Nitrous Oxide
use of these, for purposes other than those intended,
can be dangerous. Unsafe methods include breathing for Recreational Use
directly from a cylinder using a face mask, opening Nitrous oxide is used recreationally because of its
a cylinder tank in a car or small room or filling a bag euphoric effect. The onset of the effects is immediate,
with the gas and putting it over the head. Cylinder with the peak around 1 minute after inhaling, lasting
132
7.8 Acute Harms
for approximately 2 minutes then fading.43,44,45 Users relation to bags put over the head in order to facilitate
may take many ‘hits’ over a few hours. inhalation62 or inhalation in cars. There is also evi-
The short-lasting effects typically include a rush of dence that death is often linked to polydrug use.63
dizziness, relaxation, reduction of anxiety, laughing
fits, auditory distortions, feelings of dissociation and
mild changes in perception and sometimes
7.8 Acute Harms
hallucinations.46,47,48 It has been argued that these
effects led to its use as a common recreational 7.8.1 Acute Toxicity
drug.49 It is also reported that some people use it to It has been argued that typically, the moderate recre-
self-manage pain and anxiety.50 As an anaesthetic gas, ational use of nitrous oxide is not associated with
it affects coordination and awareness51 and reduces major side effects. It has been suggested that nitrous
psychomotor performance.52 oxide typically has few short-term adverse effects,
There is variability in the subjective effects of the other than headache for some.64
drug. In one study, 12 individuals (under controlled, Nonetheless, a systematic review of the case litera-
blinded conditions) were given a choice between oxy- ture has shown an extensive number of case reports in
gen and nitrous oxide after a sampling period for the literature suggesting that nitrous oxide misuse and
both. There was significant individual variability in its sequelae occur more frequently than recognised.
the reported effects of the drug. Those who reported The vast majority of toxicities involve the neurological
feelings of ‘tingling’, ‘drunk’, ‘dreamy’, ‘coasting’, system, although there are psychiatric and other med-
‘floating’ and ‘having pleasant bodily sensations’ dur- ical presentations as well. The authors also argue that
ing the nitrous oxide sampling period chose nitrous the number of deaths related to nitrous oxide, which
oxide more often during the choice period.53 There is do not include cases where it was used to assist in
disagreement in the literature as to whether there are suicide, suggest that the risks involved with abuse are
gender differences in the effects of nitrous oxide.54,55 more significant than previously recognised.65
The use of nitrous oxide is associated with Harms are likely to result from disorientation and
unwanted effects. These include transient dizziness, unsteadiness caused by inhalation (e.g. falling
dissociation, acute ataxia, disorientation, loss of bal- down66). There are also isolated instances in the lit-
ance, impaired memory and cognition, and weakness erature of hypothermic skin trauma resulting from
in the legs. Blurred vision, nausea and headache have contact with chilled canisters.67
been reported. When intoxicated, accidents like trip- However, heavy use of nitrous oxide can be asso-
ping and falling may occur.56 There are a few cases ciated with severe adverse effects. Acute exposure to
reported from clinical practice in which patients nitrous oxide may irritate the respiratory tract and
experienced erotic hallucinations leading to accusa- acute use of inhalants in general can result in sneez-
tions of molestation against dentists and other ing, coughing, excess salivation and conjunctival
staff.57,58,59 erythema.68 The use of nitrous oxide can also cause
asphyxia, headache, nausea, vomiting, dizziness and
7.7 Mortality excitement, and to the central nervous system (CNS)
Nitrous oxide is generally considered to be safe as it depression, convulsions and death. Hypertension and
produces minimal cardiorespiratory disturbance in fit cardiac dysrhythmias are possible. Patients can pre-
patients and is rapidly and completely eliminated sent with altered mental state, paraesthesias, ataxia
from the body after exposure.60 However, recreational and weakness or spasticity of the legs.69 Nausea, cyan-
use can be associated with adverse effects and it may osis and fainting have been reported as a result of
pose significant risks in some people, especially with nitrous oxide.70
particular methods of administration.61 When nitrous oxide is inhaled from a balloon it
A number of cases of death by asphyxiation are displaces the air in the lungs, thus temporarily pre-
reported among individuals who were using nitrous venting oxygen from entering the bloodstream and
oxide at the time. Although nitrous oxide does not potentially causing tachycardia and transient periph-
depress the respiratory drive significantly, the normal eral neurological symptoms.71 There have been
physiological response to hypoxia is blunted when reports of fatalities after acute exposure, due to
50% nitrous oxide is given and deaths are often in asphyxiation.72,73
133
Nitrous Oxide (N2O)
Nitrous oxide is insoluble in blood, and therefore Box 7.1 Features of Acute Toxicity Associated
rapidly clears into the alveoli from the blood once with Nitrous Oxide
inhalation has ceased.74 At the high concentrations
(e.g. >70%) used in anaesthesia there is the potential Respiratory effects
for hypoxia if a high concentration of oxygen is not Asphyxia
then provided. Nitrous oxide may have effects on Hypoxia
immune function, but the evidence is unclear on this Neurological and psychiatric effects
issue.75 CNS depression
There is a risk that users may confuse the much Convulsions
more toxic or potent gases or volatile substances, such
Psychiatric symptoms
as butane, with nitrous oxide. If a patient requires
Headache
admission to an emergency department, there is
a chance that he or she has used butane, which does Myeloneuropathy
not only have different effects but also different Polyneuropathy
harms. The use of nitrous oxide is not as life- Dizziness
threatening as the use of butane, which can cause Excitement
arrhythmia and increases the risk of sudden cardiac Paraesthesias
arrest. Life-threatening risks of nitrous oxide are Paralysis
linked to mode of use, which may lead to hypoxia or Psychosis
anoxia.
Cardiovascular effects
High concentrations of inhaled nitrous oxide con-
Hypertension
stitute a hypoxic inspired mixture and the likelihood
and severity of resultant hypoxaemia will depend on Cardiac dysrhythmias
the effectiveness of nitrous oxide delivery, air entrain- Megaloblastic anaemia
ment, depth of respiration, and breath-holding to Leukopenia
alter washout of nitrogen, oxygen, and carbon dioxide Anoxia
from the lungs. It is argued that such hypoxaemia Metabolic features
should be well tolerated by a fit person, but could Thrombocytopenia
give rise to seizures, arrhythmias, or even respiratory Gastrointestinal symptoms
or cardiac arrest in patients with epilepsy, cardiac
Nausea and vomiting
disease, or other co-morbidities, especially if com-
bined with other drugs that tend to produce
cardiac arrhythmia.76
In a systematic review of the case literature, where
Patients present to hospital with changes in gait or
91 individual cases across 77 publications were
coordination, difficulty walking and falls.
included, a study found that the majority of cases
(n=72) reported neurologic sequelae including mye-
loneuropathy and subacute combined degeneration, 7.8.2 Acute Withdrawal
commonly (n=39) with neuroimaging changes. For withdrawal see Section 7.10.1.1
Psychiatric (n=11) effects included psychosis while
other medical effects (n=8) included pneumomedias- 7.8.3 Poly-drug Use and Drug Interactions
tinum and frostbite. Across all cases, nitrous oxide
There may be some increase in the effects of nitrous
misuse was correlated with low or low-normal
oxide when it is combined with alcohol.79 It is possible
Vitamin B12 (cyanocobalamin) levels (n=52) and
that nitrous oxide ingested at the same time as stimu-
occasionally elevated homocysteine and methylmalo-
lants has a greater effect on blood pressure and heart
nic acid.77
rate. There is anecdotal evidence that nitrous oxide
The chronic use of nitrous oxide is associated with
can briefly enhance the effects of psychedelics like
problems relating to the depletion of vitamin B12 and
LSD, or bring the effects back strongly when the
is discussed in Section 7.10.2.
drug is wearing off, which could be very frightening
The features are summarised in Box 7.1.78
if unexpected.
134
7.10 Harms Associated with Chronic Use and Dependence
Generally speaking, it has been suggested that the potential is low as it is only a partial opiate agonist,
odds of nitrous-oxide-related disorders may be sub- and its euphoric effects fade rapidly.83 On the other
stantially higher in patients with comorbid substance hand, cases of tolerance and psychological depend-
use disorders.80 ence have been reported in chronic users84,85 and it
As it is not metabolised by the liver, the potential has been recommended that daily use of nitrous oxide
for drug interactions with other agents is low. should be avoided in particular by people with mental
health problems or other psychological vulnerability.
7.9 Clinical Management of Acute 7.10.1.1 Withdrawal
Toxicity Nitrous oxide is sometimes used in a compulsive way
by some individuals, possibly explaining one of its
7.9.1 Identification and Assessment street names, ‘hippie crack’. There are no significant
of Acute Toxicity withdrawal symptoms aside from the desire to use
The diagnosis of acute nitrous oxide toxicity should more nitrous oxide.
be made by clinical assessment. There are no rapid
urine or serum field tests, so analytical assessment 7.10.2 Other Harms –
should not be considered a component of routine Mental Health – Vitamin B12 Deficiency
diagnosis. Assessment should be based on the recog-
Although the evidence is limited, it is possible that
nition of the clinical toxidrome associated with
nitrous oxide can worsen some mental health prob-
nitrous oxide and the potentially harmful modes of
lems, and its use has been linked to manic relapse.86
use.
One case report describes a psychotic episode occur-
ring in a patient with no history of psychosis who had
7.9.2 Clinical Management of Acute been regularly using nitrous oxide.87
Toxicity The chronic use of nitrous oxide has been linked
The management of acute harms resulting from to psychiatric symptoms which include cases of mild
nitrous oxide must be based on local, national and mood disorders, psychotic behaviour, fatigue, gener-
international protocols and guidelines. alised weakness, and loss of memory. These symp-
Management of acute nitrous oxide harms must toms often preceded the neurological impairments.88
include removal from exposure and providing symp- The adverse effects of chronic nitrous oxide use
tomatic treatment for any resultant problems. It is are dominated by vitamin B12 deficiency. The vast
recommended that patients are observed for at least majority of toxicity described in the literature and
1 hour after exposure. A 12-lead ECG and a full blood associated with nitrous oxide use involve the neuro-
count may be needed for symptomatic patients. logical system, although there are psychiatric and
Where there is chronic use of nitrous oxide, it is other medical presentations as well.89 By inactivating
recommended that B12 concentration is checked in vitamin B12, nitrous oxide can cause anaemia as well
symptomatic patients (see Section 7.10.2). Guidance as neuropathy.
on diagnosis for psychiatrists has also been The harms caused by nitrous oxide tend to stem
published.81 from heavy usage and the ensuing depletion of vita-
min B12 leading to neurological problems.90,91,92
Neurological deficits are more likely to occur when
7.10 Harms Associated with Chronic nitrous oxide is used at high doses and for prolonged
Use and Dependence durations.93 Case reports describe vitamin B12 defi-
ciency after repetitive use (e.g. 50–100 bulbs) of
nitrous oxide within a few hours or heavy use over
7.10.1 Dependence prolonged time, e.g. more than 10–20 ‘bulbs’ (or can-
As the effects of nitrous oxide are short-lasting and isters), daily for 10 days.94,95,96,97
pleasurable, people may use it frequently. There is no Studies have shown that the most common com-
consensus on the dependence liability of nitrous plaints were ‘numbness’, ‘paraesthesias’ and
oxide. Some argue that nitrous oxide use does not ‘weakness’.98 A meta-analysis comprising of patients
seem to result in dependence,82 that its addictive associated with adverse effects of nitrous oxide
135
Nitrous Oxide (N2O)
exposure in medical and recreational settings has partial or complete recovery, although this can take
shown that the most frequent clinical manifestations months.145 High-dose intramuscular B12 replacement
included paraesthesia (80%; 72.0–88.0%), unsteady is recommended.146 Educating patients about the risks
gait (58%; 48.2–67.8%), and weakness (43%; 33.1– of nitrous oxide has also been recommended.147,148
52.9%). At least one haematological abnormality was A review of 18 published cases of nitrous oxide
reported in 71.7% (59.9–83.4%) of patients.99 toxicity identified the most common neurological
The most frequent outcomes were subacute com- presentations as paraesthesiae and gait disturbance,
bined degeneration (28%), myelopathy (26%), gener- improving over weeks to months with high-dose B12
alised demyelinating polyneuropathy (23%) or replacement (although only 25% of cases regained
peripheral neuropathy.100 Other common diagnoses their original level of function).149
include myeloneuropathy. An early sign of peripheral It has been suggested that recovery is slow and
neuropathy is numbness in fingers101 and heavy long-term deficits can result.150,151 Neurological
nitrous oxide use was associated with persistent recovery may be incomplete, particularly when
numbness. patients continue to use nitrous oxide.152 It has also
Studies and reports have described peripheral neur- been argued that B12 supplementation is not effective
opathy102 myelopathy103–114 and polyneuropathy.115 when nitrous oxide use persists.153
Severe myeloneuropathy116,117,118 leukopenia and One case report suggests that where symptoms
thrombocytopenia119,120,121,122,123 have been reported. persist, methionine treatment has been successful
Nitrous oxide causes peripheral neuropathy in a dose- where B12 treatment alone has failed.154
dependent manner.124 A review of 143 patients with B12 deficiency found
Less common neurological signs and symptoms at that early diagnosis and treatment are crucial and that
the time of presentation include changes in cognitive the severity of ataxia and paraesthesias after treatment
functioning, bowel and bladder dysfunction, sexual was strongly related to the duration as well as the sever-
dysfunction, and Lhermitte’s sign (an ‘electric’ sensa- ity of symptoms prior to therapy.155 It also similarly
tion that travels down the limbs and back upon neck suggested that the extent of recovery under treatment
flexion).125,126,127,128 In addition to neurological was inversely related to the duration of symptoms.156
symptoms, functional vitamin B12 deficiency causes At a global level, it has been argued that popula-
skin hyperpigmentation and vascular disease from tion studies are needed to evaluate whether the
hyperhomocysteinaemia, and is teratogenic.129,130,131 correction of vitamin B12 deficiency prevents
A case report of cardiac arrest has been published.132 nitrous-oxide-related toxicity in the context of
anaesthesia and recreational use, particularly in
countries with a high prevalence of vitamin B12
7.11 Management of Harms Related deficiency.157
to Chronic Use
It has been suggested that there is a need to consider 7.11.1 Psychosocial and Pharmacological
vitamin B12 deficiency in patients who arrive at
a hospital with psychiatric manifestations who report
Support
a history of nitrous oxide exposure or misuse in the There is no relevant pharmacological support. For
recent or remote past.133 psychosocial support, see Chapter 2.
The treatment for neuropathological effects of
nitrous oxide toxicity is abstinence from nitrous 7.12 Harm Reduction and Public
oxide use, high doses of vitamin B12 therapy and Health
physiotherapy.134,135
It has been argued that health professionals should be
Suggested treatment for the chronic harms related
aware of the toxic effects of nitrous oxide and be able
to the use of nitrous oxide resulting from vitamin
to identify potential nitrous oxide abuse.158
B deficiency include parenteral folic acid,136,137 intra-
The inhalation of nitrous oxide through the bal-
muscular vitamin B12 injection138,139,140,141,142 and
loon method may carry less risk than other methods
intravenous methylprednisolone.143 A number of stud-
and minimises the risk of anoxia. Users will drop the
ies have shown that stopping exposure and introducing
balloon if they are getting too hypoxic or lose con-
vitamin B supplementation144 may result in either
sciousness. Other methods may carry more risk, in
136
7.12 Harm Reduction and Public Health
that the user may become unconscious through 10. Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric,
anoxia and continue to have insufficient access to and other medical manifestations of nitrous oxide abuse:
a systematic review of the case literature. Am J Addict
oxygen. The following harm reduction measures 2016;25:358–369.
should be taken:
11. Gillman MA, Lichtigfeld FJ, Young TN. Psychotropic
• Users should always inhale nitrous oxide from analgesic nitrous oxide for alcoholic withdrawal states.
a balloon – never from a tube or mask, or directly Cochrane Database Syst Rev 2007;18(2):CD005190.
from a dispenser or compressed air tank. 12. Kripke BJ, Hechtman HB. Nitrous oxide for pentazocine
• Users must be careful not to confuse nitrous oxide addiction and for intractable pain: report of case. Anesth Analg
with other gases and volatile substances, which 1972;51(4):520–527.
have far greater risks. 13. Lichtigfeld FJ, Gillman MA. The treatment of alcoholic
• Users should avoid inhaling while standing up and withdrawal states with oxygen and nitrous oxide. S Afr Med J
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(6):784–785.
particular by people with problems with low blood
pressure or any mental health issues. 15. Carey C, Clark A, Saner A. Excellent results with analgesic
nitrous oxide for addictive withdrawal states in general
• Users should stop inhaling if they feel any physical practice. S Afr Med J 1991;79(8):516.
discomfort, such as ‘pins and needles’ or
16. Alho H, Methuen T, Paloheimo M, et al. Nitrous oxide has
numbness. no effect in the treatment of alcohol withdrawal syndrome:
Regular and long-term users of nitrous oxide in par- a double-blind placebo-controlled randomized trial. J Clin
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Subst Abuse Rehab 2016:7:155–159.
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myelopathy with functional vitamin B 12 deficiency. BMJ Case
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104. Cheng HM, Park JH, Hernstadt D. Subacute combined joyful? Neth J Med 2017;75(7):304–306.
degeneration of the spinal cord following recreational nitrous
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106. Shulman RM, Geraghty TJ, Tadros M. A case of unusual
123. Suruda AJ, McGlothlin JD. Fatal abuse of nitrous oxide in the
substance abuse causing myeloneuropathy. Spinal Cord
workplace. J Occup Med 1990;32:682–684.
2007;45:314–317.
124. Winstock AR. Ferris JA. Nitrous oxide causes peripheral
107. Tatum WO, Bui DD, Grant EG, et al. Pseudo-Guillain-Barre
neuropathy in a dose-dependent manner among recreational
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J Neuroimaging 2010;20:400–401.
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cervical myelopathy. J Neuroimaging 2004;14(3):277–280.
126. Stabler SP. Vitamin B12 deficiency. N Engl J Med
110. Hsu CK, Chen YQ, Lung VZ, His SC, Lo HC, Shyu HY. 2013;368:2041–2042.
Myelopathy and polyneuropathy caused by nitrous oxide
127. Massey TH, Pickersgill TT, Peal KJ. Nitrous oxide misuse and
toxicity: a case report. Am J Emerg Med 2012;30(6):1016.e3–6.
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128. Mishra VA, Harbada R, Sharma A. Vitamin B12 and vitamin
Teaching neuroimages: myelopathy due to B12 deficiency in
D deficiencies: an unusual cause of fever, severe hemolytic
long-term colchicine treatment and nitrous oxide misuse.
anemia and thrombocytopenia. J Fam Med Prim Care
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practice. S Afr Med J 1991;79(8):516.
145. Diamond AL, Diamond R, Freedman SM, Thomas FP.
130. Cheng HM, Park JH, Hernstadt D. Subacute combined ‘Whippets’-induced cobalamin deficiency manifesting as
degeneration of the spinal cord following recreational nitrous cervical myelopathy. J Neuroimaging 2004;14(3):277–280.
oxide use. BMJ Case Rep 2013;2013:bcr2012008509. https://d
146. Thompson AG, Leite MI, Lunn MP, Bennett DLH. Whippits,
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nitrous oxide: history revisited. Br J Anaesthesia 2016;116 001071
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147. Keddie S, Adams A, Kelso ARC, et al. No laughing matter:
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133. Sethi NK, Mullin P, Torgovnick J, Capasso G. Nitrous oxide
‘whippit’ abuse presenting with cobalamin responsive 148. Vasconcelos OM, Poehm EH, McCarter RJ, Campbell WW,
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134. Al-Sadawi M, Hidalgo C, Chinyere A, Apoorva J, Modupe O,
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McFarlane SI. Inhaled nitrous oxide ‘whip-its!’ causing
subacute combined degeneration of spinal cord. Am J Med Case 149. Massey TH, Pickersgill TT, Peal KJ. Nitrous oxide misuse and
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‘whippit’ abuse presenting as clinical B12 deficiency and ataxia. Quezado ZMN. Potential outcome factors in subacute
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(1):73–75. subacute degeneration of the spinal cord due to nitrous oxide
inhalation. J Neurol 2018; 265:1089–1095. https://doi.org/10
138. Cheng HM, Park JH, Hernstadt D. Subacute combined
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Am J Emerg Med 2004;22:124. 154. Stacy C, DiRocco A, Gould R. Methionine in the treatment of
nitrous oxide induced neuropathy and myeloneuroapthy.
140. Richardson PG. Peripheral neuropathy following nitrous
J Neurol 1992;239(7):401–403.
155. Ives R, Ghelani P. Polydrug use (the use of drugs in
141. Diamond AL, Diamond R, Freedman SM, Thomas FP.
combination): a brief review. Drugs Educ Prev Policy 2006;13
‘Whippets’-induced cobalamin deficiency manifesting as
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cervical myelopathy. J Neuroimaging 2004;14(3):277–280.
156. Mancke F, Kaklauskaite G, Kollmer J, Weiler M. Psychiatric
142. Probasco JC, Felling RJ, Carson JT, Dorsey ER, Niessen TM.
comorbidities in a young man with subacute myelopathy
Teaching neuroimages: myelopathy due to B12 deficiency in
induced by abusive nitrous oxide consumption: a case report.
long-term colchicine treatment and nitrous oxide misuse.
Subst Abuse Rehab 2016:7 155–159.
Neurology 2011;77(9):e51. https://doi.org/10.1212/WNL
.0b013e31822c910f 157. Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric,
143. Ghobrial GM, Dalyai R, Flanders AE, Harrop J. Nitrous oxide
myelopathy posing as spinal cord injury. J Neurosurg Spine
2016;25:358–369.
2012;16(5):489–491. https:// doi.org/10.3171/2012
.2.SPINE11532 158. Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric,
2016;25:358–369.
141
Part III Drugs with Primarily Stimulant Effects
Chapter
Introduction to Stimulant Club Drugs
8A and Novel Psychoactive Substances
8A.1 An Introduction to Drugs nucleus accumbens – is the most important action of

cocaine.
with Stimulant Effects On the other hand, enhancing the release of dopa-
Substances with a stimulant effect have been used by mine in the nucleus accumbens appears to be the medi-
successive generations of people. A wide range of ating effect of amphetamines3,4 and amphetamines
substances have been used, notably of course caf- increase the release of newly synthesised noradrenaline
feine and nicotine. Psychostimulants can be plant- and dopamine.3,5 The effects of amphetamines (and
based substances or can also be of a synthetic especially of methamphetamine, discussed in
nature. Chapter 10), also last longer than those of cocaine.3
Currently, the illicit market for stimulants The extent to which a specific drug elevates these
includes cocaine and amphetamine-type stimulants levels will determine the effect. Drugs that elevate dopa-
(ATS), including new psychoactive substances with mine significantly will induce greater reward and pleas-
stimulant effect and ATS. The 2020 World Drug ure or even euphoria, but are also more likely to increase
Report states that the manufacture of amphetamine- a desire to re-dose. Those that elevate noradrenaline will
type stimulants continues to be dominated by be less euphoric, but may increase alertness and cause
methamphetamine.1 anxiety. They also increase strain on the heart and circu-
Stimulants constitute the main category of novel latory system.
psychoactive substances (NPS) reported to the Some stimulants act on serotoninergic recep-
UNODC early warning advisory since 2009. The 2020 tors and exhibit monoamine reuptake as well.
World Drug Report states that at this time, most of the Stimulants that are linked with the release of
NPS found on the drug markets of member states were serotonin are associated with feelings of empathy
stimulants, followed by synthetic opioid receptor and compassion (sometimes referred to as
agonists.2 Simulant NPS include several synthetic cath- empathogenic and entactogenic effects) and
inones, other phenethylamines, dimethoxyamphetamine increased sociability and sex drive. Stimulants
and piperazines. that act on the serotoninergic receptors exhibit
hallucinogenic effects in addition to their stimu-
8A.2 Pharmacology in Brief lant effects.
The patterns of effects of the various stimulant Like other NPS, the toxic effects of NPS with
agents vary, but stimulant drugs overall stimulate stimulant effects have not been well studied, but are
the brain and central nervous system by increasing expected to be similar to those of better understood
the activity of key neurotransmitters, such as nor- stimulants (see Box 8A.1).
adrenaline, dopamine and serotonin. This takes
place through a number of mechanisms, including 8A.3 Stimulant Novel Psychoactive
increasing release of and/or inhibiting reuptake of
these chemicals.
Substances in Europe
Different stimulants will work in different ways. Recent data from Europe also suggest greater geograph-
Cocaine prevents dopamine reuptake while amphet- ical diffusion and an overall increase in the consumption
amines increase its release. It is generally believed that of all the commonly used classes of stimulant drugs.12 As
dopamine reuptake blockade – in particular in the is the case world-wide, the main illicit stimulant drugs
143
Part III Drugs with Primarily Stimulant Effects
Chapter
Introduction to Stimulant Club Drugs
8A and Novel Psychoactive Substances
8A.1 An Introduction to Drugs nucleus accumbens – is the most important action of

cocaine.
with Stimulant Effects On the other hand, enhancing the release of dopa-
Substances with a stimulant effect have been used by mine in the nucleus accumbens appears to be the medi-
successive generations of people. A wide range of ating effect of amphetamines3,4 and amphetamines
substances have been used, notably of course caf- increase the release of newly synthesised noradrenaline
feine and nicotine. Psychostimulants can be plant- and dopamine.3,5 The effects of amphetamines (and
based substances or can also be of a synthetic especially of methamphetamine, discussed in
nature. Chapter 10), also last longer than those of cocaine.3
Currently, the illicit market for stimulants The extent to which a specific drug elevates these
includes cocaine and amphetamine-type stimulants levels will determine the effect. Drugs that elevate dopa-
(ATS), including new psychoactive substances with mine significantly will induce greater reward and pleas-
stimulant effect and ATS. The 2020 World Drug ure or even euphoria, but are also more likely to increase
Report states that the manufacture of amphetamine- a desire to re-dose. Those that elevate noradrenaline will
type stimulants continues to be dominated by be less euphoric, but may increase alertness and cause
methamphetamine.1 anxiety. They also increase strain on the heart and circu-
Stimulants constitute the main category of novel latory system.
psychoactive substances (NPS) reported to the Some stimulants act on serotoninergic recep-
UNODC early warning advisory since 2009. The 2020 tors and exhibit monoamine reuptake as well.
World Drug Report states that at this time, most of the Stimulants that are linked with the release of
NPS found on the drug markets of member states were serotonin are associated with feelings of empathy
stimulants, followed by synthetic opioid receptor and compassion (sometimes referred to as
agonists.2 Simulant NPS include several synthetic cath- empathogenic and entactogenic effects) and
inones, other phenethylamines, dimethoxyamphetamine increased sociability and sex drive. Stimulants
and piperazines. that act on the serotoninergic receptors exhibit
hallucinogenic effects in addition to their stimu-
8A.2 Pharmacology in Brief lant effects.
The patterns of effects of the various stimulant Like other NPS, the toxic effects of NPS with
agents vary, but stimulant drugs overall stimulate stimulant effects have not been well studied, but are
the brain and central nervous system by increasing expected to be similar to those of better understood
the activity of key neurotransmitters, such as nor- stimulants (see Box 8A.1).
adrenaline, dopamine and serotonin. This takes
place through a number of mechanisms, including 8A.3 Stimulant Novel Psychoactive
increasing release of and/or inhibiting reuptake of
these chemicals.
Substances in Europe
Different stimulants will work in different ways. Recent data from Europe also suggest greater geograph-
Cocaine prevents dopamine reuptake while amphet- ical diffusion and an overall increase in the consumption
amines increase its release. It is generally believed that of all the commonly used classes of stimulant drugs.12 As
dopamine reuptake blockade – in particular in the is the case world-wide, the main illicit stimulant drugs
143
Introduction to Stimulant Club Drugs and Novel Psychoactive Substances
available in Europe are cocaine, amphetamine, metham- and MDMA seizures are predominant in northern and
phetamine and MDMA. eastern Europe.12 There is also some evidence of
The extent of stimulant use and the types that are a potential increase in stimulant injecting (see
most common in Europe vary across countries, Overall, Box 8A.2).12
cocaine is the most frequently seized stimulant in many
western and southern countries, while amphetamines
Box 8A.1 Novel Psychoactive Substance Stimulants
Over one third of all NPS identified at a global level since 2009 are stimulants. Up to December 2021 stimulant NPS
have been the largest group of NPS identified and reported by Member States of the UN, followed by synthetic
cannabinoids.6
The UNODC has reported that the number of stimulant NPS identified over the period 2009–2017 increased
more than fourfold, from 48 new substances reported in 2009 to 206 reported in 2015. In 2017, 39% of all NPS
identified that year were stimulants (26 out of 79), mostly cathinones or other phenethylamines.7
NPS with stimulant effects belong to the following groups:8 phenethylamines, amphetamine, synthetic
cathinones or beta-keto (bk) amphetamines, piperazines, pipradrols/piperidines, aminoidanes, benzofurans,
tryptamines, 2C agents-substituted phenylethylamines, 2D agents-substituted phenylethylamines and NBome
agents-substituted phenylethylamines.
Globally, the most widely seized NPS stimulants were synthetic cathinones9 and cathinones form a significant
part of the NPS drugs with stimulant effects that are used in Europe.10
There are others which are also used, including other amphetamine-type substances. These include a number
that are novel derivatives of drugs such as 3,4-methylenedioxy-methamphetamine (MDMA), or ‘ecstasy’. These
amphetamine-type stimulants are discussed in Chapter 9.
Piperazines are also used because they have effects similar to MDMA/‘ecstasy’. N-Benzylpiperazin (BZP) is one of
the commonly used piperazines. It triggers the release of dopamine and norepinephrine and inhibits the uptake of
dopamine, norepinephrine and serotonin. BZP has only one tenth of the potency of amphetamine, but at high
doses can lead to hallucinations.11
Box 8A.2 Increase in Stimulant Injecting
There is increasing evidence of a potential rise in stimulant injecting in Europe.12 A study examining the residue of
syringes collected from the bins of street automatic injection kit dispensers and at harm reduction services in five
sentinel EU cities in 2017 (Amsterdam, Budapest, Glasgow, Helsinki and Paris) reported that injected substances
varied between and within cities but that traces of stimulants (cocaine, amphetamines and synthetic cathinones)
were found in a high proportion of the syringes tested in each of the cities. The study also showed that half of the
syringes tested contained two or more drugs; the most frequent combination being a mix of stimulant and opioid.12
The study findings may indicate a high prevalence of stimulant use among people who inject drugs. However,
the high number of syringes containing residues of stimulants could reflect the higher frequency of injecting
among stimulant users, rather than a high prevalence of stimulant use among people who inject drugs.
In some countries, there is increasing evidence of high levels of stimulant injection among people who inject
drugs. A high prevalence of synthetic cathinones injection was reported in 2014 among clients of low-threshold
programmes in Hungary (>50%).13 In 2016, in Finland, 28% of treatment entrants reported injecting as a main route
of administration of amphetamine. In Glasgow, a 2015 HIV outbreak among people who inject drugs has been
strongly linked, among other factors, to injecting cocaine.14,15
The injecting of stimulants predominates in some countries,16 as shown by data from drug services in Czechia,
France, Hungary and Latvia.21 Stimulants are reported as one of the main injected drugs in these four countries,
where the substances used include synthetic cathinones (Hungary), cocaine (France), amphetamine (Latvia) and
144
8A.3 Stimulant Novel Psychoactive Substances in Europe
Box 8A.2 (cont.)

methamphetamine (Czechia).17 Synthetic cathinones were found in a majority of syringes from Budapest and in
particular the synthetic cathinones pentedrone and MDPV18 (see also Chapter 11).
Harms of Injecting Stimulant Drugs
Injecting drugs in general is associated with high levels of harms, including increased risk of overdose and likelihood
of dependence. They are also associated with other harms. Simulants can be associated with compulsive and
frequent injecting, making their users at particular risk of the acquisition and transmission of blood-borne viruses.
To this are added the risks specifically linked to the injection of the various stimulants, which can include limb
abscesses and vein clotting, damage and recession. This places injectors at risk of septicaemia, endocarditis, deep-
vein thrombosis and other complications.
The injection of stimulants – including cocaine and synthetic cathinones – has been linked to increased risk of
HIV and HCV transmission, through increased frequency of use and sharing of injecting paraphernalia.19
Despite overall decline in Europe, in recent years localised HIV outbreaks associated with stimulant injecting
have been documented among marginalised populations of people who inject drugs in Bavaria20 and Dublin 2014–
2015 (synthetic cathinones, alpha-PVP), Luxembourg 2014–2017 (cocaine) and Glasgow 2015 (cocaine).20,21
Information from low-threshold services in the area affected suggested that there might be an association between
the increase in HIV cases and group consumption of stimulant new psychoactive substances, including synthetic
cathinones.22
Regarding the risks associated with the injection of stimulants, high-HIV risk as a result of higher levels of unsafe
sexual practices is discussed in Section 8.3.
145
Chapter
Amphetamine-type Stimulants:
8B
An Overview
8B.1 Introduction Chemically, amphetamines are weak basic drugs

(with pKa value of approximately 9.9); they also have
Amphetamine-type stimulants (ATS) are world-wide
low molecular weight. This means that they can cross
the second most popular group of drugs after canna-
cellular membranes and lipidic layers easily, reaching
bis (UNODC, 2019)23 and a significant proportion of
high levels in tissues and biological fluids with a pH
NPS with stimulant effects are ATS.
lower than blood, including saliva and sweat.36,27
The World Health Organization (WHO) defines
ATS share common properties, but their effects
amphetamine-type stimulants (ATS) as a group of
must not be seen as homogeneous. There are signifi-
drugs whose principal members include amphetamine
cant variations between the various ATS.
and methamphetamine. A range of other substances
Phenethylamines are a broad range of compounds
also fall into this group, such as methcathinone, ephe-
that share a common phenylethan-2-amine structure.
drine, pseudoephedrine, methylphenidate and
Studies have shown that phenethylamines have three
3,4-methylenedioxy-methamphetamine (MDMA).
different principal effects: central stimulant action;
Globally, seizures of ATS increased sharply from
hallucinogenic action; and ‘other’ psychoactive
the second half of the 1990s until 2001 and over the
action.28 Some produce more than one of these
period 2009–2017.24 The largest number of seizures in
effects.29
the past few years have been methamphetamine, fol-
The subjective effects of these drugs range from
lowed by amphetamine, ‘ecstasy’ type substances,
stimulant effects (e.g. amphetamine, methampheta-
other stimulants (MDPV, methcathinone, methylone,
mine), empathogenic or entactogenic effects (e.g.
several other cathinones, dimethoxyamphetamine
MDMA, considered in Chapter 9), and hallucinogenic
and several piperazines) and prescription stimulants.
effects (e.g. the 2DC series such as 2CB, the ‘D series’,
benzodifurans and others such as p-methoxymetham-
8B.2 Pharmacology phetamine and PMMA).
Amphetamine itself, as well as the ATS, are derivatives It has been suggested that the predominant actions
of a beta-phenylethylamine core structure and are of a stimulant on serotonin versus dopamine trans-
kinetically and dynamically characterised by easily porters will determine its predominant effect. For
crossing the blood–brain barrier; resistance to brain example, among the NPS ATS, it is suggested that
biotransformation; and the release of monoamine dimethylmethcathinones, 4-MA, and MMAI cause
neurotransmitters from nerve endings. All the struc- entactogenic/empathogenic effects similar to MDMA,
tural features that enable these physiological charac- whereas 3-MMC, 5-IT, and N-methyl-2-AI have more
teristics are present in the simplest derivative, stimulant-type properties like amphetamine.30,31
amphetamine, as well as other ATS.25
Pharmacokinetically, amphetamines have a high 8B.3 Medical and Other Legitimate
oral bioavailability and low plasma protein binding
(typically less than 20%). Their elimination half-lives Uses of Amphetamines
range from 6 to 12 hours and renal and hepatic elim- The clinical uses of amphetamines are currently
ination occurs. Many amphetamines are extensively limited. They have been utilised in the treatment of
metabolised by the liver, but a significant proportion adults with attention deficit hyperactivity disorder
of several of these drugs is usually excreted without (ADHD).32 Dexedrine (dexamphetamine sulphate)
prior biotransformation.36,26 is used in the treatment of narcolepsy and ADHD.
146
8B.7 High-risk Injecting and Sexual Behaviours
Methylphenidate has a similar chemical structure The effects of ATS generally appear 30–40 minutes
and effects to amphetamine and is also used for the after ingestion and can last for 4–8 hours, but there are
treatment of ADHD. Methylphenidate is sometimes variations, depending on the ATS used, the dose, the
misused, including as a ‘smart drug’ or cognitive potency and the length of the effects, as well as tolerance.
enhancer. In recent years, ethylphenidate, an NPS Some new ATS, such as the 2 desoxy form
that mimics the effects of methylphenidate, has been (2-DPMP,) have particularly long-lasting effects and
manufactured in clandestine laboratories and some- have longer half-lives.37,38,39
times sold on the illicit market or the Internet. There are also wide differences in physiological
effects, with paramethoxyamphetamine (PMA) for
8B.4 Prevalence and Patterns of Use example, having a much steeper dose–response
curve than MDMA.
The 2019 World Drug Report has confirmed that after
cannabis, stimulants continue to constitute
the second most widely used category of drugs glo- 8B.6 Desired and Unwanted
bally. The type of stimulants used, however, varies Subjective Effects
considerably across the different sub-regions,33
mainly cocaine, amphetamine, methamphetamine of Amphetamine-type Stimulants
and ‘ecstasy’; polydrug use is common. Overall, ATS are used for their stimulant, euphoric,
The WHO suggested that there is no typical profile anorectic and, in the case of some substances,
for ATS users and there is a wide range of desired empathogenic/entactogenic and hallucinogenic prop-
effects from ATS. ATS are used by students and erties. ATS produce feelings of euphoria and relief
drivers to stay awake and concentrate, used by athletes from fatigue; they may improve performance on sim-
to enhance performance, and used at parties and clubs ple tasks and increase activity levels.3 It is thought that
to increase sociability.34 ATS are also used to increase the misuse liability of amphetamines is related to their
confidence and lift mood, lose weight and increase sex euphorigenic effects.3,40 A systematic review of the
drive. A WHO 1997 report on ATS classified the qualitative research evidence showed the heteroge-
patterns of use in the following way:35 neous nature of ATS users and the complicated
1. Instrumental use. Amphetamines are exploited by dynamic of individual, social and environmental fac-
users to achieve desired goals, such as improve tors that shape different consumption trajectories.41
concentration and ward off fatigue. Unwanted subjective effects of amphetamines
include increased anxiety, insomnia, irritability,
2. Sub-cultural/recreational use. Their stimulant
aggression, restlessness and paranoia, and in some
properties are exploited to allow the user to
cases violent behaviour. Psychotic symptoms can
remain active for longer periods in social and
occur when using amphetamines and can last for
recreational settings, such as at music and dance
days or weeks. The ‘come-down’ from ATS, which is
events and all-night drinking venues.
distinct from the physiological withdrawal observed in
3. Chronic use. For several reasons, including
many dependent users, can last up to a few days; users
craving, tolerance and withdrawal, some
may feel tired, anxious, depressed and some instances
amphetamine users develop chronic patterns of
may experience restlessness, insomnia, muscle ache
consumption to relieve unwanted effects of
and fasciculation. Its intensity will depend on the
abstinence or in the context of dependence.
substance, the dose consumed and the individual.
Serotonin syndrome or toxicity is a potential risk (see
8B.5 Routes of Ingestion and Dosing Section 8B.9.2 for details on the serotonin syndrome).
Depending on the substance, ATS can be taken orally,
by insufflation, smoking or injected. 8B.7 High-risk Injecting and Sexual
The association between route of administration
and risks associated with use has been well docu-
Behaviours
mented. Smoked and injected ATS are more likely to There is evidence that injection of ATS is associated
lead to dependence than oral use,36 while injecting with high levels of infection risk.42
also increases the risks of transmission of blood-borne • People who inject ATS do so more frequently than
viruses.36 those who inject other substances such as heroin.53
147
Amphetamine-type Stimulants: An Overview
• There is evidence that the injecting of ATS is are associated with a sympathomimetic
associated with a high HIV and blood-borne virus toxidrome.
(BBV) risk behaviour. In the UK for example, data • Serotonergic effects predominate in toxicity of
from the Unlinked Anonymous Monitoring stimulants that provoke central serotonin release,
(UAM) survey of people who inject drugs (PWID) or serotonin receptor agonists and therefore.50
showed that people who injected amphetamine Our knowledge of new ATS remains limited, although
and ATS as their main drug were more likely to effects are expected to be broadly similar to the drugs
report the sharing of injecting equipment than they mimic. However, within each of these classes of
those who reported using other main drugs.53 ATS, there are variations between the various com-
Those who reported injecting ATS alone as their pounds based on the intrinsic toxicity of the substance
main drug were also significantly less likely to have consumed, the severity of effects and also their dur-
ever had an HIV test or a hepatitis C test than ation. There are however differences, including differ-
those who reported other main drugs. ences between the various new ATS. For example:
ATS have also been linked to high-risk sexual behav- • There are reports of symptoms of 2-DPMP
iours, and risks related to HIV/AIDS and other blood- toxicity still being manifested 5–7 days after
borne infections and sexually transmitted diseases. ingestion.51
Some have argued that ATS can impair judgement • Phenethylamines in the ‘D series’ are described as
and inhibition, and lead people to engage in high-risk longer lasting, more potent and more liable to
sexual behaviours.43 Some ATS, such as metham- induce vasoconstriction than other members of
phetamine, has been reported to have pro-sexual the phenethylamine family.61
effects, as discussed in Chapter 10. These drugs are
• PMA, PMMA and 4-methylthioamphetamine have
sometimes used by gay men and other men who have
been more often associated with incidental deaths
sex with men, among other groups of people, as they
than other phenethylamines. PMA and PMMA are
are reported to increase sexual desire and make sexual
known to have a particularly high toxicity.52
intercourse less painful and more pleasurable44 (see
Chapter 10). Other factors that have an effect on the severity of
acute ATS-related harm include the following:36
• Dose and frequency of use;
8B.8 Mortality • Route of administration;
Mortality among amphetamine users is relatively low
• Environmental conditions (including
in comparison with other ‘problem drugs’, such as
temperature, stressful environment and
opioids. It is associated with longer drug careers and
overcrowding, intense physical activity, too much
with injecting.45 Deaths are often caused by blood-
or too little fluid intake);
borne viruses and infectious diseases or damage to the
• Individual variations and characteristics
cardiovascular system. Non-fatal overdoses related
to amphetamine use, on the other hand, are (including age, ethnicity, gender, physical and
common.47,46,47 Amphetamine overdoses constitute mental health co-morbidities, co-ingestion of
only a small proportion of fatal overdoses, and are more than one substance/poly-use, by-products of
mainly associated with co-ingestion of opioids.48 chemical synthesis).
Direct amphetamine-related mortality typically
occurs as a result of heart attacks, seizures, arrhyth- 8B.9.1 Features of Acute Toxicity
mias or respiratory failures.58 Deaths due to NPS with Chapters 9–11 give detailed information on the fea-
stimulant effects have been reported.49 tures of acute toxicity of selected drugs. Overall, ATS
increase heart rate, blood pressure and breathing
8B.9 Acute Harms rates, constrict blood vessels, dilate pupils and release
Stimulants have actions on multiple receptor sites glucose and lipids into the bloodstream.53 The tox-
within the central nervous system, with patterns of icity, neurotoxicity and cardiotoxicity of amphet-
effects varying between drugs. amines has been well documented, as has its impact
• Predominantly stimulant drugs inhibit
on mental health.47
monoamine (especially dopamine) reuptake and The acute toxic effects of amphetamine-type
substances are summarised in Box 8B.1.
148
8B.9 Acute Harms
Box 8B.1 The Acute Toxic Effects understood;36 it may arise from both acute and
of Amphetamine-type Substances chronic use of amphetamine.36,66 (For more informa-
tion on hyperthermia and its management, see
Sweating Chapter 10, Sections 10.11.2 and 10.11.2.1).
Dilated pupils
Agitation 8B.9.2 Serotonin Syndrome
Confusion Serotonin syndrome is a clinical condition that occurs
Headache as a result of a drug-induced increase in intrasynaptic
Vomiting serotonin levels, primarily resulting in activation of
Abdominal pain serotonin 2A receptors in the central nervous
Tremor system.60 Serotonin syndrome classically presents as
Anxiety the triad of autonomic dysfunction, neuromuscular
Seizures
excitation, and altered mental status.61
It is argued by some that the term ‘serotonin
Hallucinations or delusions
toxicity’ is preferable to ‘serotonin syndrome’, espe-
Chest pain
cially in relation to more severe cases, because it
Tachycardia describes the serotonin excess more accurately.71,62
Narrow-complex tachycardias In this document, the term ‘serotonin syndrome’
Dyspnoea and ‘serotonin toxicity’ are used interchangeably.
Systemic hypotension Serotonin syndrome is a potentially life-
Hypertension threatening adverse reaction to the use of particular
Ventricular tachycardia drugs (illicit or prescribed) or the interaction between
Ventricular fibrillation drugs. A number of ATS used for recreational pur-
poses are associated with serotonin syndrome, includ-
Hyperpyrexia
ing (but not limited to) MDMA, MDPV, PMA and
Metabolic acidosis
mephedrone, as well as methamphetamine and
Serotonin syndrome cocaine. There is also a dose–effect relationship; high
doses or repeated doses of MDMA, for example,
intensify serotonin release.63 In addition, the simul-
There is a risk that the use of amphetamine taneous use of multiple serotonergic substances (e.g.
induces strokes and heart attacks because it raises ecstasy and methamphetamine) increases the risk of
blood pressure and constricts blood vessels. Overall, serotonin syndrome.64 Drugs used therapeutically are
there is evidence that psychostimulant use is associ- also associated with serotonin syndrome (see
ated with increased stroke risk, including fatal strokes Table 8B.1).65,66,67,68,69,70,71,72,73,74,75
among young adults. It has been recommended that It has been reported that the syndrome occurs in
in cases of haemorrhagic stroke among young adults, approximately 14–16% of individuals who have over-
psychostimulant use should be considered.54 dosed on SSRIs,76 but a single therapeutic dose of SSRI
People at risk of heart disease or strokes are has also been associated with it.77 The use of illicit
more likely to experience such complications.36,55 substances with therapeutic drugs increases the risks of
Hyperthermia is one of the most life-threatening acute serotonin toxicity. There is evidence that some users
physiological consequences of ATS intoxication, with deliberately use monoamine oxidase inhibitors
case reports suggesting that its incidence and severity (MAOIs) to enhance the effect of psychoactive sub-
varies between drugs, with those most implicated being stances and/or help during the recovery period. For
methamphetamine, MDMA, MDEA and PMA.36,56,57 example, in an Australian study of ‘ecstasy’ users, 1 in
Hyperthermia associated with these drugs appears 25 reported deliberately combining ecstasy and
to be responsible for fatal complications, including moclobemide.77,78
rhabdomyolysis, acute renal failure, disseminated Three features have been described as critical in
intravascular coagulation, multiple organ failure and understanding the disorder:
acidosis.36,66,58,59 Hepatocellular injury caused by • Serotonin syndrome is a predictable consequence
ATS is well established, although not yet completely of excess serotonergic agonism of central nervous
149
system receptors and peripheral serotonergic Table 8B.1 Clinical symptoms of the serotonin syndrome:
severity spectrum
receptors;
• Excess serotonin produces a spectrum of clinical Mild Patients can be afebrile. Tachycardia possible,
features; shivering, diaphoresis, mydriasis
• The clinical manifestations range from the barely Moderate Tachycardia, hypertension, hyperthermia (40°
C is common), mydriasis, hyperactive bowel
perceptible to lethal. Signs of excess serotonin sounds, diaphoresis, hyperreflexia and clonus
range in mild cases from tremor and diarrhoea to (considerably greater in lower extremities
neuromuscular rigidity and hyperthermia in life- than upper); patient may exhibit horizontal
ocular clonus; mild agitation or
threatening cases.79 hypervigilance, slightly pressured speech;
Serotonin syndrome has three classic features of: repetitive rotation of the head with the neck
held in moderate extension
• Mental state changes
Severe Severe hypertension and tachycardia that
• Autonomic hyperactivity might deteriorate abruptly into frank shock.
• Neuromuscular abnormalities Patient may have agitated delirium, muscle
rigidity and hypertonicity and increase in
Not all patients with the syndrome manifest signs and muscle tone (considerably greater in lower
symptoms of all three features.90 In a study of 2,222 extremities than upper). Muscle hyperactivity
may produce a core temperature of more
consecutive cases of self-poisoning with serotonergic than 41.1°C in some cases. Metabolic acidosis,
drugs, the clinical findings that had a statistically sig- rhabdomyolysis, elevated levels of serum
nificant association with serotonin syndrome were aminotransferase and creatinine, seizures,
renal failure, disseminated intravascular
primarily neuromuscular (including hyperreflexia, coagulopathy.
inducible clonus, myoclonus, ocular clonus, spontan-
eous clonus, peripheral hypertonicity and shivering),
as well as autonomic derangement (including tachy-
cardia on admission, hyperpyrexia, mydriasis, dia-
phoresis and diarrhoea) and mental health/ Box 8B.2 Therapeutic Drugs Used that Are
psychiatric symptoms (agitation and delirium).80 Associated with Serotonin Syndrome
There is also evidence that, in severe cases, stroke,
Monoamine oxidase inhibitors (MAOIs); tricyclic
myocardial infarction, severe hyponatraemia, antidepressants; selective serotonin reuptake
rhabdomyolysis, disseminated intravascular coagula- inhibitors (SSRIs); opiate analgesics; tramadol; over-
tion (DIC) and renal failure may occur. the-counter cough medicines; antibiotics; weight-
Hepatocellular damage has also been reported.71 reduction agents; antiemetics; antimigraine agents;
The clinical symptoms are on a spectrum of sever- herbal products
ity, from mild to life-threatening (Table 8B.1).90
There is a dose–effect relationship, with more
severe cases involving a combination of serotonergic
drugs, rather than a single one. The simultaneous use including mephedrone, methylenedioxypyrovaler-
of multiple stimulants increases the risk of serotonin one (MDPV),78,95,96,97,98,99 butylone, methylone110
toxicity and problems relating to sympathomimetic and phenethylamines (2C-I).100 The potentially
over-stimulation, such as dehydration and life-threatening interaction may have serious
hyperthermia,81 and cardiovascular problems,82 as implications for people on antidepressants who
well as increasing the chances of neurotoxicity.83 The also use these recreational substances.101
risk is not only increased when two serotonergic psy- Serotonin toxicity generally presents abruptly and
choactive substances are co-ingested, but also when can progress quickly, sometimes within minutes,102
one psychoactive substance is ingested with a range of especially when a combination of serotonergic drugs
serotonin-releasing illicit drugs as well as a range of has been used.71 It has been suggested that patients
medications (Box 8B.2). 84,85,86,87,88,89,90,91,92,93,94 with serotonin toxicity will develop clinical manifest-
Monoamine oxidase inhibitors (MAOIs) are ations within 6 hours.71 Where a combination of
strongly associated with serotonin syndrome or drugs has been used, signs and symptoms will start
toxicity, especially when these are used in when the second drug reaches effective blood levels,
combination with a number of other drugs, usually after one or two doses.71
150
8B.10 Management of the Acute Harms Associated with the Use of Amphetamine-type Stimulants
8B.10 Management of the Acute It has been argued that when assessing a patient
with serotonin syndrome, the key elements of the his-
Harms Associated with the Use tory include the quantity and type of drugs ingested
of Amphetamine-type Stimulants and the evolution and rate of progression of
symptoms.104 Boyer et al. suggest that clinicians should
consider serotonin syndrome for patients who present
8B.10.1 Identification and Assessment with tremor, clonus or akathisia with no additional
of Acute Toxicity extrapyramidal signs, after consideration of the patient
Chapters 9–11 provide detailed information on the history and physical examination.90
identification and diagnosis of acute toxicity specific Three diagnostic classification systems are avail-
to each drug discussed. Overall, for ATS, clear airway able, the Sternbach (SC), Radomski (RC) (see
management and adequate ventilation in the case of Box 8B.3) and Hunter (HC) criteria (see
unconsciousness should be carried out. In the case of Box 8B.4).105,106,107 These classification systems try
cardiac arrest, cardiopulmonary resuscitation (CPR) to reflect symptoms and symptom constellations
should be continued for at least 1 hour and stopped thought to be indicative of serotonin syndrome.
only after discussion with a senior clinician. Whereas SC and RC draw on neuromuscular, cogni-
Prolonged resuscitation for cardiac arrest is tive and autonomous symptoms, HC focuses on
recommended following poisoning, as recovery with neuromuscular symptoms such as clonus in its vari-
good neurological outcome may occur. This should be ous forms, hyperreflexia and tremor.108
the case for all overdoses of recreational drugs, par- Diagnostic criteria for serotonin syndrome have also
ticularly as most patients are young and fit. been adapted from Radomski et al.109 and identified the
The benefits of gastric decontamination are uncer- following (Box 8B.3):
tain, but it is suggested that oral activated charcoal be
used if any amount of an ATS has been ingested
within 1 hour, provided the airway can be protected. Box 8B.3 Features of serotinin syndrome
It also recommends that asymptomatic patients are 1. Manifestation of at least four major symptoms or
observed for at least 4 hours, or 8 hours for patients three major symptoms plus two minor ones
who have ingested sustained-release preparations. Mental (Cognitive and Behavioural) Symptoms
• Major symptoms: confusion, elevated mood, coma
8B.10.2 Management of Serotonin or semi-coma
• Minor symptoms: agitation and nervousness,
Syndrome insomnia
It has been suggested that people with serotonin syn- Autonomic Symptoms
drome related to the use of psychoactive substances such • Major symptoms: fever, hyperhidrosis
as ecstasy usually present to hospitals with advanced • Minor symptoms: tachycardia, tachypnoea and
symptoms because some of the early, mild signs of the dyspnoea, diarrhoea, low or high blood pressure
syndrome are often perceived as normal drug Neurological Symptoms
effects.78,112 • Major symptoms: myoclonus, tremors, chills,
There are no laboratory tests to confirm the diagno- rigidity, hyperreflexia
sis. The diagnosis of serotonin syndrome remains chal- • Minor symptoms: impaired co-ordination,
lenging since it can only be made on clinical grounds. mydriasis, akathisia
There is no objective diagnostic test. Yet, it has been 2. These symptoms must not correspond to
suggested that failure to diagnose signs of serotonergic a psychiatric disorder, or its aggravation, that
toxicity can turn mild and relatively harmless drug occurred before the patient took the
interactions into life-threatening, catastrophic events.103 serotonergic agent.
Serotonin syndrome is difficult to diagnose for 3. Infectious, metabolic, endocrine or toxic causes
a number of reasons, including the variability in clin- must be excluded.
ical manifestations, lack of awareness of the syndrome 4. A neuroleptic treatment must not have been
and limitations of the diagnostic criteria, which in introduced, nor its dose increased, before the
symptoms appeared.110
turn may contribute to the lack of recognition.71
151
Box 8B.4 Hunter Serotonin Toxicity Criteria this, and there is a risk of convulsions as serotonin
toxicity lowers the seizure threshold.
The ‘Hunter Serotonin Toxicity Criteria: decision rules’111 An important part of the clinical management is
is based on the presence or absence of the seven clinical control of agitation, autonomic instability and
features below (see Figure 8.1). hyperthermia.90,117 In moderate cases of serotonin
Of all the clinical features, clonus was considered the
syndrome, patients may have cardiorespiratory
most important sign (spontaneous, inducible and ocular).
abnormalities and pyrexia, which should be treated
IF (spontaneous clonus = yes)
aggressively.71 Death of patients with serotonin syn-
THEN serotonin toxicity = YES
drome is normally due to hyperpyrexia-induced
ELSE IF (inducible clonus = yes) multi-organ failure and it is therefore essential to
AND [(agitation = yes) OR (diaphoresis = yes)] rapidly lower the patient’s temperature if it exceeds
THEN serotonin toxicity = YES 39°C (ice-baths and internal cooling devices are
recommended wherever available). Critically ill
ELSE IF (ocular clonus = yes)
patients may require neuromuscular paralysis, sed-
AND [(agitation = yes) OR (diaphoresis = yes)]
ation and intubation.123
THEN serotonin toxicity = YES
It has been suggested that for severe cases, esmo-
ELSE IF (tremor = yes) AND (hyperreflexia = yes) lol or nitroprusside may be used along with sedation
THEN serotonin toxicity = YES and paralysis with non-depolarising agents,118 but
more research is needed. Intubation and intensive
ELSE IF (hypertonic = yes) AND (temperature >38˚C)
care unit admission should be considered in severe
AND [(ocular clonus = yes) OR (inducible clonus =yes)] cases.4,61
THEN serotonin toxicity = YES Life-threatening serotonin syndrome may occur
in 50% of cases of combined ingestion of an MAOI
Figure 8.1 The ‘Hunter Serotonin Toxicity Criteria: decision
rules’ (in the presence of a serotonergic agent) and an SSRI recreational drug, such as ecstasy. Rapid
deterioration generally occurs and it has been
recommended that patients be transferred to inten-
sive care; toxicology investigations are also strongly
recommended.71
Most cases of serotonin syndrome are mild and The long half-life of some MAOIs (e.g. phenele-
may be treated by withdrawal of the offending zine, tranylcypromine) means that users could still be
agent and supportive care. Most mild cases will susceptible to interactions with ATS such as ecstasy
resolve spontaneously within 24 hours. Patients up to 2 weeks after they have stopped using the
with moderate or severe cases of serotonin syn- drug.119,120
drome require hospitalisation. Although many The principal differential diagnosis is neurolep-
cases will resolve within 24 hours after cessation tic malignant syndrome,121 however, their treat-
of the drugs involved and initiation of treatment, ments are distinct.122 Whereas serotonin syndrome
clinical symptoms may persist for longer in cases is associated with the use of a serotonergic agent,
involving serotonergic drugs with long duration of neuroleptic malignant syndrome is associated with
action, active metabolites or long half-lives.90 If the use of dopamine antagonists, which include
serotonin syndrome is recognised and complica- first- and second-generation antipsychotics, as well
tions are managed appropriately, the prognosis is as antiemetics.
favourable.112 In contrast to neuroleptic malignant syn-
Benzodiazepines are the standard treatment for drome, the onset of serotonin syndrome is usually
agitation and tremor. Some have advised admission rapid, although differential diagnosis between
to the hospital for cardiac monitoring.113 It has been serotonin syndrome and neuroleptic malignant
suggested that 5-HT2A antagonists (cyproheptadine syndrome is not always clear-cut.123 Both sero-
and chlorpromazine) could be used in more severe tonin syndrome and neuroleptic malignant syn-
cases,71,114,115,116 as they have been successfully used drome can present with nonspecific laboratory
to treat serotonin syndrome following overdose. abnormalities including metabolic acidosis,
However, there are no controlled trials to support rhabdomyolysis, transaminitis, elevated creatinine,
152
8B.11 Harms Associated with Chronic Use of Amphetamine-type Stimulants
myoglobinuria, leukocytosis, and elevated creatine discussed in Chapters 9–11. For amphetamine
kinase.124 withdrawal127 (amphetamine, dextroamphetamine
and methamphetamine), when heavy chronic users
8B.11 Harms Associated with Chronic discontinue their use abruptly, many will report time-
limited withdrawal symptoms that commence up to
Use of Amphetamine-type Stimulants 24 hours after their last dose and can last for three
weeks or more. These can be sufficiently severe to
8B.11.1 Dependence and Withdrawal result in relapse to drug use.
The WHO has estimated that 11% of ATS users Phases of withdrawal include the initial ‘crash’,
become dependent and may require specialist inter- which resolves within approximately 1 week.128,129
ventions. However, even occasional users may experi- Severe symptoms include increased sleep (but of
ence physical, social or psychological harms and may poor quality), increased appetite and a cluster of
progress to more harmful or dependent drug use.125 depression-related symptoms. Phase 2 is a sub-acute
Dopamine dysfunction has been reported as the protracted set of withdrawal symptoms which are not
main neurobiological mechanism in amphetamine well defined but include continued sleep disturbances
dependence.64 Amphetamines in general have low and increased appetite.139,140 Some symptoms may
protein binding, which gives high bioavailability and continue for weeks or months.
supports their easy diffusion from the plasma to the The WHO Technical Brief 2 on ATS136 outlines
extravascular compartment.38 It has been reported three phases of ATS withdrawal. These are set out in
that people dependent on amphetamines may have Table 8B.2.136
a larger volume of distribution and longer plasma
elimination half-life relative to drug-naïve individuals 8B.11.2 Physical and Psychiatric/
(6 versus 4 l/kg). This is probably due to tissue seques- Psychological Harms from Chronic Use
tration as a result of the development of pharmaco- It is clear that amphetamine has a cardiotoxic
kinetic tolerance to the drug.36,38 effect and has been associated with chronic car-
Dependence on ATS is characterised by increased diac pathology. The risks of coronary artery dis-
tolerance and withdrawal symptoms on cessation, ease are probably compounded by the chronic
which include sleep and appetite disturbances, fatigue, effect of amphetamines (including methampheta-
depression, irritability, craving, depression, anxiety mine) in the heart tissue, as well as the effects of
and agitation. It is also characterised by the inability amphetamine intoxication, and this may be
to reduce drug use despite significant negative social, a cause of premature mortality, although other
health and psychological problems associated with use. factors – such as tobacco and alcohol use – are
Amphetamine withdrawal is extremely common often additional factors.130 Hepatocellular damage
in people who are dependent on amphetamine.126 may also occur from the chronic use of
There are variations in the level of intensity as amphetamine.36,66
Table 8B.2 Phases of amphetamine-type stimulant (ATS) withdrawal
Phase Time since last stimulant use Common signs and symptoms
‘Crash’ Typically commences 12–24 hours after last Exhaustion, fatigue, agitation and irritability, depression,
amphetamine use and subsides by 2–4 days muscle ache, akathisia, sleep disturbances (typically
increased sleep, although insomnia or restless sleep may
occur)
‘Withdrawal’ Typically commences 2–4 days after last use, Strong cravings, fluctuating mood and energy levels,
peaks in severity over 7–10 days and then alternating between irritability, restlessness, anxiety and
subsides over 2–4 weeks agitation, fatigue, lack of energy, may mimic narcolepsy
‘Extinction’ Weeks to months (requires integration between Gradual resumption of normal mood with episodic
withdrawal and post-withdrawal services) fluctuations in mood and energy levels, alternating between
irritability, restlessness, anxiety, agitation, fatigue, lack of
energy, episodic cravings, disturbed sleep
153
Amphetamine dependence has been associated varied considerably between drugs, but was
with mood disorders, depression and anxiety.131 a significant problem in amphetamine and metham-
The prolonged use of ATS results in a series of phetamine poisoning, where it was seen in a large
mental and physical symptoms that include anxiety, proportion of presentations with acute amphetamine
confusion, insomnia, mood disturbances, cognitive toxicity. The number of cases in this study of presen-
impairments, paranoia, hallucinations and tations linked to NPS use was small, but suggests that
delusion.132 psychosis was rare in mephedrone and methedrone
ATS are also linked to psychotic disorders,133 poisoning, but occurred frequently with tryptamines,
attention deficit hyperactivity disorder (ADHD)134 MDPV and the synthetic cannabinoid receptor agon-
and antisocial personality disorder.135 It has also ists; psychosis was also common in presentations
been associated with sexual risk behaviour and involving methylphenidate.139
increased risk of HIV57 and suicide.136 Studies have suggested that there are similar-
The use of sympathomimetic drugs like amphet- ities in clinical presentation between amphet-
amine, methamphetamine and cocaine can induce amine-induced psychosis and schizophrenia, but
acute psychosis. Overall, a wide range in prevalence the psychotic symptoms may be due solely to the
of drug-induced psychosis among regular drug heavy use of amphetamine, or heavy use of
users has been reported, ranging from 8–46% for amphetamines may underlie a vulnerability to
amphetamine.137 schizophrenia.149 There are some indications that
A minority of people who use amphetamines will the two disorders may be linked genetically, with
develop a psychotic episode that requires care from a study suggesting that relatives of users of meth-
emergency departments or psychiatric units.138 amphetamine with a lifetime history of amphet-
A Cochrane review of treatment for amphetamine amine psychosis are five times more likely to have
psychosis noted that it is difficult to determine in schizophrenia than methamphetamine users with-
any robust way the prevalence of amphetamine- out such a history.140
induced psychosis at local or global levels. The epi-
demiology of the disorder indicates that patients with 8B.12 Management of Harms
the symptoms of psychosis due to amphetamine pre-
sent to emergency departments and psychiatric units Associated with Chronic Use
at low rates compared with the census of all patients; it
also reports that significant psychotic symptoms are 8B.12.1 Identification and Assessment
common to users with more extensive and severe
patterns of amphetamine use.149 Psychosis seems to
of Amphetamine-type Stimulant Use
be particularly associated with methamphetamine and Dependence141
use. Chapters 9–11 will look in greater detail at dependence
Common symptoms of amphetamine-induced to various ATS. Overall, the diagnosis of amphetamine
psychosis include paranoid and/or persecutory delu- use and dependence is based on criteria listed in the
sions, as well as auditory and visual hallucinations, International Classification of Diseases (ICD-11). See
with extreme agitation. However, even among those Box 8B.5.
who use amphetamine frequently, psychotic symp- Daily use of amphetamine is considered to be
toms are more likely to be sub-clinical and not to the most harmful pattern; it often has adverse
require highly intensive interventions. The develop- outcomes for the health and psychosocial func-
ment of psychosis and sub-clinical symptoms is tioning of the user. However, the use of amphet-
related to the cumulative quantity of amphetamine amines on a weekly basis or more has been
ingestion, or the individual’s lifetime history of associated with adverse effects, and injecting and
amphetamine use.149 smoking are associated with higher risk.
A European case series investigating psychosis Typically, the threshold signalling a high risk of
associated with acute recreational drug toxicity developing dependence starts after 6–12 months
found that psychosis was present in 6.3% of presenta- of weekly use, although there are reports of users
tions to emergency departments in acute recreational experiencing problems even after relatively low
drug toxicity cases (or 348 of 5,529 cases). Psychosis levels of exposure.47
154
8B.12 Management of Harms Associated with Chronic Use
Box 8B.5 International Classification intervention. In addition, current evidence does not
of Diseases (ICD-11) support a single treatment approach that is able to
tackle the multi-dimensional facets of addiction and
Stimulant Dependence Including Amphetamines,
to yield better outcomes to resolve the chronic relaps-
Methamphetamine or Methcathinone
ing nature of addiction and its consequences.143,144
Stimulant dependence including amphetamines,
Nonetheless, a comparison between different types of
methamphetamine or methcathinone is a disorder
of regulation of stimulant use arising from repeated behavioural interventions by the Cochrane review154
or continuous use of stimulants. showed results in favour of treatment with some form
The characteristic feature is a strong internal of contingency management in respect to reducing treat-
drive to use stimulants, which is manifested by ment drop-outs and decreasing use and increasing
impaired ability to control use, increasing priority abstinence.154 The more comprehensive behavioural
given to use over other activities and persistence of treatment, in which a contingency management pro-
use despite harm or negative consequences. These gramme is provided in addition to a community
experiences are often accompanied by a subjective reinforcement approach, had significantly better results
sensation of urge or craving to use stimulants. when compared to groups of patients receiving drug
Physiological features of dependence may also be
counselling or behavioural treatment only, without the
present, including tolerance to the effects of
added incentive programme involving vouchers to be
stimulants, withdrawal symptoms following
cessation or reduction in use of stimulants, or exchanged for goods contingent on cocaine-negative
repeated use of stimulants or pharmacologically urine samples.154
similar substances to prevent or alleviate withdrawal The Cochrane review’s conclusions in terms of
symptoms. implication for practice were that, until further stud-
The features of dependence are usually evident ies are available, clinicians may consider contingency
over a period of at least 12 months but the diagnosis management techniques as a good treatment
may be made if stimulant use is continuous (daily or approach, provided this can be replicated in
almost daily) for at least 1 month.142 a particular therapeutic setting. However, desired out-
comes will not be achieved if the patient’s readiness
for treatment and change is not managed and
8B.12.2 Stepped Care addressed. Treatment interventions need to be
adequate to the particular stage of recovery a patient
for Amphetamine-type Stimulant Users is in at the time she or he seeks treatment.154
The WHO Technical Brief on ATS90 recommends The Cochrane review suggests that currently, the
that services for ATS users are provided at a series of best results for treating psychostimulant dependence
levels, as set out in Table 8B.3. are those of behaviour treatment with contingency man-
agement, in association with community reinforcement
8B.12.3 Psychosocial and Pharmacological and workplace behaviour interventions, but these have
Support for the Management limitations. Reductions in the amount or frequency of
use is a benefit, but short-term reduction is of little
of Dependence lasting value. A patient must make effective changes in
At the time of writing, psychosocial interventions his/her life, including sustained abstinence and the abil-
remain the best treatment option for the management ity to work and maintain successful relationships with
of amphetamine dependence.64 others. The nature and amount of treatment must be
based on the range of problems a given patient faces. The
8B.12.3.1 Psychosocial Interventions review therefore concludes from the best available evi-
For details on psychosocial interventions see Chapter 2. dence, clinicians should take into account the fact that
Data are available on psychosocial interventions the best treatment has to match the patient’s needs.154
specific to stimulants and/or ATS. A Cochrane review A review has recently looked at the contingency
of the psychosocial interventions for cocaine and psy- management (CM) provided at the same time as
chostimulant amphetamine-related disorders pharmacological interventions and shown that CM
reported little significant behavioural changes, with and medication as treatment for stimulant misuse
reductions in rates of consumption after an disorder could act synergistically and enhance each
155
Table 8B.3 Stepped Care for Amphetamine-type Stimulant Users
Steps Type of user suited Activities/interventions

to intervention
Step 1 Occasional ATS users believed to Personal care activities: Self/family care in reducing/stopping drug
be at relatively low risk use. Self-help groups, informal community-based care. Information
about the risks of drug use, brief counselling, peer outreach and
education, drop-in centres, skills and vocational training,
rehabilitation and reintegration services
Step 2 Problem’ ATS users Drug services in primary healthcare settings: assessment, brief
counselling, harm reduction information, needle and syringe
programmes, referral to specialist services if required, assistance with
basic symptomatic detoxification and withdrawal. Referral back to the
community for support, rehabilitation and reintegration services or
referral to expert care
Step 3 Heavy/dependent ATS users Specialised drug dependence clinical care: Assessment of
dependence, pharmacologically assisted withdrawal, harm reduction,
needle and syringe programmes, outpatient and/or inpatient or
residential treatment and specialised counselling, referral to
rehabilitation and reintegration services, and back to the community
for support
Activities to be All users of ATS Case management and counselling are important at every stage –
undertaken at though the exact technique and intensity will depend on the profile
every step of the ATS user
Also important is the provision of opportunities for ATS users to
undergo vocational training and assistance to gain employment, as
well as improve family relations, deal with legal problems and assist in
the development of new recreational activities and social networks in
the community
other’s effect. The study suggests that combining CM The WHO Technical Brief 278 suggests that crisis
and medications may be a key strategy for effective interventions may be needed in some instances for
treatment, but more research is needed.145 psychiatric symptoms, such as persecutory delusions
There is also some early evidence that CM, when or perceptual disturbances. It also recommends brief
given in addition to behavioural activation, is feasible interventions, targeting ATS users to engage them in
and acceptable to people who use treatment services a discussion about their substance use and steer the
and may be an option to augment the sustained impact discussion to encourage a person to decide if they
of CM for this population, but again more research is want to change their behaviour. Brief interventions
needed.146 on their own have been shown to be successful at
A randomised controlled trial (RCT) of promoting behaviour change and can often be used
Mindfulness-Based Relapse Prevention for Stimulant as the first stage of more intensive treatment if needed.
Dependent adults provided in conjunction with contin- Information and counselling may also be needed, and
gency management as a primary intervention approach a variety of approaches have been used from client-
for stimulant dependence, found that this may be effect- centred to open-ended counselling.136
ive in reducing stimulant use among stimulant- There has recently been interest in the role of
dependent adults with mood and anxiety disorders.147 exercise as a potential treatment for substance use
We know less about the efficacy of other treat- disorder. An RCT comparing an exercise dose with
ment approaches. A review of cognitive behav- a health education dose aimed at stimulant users in
ioural treatment (CBT) for amphetamine-type residential treatment services found significantly
stimulant disorders reported that there currently lower probability of relapse to stimulant use in the
is not enough evidence to establish the efficacy of exercise group versus the health education group and
CBT for ATS-use disorders, because of a paucity significantly fewer days of stimulant use among those
of high-quality research in this area currently.148 who reported positive effects for exercise. The authors
156
8B.12 Management of Harms Associated with Chronic Use
call for further research, including research on exer- dexamphetamine suggest its benefit on secondary
cise dose sufficient to produce a significant treatment outcomes such as treatment retention, but not for
effect.149 Similarly, it was also shown that patients reducing amphetamine use. Six other medicines indi-
with methamphetamine use disorder in early recovery cate the potential for efficacy, but the number of
who participated in a structured exercise programme, studies is too small to draw conclusions.158
compared to a structured health education pro- The findings were similar to a Cochrane review of
gramme, demonstrated a greater improvement in the efficacy of psychostimulant drugs for amphet-
depressive symptoms.150,151 More research is needed. amine abuse or dependence which concluded that it
Gender differences have been described by a few does not support the use of psychostimulant medica-
studies. Some have argued that there is some evidence tions at the tested doses as a replacement for amphet-
of sexual dimorphism in response to stimulants, with amines. The review also added that these conclusions
some preliminary evidence that suggests a potential may change in the future, as the number of included
biological mechanism involving brain derived neuro- studies and participants were limited and information
trophic factor that might contribute to these differ- on outcomes was missing.64
ences and that additional research is needed.152 There are some recommendations for symptom-
Clinical and pre-clinical studies have for example atic treatment of withdrawal. The WHO Technical
found that women amphetamine users reported higher Brief 2 on ATS recommends that treatment for severe
frequency of amphetamine use than men.162,153,154 insomnia be provided with light sedatives and that
A human laboratory study suggested that women hydration is maintained. Clinicians should be aware
self-administer more frequently but a lower dose of that depressive symptoms of varying severity may
amphetamine than men.155 It can be argued that occur during or after withdrawal and there may be
although more research is needed before any conclu- risk of suicide.136
sions are made, clinicians may want to consider gen- In terms of future developments, some have
der-specific issues as an important element in the argued that these should target the restoration of
management of amphetamines. dopaminergic function as a goal for the treatment of
stimulant addiction.159
8B.12.3.2 Pharmacological Interventions
Pharmacological interventions specific to each drug will 8B.12.4 Management of Amphetamine
be discussed in detail in all relevant chapters that follow.
Overall, and at the current time, no pharmaco- Psychosis
logical intervention has demonstrated sufficient, con- The resolution of symptoms among those who experi-
sistent evidence of effectiveness to support its use in ence amphetamine-induced psychosis usually occurs
routine treatment. with abstinence, although it may be incomplete, thus
A systematic review on treatment for amphet- increasing risks of relapse.160 Symptoms usually
amine/methamphetamine dependence showed that resolve with medication, which,161 include anti-
currently no pharmacotherapy has provided convin- psychotics and benzodiazepines.149
cing results; mostly studies were underpowered and The prescribing of antipsychotic medication
had low treatment completion rates.156 should consider the fact that there is an increasing
For example, a placebo-controlled trial investigat- risk of seizures and cardiac arrhythmias in patients
ing the effectiveness of extended-release injectable who have taken a stimulant NPS and/or established
naltrexone (XR-NTX) with intensive psychosocial recreational drug and that antipsychotics should
therapy for amphetamine-dependent persons showed probably be avoided while prominent sympatho-
that adding naltrexone to treatment as usual did not mimetic features are present. Prescribers should also
improve outcomes.157 consider the differences of typical vs. atypical anti-
A recent systematic review identified five medica- psychotics; atypical antipsychotics may include sero-
tions subject to multiple RCTs. Four of these demon- tonergic properties (5HT1A-receptor agonism) which
strated some limited evidence of benefit for reducing could be unfavourable in subjects intoxicated with
amphetamine use: methylphenidate (three studies), serotonergic agents.
bupropion (three studies), modafinil (two studies), A study found short-term olanzapine and halo-
and naltrexone (one study). Four RCTs of peridol treatments had equivalent efficacies in the
157
treatment of acute symptoms of mental disorders due 1 hour when dancing) as this can cause
to ATS. However, in this study olanzapine adminis- hyponatraemia (an electrolyte disturbance in
tration resulted in relatively earlier remission of which the sodium ion concentration in the plasma
symptoms, with less adverse reactions.162 Several dif- is lower than normal).
ferent types of antipsychotic medication have been • Users should not combine ATS with other drugs,
used for treating agitation and psychosis, but it has including alcohol. The simultaneous use of more
been recommended that drugs with high DRD2 than one drug can cause serotonin syndrome,
blockade should be used with caution.163 which can be severe.
A Cochrane review149 of the pharmacological • Users should think about safe sex.
treatment for amphetamine psychosis identified only Methamphetamine in particular can increase
one study that met criteria for inclusion. This RCT sexual desire and the ability to have sex for longer
with 58 participants showed that antipsychotic medi- periods. Users should always protect themselves
cation reduced symptoms of amphetamine psychosis by using condoms.
effectively, with the newer-generation medication • Straws used for snorting should not be shared, as
olanzapine showing significantly greater safety and they carry the risk of transmission of blood-borne
tolerability than the more commonly used haloperi- viruses.
dol controls, measured by the frequency and severity • Where ATS are injected, users should never share
of extrapyramidal symptoms.164 However, the review equipment. They should also rotate sites to avoid
also added that although antipsychotic medications vein damage.
have shown their efficacy in providing short-term
Users should avoid taking ATS too many days in
relief when a heavy user of amphetamines experiences
a row, to avoid dependence and to give their bodies
psychosis, there is no evidence regarding the long-
a rest.
term use of these medications for preventing relapse
into psychosis.149
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‘Ecstasy’: MDMA (3,4-Methylenedioxy-
Chapter
9 N-Methylamphetamine), MDMA Analogues

and Drugs with Similar Effects
9.1 Introduction 9.2 MDMA Analogues and Other

MDMA (3,4-methylenedioxy-N-methylamphetamine) Novel Psychoactive Substances with
has been popular among recreational drug users for
a number of decades. This chapter also addresses issues Similar Effects
pertaining to the consumption of MDMA analogues A number of analogues and NPS with similar effects
and other novel psychoactive substances (NPS) with have been developed in recent years and sold, either as
MDMA-like effects1 (see Table 9.1). an alternative to MDMA, or mis-sold as MDMA to
MDMA is sometimes referred to as ‘ecstasy’, and unsuspecting users.11,12
this chapter will use the term interchangeably, especially It has been reported that the euphoric and
when this has been used by research cited. The term is empathogenic/entactogenic effects of MDMA
also used to allude to the fact that the substance used have proven very difficult to replicate.13 For
may be MDMA, or may be another NPS with similar example, cathinones, benzofurans and others can
effect. mimic the effects of MDMA (see Chapter 11), but
As is the case with other drugs, products sold as there are subtle differences in their psychoactive
MDMA continue to change in form, purity and the effects.1
product’s primary psychoactive molecule, including Overall, numerous NPS have been used as adul-
NPS substituted for MDMA. terants/substitutes in products sold as ‘ecstasy’, but
In recent years in Europe there has been a resurgence most seem to produce less desirable effects.14 Some
in the use of MDMA, the emergence of high-strength are also associated with high levels of toxicity, as
products and a shift from subcultural towards more discussed in this chapter.
mainstream use of the drug. It is argued that MDMA A range of substances can produce different
on Europe’s contemporary market is in some respects levels of empathogenic effects. These can be chem-
a third-generation product with a different user profile ically divided into phenethylamines, amphet-
and that this reflects the need to review interventions.2 amines, synthetic cathinones, piperazines,
MDMA is structurally similar to both amphet- pipradrols/piperidines, aminoindanes and benzo-
amine-type stimulants and to mescaline-type hallu- furans. Some hallucinogenic tryptamines can also
cinogens, but is pharmacologically different from produce empathogenic effects.15
other substance classes.3 In addition to their stimulant Table 9.1 below lists some of the MDMA ana-
and hallucinogenic effects, MDMA and similar sub- logues and other substances with empathogenic prop-
stances share properties that are sometimes referred to erties that have been reported in the literature,
as ‘entactogenic’4,5 or empathogenic.6,7 This has been including some cathinones, as seen in Chapter 11
defined as combining a psychostimulant effect with (particularly those which are also beta-keto analogues
changes in consciousness, leading to euphoria and of methylenedioxyphenethylamines16).
feelings of empathy and closeness to others.7 It has Some benzofurans derivatives, indanylalkyla-
been argued that MDMA is the prototypical entacto- mine derivatives and aminoindane derivatives
genic/empathogenic drug and induces fewer psychos- are also used recreationally for similar effects.
timulant effects than amphetamine,8 but retains some They are addressed briefly at the end of this
psychostimulant effects.9,10 chapter.
165
‘Ecstasy’: MDMA (3,4-Methylenedioxy-N-Methylamphetamine), MDMA Analogues & Drugs with Similar Effects
Table 9.1 MDMA and MDMA-like novel psychoactive substances with ‘empathogenic’ effects
Substituted methylenedioxyphenethylamines17
• 3,4-methylenedioxy-N-methylamphetamine MDMA
• 3,4-methylenedioxy-N-ethylamphetamine MDEA
• 1,3-benzodioxolyl-N-methylbutanamine (N-methyl-1,3-benzodioxolylbutanamine) MBDB18
• 3,4-methylenedioxyamphetamine MDA12
Other substituted amphetamines

• 4-methylthioamphetamine 4-MTA18,19
• para-methoxyamphetamine 4-methoxyamphetamine PMA, 4-MA para-methoxy-N-methylamphetamine
4-methoxy-N-methylamphetamine PMMA, 4-MMA
Other substances with empathogenic properties

• 3,4-methylenedioxy-N-methylcathinone, bk-3,4-methylenedioxymethamphetamine bk-MDMA (MDMC, methylone)
• β-keto-N-methylbenzodioxolylbutanamine B1 bk-MBDB (beta-ketone-MBDB) (butylone)
9.3 MDMA Alternatives the market, often at higher levels of purity. The
EMCDDA reported that the first powders that appeared
and Variations Over Time after the MDMA shortage were reportedly very pure,
There are significant variations in the compounds although their quality declined over time. There was
found in products sold on the illicit market as also a growing popularity of MDMA crystals, which
MDMA or ‘ecstasy’. Studies have shown variations were perceived to be less easy to adulterate, although
in the purity of MDMA over time and location, and this was not always the case. It has also been reported
variations in the compounds found in tablets sold as that in 2015/2016 batches of MDMA tablets contained
ecstasy.10,12,20,21,22 discernible crystals, apparently as a strategy to increase
The adulteration of MDMA was common in the user trust.29
late 2000s, which saw the virtual disappearance of Many people choose to use crystals, assuming that
MDMA as the active ingredient in ‘ecstasy’ products, these will be of better purity in comparison to tablets;
to be replaced by other psychoactive substances. By there was a user preference for these as a ‘premium’
2009, police seizure data suggested that the majority product, a purer and more reliable product than
of MDMA tablets on European markets contained no tablets.30
MDMA at all.23 Over the years, the latter have However, this is not necessarily the case and pow-
included non-MDMA products such as MDA, benzo- ders and crystals were not necessarily less adulterated
furan, methylone,24 piperazines such as BZP,25 PMA than tablets, with one study for example showing that
and PMMA or a synthetic cathinone. ‘MDMA’ crystals analysed were in fact methylone.31
This was not limited to Europe; for example, in Similarly, information from the Spanish drug check-
a study in an Australian emergency department, none ing services Energy Control for example, has shown
of the 22 people seen with PMA toxicity reported that caffeine was an adulterant in both tablets and
deliberately taking the drug; rather, they had all crystal samples tested; tablets also contained the
intended to take ecstasy or MDMA.26 Similarly, piperazines mCCP and TFMPP, while crystals were
a report showing that among 150 seizures by police in more commonly adulterated with procaine and
Brazil, of drugs labelled as ‘ecstasy’, MDMA was found methamphetamine.32
in only 44.7% of samples.27 In the US, a study found More recently, this situation changed. The 2019
that half of MDMA users in the sample reported that European Drug Report has shown that data on drug
they had found out the products they bought as purity obtained from eight drug checking services
MDMA contained a drug other than MDMA or during the first half of 2018 confirmed recent reports
reported suspecting that they contained another drug.28 on the increased availability of high-purity MDMA
The large-scale substitution of MDMA with other observed in drug markets in western Europe.
products sold as ‘ecstasy’ subsided to a great extent in In recent years, there has been some evidence of an
2010/2011. MDMA products gradually re-emerged on increase in the purity of MDMA sold on the illicit
166
9.4 The Increase of MDMA and Rise in Purity
market in European countries, but not in other parts drug, resulting in increased harm and even death.38
of the world (US).33 Indeed, in the 2000s in Europe, the mean dose of
In comparison to previous years, MDMA users in MDMA in a product was estimated to be 50–80 mg.
Europe at least were less likely to be unknowingly By 2016, the mean dose reported in Europe was
using products that did not contain MDMA or also approximately 125 mg and batches of very high
contained other substances. The report shows that potency tablets, for example containing up to
samples presented to drug checking services as 340 mg have been identified.39,40,41,42
MDMA were unlikely to contain any unexpected Similarly, a study analysing samples in 2016–2018
active component, with adulterated MDMA powder also found that products tend to have higher MDMA
or tablets representing less than 10% of all MDMA content compared to earlier years and that in 2018,
samples tested. Caffeine was the most common adul- the median MDMA content exceeded 100 mg free-
terant in these samples.34 base for the first time.43 Individual tablets containing
However, although it is now more likely that prod- more than 250 mg of MDMA were reported in
ucts sold as MDMA only contain MDMA as the active a number of countries,44 with ‘super pills’ found on
ingredient, products that also contain other NPS are the illicit market with a reported range of 270–
still sold on the illicit market and services that test 340 mg.45
drugs across Europe have also reported finding alpha It has been suggested that the predominance of
PVP, 2CB, ketamine, piperazines (TMFPP, mCPP, high-strength MDMA products on the illicit market
BZP), amphetamine, PMA and PMMA,35 mCCP encouraged some people to seek lower-strength sub-
and TFMPP (both piperazines), procaine and meth- stances with similar effects. In the Netherlands,
amphetamine in samples sold as MDMA.36 4fluoroamphetamine (4FA), known as ‘ecstasy light’,
This chapter will discuss the potentially increased has gained popularity because its effects reportedly
risk of toxicity posed by some of these NPS. Data from range between those of amphetamine and MDMA.46
European countries that collect this information show The higher doses are likely to cause toxicity,47,48 as
the MDMA content of tablets has been increasing will be discussed in detail in the following section. An
since 2010 and reached a 10-year high in 2017.37 additional risk to people who use MDMA is therefore
the unpredictability of content and the wide vari-
9.4 The Increase of MDMA and Rise in ations that exist between the potency of the various
MDMA products. Studies reported for example that
Purity the MDMA content of a single ecstasy tablet or cap-
As shown above, people who currently set out to use sule of powder has varied from no MDMA content at
MDMA are significantly more likely than they were all to doses as high as 245 mg or 270 mg.49,50
a decade ago to purchase an MDMA product that Similarly, a study of 24 separate groups of tablets
contains MDMA. sold as ‘ecstasy’ in Scotland were analysed to quantify
However, although there was more consistency in their MDMA content, to determine the common dose
the purity of MDMA sold on the illicit market, as and to identify any other drugs in the tablets. There
discussed previously, this did not mean the elimin- was a 5.7-fold difference in the lowest to the highest
ation of variability between the various products sold, concentration found. Variations were even found
nor risk of adverse effects associated with MDMA use. between tablets that carried the same logo and looked
Two issues have been identified: (1) the increase in identical.51 A more recent analysis of MDMA tablets
the average dose of MDMA and the rise of high- (2016–2018) in the UK also showed dramatic within-
strength MDMA products, and (2) the significant batch content variability (up to 136 mg difference).52
variations in the potency and the onset of effects of The variations in unpredictability of the MDMA
MDMA products. dose in a tablet poses the risk of acute harms, espe-
A significant development in recent years was the cially at high doses. To this is added variations in the
high strength of MDMA sold on the illicit market in onset of the effects of the MDMA, which may encour-
Europe. The average MDMA content of tablets more age people to re-dose, assuming that the MDMA they
than doubled over the period 2006–2016 in the coun- had already consumed had no effect.
tries of the European Union, with some very large A study based on the statistical evaluation of dis-
amounts of MDMA found in some batches of the solution profiles at 15-minutes allowed tablets to be
167
categorised as fast-, intermediate-, or slow-releasing, accurate comparisons with illicit MDMA use cannot
but showed that no tablet characteristics correlated be made, they nonetheless provide important
with dissolution classification. The authors argue that findings.61 The evidence relating to specific NPS ana-
this means that there would be no way of users know- logues of MDMA is much more limited. However,
ing before they take a tablet whether it is more likely reports of their effects and toxicity generally fall
to be fast- or slow-releasing. There is significant risk within the range described in the larger literature on
of users re-dosing if absorption is delayed and this can MDMA,17 and on amphetamine-type stimulants
cause MDMA toxicity and have severe adverse health (ATS), so useful inferences can be made from the
effects, especially for high-content, slow-releasing existing literature.
tablets.53
9.7 Brief Summary of Pharmacology
9.5 Legal Status MDMA and other ecstasy-type drugs have phenethy-
MDMA was placed on Schedule I of the 1971 United lamine-derived molecular structures, and can be
Nations Convention on Psychotropic Substances in thought of pharmacologically, as atypical ATS.
1986. MDMA has multiple actions at different targets: it is
a releaser and reuptake inhibitor of the monoamines
serotonin, dopamine and noradrenaline.62,63 It also
9.6 Quality of Research Evidence has an MAOI effect and acts directly as an agonist at
Although much more is known about MDMA than receptors, including the 5HT2A receptor, the sero-
other club drugs, the evidence is limited albeit grow- tonin receptor responsible for the hallucinogenic
ing. It remains particularly limited about the use of effects.62 Its action on the noradrenaline transporter
illicit MDMA and its association with acute and appears to explain much of the euphoric psychosti-
chronic harms, and on the management of those mulant effect,64 with the powerful serotonergic action
harms. Much of the clinical evidence is derived from being chiefly responsible for its pharmacological
individual case reports and case series and a small divergence from typical psychostimulants.65,66
number of prospective observational studies, retro- However, among the stimulant and hallucino-
spective audits and analysis of patient records. genic drugs, the risk–effect profile of MDMA is
As with other NPS and club drugs, the reliability of unique, and comparison with drug classes with diver-
case reports is inconsistent. Many lack toxicological gent properties can misguide as much as inform, so
confirmation. Some authors have suggested that such they have been increasingly seen as neither classical
case studies fail to convince that MDMA use is, on hallucinogens nor classical stimulants.4
balance, the most plausible explanation for the clinical In addition to its stimulant effects (such as
observations.54,55 However, despite these limitations, increased energy, euphoria) and cardiovascular effects
these sources have built up a consistent picture of common to ATS and cocaine, MDMA produces char-
common patterns of acute ‘ecstasy’ toxicity. acteristic alterations of mood and perception, particu-
A number of reviews of the evidence have been larly increased empathy, feelings of emotional
carried out,56,57,58 but there is still no consensus on wellbeing, sociability and sensuality.4,67 MDMA has
some of the harms among leading researchers.59,60 been described as intermediate between (or combin-
For example, Parrott emphasises the accumulation ing some properties of) stimulants and
of literature detailing the harms of the drug, particu- hallucinogens.4
larly chronic neurotoxic effects.57,58 However, his Drugs with shared MDMA-like emotional and
conclusions are not universally accepted.59 A review behavioural effects are sometimes described as ‘entac-
by Cole takes a more critical approach to the evidence togens’ or ‘empathogens’,3,6,68 although this termin-
base, emphasising the lack of certainty about many of ology has not gained universal use. These drugs have
the harms putatively attributed to MDMA . He sug- been described as capable of inducing a reversible
gests that the number of clinical presentations relating controlled alteration of consciousness in humans
to MDMA is far smaller than would be expected, characterised by emotional relaxation, feelings of hap-
given the high prevalence of its use.60 piness and empathy with other persons4 that has been
There are some controlled studies using legally called the ‘entactogenic syndrome’.69 MDMA induces
obtained MDMA for research purposes and although altered states of consciousness characterised by
168
9.8 Clinical Uses
increased empathy with others70 and an ‘open mind’ PMA, PMMA and 4-MTA are often characterised
state, characterised by heightened self-acceptance and by severe hyperthermia, probably resulting from
openness for communication, and a decrease of fear severe serotonin toxicity arising from the combined
responses, without hallucinogenic-like effects.4 Other effects of marked serotonin release and strong mono-
typical effects, including subjective ‘relaxation’,71 amine oxidase inhibition.83,84,85,86,87,88 Their hyper-
‘peacefulness’,68 ‘closeness to others’,72 and thermic properties are stronger than those of
‘empathy’,72 may diverge from the effects expected MDMA.89 In combination with MDMA and other
from ATS, and the prosocial effects of MDMA are serotonergic drugs, this risk is multiplied further.90
unique to MDMA relative to another stimulant.73 The onset of the effects of similar substances varies.
There is uncertainty regarding the pharmacology The onset of the effects of MDMA is typically 30 min-
specific to the ‘entactogenic’ effects of MDMA and utes, but can range from 20 minutes to 1 hour. User
related drugs. In addition to the direct serotonergic reports suggest the effects of MDAI are felt within 10–
effects on mood, the serotonin transporter (SERT), 12 minutes of oral consumption. The duration of its
upon which MDMA and its analogues act, appears to effects has also been reported by users as varying
mediate the release of the neuropeptide hormones considerably between individuals, with effects peaking
oxytocin and prolactin.74 It is now believed that after 30–45 minutes, to up to 3 hours,91 a variability
MDMA’s effect on enhancing desire to socialise and that has been attributed partially to products contain-
feelings of empathy may be related to increased oxy- ing substances other than MDAI.92
tocin levels.75 The action of MDMA on SERT are The onset of the effects of PMA and PMMA is
hypothesised to contribute76 to its pro-social, entac- significantly later. This has caused concern, especially
togenic or empathogenic effects. when users take it thinking it is MDMA. Users may
Doses or serum concentrations of MDMA and take another dose, thinking that the first one has had
related drugs are often not closely associated with no effect. There is, therefore, the risk of overdose,
the level of acute harm observed, and lifetime dosage including fatal overdose.
may not be closely associated with the degree of
chronic harm either. One suggested explanation is
that genetic polymorphisms affecting the hepatic 9.8 Clinical Uses
metabolism of MDMA play a mediating role in MDMA is a Schedule 1 drug with no licensed clinical
toxicity.66 The metabolism of MDMA (via steps uses. However, prior to being classified and scheduled,
which include pharmacologically active and toxic MDMA had been used to facilitate psychotherapy.93 In
metabolites) is affected by the pattern of dosing,77 recent years, some research into its psychotherapeutic
with the metabolism of subsequent doses being use has continued, and there is increasing evidence of
inhibited by the limited availability of the cytochrome MDMA as an adjunct to psychotherapy for treatment-
P450 (CYP2D6) enzyme.62,78 resistant post-traumatic stress disorder (PTSD).
MDMA is rapidly absorbed. It typically takes 20– MDMA is hypothesised to support and enhance
60 minutes to take effect, reaching peak effects psychotherapy by increasing the subject’s access to
between 60 and 90 minutes, and lasting up to emotionally upsetting material, modulating the asso-
5 hours.79 The half-life of a typical dose of 100 mg is ciated level of arousal and strengthening the thera-
around 8–9 hours.62 While actively partying on peutic alliance.94 MDMA is known to have major
ecstasy, saliva levels of cortisol can rise to more than effects on serotonergic neurotransmission, but
eight times baseline levels.80 a downstream consequence of its effects on serotonin
Paramethoxyamphetamine (PMA) and para- is the release of oxytocin and vasopressin, which may
methoxymethamphetamine (PMMA) have often have relevance to producing trust and may reduce the
been substituted for MDMA and are associated with threat response of being asked to revisit traumatic
a high level of harm. They are potent noradrenaline memories.95 Brain imaging studies show reduced
and serotonin transporter inhibitors and releasers of amygdala activity after MDMA administration, plus
these monoamines. They are associated with higher changes in the response to angry and happy facial
morbidity and mortality, particularly attributable to expressions.6
hyperthermia.81,82 They have a potential for causing There are marked differences of opinion among
greater serotonin toxicity. experts, with some arguing that MDMA has
169
a potentially important therapeutic role, while drug appears to be increasing in several European
other scientists believe that the evidence of countries118,119,120,121 A new MDMA precursor called
MDMA’s toxicity is already sufficient to conclude PMK-glycidate became available around 2010, revital-
that ‘there are no safe clinical applications for ising MDMA production. PMK-glycidate is not
MDMA’.59,96,97 derived from safrole and is therefore not vulnerable
In recent years, there has been an increase in the to natural shortages.122
number of studies that look at the role and effectiveness There were differences between countries in the
of therapeutic effects of MDMA in controlled settings,98 prevalence of use of MDMA or ‘ecstasy’, but overall,
especially in the treatment of post-traumatic the 2019 European drug report has estimated that
stress.99,100,101,102,103,104 Studies have demonstrated 13.7 million adults aged 15 to 64 years in the
good preliminary results with minimal adverse effects, European Union have tried MDMA/ecstasy during
but larger trials are needed.105,106,107,108 and some critics their lives. MDMA is used particularly by people in
continue to argue that the potential dangers remain.109 younger age groups. It is suggested that 2.1 million
The use of MDMA in other therapeutic interven- young adults (15–34 years) used MDMA in the
tions has also been examined by a few small studies, last year (1.7% of this age group), with national esti-
including a study on MDMA-assisted psychotherapy mates ranging from 0.2% in Portugal and Romania to
for autistic adults which showed rapid and durable 7.1% in the Netherlands. Among those aged 15–24
improvement in social anxiety symptoms.110 There is years prevalence of use is higher, with 2.3%
also some research on the use of MDMA for alcohol (1.3 million) young people estimated to have used
use disorder.111 More research is needed. MDMA in the last year.123
The role of MDMA for a range of other conditions Although there has been an increase in the use of
has also been explored, but more research is needed. MDMA reported in some countries, this increased use
MDMA was found in one case to give temporary, was not found in all countries. Among the countries
dramatic relief from the symptoms of Parkinson’s where robust national surveys have been conducted
disease;112 this discovery, corroborated in animal stud- since 2016, four reported higher estimates than in the
ies, has led to drug development.113 Although not previous comparable survey, six reported stable esti-
widespread, it has been reported that some individuals mates, and two reported a lower estimate.124 Rates of
may use MDMA in an attempt to self-medicate, for use appear to be decreasing in Spain, although recent
example to manage current stresses and lifetime data suggest that this may be stabilising. Rates con-
traumas,114 including PTSD symptoms.115 In the US, tinue to be high in the Netherlands and increasing in
there appears to be some ‘underground’ use of the UK, Ireland and Bulgaria.125
MDMA for therapeutic purposes.116 Differences between countries were also found in
other data sources. A 2018 multi-city analysis of was-
9.9 Prevalence and Patterns of Use tewater in cities found the highest mass loads of
MDMA in the wastewater in cities in Belgium,
The recreational use of ‘ecstasy’ and MDMA has been
Germany and the Netherlands. Of the 37 cities that
well established in Europe for a number of decades,
have data for 2017 and 2018, 21 reported an increase,
having appeared in Europe in the 1980s. Prevalence
nine a stable situation and seven a decrease in
has varied over time. Following many years of high
MDMA. Nonetheless, analysis that investigated
popularity, there was a decline in the use of MDMA.
longer-term trends found that in most cities with
This coincided with the decline in the purity of prod-
data for both 2011 and 2018 (10 cities), wastewater
ucts sold on the illicit market, which was has been
MDMA loads were higher in 2018 than they were in
associated in part with a shortage of the precursor
2011. In 2017, the sharp increases observed over the
safrole in 2008 (3,4methylenedioxyallybenzene,
2011–2016 period appeared to be stabilising.
a liquid extracted from sassafras plants) and later
However, the most recent data in 2018 point to
PMK (piperonyl methyl ketone, itself derived from
increases in most cities.126
safrole). It has been argued that this dip in the quality
In the early years of MDMA/ecstasy’s emergence
of MDMA in earlier decades may have helped drive
as a recreational drug, it was strongly associated with
the emergence of mephedrone as a club drug.117
underground raves, ‘acid house’ and associated dance
However, following a decade of decreasing
subcultures. Clubs, parties and festivals remain the
MDMA/ecstasy use, the reported consumption of this
170
9.10 Forms, Routes of Ingestion and Frequency of Dosing
key locations for use, accompanying music and dan- current dominance of high-purity MDMA powder
cing. Ecstasy/MDMA has been reported as the favour- over pills, with Winstock suggesting that users may
ite drug of surveyed club-goers.30 More recently, a US lack awareness of how to dose with powder.134
study also found that higher frequency of nightclub/ When not consumed orally, it may be insufflated,
festival attendance was associated with increased odds (snorted)134 which is particularly common among
of reporting lifetime MDMA use. Attending once experienced users.128 User forums report that the
a month or more was associated with double the insufflation of MDMA is painful and gives a shorter
odds for reporting use as compared to those attending high, but with a rapid onset. According to the Global
less than once per month.127 Drug Survey, oral ingestion remains the preferred
As MDMA use has become more widespread, method of administering MDMA, with only 15% of
settings of use and types of users have diversified.128 users snorting it (by insufflation).134 Insufflation may
Although the use of MDMA/ecstasy is linked to the be used as an alternative to oral use,17 or sometimes as
use of the night-time economy, use in other settings, an additional route of administration for a boost,
such as homes, is not unusual.129,130 following oral ingestion. Rectal17 (‘plugging’ or
In fact, there are some indications from studies ‘booty bumping’) and injecting are uncommon.57,135
carried out in higher-prevalence countries that The latter has been described by one study as ‘too
MDMA is no longer a niche or subcultural drug intense to enjoy’, leading to reversion to oral use.136
limited to dance clubs and parties, but is used by Other NPS with effects similar to MDMA, such as
a broad range of young people in mainstream night- 5-APB and 6-APB,97, are also most often used orally.
life settings, including bars and house parties.131 It has As mentioned in Section 9.10, even tablets of the
been argued that in comparison to the 1990s, ecstasy same ‘brand’, can vary between batches, or can be
has a new consumer profile, with a shift having taken easily mimicked in an uncontrolled market. Tablets
place from subcultural towards more mainstream use of the same appearance may not deliver a consistent
of the drug.132 dose, or even contain the same psychoactive sub-
stance. For example, when two ‘Yellow Rockstar’ tab-
9.10 Forms, Routes of Ingestion lets from Glasgow were analysed, one contained
82 mg of MDMA, lower than doses administered to
and Frequency of Dosing healthy humans in a recent research study,137 and the
MDMA is sold in the form of tablets or pills, as other contained PMA and PMMA, along with
a powder or crystals. Sometimes, the term ‘ecstasy’ is caffeine.51
most often used for pressed tablets or capsules con- MDMA is often used as part of a wider repertoire
taining a dose of MDMA and the term MDMA is used of drugs. MDMA/ecstasy users are highly likely to be
for the powder or crystals. poly-drug users,138,139 and more likely to report use of
Users may also refer to such products by the vari- other drugs, including alcohol and novel psychoactive
able ‘branding’ colour, shape or imprinted logo of substances for example.140,141 Ecstasy users have
a tablet, with which manufacturers make them distin- higher levels of consumption of alcohol, cigarettes
guishable (e.g. ‘White Doves’, ‘Yellow Superman’, and cannabis than non-ecstasy users.142
‘Apples’, ‘Pink Hexagons’). Among people who use MDMA/ecstasy, heavy
MDMA is typically taken orally,17 including in its and frequent users are significantly more likely to
powder/crystal form, which can be ‘bombed’ use other stimulants and hallucinogens at higher
(wrapped in a cigarette paper or tissue and intensities than lighter ecstasy users.140 Studies sug-
swallowed).57 Some users consume MDMA by dip- gest that the heavier an individual’s ecstasy use, the
ping a finger into powder133 and licking it or through heavier and more varied their poly-drug use will be.140
‘dabbing’ it on gums. Doses consumed by the ‘bomb- This could reflect the fact that people with higher
ing’ method (powder, typically wrapped in cigarette levels of use may also be more likely to use other
paper and swallowed) may be higher than average drugs with stimulant and hallucinogenic properties.
tablet doses.57 For example, there was an apparent Scholey et al. also suggest that this may represent
increase in 2013 of the number of MDMA users who a greater need (on the part of people with high levels
accessed emergency treatment, according to reports of use) to boost drug effects as they become tolerant to
by the Global Drug Survey. Users linked this to the the effects of MDMA.140
171
9.11 Desired Effects for Recreational with erectile dysfunction in men and delayed
orgasm in both sexes.150,151 It has been hypothesised
Use that this is due to release of prolactin and oxytocin,
The unique combination of desired effects elicited by such that MDMA mimics the emotionally close but
MDMA has been roughly summarised as the ‘3 Es’ – sexually impaired features of the post-orgasmic
energy, euphoria and empathy.143 A study in six refractory period.152 Female heterosexual ecstasy
European countries has shown that the use of stimulant users, interviewed in one study, did not generally
empathogens, such as NDMA, is associated with higher think that ecstasy increases the likelihood of high-
levels of enhancement and social motives and that that risk sexual activities, although noted that they
empathogen-type psychostimulants – usually con- sometimes chose to engage in behaviours, such as
sumed within the ‘recreational scene’ – are expected anal sex, while intoxicated, which they otherwise
to increase sociability, feelings of friendliness or may not have engaged in.153 Roger et al.’s systematic
playfulness.144 review, which includes a meta-analysis, shows that
MDMA’s continued presence has been ascribed to ecstasy use is linked to small-to-moderate increases
its singular properties, combining unique desired in sexual risk.56 However, ecstasy is not one of the
effects with relatively low adverse effects at optimal drugs most linked to ‘chemsex’ and the associated
doses.47 MDMA topped a novel ‘net pleasure index’ risks.153
among a large self-selected sample (22,000 people). In Although a comparison with illicit MDMA and
this index, subjective ratings of adverse effects were those dispensed by research, a study that analysed
subtracted from ratings of desired effects to give pooled data from nine placebo-controlled MDMA
a mean score that could be used to rank a range of studies in healthy subjects in controlled clinical set-
drugs.145 MDMA was also considered the best value tings reported that acute subjective effects were pre-
drug overall by its users.147 dominantly positive. The study however also found
Questionnaire evidence from people on ecstasy in that bad subjective drug effects and other adverse
a naturalistic party setting allowed ter Bogt and Engels effects were more common in women.154 A Dutch
to identify a hierarchy of motives for taking ecstasy.146 study similarly suggested that females may suffer
Energy and euphoria were the leading motivations for a greater incidence of adverse effects, such as nausea,
a majority of users (as captured by users endorsing headache, dizziness and feeling faint.148 Similarly,
statements like ‘dance all night’ and ‘feel absolutely there is some evidence that the acute MDMA effects
great’). These were followed by sociability and flirta- discussed in Section 9.14 below are more pronounced
tiousness (e.g. ‘flirting easier’), sexiness (e.g. ‘sex bet- in women than they are in men.155
ter’) and coping (e.g. ‘forget my problems’); The subjective effects of some NPS have been
conformity (e.g. ‘be cool’) was the least important reported to be similar subjective effects to those
motivating factor.148 When they contain MDMA, reported by MDMA,24,156 especially its empathogenic
‘ecstasy’ tablets are a relatively reliable producer of effects or an ‘entactogenic syndrome’,4 but evidence is
subjective pleasure.47 Commonly reported positive limited. In combination with animal research, some
effects, such as ‘calmness’, however, contrast sharply anecdotal evidence supports the existence of subtle17
with paradoxical adverse effects that clinicians may to significant differences, with some drugs producing
encounter, such as agitation and anxiety.67 the empathogenic effects associated with MDMA, but
Based on evidence from 30 published studies, with less of the stimulant and euphoriant effect.157
Kamilar-Britt and Bedi (2015) concluded that It has been reported that many MDMA-like NPS
MDMA has ‘prosocial’ effects and that it dampens induce wellbeing, empathy, and prosocial effects and
reactivity to negative emotional stimuli.147 MDMA have only moderate psychostimulant properties.
enhances sociability and interpersonal closeness, These MDMA-like substances primarily act by
which may contribute to its recreational use, but its inhibiting the serotonin (5-HT) transporter (SERT)
potential therapeutic use is also argued.148 and NET, also inducing 5-HT and NE release.
MDMA has a pro-sexual effect149 and has been Monoamine receptor interactions vary considerably
associated with increased sensual awareness, love, among amphetamine and MDMA-like NPS.
feeling of connection, desire, sexual intensity and Clinically, amphetamine- and MDMA-like NPS can
satisfaction.148 Paradoxically this may be coupled induce sympathomimetic toxicity.158
172
9.13 Mortality
9.12 Unwanted Effects As mentioned earlier, various NPS have been used
as adulterants/substitutes for MDMA, but most seem
The use of MDMA is also associated with a number of
to produce less desirable effects.165 There is no evi-
unwanted effects. For example, a study reported that
dence that PMA and PMMA have any prominent
typical side-effects as experienced by more than half of
desired effects,47,166 although their serotonergic
a sample of users included jaw clenching (trismus,
pharmacology suggests that they could have ‘entacto-
‘gurning’), dry mouth, tachycardia and sweating,
genic’ effects. Indeed, a study linking the pharmaco-
with a minority having experienced urinary retention,
logical content of a tablet consumed and its subjective
dizziness, nausea and vomiting, and decreased
effects on users reported that desired effects were
libido.159
nearly absent with tablets containing MDMA adulter-
It has been argued that common side-effects, such
ated with PMMA.47 In this study, adverse drug effects
as nystagmus, trismus, mild confusion and feeling
were reported by 16% of 924 users who had handed in
hot, are the low end of a spectrum of serotonergic
MDMA for testing by a Dutch recreational drug-
overactivity that has at the higher end serotonin syn-
testing service.47 The testing revealed that where adul-
drome and death.160 Other adverse reactions include
terated ‘ecstasy’ had been handed in, a much greater
feeling cold and shivering.162
proportion of users had complained of adverse
Products containing MDMA (at widely varying
effects.47
doses) were reported to have been associated with
PMA and PMMA are particularly associated with
adverse effects 8% of the time and desired effects
adverse effects. The Dutch testing service found that
74% of the time. Adverse effects reported from tablets
tablets containing MDMA adulterated with PMMA
containing MDMA included nausea (most common),
had caused adverse effects in the majority of users
headache, hallucinations, dizziness, ‘allergic reac-
(56% vs. 8% for MDMA-only tablets).47 There is
tions’ (note, however, that this term may not have
limited evidence on the detail, but self-
been used by users in its medical sense) and, more
experimentation by Shulgin, Shulgin et al. found
rarely, palpitations, hyperthermic seizures, agitation
that PMA (called 4-MA in their book) produced
and abdominal cramps.47 In addition to unwanted
a sudden robust rise in blood pressure at 60 mg, and
acute side-effects, MDMA may have long-lasting
a feeling of ‘druggedness’ rather than a ‘high’ at
effects. Users have described some symptoms that
70 mg.167 PMMA also produced tachycardia, eye-
persisted up to 4 days.161
muscle twitch and compulsive yawning, and no enjoy-
Other unwanted effects include ‘mid-week blues’
able subjective effects.168 The relative lack of desired
appearing 3 to 5 days after the use of MDMA/ecstasy.
MDMA-like effects combined with a slow onset is
These ‘blues’ appear to increase in intensity and inci-
dence162 thought to lead to users believing they have taken
as users persist with the drug.161
weaker MDMA, taking more PMMA and suffering
Novice users may suffer fatigue, depressed mood
greater resulting toxicity.168
and decreased appetite in the days after use. The
majority of experienced users have experienced add-
itional symptoms, such as nightmares and difficulty 9.13 Mortality
with memory and concentration.161 The subacute The most frequently reported causes of death include
effects are associated with depleted serotonin, so the hyperthermia and hyponatremia and MDMA can be
worsening effects in experienced users,162 especially associated with fatal serotonin syndrome. While tox-
when not associated with higher doses,161 may indi- icity can be severe, review of the literature reveals
cate chronic serotonergic dysfunction, with heighten- deaths related to MDMA toxicity to be
ing sensitivity to depletion.163 Serotonin syndrome, or rare. Confounding factors in some reports are that
serotonin poisoning is discussed later. other drugs were co-ingested thus making it difficult
Depressed mood following use is not universally to find MDMA as the sole cause of death. Its effects on
found after administration of MDMA and other drugs the cardiovascular, neurologic, renal and hepatic sys-
with empathogenic effects in a therapeutic or research tems can be devastating.169
setting, and a positive mood change may even occur, Recent data show that MDMA (related deaths
as seen in a study with MDEA,5 suggesting that the (MRDs) are on the rise in several countries.170,171 And
combined effect of the drug and environmental and there has been concerns about the recent availability of
behavioural stressors in typical use is important.164 some ‘super-strength’ formulations.172
173
Deaths resulting from other MDMA-like NPS intoxication were found in more recent reviews inter-
have been reported in recent years. PMA and nationally, with alcohol, amphetamines and cocaine
PMMA have been associated with a number of deaths. being common cointoxicants.56,181
Compared with MDMA, they appear to have a high MDMA can cause severe acute harms in some
potential to cause life-threatening toxicity.84 The cases. Clinically, amphetamine- and MDMA-like
emergence of PMA47 and PMMA44 on the ecstasy NPS can induce sympathomimetic toxicity.180 Severe
market internationally dates as far back as 1973, when acute harm following use of MDMA usually falls into
PMA appeared in Canada, leading to fatalities.173 the categories described below,145,181 although the
Studies have shown a number of PMA-associated clinical picture is often complicated by concomitant
deaths, including as the sole drug.174 drug use,181 and a single case may have symptoms
Similarly, in a case of a fatality linked to con- from more than one category:
sumption of two capsules thought to be ‘ecstasy’, • Hyperthermia/hyperpyrexia and secondary
a single capsule from the batch was found to con- manifestations;
tain 422 mg bk-MDMA (methylone) and 53 mg bk- • Serotonin syndrome (a cause of hyperthermia145);
MBDB (butylone), far higher than typical reported • Dilutional hyponatraemia and hyponatraemic
doses.11 encephalopathy. Hyponatraemia in particular is
a cause of fatalities associated with MDMA and
9.14 Acute Harms similar drugs in women;179
• Acute psychiatric presentations, including
Overall, reports of health problems associated with
symptoms of anxiety, panic or psychosis;
MDMA are relatively uncommon.175 These are most
• Other isolated physiological syndromes, including
likely to be linked to:
cardiac events, liver damage182 and failure and
• The use of high-purity and high dose tablets; pneumomediastinum. It has been suggested that
• Polysubstance use. This could be associated with hypoglycaemia, hyperkalaemia183 and QRS
using MDMA with another substance. It could elongation26 may be features specific to PMA
also be due to the ecstasy product used, which poisoning. However, all these signs have been
included more than one compound, causing observed occasionally in cases of severe MDMA
possible metabolic interaction.176 toxicity not linked to PMA.184,185,186
• Toxicity associated with the use of tablets
It has also been noted that the increase in MDMA-
adulterated with other substances such as PMMA. related deaths has been mirrored by an increase in
For example, an Australian study reported that ‘high-dose’ MDMA pills in circulation, and/or the
a majority of patients presenting with severe presence of high-risk adulterants such as PMA (para-
symptoms following the use of what had been sold methoxyamphetamine) and PMMA (paramethoxy-
as ‘ecstasy’ had in fact consumed PMA.26 methamphetamine) in pills mis-sold as MDMA.187
A minority of users of MDMA/ecstasy will present When acute toxicity has occurred following the
to hospitals, often directly from parties, ‘raves’ or use of other NPS with effects similar to MDMA,
nightclubs.177,178 The majority of presentations for such as PMA or PMMA for example, patterns of
MDMA are managed in hospital emergency harms are similar to the broad spectrum of acute
departments; they are mild or moderate in severity harm associated with MDMA and are described in
and self-limiting.56,180 In an Australian study, the the following.17,84,188 However, the severity of symp-
median duration of stay in the emergency department toms may tend towards the higher or lower end of the
was 3 hours.130 spectrum seen with MDMA. PMA and PMMA are
Studies from accident and emergency units show particularly associated with severe and life-
that the most common presentations after consuming threatening symptoms, such as seizures and
MDMA include collapse and/or loss of consciousness, coma.56,82 A study from Norway, for example,
as well as feeling ‘unwell’, ‘strange’, ‘weak’ or ‘dizzy’; reported 12 fatalities and 22 recoveries from a series
nausea, vomiting and tachycardia are also of PMMA intoxications.81
common.56,180 In a series of presentations to As with other club drugs, mixed intoxications
a London emergency department, 67% had consumed (from deliberate poly-drug use, alcohol or from
other substances.180,179, Similar and higher rates of co- ecstasy adulteration) are typical in general use and in
174
9.14 Acute Harms
presentations to acute clinical settings.180 Poly-drug 9.14.1 Features of Acute MDMA Toxicity
use appears to be associated with life-threatening out-
Table 9.2 provides information on acute MDMA
comes at lower blood concentrations, as shown by
toxicity.
a study which reported a mean post-mortem
MDMA blood concentration of 2.90 mg/l in 22 ecstasy
poly-drug deaths, whereas it was 8.43 mg/l in 13 cases 9.14.2 Hyperpyrexia/Hyperthermia and Its
where only MDMA was found.180 Consequences
There is evidence that some adverse side- MDMA use can promote the development of hyper-
effects may be gender-specific. A study reported thermia in two principal ways145: by adding to heat
that women experienced more intense psycho- load and by reducing heat dissipation. It promotes
logical effects, while men showed a greater a hypermetabolic state pharmacologically,187 and
increase in physiological measures, particularly behaviourally, often leading to muscular exertion
systolic blood pressure. Although body weight through hours of dancing.181
may play a part, it also appears that there are Moreover, hot, overcrowded dance floors are
pharmacokinetic and/or pharmacodynamic differ- a typical setting for its use.215,216 Heat dissipation
ences between genders.189 can be impaired by peripheral vasoconstriction, at
Adverse effects may be dose-dependent as well as least in rats,217 or by dehydration. Another animal
gender-specific. In the analysis of clinical studies by study has suggested that high ambient temperature
Liechti et al., increasing dose was correlated with conditions potentiated the toxic and lethal effects of
greater self-reporting of hallucinogen-like perceptual MDMA.218
effects, in women in particular, and with greater Many ecstasy-using dancers who suffer adverse
reported dysphoric states in women alone. However, effects display typical symptoms of heat illness, such
increasing dose was not associated with increases in as feeling unwell and collapsing in an exhausted
measures of desired effects.191 state.180,181,218 Some will move to a ‘chill-out’ room
There is evidence from an animal study that age to recover at the dance venue, or be treated on site.
may be a risk factor, but more research is needed, Some will present to hospital, mostly with self-
especially human research. A study found important limiting symptoms, requiring minimal intervention
age differences in the toxic events promoted by beyond correcting dehydration and allowing rest.
‘ecstasy’, in relevant doses to the human scenario of However, patients with more severe acute toxicity
drug usage. The hippocampus of aged animals will present and will require intensive interventions.
revealed 5-HT neurotoxicity following MDMA use, The overheating associated with MDMA and
while no neurotransmitter changes were seen in their drugs with similar effects can produce harms across
adolescent counterparts. The study also found that a spectrum of severity; a minority of patients present
aged animals were more susceptible than adolescent with a severe hyperpyrexia that will not resolve spon-
rats to tissue damage in the heart and kidneys follow- taneously with rest in a cooler environment. This has
ing MDMA, thus suggesting a direct relationship been attributed to an idiosyncratic drug reaction caus-
between the age of the ‘ecstasy’ user and MDMA- ing a pharmacologically mediated central and periph-
related toxic events.190 eral thermogenesis.56,219
It has been argued that there are difficulties in Hyperpyrexia associated with MDMA can appear
disaggregating the harmful effects specific to MDMA across a broad dosage range.56 The hyperpyrexia and
toxicity from the confounding effects of analogues, serotonin syndrome seen in association with MDMA
co-intoxicants and environmental and individual and related serotonergic drugs are clinically distinct
factors.191 It is not yet clear how much of the overall from malignant hyperthermia and neuroleptic malig-
MDMA-related harm is attributable to the toxicity of nant syndrome.145,220,221
MDMA in isolation.56 Hyperpyrexia is one of the predominant life-
A study showed that the levels recorded at autopsy threatening adverse reactions to MDMA and similar
in 13 deaths by toxicity alone, overlapped consider- drugs and is the underlying cause of many acute
ably with MDMA levels recorded from 24 cases where MDMA-related deaths. It is also a cause of severe
the drug was detected post-mortem, but trauma was chronic harm resulting from secondary complications
the cause of death.192 such as liver failure and brain damage.56,221 A case
175
Table 9.2 Features of acute MDMA toxicity
Reported effects associated with MDMA and other NPS with similar reported effects
CNS, neurobehavioural and psychiatric effects

Dilated pupils, mydriasis11,180,181,193,194
Feeling unwell/weak/dizzy181
Restlessness5,129,195
Nystagmus19,24,82
Euphoria11
Anxiety5,195,196
Panic5,181
Agitation129,179,181,195,197,198
Disorientation/confusion19,129,181,195
Psychosis5,195,199
Paranoid ideation, delusions5,195,199
Delirium199
Sleepiness201
Collapse, loss of consciousness81,129,181,197
Self-injury199
Convulsions, seizures11,86,179,195,197,201
Amnesia19,200
Hallucinations5,82,85,195,200
Coma11,129,201
Trismus, bruxism,201 increase in jaw/facial tension,5,24,82
Headache129,181,195
Brain oedema129
Cardiovascular effects
Tachycardia5,11,82,179,180,181,196,198,202
Hyperthermia6,11,19,81,82,86,129,181,196,200
QT prolongation198,203,204
Hypertension11,129,181,196,198
Disseminated intravascular coagulation (DIC)11,181,190,197,200
Arrhythmias205 (atrial fibrillation206)
Myocardial infarction207
Chest pain181,208
Gastrointestinal effects
Nausea, vomiting5,24,19,86,181,197
Stomach cramps86
Dry mouth5
Respiratory effects
Tachypnoea11,180
‘Hyperventilation’5
Pneumomediastinum, causing subcutaneous crepitation,210 emphysema with neck/chest swelling209,210
Shortness of breath, dyspnoea, breathing difficulty86,181,200,210,212
Respiratory failure, acute respiratory distress5,81
Musculoskeletal effects
Hyperreflexia11
Shivering11,19,85,145,180,196, Shaking6,85,86,129
Tremor11,181,195,196
Muscle spasms82
Myoclonus11,181
Increased muscle tone, muscle rigidity11,82
Inability to stand86,200 Collapse86
Hyperactivity (‘thrashing around’)175,211,212
Other effects
Metabolic acidosis213
Sweating, diaphoresis19,85,86,200
Foaming at the mouth,86,200
Acute kidney injury/acute kidney failure214
Rhabdomyolysis24,129,197,200
176
9.14 Acute Harms
report of a patient with severe pyrexia associated with hyponatraemia and it is argued that hyponatraemia
MDMA reported severe multi-organ failure and pro- appears to be a significant risk when hypotonic fluids
found disseminated intravascular coagulopathy.222 are consumed during MDMA use.228
There may be considerable overlap between sero- Women make up more than 85% of symptomatic
tonin syndrome and this form of acute MDMA - cases in the literature, despite more males being users
related toxicity. Serotonin syndrome can be a trigger of MDMA.179,216,229 It seems that MDMA has the
for uncontrolled hyperpyrexia, but hyperpyrexia can potential to directly affect water balance via
also occur without serotonin syndrome.145 Acute kid- a syndrome of inappropriate anti-diuretic hormone
ney injury occurs as a consequence of the myoglobi- (SIADH) secretion, particularly in women.231
nuria seen with rhabdomyolysis, but may be The drug and the typical contexts of use promote
compounded by a number of factors, which include exertion and sweating (resulting in loss of sodium).
a direct toxic effect of the drug in the kidney and Hyponatraemia can occur when these effects are com-
volume depletion from dehydration.216 bined with the consumption of excessive quantities of
low-electrolyte fluids such as beer and water.203 The
9.14.3 Serotonin Syndrome/Serotonin psychoactive effects of MDMA and similar drugs may
encourage this, perhaps promoting obsessional repetitive
Toxicity behaviour, and masking awareness of emerging symp-
MDMA is a powerful releaser of serotonin and as such toms of hyponatraemia, such as confusion.56,230
is linked to serotonin syndrome. Further information Furthermore, mistaken, or misunderstood, harm-
on the features and management of serotonin toxicity reduction information has allegedly led to excessive
can be found in Chapter 8 and Section 9.14. drinking of water to avoid dehydration and
MDMA and similar drugs can be a cause of sero- heatstroke.232
tonin syndrome alone, or in combination with other Mild, asymptomatic hyponatraemia has recently
factors that increase serotonin to toxic levels, includ- been shown to be a common effect of the use of
ing many recreational and pharmaceutical drugs,223 MDMA and similar drugs in a typical electronic
such as MAOIs, SSRIs, tricyclics, tramadol and line- dance music context. Women are more vulnerable
zolid. In one Australian study, some ecstasy users than men, as they are more likely to have lower
reported deliberately taking these and other pharma- serum sodium levels before MDMA use. They are
ceuticals to magnify the effects of MDMA.224 more likely to become mildly hyponatraemic while
The risks of serotonin syndrome associated with using, more likely to develop symptomatic hyponatrae-
MDMA are boosted by several classes of serotonergic mic encephalopathy, and more likely to die as a result.56
drug.90,225 A recent fatality was associated with 6-APB Fatalities are mainly women under 21 years of age,
and mirtazapine.226 Some NPS entactogens inhibit although men have suffered hyponatraemia, so the
monoamine oxidase. possibility of male cases should not be ignored.56
PMA/PMMA poses a particular threat of severe In contrast to other acute syndromes caused by
serotonin toxicity.81 It has been suggested that it may MDMA and similar drugs, dilutional hyponatraemia
simultaneously promote serotonin toxicity in several often follows a uniform course, with symptoms mostly
ways – by causing serotonin release, inhibiting reuptake resulting from the progression of cerebral swelling.
and inhibiting CYP2D6 metabolism.82 Symptoms com- Initial headache, vomiting and disturbed mental state
monly seen in reports of severe PMA and PMMA tox- are followed by seizures, drowsiness, disorientation and
icity are consistent with serotonin syndrome and muteness, progressing to coma, hypoxia and death,
hyperthermia. Serotonergic and sympathomimetic fea- often due to tentorial herniation.56 Patients may already
tures may include bruxism, agitation, confusion, con- be comatose upon admission to hospital.231
vulsions, rhabdomyolysis, coagulopathy, organ failure, Relatively low doses, including single tablets, are not
coma and death.84,185,227 unusual in cases of hyponatraemia.56 Also, the excess
water intake required to cause symptomatic hyponatrae-
9.14.4 Dilutional Hyponatraemia mia, in the context of MDMA intoxication, is not
extreme; 1,700 ml and 1,200 ml have been cited in case
and Hyponatraemic Encephalopathy reports;216,233 3,500 ml was drunk in a case related to bk-
MDMA has been described as causing a ‘perfect MDMA (methylone) and ethcathinone.24 Genetic
storm’ of effects that can precipitate dilutional
177
variation in the function of alleles coding for the symptoms from those who had not used ‘ecstasy’,
CYP2D6 enzyme and the COMT enzyme may predis- including shorter hospitalisation, less blunting of
pose some individuals to MDMA-induced affect but increased hostility.237
hyponatraemia.
9.14.6 Suicidal Ideation and Suicide
9.14.5 Acute Psychiatric Presentations MDMA users have an increased risk of suicide
Anxiety and panic are common presentations among attempts,238 but it is uncertain how much of this
users seeking medical help.56 MDMA is an ATS, and is association is causal, how much may relate to acute
widely used, yet evidence linking it to psychosis is use and how much to chronic effects. Recent ‘ecstasy’
limited to a relatively small number of case reports use has been linked to suicidal thoughts and behav-
and case series.56 Collectively, these suggest that iour, in some case reports in the context of acute
MDMA and similar drugs occasionally act as a stressor psychosis as described previously, or subacutely, pos-
that precipitates acute psychosis, but at a much lower sibly triggered by the ‘ecstasy’ ‘come-down’ (for
rate than amphetamine, their molecular relative.195 example one case followed a three-day session of
Psychotic symptoms can result from poly-drug injecting ‘ecstasy’).56 MDMA overdose has been
use involving MDMA or, on occasion, from MDMA employed as a mechanism of suicide or suicide
alone, particularly in vulnerable individuals.56,195 No attempt,239,240,241 as has bk-MDMA (butylone).242
single characteristic pattern emerges from the evi-
dence base; putative cases include previously healthy 9.14.7 Acute and Subacute Cardiac Events
people experiencing sudden onset of psychosis after
There is some evidence that MDMA has cardio-toxic
taking a single pill,232,233 as well as chronic poly-drug
effects.243
users with complex vulnerabilities taking up to four
MDMA alone, and in mixed intoxication, has been
tablets of ecstasy daily before admission with acute
associated with acute cardiac events, including myo-
symptoms.234 As with psychosis linked to other drugs,
cardial ischaemia and infarction.56,244 It can also
the prognosis varies from rapid resolution within
unmask underlying cardiac dysfunction. Myocardial
hours (perhaps in those with a low intrinsic propen-
infarction probably results from coronary artery
sity to psychosis) to months or years as an inpatient
spasms, similar to those observed in cocaine users.
(perhaps in those with a high vulnerability).56,235
A series of three cases of acute coronary syndrome
The evidence base includes several cases where
and ST elevation myocardial infarction (STEMI) dem-
there is no toxicological evidence of MDMA
onstrates that, as with cocaine-induced heart problems,
consumption55,235 and, in most cases, deliberate or
they may emerge long after plasma drug concentra-
unintended co-intoxication with other drugs linked to
tions have peaked.246 Hyperkalaemia could also con-
psychosis cannot be excluded as a factor.236 It remains
tribute to cardiac arrhythmias. There is a single case
unclear whether the tendency for ATS to precipitate
report of severe dilated cardiomyopathy accompanying
psychosis is more a direct pharmacological action or
hepatic damage in a regular user of MDMA.245
toxicity, or more an indirect product of severe psycho-
Cardiac arrests occasionally occur without being
logical stress, such as that caused by sleep deprivation
precipitated by hyperpyrexia or serotonin
and bingeing behaviour.257,236 In either case, MDMA is
syndrome.181 When patients present with chest pain
an exception among ATS, with lesser effects on dopa-
and other symptoms, concomitant use of other drugs
mine and use typically confined to weekends, rather than
should be considered, especially cocaine, which is well
multi-day binges, as may occur with methamphetamine
known for provoking cardiac dysfunction.56
and cocaine. Two cases of MDMA-induced psychosis
occurred in individuals who were ‘spiked’ with the drug
without their knowledge and consent.56,238 This may 9.14.8 Pulmonary Harms: Pneumothorax,
indicate a substantial influence of psychological ‘set’ in Pneumomediastinum
determining the response to intoxication. A case report described a patient with MDMA toxicity
A case control study in a subacute population of presenting with pulmonary haemorrhage.246
males undergoing treatment for their first-episode One study has reported that MDMA has been
psychosis found that those who had a recent history associated (through uncertain mechanisms) with at
of ‘ecstasy’ use showed significantly different least 23 cases of pneumomediastinum,211 and
178
9.14 Acute Harms
a smaller number of pneumothorax cases are also 9.14.11 Diabetic Ketoacidosis

reported in the systematic review by Rogers et al.56
A small number of case reports demonstrate that
Patients usually present with pain in the chest and
people with diabetes can suffer ketoacidosis and asso-
neck and shortness of breath, but subcutaneous
ciated symptoms following MDMA use combined
emphysema and resultant swelling may also be
with exertion.252,253
apparent.211 Sometimes presentations may be
delayed as long as days after consumption. It is
hypothesised that the muscle tension caused by 9.14.12 Poly-drug Use and Drug
MDMA, combined with exertion from dancing, Interactions
jumping or sex,212,247 could lead to air pressure As discussed above, MDMA is commonly used with
against a closed glottis, similar to the Valsalva other psychoactive drugs and this can increase harm.
manoeuvre, raising alveolar pressures and causing For example, cocaine co-ingested with MDMA seems
ruptures.211 This can result in air being forced out to increase the risk of severe anxiety. In an audit of 52
into spaces in the mediastinum.248 One case with acute ‘ecstasy’-related admissions, 13 with co-use of
an alternative mechanism featured a tear in the cocaine, four of the seven patients who suffered panic
oesophagus, allowing air into the mediastinum.145 reactions were among the 13 cocaine users.181 When
MDMA is co-ingested with stimulants in general, the
9.14.9 Intracranial Haemorrhage potential for toxicity is likely to be raised.254 Co-
MDMA use has been associated with intracranial intoxication with caffeine increases the risk of hyper-
haemorrhage, even in the apparent absence of co- pyrexia in rats.255 PMMA and PMA produce greater
intoxicants.56,249 Pre-existing aneurysms, or arterio- toxicity in combination with other stimulants.82
venous malformations, may rupture as a result of the Poly-drug use commonly confuses the clinical pic-
acute surge in blood pressure caused by MDMA, ture of MDMA intoxication, and can lead to paradox-
similar to the mechanisms seen with cocaine. ical features that are not those expected from
There are some reports of cases of spontaneous intoxication with MDMA alone. In a Swiss emergency
intracranial haemorrhage in patients who have taken department audit, hypothermia was, paradoxically,
MDMA. One case report describes spontaneous sub- one of the most commonly recorded features, and
arachnoid haemorrhage and small acute cerebellar brachycardia, coma, pupil constriction and hypoten-
infarction in an otherwise healthy patient after inges- sion were also noted.181 These were associated with
tion of MDMA and the authors argue it is important the co-use of substances, including GHB and
to consider subarachnoid haemorrhages and cerebro- opiates.56 Consuming alcohol with MDMA and simi-
vascular accidents as complications of MDMA use.250 lar drugs is associated with a higher rate of harm.
Concomitant alcohol use was implicated in 75% of
cases of MDMA-related presentations in an
9.14.10 Liver Failure Australian emergency department.130
MDMA may cause liver failure in two ways. In terms of drug interactions, MDMA and related
According to a review of the evidence, one group drugs are substrates and inhibitors of CYP2D6, so
develop acute liver failure secondary to a severe combining them with other drugs or pharmaceuticals
hyperthermic reaction to MDMA. The other group which compete for, inhibit or block CYP2D6 may
appear to suffer isolated hepatotoxicity without any cause greater unwanted effects or toxicity. For
hyperthermia. This is generally a subacute effect example, people taking the HIV antiretroviral drug
which may emerge over the days following use, in ritonavir are likely to be at particular danger from
contrast to the rapid onset of organ failure in hyper- MDMA toxicity.256 Similar reactions may be possible
thermic patients.56 Despite its rarity, this constitutes with any drug sharing ritonavir’s capacity to compete
one of the more common causes of liver failure in this with MDMA as a substrate of CYP2D6 and inhibit the
young age group. Patients may present in a critical enzyme. Other drugs linked to apparent cases of
condition, with hepatic encephalopathy, and some adverse interactions include dextromethorphan
will require transplantation.251 It has been suggested (DXM), fluoxetine, paroxetine and moclobemide.17,78
that MDMA may cause a greater amount of ‘silent’ Drugs which could theoretically cause similar prob-
liver damage than is recognised.56 lems include haloperidol, thioridazine and
179
quinidine.17 CYP3A4 is also involved in the metabol- 9.15.1 Hyperpyrexia and Hyperthermia
ism of MDMA and its derivatives, and co-ingestion of
Patients presenting with high body temperatures
ritonavir has been linked with several cases of
(above 39°C) need aggressive cooling measures, such
toxicity.17 There may be risks associated with many
as ice baths or internal cooling, and benzodiazepine
other substances which affect CYP3A4.17,257
sedation.
Importantly, MDMA is metabolised by CYP2D6
It has been suggested that dantrolene may be
and inhibitors of this metabolic pathway may there-
considered when hyperthermia persists. However,
fore increase its level and consequently toxicity.
this has been contested by some. No clinical trials
have been conducted but a review has reported
9.15 Clinical Management of Acute better survival rates for patients with temperatures
Toxicity above 40°C who received dantrolene, with minimal
Because of its common use in nightlife leisure adverse effects.259 However, a 2011 evaluation of
settings, admissions to emergency departments fol- options in MDMA-induced hyperthermia recom-
lowing MDMA use often occur at peak times and mended against the use of dantrolene and
therefore put pressure on resources.130 PMA and antipyretics.260
PMMA may account for many cases of severe An animal study suggests that by acting dir-
‘ecstasy’ toxicity encountered in an emergency ectly on blood vessels, carvedilol is modestly
department.81,84 effective in attenuating MDMA-induced brain
Due to the number of symptoms and complica- and body hyperthermia. The study also suggests
tions associated with MDMA, the management of that clozapine induces much more rapid and
acute toxicity varies from initial management and powerful hypothermic effects by both decreasing
assessment to supportive management of severe MDMA-induced brain activation and diminishing
symptoms.258 the sympathetic outflow to peripheral vessels.
The most common interventions required are A therapeutic agent such as clozapine that not
clinical monitoring, observation and reassurance, only mitigates, but reverses, MDMA-induced
and symptomatic treatment, including fluids.181 hyperthermia could be indispensable for emer-
The average duration of hospital stay reported by gency situations and could save the lives of highly
the Australian study was 3 hours,130 but others intoxicated individuals.261 However, much more
recommend observation of asymptomatic patients research is needed before this can be recom-
for at least 4 hours. In an Australian emergency mended for humans
department, 14% of people presenting to hospital
after MDMA consumption required admission.130 9.15.2 Serotonin Syndrome
Dehydration should be addressed. Following The assessment, diagnosis and management of sero-
MDMA-related presentation to a hospital emergency tonin syndrome is described in detail in Chapter 8.
department, intravenous fluids were administered to A case report describes extracorporeal life support
31% of patients in a UK study,180 and to 71% of cases as part of the management of haemodynamic instabil-
in a Swiss study,181 but it is important to note that ity induced by serotonin syndrome.262
symptoms following MDMA use range from severe A case series showed that supportive treatments
dehydration to severe hyponatraemia; the latter in addition to the early use of cyproheptadine
patients require fluid restriction, so it is dangerous might have some beneficial effects in reducing the
to give hypotonic fluids or normal saline to patients severity and hospital stay in patients presenting
prior to proper assessment203,216 (see Section 9.14.4 with life-threatening serotonin syndrome related to
for more detail). MDMA. Cyproheptadine has anti-histamine and
There is no evidence to support gastric decontam- 5-HT antagonist properties which are reported to
ination with activated charcoal, but it may be appro- be an effective agent in managing serotonin syn-
priate for cases of presentation within 1 hour of drome of moderate severity. However, more
ingestion. Gastric lavage was used in a case with research is needed as there is little information
a positive outcome following an attempted suicide concerning whether it is useful in life-threatening
with 30 tablets.241 situations.263
180
Other harmful chronic consequences that have

For up-to-date guidance on the management of been attributed to long term and frequent use of
ecstasy/MDMA acute toxicity, it is recommended that MDMA include cardiovascular damage, particularly
information be sought from National or Regional
serotonergic valvular heart disease.
Poisons Information Services and local protocols and
national guidance be followed.
Evidence of long-term effects of NPS similar to
MDMA use is not available, and so the potential for
each of these to cause harm remains unknown.
Chronic use of an NPS product containing MDAI
9.15.3 Acute Psychiatric Presentation and 2-AI (the latter of which appears to be more
Clinical Management amphetamine-like than MDMA-like) has been linked
to one case of cyanosis caused by methemoglobinae-
Most of the common features observed in acute
mia. Such effects may also result from chronic use of
patients can be at least partially attributable to anxiety,
the many NPS products containing benzocaine as
agitation and panic (e.g. dizziness, palpitations, hyper-
a cutting agent.265
thermia, hypertension). Some features (e.g. tachycar-
dia) can act as internal stimuli to anxiety and panic
attacks. It is suggested that controlling agitation with 9.16.1 Neurotoxicity
benzodiazepines may relieve hypertension. Differences in the serotonergic function of MDMA
Many cases are resolved in a preclinical setting, or users, compared with controls, have been observed
upon reassurance during the initial assessment. in neuroimaging studies.266,267,268,269,270,271
Agitation, anxiety and panic can be managed as they Observed differences in markers of serotonergic
would be in the absence of a drug trigger, but cardiac function have been interpreted as indicating the
monitoring is a higher priority.180 Reassuring patients degeneration and loss of serotonergic neurons and
that they are not likely to be in physical danger may be their terminals, i.e. ‘neurotoxicity’.271 Correlations
sufficient, but benzodiazepines are the first-line have been demonstrated between presumed markers
pharmacological treatment. One study reported that of toxicity seen in users and functional deficits in
benzodiazepines were administered to a quarter of all memory.272,273 This supports the hypothesis that
patients presenting following MDMA use at a Swiss serotonergic neurotoxicity is the cause of the cogni-
emergency department.145,181 Some suggest that halo- tive deficits and worsened neuropsychiatric status of
peridol is contraindicated as a second-line option, MDMA users.58
because of possible dangerous interactions with The idea that MDMA is neurotoxic in typical
MDMA and related drugs.17 human users is supported by some animal
research,268 but some experts do not consider the
9.16 Harms Associated with Chronic evidence to be conclusive.60,274 Some have argued
that the observations in such studies may be con-
Use sistent with changes and loss of serotonergic
While the association between MDMA and similar markers, without loss of the neurons themselves
drugs consumption and several types of acute harm (i.e. serotonergic dysfunction occurs but this may
is relatively clear, current understanding of the or may not amount to ‘neurotoxicity’).275,276 Other
chronic harm caused by MDMA use is limited, due authors highlight limitations in the predominantly
to incomplete and disputed evidence. retrospective and non-randomised studies sup-
Chronic use of MDMA has been linked to seroto- posedly indicative of ‘neurotoxicity’, claiming that cur-
nergic neurological damage and dysfunction, which rent evidence is insufficient to exclude non-causal
some researchers have suggested may be responsible explanations,276 such as pre-existing lower levels of
for a broad range of neuropsychiatric symptoms and serotonergic markers in the brains of MDMA
cognitive impairments. A meta-analysis shows these users.60,277 While poly-drug use in virtually all
to be predominantly small, subclinical effects.56 MDMA users has been cited as a confounding factor,
Significant trends indicating impairment are typically recent investigations comparing MDMA users with
not identified in samples of ‘ecstasy’ users who have LSD users278 and other poly-drug users279 add weight
taken the drug on fewer than 50 occasions.264 to the evidence for MDMA-specific neurotoxicity.
181
High lifetime intake may not necessarily be 9.16.2 Cognitive Deficits

required for neurotoxicity to occur. One prospective
A number of studies have compared the performance
study found evidence indicative of some brain
of community samples of MDMA users (current or
changes in new users with an average lifetime
past) against that of matched controls on many stand-
intake of only six tablets. These changes did not,
ard tests of cognitive performance. Weaker perform-
though, include losses in serotonin transporter
ance in certain domains has been identified in the
density, which is the marker of toxicity most com-
MDMA users, with the greatest and most consistent
monly observed. The authors concluded that it is
effects seen on aspects of memory and recall,56 such as
possible that MDMA is neurotoxic even in small
verbal memory275 and visual paired associate
quantities.280
learning.289
Studies have found evidence consistent with some
One explanation for the poorer performance of
recovery281 and adaptation of the altered serotonin
the MDMA users is typically considered to be seroto-
system,273 but, conversely, other results indicate the
nergic neurotoxicity associated with the drug.
persistence of serotonergic dysfunction following ces-
However, there is no consensus on this,59 with many
sation of MDMA use.269
findings open to alternative, non-causal, interpret-
The degree of any lasting dysfunction or neuro-
ations, such as confounding cannabis use, or tenden-
toxicity caused by MDMA is thought to be a function of
cies towards impulsivity and boredom leading to both
the bioenergetic stress undergone during acute
ecstasy use and poorer performance on tests.290
intoxication.282 This theory has led to the hypothesis
The weaker performance of ecstasy users remains
that there are mediating factors for the bioenergetic
limited, according to some,292 and deficits appear to
stress experienced, and thus the vulnerability or resili-
be specific to certain domains rather than general,
ence an individual may have to neurotoxicity, beyond
with one meta-analysis finding general intelligence
the MDMA dose per session and frequency of use.
unaffected and no impairments seen in simple cogni-
These factors include: ambient temperature and level
tive functions like basic attention and reaction
of exertion (increases of each may promote neurotox-
times.56
icity), poly-drug use (with stimulants likely to promote
Deficits in verbal memory have been identified,
neurotoxicity283,284) and others ranging from users’
whereas deficits in executive function and visual
genetics and nutritional status to how well rested they
memory have been identified in some studies but
are.57
not others.292 The performance of users typically
A study suggests that people’s age when they first
overlaps substantially with the performance of
used MDMA may be strongly linked to brain changes
controls, and uncertainty and controversy remain
brought about by the drug, with those first exposed
over the clinical significance and real-world impact
while their brains were still developing showing greater
of the apparent deficits identified in these
apparent deficits. The authors suggest that these age-
samples.58,60
related differences may reflect differences in the mat-
A relatively high intensity of use may be neces-
uration stage of the 5-HT projection fields at the time
sary to produce significant deficits. In one study,
of first exposure and enhanced outgrowth of the 5-HT
which excluded anyone with significant poly-drug
system due to 5-HT’s neurotrophic effects.285
or alcohol use from the ecstasy-user sample, and
Some NPS with empathogenic effects, for
which used controls who also shared the ‘rave’ or
example 4-MTA,86 have been referred to in the lit-
partying lifestyle, no marked deficits were found. The
erature as ‘non-neurotoxic’ analogues of
authors argued that the confounding influences of
MDMA,286,287 and some were developed for this
poly-drug use and lifestyle may lead to overesti-
purpose.288 However, these assessments were based
mation of the harm associated with MDMA .291
on pre-clinical evidence, and evidence from long-
However, in response, it has been argued that this
term human use is not available to confirm that
study was nonetheless consistent with the serotoner-
these drugs do not cause serotonergic neurotoxicity.
gic neurotoxicity of MDMA causing cognitive def-
Animal and in vitro evidence suggests that among
icits, since it was not highly powered enough (with
MDMA-like drugs, some are likely to be more neuro-
fewer than 50 users) to show subtle deficits associated
toxic (e.g. MDA) and some less neurotoxic (e.g.
with an average lifetime history of use.266
MDEA) than MDMA.17
182
9.16.3 Psychiatric Symptoms and Harms relationship.302 Early onset of cannabis use,301 and
tobacco use, have been shown to correlate with greater
Community samples of current or past MDMA users
anxiety among MDMA users, where neither lifetime
have been compared with matched controls on meas-
nor recent ecstasy use did.301 However, in one sample
ures of psychiatric and psychological health. A study
of 30 users, the users were not more likely than controls
has shown poorer results among MDMA users on
to report pre-existing depression or anxiety
several of these indices.292 MDMA acutely increases
symptoms.303
cortisol levels, especially when the bioenergetic stress
The come-down period after MDMA use is char-
is magnified by behaviour and environment, but
acterised by low mood and serotonin depletion, and it
recent studies have also associated MDMA use with
is possible that, for people vulnerable to depressive
more chronic increases in cortisol and related dys-
symptoms, this could exacerbate symptoms or poten-
function of hypothalamic–pituitary–adrenal axis.
tially cause suicidality.56
This in turn has been linked in chronic users to
In an experimental set-up, 12 male MDMA users
symptoms of distress, anxiety, aggression293 and
performed a laboratory task involving monetary
impaired coping.294,295
rewards. They were more ‘aggressive’ and ‘irritable’
A meta-analysis in 2005 of 25 studies found
than controls towards fictional co-players. It is not pos-
a small but significant link between ecstasy use
sible to exclude personality factors that pre-existed
and depressive symptoms. However, the authors
ecstasy use, and it is uncertain how this ‘aggression’
noted several methodological limitations and
would translate to real-world face-to-face
showed that publication bias may have occurred.
interactions.295
They concluded that any effect of ecstasy on depres-
In addition to this evidence of poorer mental
sion is unlikely to be clinically significant.296 More
health in samples of MDMA users, mostly relating
recently, in a sample of 3,880 disadvantaged
to subtle, subclinical differences, there is evidence
Canadian adolescents, those who self-reported
from case reports of more profound psychiatric
ecstasy use were more likely to have elevated
disturbances and disorders in individual users.
depression symptoms 1 year later (odds ratio 1.5)
One paper detailed two case studies of severe obses-
and those who used MDMA with methampheta-
sive-compulsive disorder developing in chronic
mine had even higher rates (odd ratio 1.9).297
heavy users of MDMA, leading, in one case, to
However, studies have shown that circumstances
depression with psychotic features, and, in the
such as a deprived home environment can provide
other, to psychosis.304 The former patient (a 16-
a partial or even complete explanation for the
year-old female who took four or five tablets per
higher incidence of depressive symptoms in ecstasy
week for 1 year) was judged to have vulnerabilities
users.298,299
to mental disorder, but the second patient did not
A US study using a national sample reported that
(a 23-year-old male who took one or two tablets
suicide risk appears to be elevated among adolescent
a week for more than 2 years). Both cases resolved
users of ecstasy, almost twice that of users of other illicit
with treatment. The authors conclude that caus-
drugs and nine times the risk among non-users.240
ation cannot be determined, but is suggested by
A number of factors may be associated with long-
the case histories.
term harms. A study by Soar et al. found that the 57
people who reported their MDMA use as having
caused them problems (such as increased depression, 9.16.4 Harmful and Dependent Use
somatisation and anxiety) did not differ from those
who reported no harm in the duration of their use of and Withdrawal
ecstasy. However, those who reported problems also MDMA is typically used occasionally.57 Most people
reported higher doses, in a pattern the authors call who try ecstasy will not escalate to regular or sus-
‘binge consumption’, without further defining this.300 tained use.57 For example, UK population-level data
Concomitant use of other drugs is a confounding suggest that although use of MDMA is relatively high
factor193 that may explain much of the apparent height- in comparison to other drugs (except cannabis), only
ened prevalence of various markers of psychopathology, small percentages of people report using ‘ecstasy’ fre-
such as depression and anxiety experiences.301 Cannabis quently and that the proportion of ‘frequent’ users of
use, for example, has been found to mediate this ecstasy has declined in the past 10 years. The majority
183
of ecstasy users aged 16 to 59 reported having taken Users may fulfil dependence criteria,312–317
the drugs once or twice a year rather than more develop problematic chronic use patterns, have con-
frequently.305 cerns about their use and seek treatment.313 Several
Nevertheless, using MDMA on many or most studies have demonstrated some features of depend-
weekends is not uncommon among people sampled ence among MDMA users, such as worrying about
at clubs and raves.148 Use of ecstasy several times use, thinking use was out of control and finding it
a week, or even daily,306 has been recorded, although difficult to abstain.313,315
this is exceptional and very likely to be linked to A number of studies have shown that approxi-
comorbidities.137,236,308 One case has been reported mately one in five users have been found to be poten-
of a poly-drug user who self-reported the consump- tially dependent,317,318,319,320 although studies which
tion of 40,000 tablets between the ages of 21 and 30 carried out detailed investigation of withdrawal symp-
years, before ceasing use following several toms have shown higher rates, as much as 43% in a US
collapses.307 Bingeing for up to 48 hours and using study of adolescents and young adults,316,318 and as
up to 25 tablets has been reported,57 but there is a lack high as 64% in a study using DSM-IV criteria for
of recent evidence, and the number of tablets is an amphetamine dependence.322
imprecise guide to the total dose taken. Some studies have suggested that how ecstasy is
The tendency is for tolerance to the positive effects used, rather than how often, may be of key import-
of MDMA to build up with use,308 leading to dimin- ance in ecstasy dependence, with ‘binge’ use and
ishing returns from consumption. This may be pro- higher doses being associated with dependence.315
tective against sustained heavy use or addiction.57 It Users who ‘binge’, who use ecstasy more frequently,
has been suggested that regular users often follow and who experience more social and physical harm
a trajectory of discovering and strongly liking are more likely to become dependent users.138
MDMA, using it most weekends, sometimes with Ecstasy ‘craving’ does not tend to follow the pat-
escalating dosages, for a year or two, suffering increas- tern typical with other drugs, as a symptom of
ing adverse effects with decreasing enjoyment (‘losing dependence, but instead resembles anticipation of an
the magic’) and then reducing or ceasing use enjoyed activity, typically being low during the week,
spontaneously.309 This pattern of decline has been but rising in the hours before weekend use.144
described as almost unique among recreational A withdrawal syndrome associated with MDMA
drugs.311 Nonetheless, a minority of ecstasy users has been reported. However, it has been argued that
will develop problems and drug-using patterns asso- the wide between-study variations in the incidence of
ciated with harmful use even when no other problem withdrawal symptoms indicate the need for improved
drugs were also involved. distinction between the short- and the long-term
According to the 2019 European Drug Report, effects of MDMA in standardised assessment tools,
MDMA use is rarely cited as a reason for entering despite recent advances. As with other stimulants, the
specialised drug treatment. In 2017, MDMA was period following acute use is marked by a number of
reported by less than 1% (around 1,700 cases) of phases: an initial dysphoric ‘crash’, followed, in
treatment entrants in Europe, with France, Hungary, chronic users, by an extended ‘withdrawal’ phase,
UK and Turkey accounting for 68% of these.310 marked by anhedonia and anergia.321 It has been
While MDMA is generally considered to have some argued that the application by some studies of with-
potential for dependence,5 use is often self-limiting and drawal criteria related to the ecstasy come-down may
focused around weekend activities.5 Reasons suggested have led to inflation of estimates of rates of potential
for the low dependence potential include the relatively dependence and withdrawal.322 While ‘true’ with-
long period of recovery after one dose.57 drawal symptoms lead to users taking more of the
It has been argued that although the physiological drug to relieve them, adverse effects following an
basis of MDMA dependence is relatively weak in episode of ecstasy use have been seen as one reason
comparison with some other drugs, other factors why heavy users sometimes spontaneously quit
related to the behavioural and psychological aspects MDMA.311
of reward and dependence may have a relatively Some animal studies have shown that chronic use
greater contribution to dependence for ecstasy than can lead to MDMA acting increasingly like an addictive
for other drugs.311 stimulant. If chronic use of MDMA causes significant
184
9.17 Management of Chronic Harms
serotonergic damage but little or no dopaminergic fibrotic thickening and valve dysfunction.332 There is
damage (as supported by brain imaging274), then the some limited evidence that MDMA may be capable of
dopaminergic effects may become more prominent causing such reactions in chronic, heavy users.
than the serotonergic ones, similar to amphetamines A blinded study using echocardiography to identify
with greater addictive potential.323 This is partially sup- abnormalities reported that MDMA may lead to mild
ported by user experiences; many report ‘losing the to moderate valvular heart disease and valvular
magic’311 of the serotonergic effects with overuse and, strands.334
outside the academic literature, users of drugs online A 33-year-old male smoker with an exceptionally
fora note how, after overuse, MDMA feels more typic- high level of lifetime ‘ecstasy’ use (several pills per
ally amphetamine-like. week since the age of 17)333 reported shortness of
MDMA dependence presents unique features.315 breath and chest pain. He had severe mitral valve
In an online survey promoted to users of a dance- disease, with fibrotic thickening of the leaflets and
music website, ecstasy users were more likely than resulting severe regurgitation, necessitating a valve
users of cocaine, ketamine or mephedrone to endorse replacement. It was suggested that the lack of reports
three or more DSM-IV criteria, yet reported less of similar cases may be explained by the typically
harm, more pleasure and less desire to seek help short ‘ecstasy career’ of most users, and the potential
than users of these other club drugs.314 reversibility of the valve damage.333
MDMA is rarely reported as an individual’s prin- In addition to valvular heart disease, chronic
cipal problem drug.315,324 MDMA use has been linked to cardiomyopathy
Although MDMA is rarely a primary problematic more generally,333 although the evidence remains
drug, users of ecstasy are more likely than other drug inconclusive. A retrospective analysis of autopsy
users to have experienced substance use disorders in records shows that the hearts of people who had
the past year involving drugs other than MDMA.325 MDMA in their bodies at post-mortem were more
This was the case for 7 out of 10 MDMA users in an likely to have enlarged hearts, consistent with myo-
American population sample.328 cardial hypertrophy, as seen in users of cocaine and
methamphetamine. However, this study did not
9.16.5 Sleep Problems appear to be controlled in a way that could exclude
the confounding factor of poly-drug use.334 A single
A history of MDMA use has been linked to poorer
case study of dilated cardiomyopathy associated with
sleep in some studies but other studies have found no
MDMA has been reported.247
differences.56,326,327 Dysfunctional sleep processes
may be involved in the memory deficits associated
with MDMA use.328 9.17 Management of Chronic Harms
9.16.6 Vascular Problems 9.17.1 Treatments for Harmful Use
The typical surge in blood pressure that MDMA and Dependence
causes may, over time, damage the blood vessels, in
As with other ATS, the treatment of harmful MDMA
particular the walls of aneurysms and arteriovenous use is primarily psychosocial. No specific guidelines
malformations.56 This could lead to haemorrhage.329 for psychosocial intervention have been described and
Therefore, patients with aneurysms, or any other his-
validated for chronic MDMA users, but for general
tory of vascular disorders, should be strongly advised
guidance on treatment options see Chapter 2.
of the risks from any drug with a hypertensive effect.
In most cases, chronic ecstasy users will be poly-
drug users, and existing interventions would be unlikely
9.16.7 Heart Disease to focus on MDMA in isolation. For example, an inter-
A link between heavy, chronic MDMA use and valvu- vention in the form of 45–60 minutes of structured
lar heart disease has been proposed, due directly to its motivational discussion was trialled in young stimulant
serotonergic effects.330,331 Activation of the 5-HT2B users, most of whom had recently used ecstasy and
receptor in heart valves by (now obsolete) serotonergic cocaine, and most of whom were also regular users of
pharmaceuticals such as fenfluramine and ergotamine cannabis and alcohol.335 This discussion included
have been demonstrated to cause cell proliferation, exploration of the individual’s pattern of use, ‘good’
185
and ‘bad’ effects of use, plans for behaviour change, possible.344 This can be attempted by exploring users’
likely outcomes of this and, for users with no immediate experiences of the common unpleasant side-effects
plans to change behaviour, reflection on what future during and following use, and the disruption to other
scenarios would lead to a change (boundary setting).338 areas of life.344 This approach may be supported by
In this study, the majority (59%) of participants did sharing the evidence that lighter users tend to main-
report making efforts to reduce or cease their stimulant tain the positive effects from ecstasy, without the nega-
use following the intervention, but 41% of the control tive effects increasing much over time, whereas heavy
group did as well. Average number of days with users tend to find that the positive effects reduce
MDMA use in the previous 90 days fell from around sharply and unpleasant effects rise over time, to the
18 at baseline to around 8 at 6-month follow-up, and point where they outweigh the enjoyment.311 Doses
average dose fell from more than 2 tablets per session to higher than one average pill, or equivalent, are more
around 1.5, with no significant difference seen between likely to decrease the positive effects, with adverse
intervention and control groups.338 Both the interven- effects rising steeply above 120 mg.47,342
tion and the control groups participated in baseline self-
assessment and read health information, so the authors 9.17.2 Treatment of Depression
speculate that while there was no additional benefit
from the intervention, contact with personnel and in the Context of MDMA Use
actions that focus attention on substance use may be It is recommended that clinicians prescribing anti-
enough to change behaviour.338 depressants ask about recreational drug use and discuss
Similar results were found in a trial aiming to the risk of drug interactions with those who use
reduce MDMA use among Australian university stu- MDMA.90 One study has reported that citalopram
dents. A 50% reduction in use and a 20% reduction in strongly reduces the desired effects of MDMA, and
reported severity of harm were recorded 24 weeks other SSRIs would be likely to act similarly.343 Despite
after ‘motivational enhancement therapy’, but the this reduction in enjoyment, it is possible that SSRIs or
same changes followed the control condition, a 15- SNRIs could increase the risks of MDMA toxicity.90,225
minute information session.336 Another brief inter- In rats, some effects of MDMA, including hyperthermia,
vention for regular users did not produce significant are not diminished by citalopram, suggesting that if
reductions in quantity or frequency of use compared human users attempt to compensate for diminished
with the control condition (assessment only), but did enjoyment with higher doses, the risk of acute harm
significantly reduce reported symptoms of depend- could be increased.344 Furthermore, the pharmaco-
ence, and a greater proportion (16%) achieved abstin- logical effects of these drugs involve multiple actions
ence, although the study was underpowered to show on serotonin release and reuptake, and this complexity
whether this was statistically significant.337 may allow for unexpected interactions, including sero-
It has been noted that ‘ecstasy’ users may not tonin syndrome. MAOIs are strictly contraindicated in
always accurately assess the harm that their drug use those who are unlikely to be able to abstain from
may be causing. The degree of apparent subclinical MDMA and other similar serotonergic drugs, because
cognitive impairment in users appears to correlate not the combination has a high risk of causing serotonin
with the users’ own assessments of how problematic syndrome.
their use is, but with the cumulative dose.338
However, most ‘ecstasy’ users are aware that there 9.18 Public Health and Harm
are risks associated with the drug, and will have
reflected upon, contextualised and rationalised that Reduction
risk.339,340 Reducing risk of harm by encouraging Taking precautions and limiting dose were not found
ecstasy users to cease use (especially early in their to be associated with experiencing a lower rate of
career338) may be difficult because acute harm may adverse effects in a sample of 159 ecstasy poly-drug
be perceived as rare, and chronic harm too subtle to users, although most of this sample did not associate
motivate behavioural change.341 their use with adverse effects.345 Ecstasy users some-
Consequently, it has been suggested that the best times believe that MDMA itself is virtually risk-free
approach to reducing the risk of harm may be to when it is ‘clean’,346 i.e. that adulteration is respon-
encourage users to minimise their intake as much as sible for most or all of the adverse effects, minor and
186
9.19 Benzofurans
severe. It may be beneficial to tell patients that while Table 9.3 Benzofuran derivatives347 (often referred to as
Benzofury)
adulteration certainly does contribute to the risks,
pure MDMA can cause harm and death,349 especially 5-(2-aminopropyl)benzofuran 5-APB18
in high doses and in environments that contribute to 6-(2-aminopropyl)benzofuran 6-APB18
5-(2-aminopropyl)-2,3-dihydrobenzofuran 5-APDB
overheating and overexertion.50 The principles for the
6-(2-aminopropyl)-2,3-dihydrobenzofuran 6-APDB
reduction of the harms of ecstasy are similar to those 1-(benzofuran-5-yl)-N-methylpropan-2-amine 5-MAPB
for the reduction of ATS harms in general. 1-(benzofuran-6-yl)-N-methylpropan-2-amine 6-MAPB
In addition: 1-(benzofuran-5-yl)-N-ethylpropan-2-amine 5-EAPB
• Ecstasy users should be made aware that not all Indanylalkylamine derivative18
5-(2-aminopropyl)-2,3-dihydro-1 H-indene 5-APDI IAP18
ecstasy pills contain the same dose, and that some
Aminoindane derivatives348
tablets sold as ecstasy may contain other drugs, 5,6-methylenedioxy-2-aminoindane MDAI91
like PMA, which can be stronger, take longer to 5-iodo-2-aminoindan 5-IAI158
take effect and have higher risks.
• Users should be advised to start with a small dose
(half or quarter of a tablet). They should be made
aware that taking more than one pill at once might (5-APB) and 6-(2- aminopropyl)-benzofuran (6-APB)
not increase the effect, but can make a come-down were the first appear on the European market.
worse and increase the risk. Benzodifurans include a group also known as the
‘fly’ drugs (for example, bromo-dragon fly, 2 C-B-fly).
• Users should be advised to take regular breaks
They are hallucinogens and are discussed in
from dancing and be sensitive to the possibility of
Chapter 12.
exhaustion or overheating.
Benzofurans are ring-substituted amphetamine
• Users should be advised to stay hydrated, but not
derivatives. Similar compounds have also appeared on
to over-drink. It is best to take regular small sips of
the market in recent years, including 5- and 6-APB and
water and to drink no more than one pint of water
their N-methyl derivatives. It was found that when these
per hour if dancing in a hot environment and half
two materials were subjected to standard analytical
a pint if not dancing.
techniques, it was not possible to distinguish between
• Users should be advised to avoid mixing ecstasy
them. It is therefore very unlikely that those selling these
with alcohol and other drugs, as this increases the drugs will know which form they are selling.350
risks. Benzofurans were initially sold as ‘legal ecstasy’.
• Users should avoid mixing MDMA with other They were also sold as psychoactive substances in
stimulants as this increases the risk of their own right, as ‘Benzofury’. A study of Internet
cardiovascular adverse effects. sites showed that when mephedrone became con-
• Users should be aware that serotonin syndrome is trolled, the vendors aggressively promoted the sale
dangerous and that they should watch out for of Benzofury, as well as other new compounds (e.g.
anyone who looks flushed, hot and rigid and call NRG-1 and NRG-2).351
emergency services immediately. The term Benzofury was originally applied to
• A person on antidepressants who also takes 6-APB; however, the name was later used inter-
ecstasy pills will be at greater risk of serotonin changeably for 5-APB and 6-APB, as differentiation
syndrome. of the two isomers, even in laboratory analysis, is
difficult.
9.19 Benzofurans
Other substances used for their ‘emphathogenic’, and 9.19.1 Pharmacology
well as their stimulant effects, include benzofurans, Understanding of benzofurans remains limited. Both
principally 6-(2-aminopropyl)benzofuran (6-APB) 5- and 6-APB are phenethylamine-type materials and
and 5-(2- aminopropyl)benzofuran (5-APB), but are related to methylenedioxyphenethylamines, such
also the other substances listed in Table 9.3. as MDMA and MDA.353 They are potent inhibitors of
Benzofurans are structurally very similar to MDMA the reuptake of noradrenaline, dopamine and sero-
and its active metabolite 3,4-methylenedioxyampheta- tonin with a potency on monoamine transporters
mine (MDA)349 5-(2-aminopropyl)-benzofuran similar to that of MDMA.352 An animal study has
187
shown that 5-APB and 6-APB are potent full agonists A case reported that (5-MAPB) (N-methyl-5-(2
at 5-HT2B receptors.353 aminopropyl)benzofuran) seems to have an acute tox-
icity profile similar to that of 5-APB and MDMA, with
9.19.2 Patterns of Use, Modes of Ingestion marked vasoconstrictor effect. In this case, observed
As with other substances, benzofurans are used as part symptoms and signs included paleness, cold and
of a wider drug repertoire.196 Benzofurans are typic- clammy skin, hypertension, elevated high-sensitive
ally sold as a white powder, or in the form of pellets.354 troponin T level, tachycardia, ECG change, diaphoresis,
Routes of administration of benzofurans include nasal mild hyperthermia, mydriasis, tremor, hyperre-
insufflation of powder and ingestion. flexia, clonus, agitation, disorientation, hallucin-
ations, convulsions, reduced level of consciousness,
and creatine kinase level elevation.362
9.19.3 Desired Effects Other reports also mentioned adverse effects,
The desired effects of benzofuran include increased which include nausea, sympathomimetic stimulation
empathy, euphoria, visual stimulation, appreciation and agitation.259 Stimulant features of acute intoxica-
for music and dancing, and an increase in mood and tion with benzofurans are most common, followed by
self-acceptance.355 Users report that the effects of mental health disturbances.196 A study of the UK’s
5-APB and 6-APB are comparable to those of National Poisons Information Service patient-specific
MDMA but more intense.356 and that they have mood- telephone enquiries and user sessions for TOXBASE®
enhancing, emphathogenic and stimulant effects; they from March 2009 to August 2013 was conducted,
suggest that 5-APB is stronger than 6-APB.353 focusing on (2-aminopropyl)-2,3-dihydrobenzofur-
ans. These data were compared with those of mephe-
9.19.4 Clinical Uses drone collected over the same period. Ingestion of
A patent application has been made for benzofuran benzofuran was associated with similar toxic effects
compounds and their use as antidepressants and to those of amphetamines and cathinones. However,
anxiolytics. The compounds inhibit serotonin mental health disturbances and stimulant features
reuptake, exhibit serotonin agonistic and antagonistic were reported more frequently following reported
properties and are claimed to be suitable as anti- ingestion of benzofuran compounds than after inges-
depressants, anxiolytics, antipsychotics, neuroleptics tion of mephedrone. However, there are limitations to
and/or antihypertonics.357 these findings, resulting from a number of factors,
including lack of analytical confirmation.196
9.19.5 Acute Harms Comparing the 57 patients who reported ingesting
The unwanted effects of benzofurans include nau- benzofuran compounds alone with 315 patients
sea, bruxism, dry mouth and eyes, diaorrhea, sen- ingesting mephedrone alone, benzofurans were
sitivity to light, palpitations, increased heart rate, more often associated with stimulant features, includ-
blood pressure and temperature, hot flushes, head- ing tachycardia, hypertension, mydriasis, palpitation,
aches, drowsiness, and clonus of the hands and fever, increased sweating and tremor (72% vs. 38%)
feet. Benzofurans are also linked to psychological and mental health disturbances (58% vs. 38%). Other
symptoms like hallucinations, depression, anxiety, features reported after benzofuran compound inges-
panic attacks, insomnia and severe paranoia. tion included gastrointestinal symptoms (16%),
Psychosis has been reported.358 Some users also reduced level of consciousness (9%), chest pain (7%)
described an unpleasant ‘comedown’ that could and creatinine kinase elevation (5%).196
last for several days.359 One case report describes agitation and paranoia,
Very little information has been published on the but as a number of other drugs were ingested it is
acute harms of benzofuran, but a body of research is possible that another substance – or all – contributed
emerging.360 It is suggested that such compounds to acute psychosis.199
produce clinical features similar to those of amphet- It has been argued that the serotonin agonism of
amine, MDMA and mephedrone. Acute toxicity is benzofuran raises the possibility that chronic use of
characterised by serotonergic and sympathomimetic this compound could be associated with valvular heart
toxidrome, with nausea, agitation, anxiety, dizziness disease similar to that caused by fenfluramine and
and hyperthermia.361 ergoline derivatives.363,364
188
9.19 Benzofurans
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See Section 9.15 for MDMA and drugs with similar changing perceptions of purity. Psychopharmacology
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201
Chapter
Methamphetamine
10
10.1 Introduction a synthetic stimulant and a derivative of
amphetamine.3 Methamphetamine is a potent psycho-
It has been argued that globally, methamphetamine
motor stimulant with strong physiological effects on the
use represents the greatest challenge from all synthetic
peripheral and central nervous systems, resulting in
drugs. Whereas the highest prevalence of its use con-
physical and psychological effects.4 It is typically
tinues to be the US, where some commentators are
described as a more potent stimulant than non-
suggesting it is developing into an epidemic,1 new
methylated amphetamines. It is highly lipophilic, and
markets are emerging in many parts of the world,
in comparison to amphetamine at similar doses, crosses
with Southeast Asia currently emerging as the world’s
the blood–brain barrier more easily, is more potent and
fastest-growing methamphetamine market.2
has a more pronounced and a longer-lasting stimulant
effect.5 Methamphetamine has short-term and long-
10.2 Street Names term effects that are similar to those produced by
Street names at the time of publication include Crystal cocaine, but they last longer and can be more severe.6
Meth, Tina, Christine, Ice, Glass, Crank, Yaba and The action of methamphetamine and other
Crazy Medicine. Other street names may be used locally. amphetamines have been well described.5,7,8,9
Methamphetamine increases the activity of the nor-
10.3 Legal Status adrenergic and dopamine neurotransmitter systems.
Methamphetamine is placed in Schedule II of It increases the release and blocks the reuptake of
the United Nations Convention on Psychotropic dopamine. It has an active metabolite, amphetamine,
Substances. and two inactive metabolites, p-OH-amphetamine
and noradrenaline. It is oxidised and metabolised
10.4 Quality of the Research Evidence in the liver through enzymatic degradation primarily
involving cytochrome P450-2D6. Approximately
There is a much larger and more robust body of
10% of Caucasians are deficient in this enzyme, and
evidence on methamphetamine harms and treatment
a study has suggested that this makes them particu-
than for other club drugs. This includes a number of
larly sensitive to the effects of methamphetamine, as
well conducted randomised controlled trials (RCTs)
they lack the ability to metabolise and excrete the
and Cochrane reviews, especially in relation to
drug efficiently.10
dependence.
Chronic methamphetamine alters brain function.
However, most of the research evidence on meth-
Brain imaging studies have shown changes in the activ-
amphetamine comes from the US, Australia and
ity of the dopamine system that are associated with
Southeast Asia. European research is much more
reduced motor skills and impaired verbal learning.11
limited, reflecting the currently low rates of use across
Imaging studies of methamphetamine-dependent indi-
most of Europe. Some of the findings of international
viduals have found structural abnormalities: severe
studies may be less relevant in a European context,
grey-matter deficits in the cingulate, limbic and para-
especially those relating to epidemiology and trends.
limbic cortices, smaller hippocampal volumes, signifi-
cant white-matter hypertrophy, medial temporal lobe
10.5 Brief Overview of Pharmacology damage and striatal enlargement.12,13
Methamphetamine is an N,α-dimethylphenethylamine Studies have also shown severe structural and func-
and a member of the phenethylamine family. It is tional changes in areas of the brain associated with
202
10.7 Prevalence and Patterns of Use
emotion and memory,14,14 as well as neurochemical and with long-standing problems, including the Czechia
metabolite changes in the ventral striatum.15,16 and more recently Slovakia. However, the availability
Prolonged use has been reported to lead to downregula- of methamphetamine has been slowly increasing and
tion of dopamine D2 receptors and uptake sites.17 spreading geographically in other European coun-
A state of hypo-dopaminergic activity has been tries, but it is still much lower than that of
reported.18,19 amphetamine.25,26,27 In wastewater analysis carried
The psychiatric consequences of methampheta- out in 2018 and 2019, of the 42 cities that have data
mine use are theorised to be secondary to its on methamphetamine in wastewater, 17 reported an
mechanisms of action: methamphetamine enters increase, 16 a stable situation and 9 a decrease.28
the synaptic neurons via monoamine transporters An analysis of syringes in six European cities
and, once in the neurons, displaces the mono- found methamphetamine in combinations of two or
amines from vesicular and intracellular locations, more stimulants (cocaine, amphetamine, metham-
pushing the monoamines into the extra-neuronal phetamine or synthetic cathinone) were not uncom-
spaces. Long-term use is associated with alter- mon and overall appeared in 10% of syringes (4% in
ations in the levels of monoamines implicated Budapest, 5% in Paris, and 6% in Glasgow). This was
with stimulant use, which include noradrenaline, particularly so in Helsinki, where 32% of syringes
serotonin and dopamine.20,21 contained the residues of a mixture of stimulants,
mostly of amphetamine and methamphetamine.
10.6 Clinical and Other Legitimate Interestingly, it was also found in Helsinki that in
the Finnish capital, half of the syringes containing
Uses of Methamphetamine traces of benzodiazepines tested positive for
Methamphetamine has been used in the US for the methamphetamine.29
treatment of narcolepsy and attention deficit hyper- Treatment entrants reporting primary metham-
activity disorder (ADHD) and short-term treatment phetamine use in Europe are concentrated in the
for exogenous obesity.22 Czech Republic, Slovakia, Poland and Turkey, which
together account for 92% of the 8,300 methampheta-
10.7 Prevalence and Patterns of Use mine clients reported in 2018.30
Methamphetamine is one of the most widely misused Similar figures have been reported by the 2020
drugs in the world, with over 35 million users esti- European Drug Report which states that in Czechia,
mated. Whereas the drug has been established in high-risk methamphetamine use among adults (15–
countries, such as the US, for a number of years, 64) was estimated at 0.50% in 2018 (corresponding to
more recently the use of methamphetamine has been 33,500 users). In Slovakia, the prevalence derived
rising in many regions. from a treatment multiplier was estimated at 0.15%
The methamphetamine market has been expand- in 2018. The estimate for Cyprus was 0.03% or 155
ing, in particular in the two largest ‘demand regions’: high-risk methamphetamine users in 2018.31 In the
Southeast Asia and North America. Southeast Asia Czech Republic the consumption of methampheta-
emerges as the world’s fastest-growing metham- mine has been firmly established for many years. By
phetamine market, with quantities seized in East 2013, there were approximately 44,900 problem drug
and Southeast Asia rising more than eightfold users in the Czech Republic, the majority of whom
between 2007 and 2017. Other areas where metham- were methamphetamine users (34,200 methampheta-
phetamine is one of the predominant stimulant mine users, compared to an estimated 10,700 opiate/
drugs used include Southwest Asia, Africa, North opioid users).32,33
America, Central Asia and Trans-Caucasia, In the Czech Republic, methamphetamine is
Australia and New Zealand.23 More recently, there mainly produced in small-scale domestic cooking
have been signs of growth of the methamphetamine laboratories. (so-called kitchen laboratories) by users
market in Iraq and in Afghanistan, where it is for their own or local use.34 Home-produced meth-
increasingly manufactured.24 amphetamine powder is based on ephedrine and
At a European level, the use of methamphetamine pseudoephedrine extracted from over-the-counter
has historically been low in comparison with other pharmaceutical products or, more recently, medicines
stimulant drugs, and mainly found in a few countries imported from neighbouring countries.35
203
Methamphetamine
10.7.1 Population Sub-groups Using An Australian qualitative study of the motivations

for methamphetamine and opioid co-injection/co-use
Methamphetamine has shown that the aim is to facilitate intoxication,
In Europe at the current time, methamphetamine is sometimes as the result of ineffective opioid substitu-
used by varied population sub-groups, ranging from tion therapy (OST) treatment and perceived lack of
socially integrated users who snort or swallow the pleasure after stabilisation on OST treatment.43
drug, to marginalised users who inject or smoke
methamphetamine.36 10.7.1.2 Clubbers
The demographic profile of methamphetamine In some countries, the prevalence of methampheta-
users may change over time. For example, US and mine use is higher among people who frequent night-
other studies have shown a change over time in the clubs and night-time economic venues, sometimes
sociodemographic characteristics of methampheta- referred to as ‘clubbers’. For example, UK sample
mine users. A study of treatment admissions from from the Global Drug Survey in 201 showed that the
the California Alcohol and Drug Data System from percentage of methamphetamine users among those
1992 to 2002 showed not only a fivefold increase of described as ‘regular clubbers’ was higher, with 1%
methamphetamine admission, but also a shift towards reporting use in the last 12 months.
usage by minority ethnic groups and a more vulner-
able population in terms of homelessness, chronic 10.7.1.3 Gay Men and Other Men Who Have Sex
mental health problems and disability. There was with Men (MSM)
also a substantial increase in people reporting a legal There is also some evidence that in some regions at
supervision status (criminal justice intervention).37 least, methamphetamine use is more common among
A recent report from the US on data from the gay men and other MSM, than it is among the general
2015–2018 National Surveys on Drug Use and population and in some regions, its use is mainly
Health (NSDUHs) has reported concerns about high concentrated in this population, such as the UK.44
rates of co-occurring substance use and/or? mental Data from the UK45,46,47,48 and Australia show that
illness among adults using methamphetamine.38 bisexual men report higher rates of methamphetamine
use compared to heterosexual men49,50 a fact also
10.7.1.1 Problem Drug Users reported in the US.51,52,53,54,55 Amphetamine-type-
In Europe and specifically the Czech Republic and stimulants and methamphetamine have also been
Slovakia, data show that there has been a spread of reported to be popular among MSM in Asia, where
‘pervitin’ (methamphetamine street name) use among the drug is also used in a sexual context.56
problem drug users, which is reflected in increases in Methamphetamine can be used in a sexual context
problem drug use estimates and in the number of people to enhance sexual performance and pleasure.
entering treatment for the first time who report ‘pervi- Methamphetamine is sometimes combined with
tin’ problems.39 Frequent methamphetamine use was other stimulants such as mephedrone and other
associated with injecting, sharing injecting parapherna- drugs including gamma-hydroxybutyric acid (GHB),
lia, criminal behaviour and depression symptoms.40 ‘poppers’ and medicines used for erectile dysfunction
A number of other European countries have also (e.g., sildenafil, tadalafil and vardenafil).57 There is
reported methamphetamine use, including Germany evidence that methamphetamine is sometimes
and in Norway where methamphetamine use appears injected by gay men and MSM who are using it in
to be interlinked with the older, more established a sexual context.58
amphetamine market. However, this is not always Studies have reported that HIV-positive men are
the case. The smoking of methamphetamine by inject- more likely to use methamphetamine than other
ing opioid users has been noted in Greece, and to MSM.59,60,61,62,63 US studies have shown that the inci-
a lesser extent Cyprus and Turkey.41 dence of HIV among MSM who use methampheta-
The increase in the use of methamphetamines by mine is more than double that among MSM who do
people admitted to heroin treatment has also been not use methamphetamine.64 One study suggested
reported in the US, whereby a study has shown an that there is also evidence that initiation of metham-
increase from 1 in 50 primary heroin treatment phetamine use increases sexual risk behaviour among
admissions in 2008 to 1 in 12 admissions in 2017.42 HIV-uninfected MSM.65,66
204
10.9 Desired Effects for Recreational Use and Unwanted Effects
Among heterosexuals, a study has found that and a higher addictive potential than snorting or
methamphetamine use also associated with an swallowing the drug, and that smokers have levels of
increase in being sexually active, having multiple sex dependence approaching those seen among metham-
partners and casual sex partners and having condom- phetamine injectors.71,72 Methamphetamine is rap-
less sex with casual partners, but it is not associated idly absorbed after ingestion and its half-life is 8–13
with a change in condom use per se. The study also hours depending on route ingested.73
found a dose-related increase in the likelihood of The stimulant effects depend on a number of fac-
people having multiple sex partners.67 tors, including route of ingestion and dose; they may
last between 6 and 12 hours, but longer durations have
been reported.74 Intravenous injection and smoking
10.8 Routes of Ingestion and Dosing have a rapid onset of action. Following oral adminis-
Overall, methamphetamine on the illicit market is tration, peak concentrations are seen in 2.6–3.6 hours
sold in Europe in two forms: (1) methamphetamine and the mean elimination half-life is 10.1 hours (range
hydrochloride, in the most prominent crystalline 6.4–15 hours). Following intravenous use, the mean
solid form often called ‘ice’ or ‘crystal meth’; and (2) half-life is slightly longer (12.2 hours).
powdered methamphetamine, which is similar to
powdered amphetamine in many ways. It can also
come in tablets, which carry logos similar to those
10.9 Desired Effects for Recreational
on ecstasy tablets. Use and Unwanted Effects
The most common form of methamphetamine is The effects of methamphetamine result from a surge
a hydrochloride salt, which comes as a white or off- in newly synthesised catecholamines and serotonin;
white bitter-tasting powder, or as purer crystals that these include excitation, wellbeing, increased alert-
are soluble in water. Methamphetamine hydrochlor- ness, energy and confidence, highly focused attention
ide is stable and volatises easily so can be smoked, and decreased appetite. Methamphetamine use cre-
unlike amphetamine sulphate. ates feelings of increased confidence, sociability and
Whereas all methamphetamine is associated with euphoria.75 In methamphetamine-naïve individuals,
adverse effects, an Australian study has reported that acute doses can improve cognitive processing. Studies
the increased availability and use of crystalline meth- show that single low to moderate doses increase
amphetamine has been associated with increased arousal and alertness, and improve attention and
regular use and harms.68 concentration, particularly among those who are
The method by which methamphetamine is sleep-deprived. Methamphetamine has an apparent
administered depends on the form of the drug avail- aphrodisiac effect, with increased sexual drive,
able. Methamphetamine is usually administered in decreased fatigue and loss of sexual inhibition. It can
the same way as amphetamine powder, either inhaled delay ejaculation, assist longer intercourse and
intra-nasally (snorted), ‘bombed’ (wrapped in cigar- decrease humoral secretions.76,77 Paradoxically,
ette paper and swallowed) or dissolved and ingested there is evidence that long-term use is associated
or injected. Although smokable as a powder, it is the with decreased sexual functioning in some men.78
larger crystals of relatively pure d-methamphetamine Higher doses of methamphetamine can cause dys-
hydrochloride that are normally smoked, often in phoria, restlessness and anxiety, and are associated
small glass pipes, and these crystals may also be dis- with tremors and dyskinesia. In binge use of metham-
solved and injected or crushed and snorted.69 phetamine, the euphoric effects decrease over time,
Methamphetamine can also be used anally or while dysphoria and compulsive behaviour increase.
inserted into the urethra. It has been noted that if Bingeing has also been reported to induce sleepless-
too much methamphetamine is inserted anally, it ness, hallucinations and paranoia.79
may not all be completely dissolved and there is The negative psychological effects of metham-
a risk of abrasion of condoms resulting from friction phetamine use may include anxiety, restlessness,
with this undissolved methamphetamine, which can insomnia, grandiosity, paranoia, psychosis, hallucin-
contribute to the condom breaking.70 ations (including delusional parasitosis), depression,
There is some evidence that smoking metham- unprovoked aggressive or violent behaviour and irrit-
phetamine has more harmful psychological effects ability. Individuals can talk excessively, be agitated,
205
Methamphetamine
aggressive and restless, and may be observed perform- 10.11 Acute Harms
ing repetitive meaningless tasks.11,80
Methamphetamine use is associated with a range of
Unwanted effects of methamphetamines have been
health harms, including psychosis and other mental
reported to be common. A US study of 350 individuals
disorders, cardiovascular and renal dysfunction,
found that the majority reported problems associated
infectious disease transmission and overdose.91
with methamphetamine use, which included weight
loss (84%), sleeplessness (78%), financial problems
(73%), paranoia (67%), legal problems (63%), hallucin- 10.11.1 Acute Toxicity
ations (61%), work problems (60%), violent behaviour The features of acute toxicity are summarised in
(57%), dental problems (55%), skin problems (36%) Box 10.1.
and high blood pressure (24%).81 In a survey of gay
men, 40.4% of men who had used methamphetamine 10.11.2 Cardiovascular and Respiratory
in the past year reported concerns about this drug.47
The ‘come-down’ from methamphetamine is one Harms
of the most common unwanted effects reported by The link between the use of methamphetamine
users.82 Users may feel irritable, restless, anxious, and cardiovascular disease is well established,92 with
depressed and lethargic, and there are reports of the a study reporting that cardiovascular disease represents
use of benzodiazepines or heroin to soften the come- the second leading cause of death among
down. It has been reported in New Zealand that
methamphetamine is often sold in a package with
GHB/GBL so that the GHB/GBL can be used to help Box 10.1 Features of Acute Methamphetamine
with methamphetamine come-down effects.83 Toxicity
Cardiovascular and Respiratory

10.10 Mortality Narrow-complex tachycardias (common)
A study of cohorts of individuals in California hospi-
Chest pain
talised from 1990 to 2005 with a diagnosis of disorders
Tachycardia
relating to methamphetamine, cocaine, alcohol, opi-
ates and cannabis and followed up for 16 years (74,139 Systemic hypotension or hypertension
individuals and 4,122 deaths) found that hospitalised Ventricular tachycardia or ventricular fibrillation
methamphetamine users had a higher mortality risk Dyspnoea
than the users of all substances, except for opiates. The Gastrointestinal and Urological
standardised mortality rate for methamphetamine Abdominal pain
found by the study was 4.67, which is similar to rates Vomiting
found by studies in inpatient or treatment settings in Metabolic acidosis
the Czech Republic,84 Denmark85 and Taiwan,86 but Neurological and Psychiatric
slightly larger than those reported by a community- Sweating
based sample of amphetamine users in Sweden.87 Dilated pupils
Deaths associated with methamphetamine have Agitation
been attributed to homicide, suicide, motor vehicle Confusion
accidents, manufacturing, distribution and sales of
Headache
the drug as well as its direct toxic effects.88
Anxiety
Biologically based causes include stroke, cardiovascu-
lar collapse, pulmonary oedema, myocardial infarc- Hallucinations or delusions
tion, hyperpyrexia and renal failure.89,90 Psychotic symptoms
Seizures
For up-to-date guidance on the management of Tremor
methamphetamine acute toxicity, it is recommended Hyperpyrexia (may be severe)
that information be sought from national and Serotonin syndrome (especially if more than one
regional Poisons Information Services. Local or stimulant drug has been used) (serotonin
national guidelines should also be consulted. syndrome is discussed in depth in Chapter 8).
206
10.11 Acute Harms
methamphetamine users following only accidental use accounts for 40% of all admissions of patients under
overdose.93 The association between methamphetamine the age of 45 years with cardiomyopathy. More than 20%
use and cardiomyopathy has been established for many of patients with heart failure were former or current
decades.94 methamphetamine users.106 A US registry containing
Methamphetamine exerts cardiovascular effects information on more than 11,000 patients with decom-
on people who use it by causing catecholamine excess, pensated heart failure reported that more than 5% were
through excessive noradrenaline release and reuptake stimulant users.107
inhibition at the sympathetic synaptic receptors. One case series reported that more than a quarter
The acute (and chronic) use of methamphetamine (27.2%) of methamphetamine-intoxicated patients had
can severely affect the cardiovascular system.11 It a prolonged corrected QT interval (QTc>440ms), sug-
causes an acceleration of heart and lung action gesting that methamphetamine-induced alterations in
through vasoconstriction and bronchodilation, while cardiac conduction may be partly responsible for the
muscle activity is primed via transient hyperglycaemia drug’s dysrhythmogenic effects.108
and dilation of blood vessels in skeletal muscles.95 Other conditions related to methamphetamine
Some non-essential physiological activity is inhibited intoxication include premature ventricular contrac-
(e.g. stomach and intestinal function); levels of stress tions, premature supraventricular contractions, accel-
hormones – including cortisol and adrenocortico- erated atrioventricular conduction, atrioventricular
tropic hormone – are increased by 200% in humans block, intraventricular conduction delay, bundle
following ingestion96 and remain elevated for hours.5 branch block, ventricular tachycardia, ventricular fib-
Tachycardia and hypertension are common features rillation, and supraventricular tachycardia.102,110,109
of methamphetamine toxicity.7 Methamphetamine-induced dysrhythmias may also
Chest pain is a common complaint associated with occur because of myocardial ischaemia or infarction.99
methamphetamine use,97 with one study reporting that Methamphetamine use may also be associated
they account for 38% of emergency department visits with aortic dissection and carries a greater risk for
and 28% of admissions among patients using that than cocaine; it may be second only to hyperten-
methamphetamine.98 It has also been suggested that sion in its importance as a risk factor for aortic
although in some patients chest pain is due to metham- dissection.110 Methamphetamine can cause cerebral
phetamine-induced hypertension, tachycardia or anx- infarct, haemorrhage and hypertension,75,111 and is
iety, acute coronary syndrome (ACS) is also common a risk factor for intracerebral haemorrhage.112 The
among methamphetamine users. One study recom- ingestion of large quantities of methamphetamine in
mended that patients with chest pain in the context of particular has been associated with cerebrovascular
methamphetamine use should be evaluated for ACS.99 haemorrhage.113,114,115
The prevalence of ACS was found to be 25% in a small Haemorrhagic strokes have been associated with
series of patients presenting to an emergency depart- methamphetamine use and methamphetamine-related
ment with chest pain after methamphetamine use.100 stroke linked with poor clinical outcomes.116,117 Cardiac
Methamphetamine users have significantly higher and systemic thrombus caused by methamphetamine
rates of coronary artery disease than the general has been reported.118
population.101 Even those with normal coronary arteries Like other drugs injected, the injection of
are at risk of methamphetamine-induced myocardial methamphetamine has been associated with
infarction, because of coronary spasm, which may be endocarditis.99 Cardiovascular events are often involved
refractory to intracoronary vasodilator therapy.102 The in medical complications and death associated with
putative mechanisms of myocardial infarction in the methamphetamine.119
context of methamphetamine use include accelerated The risks associated with the long-term use of
atherosclerosis, rupture of pre-existing atherosclerotic methamphetamine are discussed in Section 10.13.
plaques, hypercoaguability and epicardial coronary
artery spasm.104,103,104 Acute myocardial infarction fol-
lowing methamphetamine use can be severe and can
10.11.3 Hyperthermia
result in cardiogenic shock and death.105 and Rhabdomyolysis
A study in Hawaii (where the prevalence of metham- The ingestion of large quantities of methampheta-
phetamine use is high) reported that methamphetamine mine has been associated with hyperthermiaby
207
Methamphetamine
promoting heat generation and preventing heat dissi- internationally and across a number of European
pation and by its effects on increasing body metabol- countries.135,136,137,138,139,140,141,142
ism and causing vasoconstriction.115,116,117 and, A number of drugs are typically used within the
Methamphetamine has also been associated with context of ‘chemsex’, with some differences by coun-
rhabdomyolysis.120,121 try. For example, in addition to methamphetamine, in
the UK γ-hydroxybutyrate (GHB), γ-butyrolactone
10.11.4 Urological/Liver (GBL), and previously mephedrone, were used in
chemsex.143 In Spain in contrast, a retrospective
The ingestion of large quantities of methampheta-
study of the role of chemsex in episodes of acute street
mine has been associated with renal and liver
drug poisoning in HIV-infected patients in an emer-
failure.115,116,117
gency department over a period of 1 year suggest that
cocaine had a significant role, with methamphetamine
10.11.5 Mental Health Effects and GHB the next street drugs implicated.144
Acute intoxication can cause panic, agitation and High-risk behaviours associated with metham-
transient symptoms of hallucinations and paranoia. phetamine have been reported,145 Three patterns of
It can increase aggressive responses to threatening behaviour are associated with methamphetamine use:
situations.122,123,124 Amphetamines and metham- high-risk sexual practices, sexualised injecting and the
phetamine have been consistently associated with ele- sharing of injecting equipment. For example, a study
vated rates of suicide and evidence suggests a likely of gay and bisexual men found that methampheta-
causal link.125,126 mine and poly-drug use were independently predict-
A recent systematic review and meta-analysis ive of reporting >20 recent partners, unprotected anal
found compelling evidence for a causal association intercourse with a casual partner and a sexually trans-
between the use of amphetamines and increased risk mitted infection.146
of psychosis. There also appeared to be some level of The use of club drugs in a sexual context has been
specificity in this effect, with elevated risk relative to described.147,148 Methamphetamine is one of the
other substance use.127 drugs most commonly used in a sexual context
Methamphetamine can also exacerbate psych- (chemsex)147 and elsewhere. In a US study of 60
osis in people with schizophrenia.128,129,130 It can MSM, 68% reported using methamphetamine during
also crease the severity of a range of psychiatric sex more than 50% of the time.149
symptoms, and the need to distinguish these A relatively large body of evidence shows height-
symptoms from underlying psychiatric disorders, ened sexual risk-taking associated with metham-
to avoid misdiagnosis and sub-optimal care, has phetamine use.150,151,152,153,154,155,156 There is some
been recommended.131 evidence that compared with use of other drugs,
methamphetamine use is a particularly strong pre-
10.11.6 Methamphetamine Use dictor of unprotected anal sex among MSM.157,158
Methamphetamine use has also been associated
and High-risk Sexual Behaviours with sexually transmitted infections (STIs), with
There is evidence that methamphetamine in particu- increased rates of STIs,66,159,160 including HIV
lar is associated with high-risk behaviours and infection.149,161,162,163,164,165,166,167,168,169 There is also
chemsex,132 especially by gay men and other men an association between methamphetamine use and
who have sex with men (MSM). There is also some rates of HIV and hepatitis C.170,171,172,173,174,175,176,177
evidence that initiation of methamphetamine use and a relationship has been observed between
increases sexual risk behaviour among HIV- increased severity of methamphetamine use and HIV
uninfected MSM.133 risk.157
‘Chemsex’ is sometimes referred to as ‘party and Studies have shown that MSM who use metham-
play’ and is a term that is used to describe sex between phetamine, regardless of their HIV status, have
men that occurs under the influence of drugs taken a greater risk of STIs than those who do not.63,178
immediately before and/or during the sexual session Men who use methamphetamine are 1.5–2.9 times
in order to enhance and prolong the sexual more likely to acquire HIV than those who do
experience.61,134 Chemsex has been reported not.156,179,180,181,182
208
10.11 Acute Harms
Studies also suggest that HIV-positive MSM who However, it is important to note that a causal link
use methamphetamine are significantly more likely between methamphetamine use and STIs, HIV and
than MSM who do not use methamphetamine other blood-borne viruses (BBV) has not been estab-
(regardless of their HIV status) to engage in unpro- lished. There is some evidence that individuals who
tected anal sex63,183,184,185 and group sex,186 to have engage in high-risk sexual activity are more likely to
multiple sexual partners,50,63 101 ,187,188 to find sexual use recreational drugs203 and evidence that among
partners on the Internet,63 to have sex with an inject- MSM, recreational drug use in general (rather than
ing drug user185 and to be intoxicated during sex.63,185 methamphetamine use specifically) is associated with
Among HIV-infected MSM men who have a sero- high-risk activity.204,205
discordant partner (i.e. HIV negative, or status The link between methamphetamine use and
unknown), the use of methamphetamine is signifi- high-risk sexual activities is not unique to MSM,
cantly associated with unprotected anal sex.64,189,190 although most of the research has been carried out
It has been noted that HIV-positive men are more among MSM and less evidence is available for
likely to inject psychoactive substances (including heterosexuals.206 Studies of male and female hetero-
methamphetamine) than other MSM, with injecting sexual populations also suggest that methampheta-
increasingly common with older age, peaking among mine users have a higher frequency of sexual
men in their 40s.61 There are some reports from activity, have more sexual partners and engage in
methamphetamine users of increased sexual desires higher-risk sexual behaviours (unprotected vaginal
with injecting methamphetamine, in comparison with sex and anal sex) than the users of any other
other forms of methamphetamine use.191,192 drugs.207,208,209,210,211
Social media and mobile phone applications
(Apps) have been described by Bourne et al. as
a facilitator of drug use during sex among gay men
10.11.7 Injecting Risks
in London, or ‘chemsex’.193 Location-based, social Methamphetamine injecting is a serious public health
networking applications (mobile phone apps) are pro- concern, as well as heightening risks and harms to the
viding men with the opportunity to source both sex- individual user.212 The evidence on the elevated
ual partners and drugs in their local area. ‘Apps’ have injecting-related risk behaviours among metham-
been described as playing a major role in the organ- phetamine users in comparison with other injectors
isation of sex parties and ‘chemsex’, typically linked has been ambiguous.153,213,214,215 Regardless, meth-
with high-risk drug use and sexual behaviours.194 amphetamine injecting has been identified as
An outbreak of syphilis has also been linked to a significant risk factor and injectors often present
seeking sex partners through an online chatroom, as with more complex needs. Studies have shown that
well as to the use of methamphetamine.195 methamphetamine injectors are more dependent than
A number of factors and sub-groups of metham- non-injectors,216 are at increased risk of non-fatal
phetamine users have been associated with particu- overdose,217 and are more likely to engage in HIV-
larly high-risk behaviours for transmission of HIV risk behaviours; 215,218,219,220 a study has reported
and STIs. These include methamphetamine users a higher prevalence of STIs than among non-
who use sildenafil (Viagra)159,160,161,192,196 or other injecting methamphetamine users.221
illicit drugs during sex,197,198 those who exchange Methamphetamine injectors are more likely to
sex for methamphetamine,199 those who report high have co-morbid psychiatric disorders than non-
levels of sexual compulsivity,192,200 those who engage injecting methamphetamine users.222,223 The use of
in sexual encounters in public spaces65,201 and those methamphetamine by injecting in particular has been
who report methamphetamine binges.202 linked to suicide.224
A recent review of outcomes among MSM who use There is evidence that methamphetamine inject-
methamphetamines has reported a low adherence to ors may be more likely to attempt suicide than those
HIV medication by HIV-positive MSM who use who smoke or snort the drug,225,225 with a seven-year
methamphetamine. This, the authors believe, may study reporting that people who injected metham-
contribute to the transmission of HIV virus resistant phetamine had an 80% greater risk of attempting
to medication which has been seen in newly infected suicide than those who did not inject, even after
MSM who use methamphetamine.158 taking into account a wide range of potential
209
Methamphetamine
confounders. The study also showed a dose–response regular users of methamphetamine have a high rate of
relationship between frequency of injecting metham- presentation to ED100,231,232 and there is some evi-
phetamine and suicidal behaviour. The conclusion dence that adult methamphetamine users use ED
was that individuals who inject methamphetamine and other hospital resources more than the users of
should be considered at high risk of suicide among other substances.100,233 A Canadian study of homeless
populations of methamphetamine users, as well as the and street-based youth reported that frequent inject-
broader injecting population.226 ing of methamphetamine was associated with
increased risk of ED utilisation.228
10.11.8 Acute Harms of Poly-drug Use Studies have also shown relatively high levels of
methamphetamine-related hospital presentations for
and Drug Interactions psychiatric problems. Psychiatric symptoms, includ-
The high level of poly-drug use among methampheta- ing acute psychosis, depression and anxiety disorders,
mine users has been well established.227 Cross-sectional have been associated with both acute and chronic
population surveys suggest that the concurrent use of methamphetamine
alcohol and cocaine is particularly common.228 This can use.227,234,235,236,237,238,239,240,241,242,243,244,245,246,247
cause harm as it increases blood pressure. In methamphetamine-endemic areas, studies have
Methamphetamine can also mask the effects of alcohol, shown that 1–2% of all ED visits are related to meth-
which may increase the risk of alcohol poisoning and amphetamine use, with psychiatric conditions being
accidents due to false feelings of being sober. Concurrent the most common complaints.227,236–246
use of amphetamine including methamphetamine and Some studies have also suggested that more
cannabis can increase psychotic symptoms in some methamphetamine-related presentations to EDs
users. The combination of methamphetamine and were for psychiatric problems than for other prob-
cocaine has been shown to increase substantially the lems. For example, a US study reported that meth-
cardiotoxic effects of both drugs.229 amphetamine-related psychiatric visits to EDs
The co-ingestion of GHB and methamphetamine represented 7.6% of all psychiatric attendances,
might increase the risk of GHB overdose, as metham- a percentage which the authors described as ‘dispropor-
phetamine can mask the signs of acute toxicity and tionate’. In comparison, 1.8% of all trauma visits were
can impair the accurate measurement of GHB doses, methamphetamine-related and 2.1% of presentations
which increases the risk of GHB overdose. There are with chest pain were methamphetamine-related.249
also risks associated with the use of methampheta- Other studies also showed that methamphetamine-
mine with other serotonergic substances, leading to related ED visits associated with psychiatric complaints
the risk of serotonin syndrome. The potential for drug or diagnosis represented the largest patient sub-group
interactions with CYP2D6 inhibitors is high and visiting EDs with psychiatric issues.236,249 For example,
coadministration of these agents may increase the a study of 378 presentations with methamphetamine
toxicity of methamphetamine. Well known CYP2D6 toxicity to an Australian ED reported that the most
inhibitors include: amiodarone, citalopram, codeine, common clinical effect was acute behavioural dis-
fluoxetine, haloperidol, methadone, paroxetine and turbance, occurring in 295 (78%) presentations.
valproic acid. Among the antiretrovirals, while low- Other effects included tachycardia in 212 (56%),
dose ritonavir does not seem to affect CYP2D6 hypertension in 160 (42%) and hyperthermia in 17
activity,230 the newer booster cobicistat is included (5%) presentations.248
in the list of CYP2D6 inhibitors. A study of psychiatric admissions to EDs reported
that there were no differences in heart rate, admission
10.11.9 Acute Withdrawal route or cost of care of methamphetamine-related
visits and other visits. This, according to the study,
For withdrawal see Section 10.13.2.
suggests that methamphetamine users presenting for
psychiatric problems are clinically similar to non-
10.11.10 Emergency Hospital Admissions amphetamine users with psychiatric problems.249
In countries where rates of methamphetamine use are However, in comparison with other patients pre-
high, admissions to emergency departments (EDs) are senting to EDs for toxicology-related issues, some
reportedly very common. US data demonstrate that studies have shown that those presenting with
210
10.13 Harms of Chronic Use and Dependence
methamphetamine-related problems are more anti-psychotics are prescribed, it is recommended

agitated, violent and aggressive and more likely to that treatment also includes psychosocial interven-
present on arrival with tachycardia and tions and relapse prevention. It is also good practice
hypertension.247,248 It has been argued that metham- to deliver treatment for other co-occurring psychi-
phetamine use presents a significant challenge to EDs atric disorders including depression and anxiety.254
and acute mental health services.249
10.13 Harms of Chronic Use
10.12 Management of Acute Harms and Dependence
Interventions required are clinical monitoring, obser- People who use methamphetamine regularly are at the
vation and symptomatic treatment. It is recom-
risk of dependence. Regular or dependent use is asso-
mended that where a patient has impaired
ciated with comorbidities including depression, anx-
consciousness, emergency clinicians should ensure
iety, psychosis and cardiovascular disease. In
clear airways and adequate ventilation. As with other
addition, there are risks associated with contextual
amphetamines, in the event of cardiac arrest, resusci-
social factors related to the use of methamphetamine
tation should be continued for at least 1 hour and only
including sexually transmitted or blood-borne infec-
stopped after discussion with a senior clinician. tions and legal issues.255
Prolonged resuscitation for cardiac arrest is recom-
mended following poisoning, as recovery with good
neurological outcome may occur. 10.13.1 Dependence
The benefit of gastric decontamination is uncer- Methamphetamine is a potent central nervous system
tain. Clinicians should consider oral activated char- stimulant and the risk of dependence is high.256
coal if methamphetamine has been ingested within Dependence on methamphetamines follows the
1 hour, provided the airway can be protected. same principles discussed in Chapter 8.
Asymptomatic patients should be observed for at Tolerance to methamphetamine takes place when
least 4 hours, or 8 hours for patients who have the drug is taken frequently, leading to users taking
ingested sustained-release preparations. Agitated higher doses or using more frequently or changing the
adults can be sedated with an initial dose of oral or route of administration in order to achieve the desired
intravenous diazepam. effect. There is some emerging evidence that craving to
A study of 378 methamphetamine-related presen- methamphetamine cues can be measured in dependent
tations to EDs in Australia reported that acute behav- individuals257,258,259 and that cue-elicited methampheta-
ioural disturbance, occurring in almost 80% of mine craving is a strong predictor of subsequent use.260
presentations, was successfully managed with oral There is some evidence that methamphetamine-
sedation alone in 180 (61%) patients, with the remain- dependent users show a decrease in everyday func-
der receiving parenteral sedation.250 tioning, disruption in everyday activities and
increased errors in planning a daily schedule.
10.12.1 Treatment Methamphetamine dependence has also been linked
to impairments in the domains of communication,
of Methamphetamine-induced Psychosis work and recreation.261,262 There is also evidence
Any treatment for methamphetamine-induced psych- that the chronic use of methamphetamine causes cog-
osis must focus on abstinence from drugs and the nitive deficits after withdrawal.263,264,265,266 Studies
prevention of relapse. It has been argued that in have also shown that this may be associated with
many patients, transient psychosis will subside after disruptions of the dopaminergic and serotonergic
a few weeks to a month of abstaining from metham- systems.266,267,268,269,270 Chronic use of metham-
phetamine and prescribing antipsychotic to these phetamine causes neurochemical and neuroanatom-
patients may not be needed in light of the mental ical changes, which include memory impairment.
and physical side effects associated with the Dependence results in deficits in memory and in
medications.251 There is no standardised treatment decision-making and verbal reasoning.271 There is
for methamphetamine-induced psychosis and studies limited evidence that this functional deficit continues
have shown the effectiveness of a range of anti- several months after abstinence.264,272 One study has
psychotic medications.252,253 However, even when reported deteriorating cognitive performance during
211
Methamphetamine
the first three months of abstinence from metham- Table 10.1 The two phases of methamphetamine withdrawal
phetamine, with abstinent patients or abstinent Acute withdrawal Longer-term
patients with a recent lapse scoring worse on neuro- symptoms withdrawal symptoms
psychological testing than patients with ongoing (can last up to 12
methamphetamine use. This reflects the difficulties months)
in attention, understanding and memory often Severe dysphoria Anhedonia
encountered in methamphetamine patients in treat-
Irritability Impaired social functioning
ment settings.267 Although it needs to be substanti-
Melancholia Intense craving
ated by larger studies, Henry et al. suggest that this
may have important implications for treatment inter- Anxiety Hyper-arousal
ventions, as individuals with poor functional ability Hypersomnia and marked Vegetative symptoms
fatigue
may have difficulty responding to cognitive-
behavioural therapy (CBT) and the cognitive Paranoia Severe dysphoria
enhancement techniques commonly used in the treat- Intensity of post-binge Mood volatility
dysphoria can lead to
ment of methamphetamine misuse.274 suicide ideation and
A recent study of 108 participants has reported attempts have also been
that methamphetamine dependence was associated linked to withdrawal91,282
(for more information on
with poorer performance in decision-making and dis- the withdrawal syndrome
inhibition over and above other predictors and that see Chapter 8
duration of methamphetamine use was linked to dis- Akathisia/restless legs Irritability
inhibition. The authors suggest the need to target Sleep pattern disruption
disinhibition and impulsive decision-making as part
of methamphetamine dependence treatment.273
Greater severity of withdrawal symptoms in meth-
10.13.2 Withdrawal amphetamine-dependent individuals has been
Methamphetamine is associated with a clear with- reported among those who are older, who have been
drawal syndrome. A time-limited withdrawal syn- using methamphetamine longer and who have more
drome may occur within 24 hours of the last dose severe methamphetamine use disorder.277,282
when heavy chronic users of methamphetamine
cease to use the drug abruptly. The withdrawal syn- 10.13.3 Physiological, Psychological
drome is common and severe enough to cause relapse
outside a contained environment.274
and Psychiatric Effects of Long-term Use
Chapter 8 (the overview of amphetamine-type and Dependence
stimulants) has discussed in greater detail the phases Chronic use has been associated with malno-
of amphetamine withdrawal and should be read in urishment.281
conjunction with this chapter. Phases of withdrawal
symptoms have also been identified with methampheta- 10.13.3.1 Cardiovascular Effects
mine users. For example, a study of 21 inpatients sug- Long-term use of methamphetamine can result in
gested that methamphetamine withdrawal has two severe cardiovascular complications related to
phases: an acute phase lasting 7–10 days, in which chronic hypertension and cardiovascular disease,
overall symptom severity declines in a linear pattern such as angina, arrhythmias, valvular disease, haem-
from a high initial peak; and a sub-acute phase lasting orrhagic/ischaemic strokes and a high incidence of
at least a further 2 weeks, with some studies reporting myocardial infarction.107,108,116,282,283,284,285,286
much longer periods.275 Withdrawal from metham- Chronic methamphetamine can be associated with
phetamine has been described as more characterised the development of a dilated cardiomyopathy.287
by psychological and psychiatric symptoms than phys- A study on patients with methamphetamine-
ical symptoms.91 associated cardiomyopathy has shown that some pre-
Table 10.1 outlines the two phases of metham- sent with an acute stress cardiomyopathy, which is
phetamine withdrawal, according to the reported often characterised by a shorter duration of metham-
symptoms.83,91,116,225,276,277,278,279,280 phetamine use, a ‘reverse Takotsubo’ (RT) pattern,
212
10.13 Harms of Chronic Use and Dependence
higher levels of cardiac enzymes and a greater scope methamphetamine users are more likely to be diag-
for early recovery of ventricular function. Others, nosed with a sexually transmitted infection than non-
particularly with a longer history of use, have evidence users.209,212 Methamphetamine users are also at
of atrial and ventricular remodelling on initial echo- greater risk of viral hepatitis, especially where the
cardiography and/or fibrosis on cardiac magnetic res- drug is injected, but even among methamphetamine
onance imaging (CMR) and present with a chronic smokers and insufflators, hepatitis C is more common
dilated cardiomyopathy; they have limited scope for than it is in the general population.295,296,297
recovery.288
10.13.3.5 Dermatological
10.13.3.2 Neurological Effects Methamphetamine users may suffer from skin
Chronic CNS hyper-stimulation can lead to frequent lesions resulting from compulsive scratching (due
headaches, tremors, athetoid movements and to formication – a sense of having insects moving
seizures.11 There is evidence that users of amphet- under the skin). These lesions can result in bacterial
amine-type substances, including methamphetamine, cellulitis and, in some cases, bacteraemia and sepsis.
may have an above-normal risk of developing In a case series of methamphetamine users present-
Parkinson’s disease (PD) because of enduring damage ing to an emergency department, skin infection
to the brain’s dopamine neurons. This was shown by accounted for 6% of the initial presentations and
a retrospective population-based cohort study of 54% of subsequent admissions to hospital.100
inpatient hospital episodes and death records from
1990 through to 2005 in California. Patients at least 10.13.3.6 Pott Puffy Tumour
30 years of age were followed for up to 16 years. The There is a case report of Pott puffy tumour (PPT)
study found that methamphetamine users had a 76% associated with the intranasal use of methampheta-
increased risk of developing Parkinson’s disease in mine. This is an anterior extension of a frontal sinus
comparison with the matched population proxy con- infection that results in frontal bone osteomyelitis and
trol group. The authors noted that this finding may be subperiosteal abscess.298
limited to high-dose, chronic methamphetamine
users and only when they reach middle and older 10.13.3.7 Ophthalmological Harms
age, when they have suffered age-related loss of dopa- Acute unilateral vision loss has been reported follow-
mine neurons.289 ing a single dose of intranasal methamphetamine use
and is believed to be due to ischaemic optic
10.13.3.3 Pulmonary and Respiratory Harms neuropathy secondary to methamphetamine-
The smoking of methamphetamine can cause respira- induced vasospasm and methamphetamine-
tory symptoms and disorders such as pulmonary associated vasculitis.299,300
oedema, bronchitis, pulmonary hypertension, haem-
optysis and granuloma.11 Methamphetamine is asso- 10.13.3.8 Mental Health, Psychological
ciated with pulmonary arterial hypertension and Psychiatric effects
(PAH),290 although its precise role remains unclear.99 The frequent and prolonged use of methampheta-
mine has a number of adverse effects. There is a well-
10.13.3.4 Blood-borne Infections and Haematological, established association between methamphetamine
Gastrointestinal and Urological effects use and mental health problems.116,301
Methamphetamine has been reported to cause acute Studies have found elevated rates of mood dis-
liver injury, with hepatic necrosis and centrilobular orders, anxiety disorders and antisocial personality
degeneration, even in the absence of hepatitis.291 behaviour and disorder, even after treatment.302
There are reports of mesenteric infarction,292 segmen- A recent systematic review and meta-analysis found
tal ischaemic colitis, vasculitis293 or vasospasm with elevated levels of psychosis, depression, suicidality
spontaneous resolution.294 Severe acute necrotic and violence amongst people who use amphetamines,
haemorrhagic pancreatitis has been reported in cases including methamphetamine.303 Depressive disorders
of sudden death of chronic methamphetamine use.99 and symptoms are frequently associated with meth-
Because of the increased likelihood of high-risk amphetamine use,243,245,246,304,305,306,307,308 with
sexual behaviours discussed in Section 10.10.2, depression being described as pervasive amongst
213
Methamphetamine
heavy users.309 The disorder is often associated with induced psychosis are associated with environmental
mood disturbances.310 and genetic risk factors, but it has also been shown that
A systematic review has found that people who higher frequency, severity, and length of use have been
use methamphetamine are at a significantly ele- reported as the most robust risk factors.328,329 Psychotic
vated risk of poor mental health when compared symptoms typically amplify over time with continued
to people who do not use the drug. The review methamphetamine use.330 Methamphetamine-induced
found that they around twice as likely to experience psychotic disorder has been associated with the chronic,
depression and psychosis and four times more high-dose and continuous use of methamphetamine.331
likely to be suicidal.311 A systematic review of the literature has found that the
The state of catecholamine and serotonin deple- most consistent correlates of psychotic symptoms were
tion after several days of methamphetamine use can increased frequency of methamphetamine use and
manifest itself as exhaustion, depression, lethargy and dependence on methamphetamine.332
anhedonia. Psychological symptoms include persist- A literature review looking at the prevalence of
ent anxiety, paranoia, insomnia, auditory hallucin- substance-induced psychosis that included 17 studies
ations, delusion, psychotic or violent behaviour and in the meta-analysis, resulted in a composite event
suicidal or homicidal thinking.11,312 The link between rate of 36.5% in methamphetamine users. It was sig-
psychotic symptoms and amphetamine-induced sleep nificantly higher when the period of assessment was
deprivation has also been reported.313 lifetime use (42.7%) and when only individuals with
Methamphetamine contributes significantly to the methamphetamine use disorders (43.3%) were
risk of psychosis, although the majority of people who included.333
use it experience only milder transient symptoms, Symptoms may include auditory, visual and tactile
which recede when they are no longer intoxicated.314 hallucinations and paranoid delusions, persecutory
Nonetheless some of the symptoms can resemble delusions and other delusions. Research seems to
those of paranoid schizophrenia,273 or symptoms suggest that delusions in methamphetamine
almost indistinguishable from schizophrenia,315 psychosis are primarily persecutory in
including persecutory delusions and auditory nature.334,335,336,337,338 A wide spectrum of psychotic
hallucinations.316 symptoms can occur in methamphetamine users, ran-
Methamphetamine-induced psychosis can occur ging from brief delusional experiences, to persistent
in individuals with no history of psychosis.74,240 psychosis characterised by first-rank symptoms and
Nevertheless, it has also been shown that metham- cognitive impairment.339
phetamine users with a family history of schizophre- Methamphetamine-induced psychosis can be
nia may be five times more likely to develop transient or persistent. Even if the psychotic symp-
psychosis than those without one. Nonetheless, it toms produced by methamphetamine are transient,
has also been shown that methamphetamine users recurrent drug use can lead to a symptom course that
with a family history of schizophrenia may be five appears chronic in nature.340
times more likely to develop psychosis than those Symptoms usually remit after acute intoxication
without one.317,318 but some individuals may develop psychosis weeks or
It is well established that substance misuse can months after stopping methamphetamine,312,341 and
exacerbate mental health problems.319 There is some may prove to be refractory to antipsychotic
evidence that serious psychiatric disorders may medication.342 Stress can precipitate spontaneous
emerge or worsen as a result of methamphetamine psychosis in former methamphetamine users who
use,83,91,225,320,321 including increased risk of are abstinent.343
suicide.322 It was also reported that a previous history Much of the literature on persistent metham-
of psychotic disorders relates to worse outcomes in phetamine psychosis comes from Japan, where meth-
methamphetamine-induced psychosis.323,324 amphetamine has been illicitly used for over 50 years,
Methamphetamine use can increase the severity of which suggests that persistent methamphetamine
a range of psychiatric symptoms.325 psychosis is not uncommon.344 Japanese studies
Risk of psychosis following methamphetamine use have also reported that psychotic symptoms may
has also been shown to be higher in victims of sexual recur where there is new exposure to the
abuse.326,327 Amphetamine and methamphetamine- drug.344,344,345,346,347,348 Japanese research has also
214
10.14 Management of Harms of Chronic and Dependent Use of Methamphetamine
reported discouraging results with standard anti- 10.14.2 Psychosocial Interventions

psychotic drugs, as many patients remain clinically
psychotic after many months of treatment.343,349 for Dependence
Studies have shown that some people dependent on
10.13.3.9 Cognitive Effects drugs may achieve abstinence, without the need for
There are direct physiological effects of metham- treatment.357,358 It has also been shown that people in
phetamine intoxication, but the cognitive and behav- treatment can remit from methamphetamine depend-
ioural changes associated with its use may be ence, reduce their frequency of use or cease entirely
secondary to neurotoxicity.350 and maintain abstinence over long periods.359 There
Neuroimaging in chronic methamphetamine is also some evidence that behavioural-based
users has shown significant neural damage in patients treatment for methamphetamine misuse can be effect-
and evidence of cognitive impairment, but it is not ive in reducing HIV infections, by reducing high-risk
established whether the link is causal.75,351 injecting behaviours and unsafe sexual
A study has shown that the effects of cocaine and practices.170,360
methamphetamine on the neuropsychological pro- An economic evaluation of the cost-effectiveness
files of people who use them are similar. However, of counselling for methamphetamine dependence
there is some evidence that cocaine use is more asso- showed that greater investment in this cost-effective
ciated with working memory impairments, which are strategy will produce significant cost-savings and
typically frontally mediated, while methamphetamine improve health outcomes as well as improve many
appears to be more associated with memory impair- externality issues associated with drug use.361
ments that are linked with temporal and parietal lobe At present, the most effective treatments for meth-
dysfunction.352 amphetamine addiction are psychosocial interven-
tions and behavioural therapies. Historically,
10.13.4 Co-morbidities treatment for stimulant dependence has relied on
cognitive-behavioural therapy (CBT), with efforts to
of Methamphetamine Use Disorders integrate contingency management (CM) (for more
and HIV information see Chapter 8).
Methamphetamine has been shown to interfere with Overall, the evidence suggests that psychosocial
the efficacy of HIV medication and treatment.353 Its interventions, such as CBT and CM, are moder-
use has been linked to non-adherence to medication ately effective in achieving methamphetamine
regimens354 and there is a suggestion that it may be abstinence.362
associated with increased viral loads, even among A number of US studies have reported the effect-
those taking antiretroviral medication.355 Both meth- iveness of CM within specific research and drug treat-
amphetamine use and HIV may be associated with ment settings,363 as well as outside those settings.364
impaired cognitive function, and in combination may CM in combination with other interventions, such as
result in greater impairment than each condition CBT, has proved to be modestly effective at reducing
alone.355 There is evidence that hepatitis C increases methamphetamine dependence.366,365,366,367
these cognitive deficits.356 CM was also shown to have superior efficacy to
CBT during drug treatment.365,368 A Cochrane review
10.14 Management of Harms of psychosocial interventions for cocaine and psy-
chostimulant amphetamine disorders reported that
of Chronic and Dependent Use comparisons between different types of behavioural
of Methamphetamine interventions showed results in favour of treatments
with some form of contingency management with
respect to both reducing drop-outs and lowering
10.14.1 Identification and Assessment use. However, the review also reports there are few
of Dependence significant behavioural changes even after reductions
The identification and assessment of chronic use of in drug consumption and conclude that there are no
methamphetamine and ensuing harms are similar to data supporting a single-treatment approach that is
those for ATS in general (see Chapter 8). able to tackle the multidimensional facets of addiction
215
Methamphetamine
and to resolve the chronic, relapsing nature of addic- to treat and manage co-occurring mental health con-
tion, with all its correlates and consequences.369 ditions. The review also recommends that more work
is needed to ensure that people who use this drug are
10.14.2.1 Implementation of Contingency provided with adequate mental health care and that
Management generic responses are tailored to make sure they are
Some studies have looked in greater detail at the acceptable, safe and effective for people who use
impact of CM and at variations in CM models used methamphetamine.375
and which specific factors were most effective in pro- As relapse rates from methamphetamine are
ducing positive treatment outcomes. Roll et al. found high,376 there have been calls for more work in
that there were significant differences in terms of improving methamphetamine treatment. Further
a CM schedule’s ability to initiate and maintain research into cognitive-behavioural and behavioural
abstinence. The schedule based on an escalating pro- treatments for methamphetamine users is required,
gramme of reinforcement with a reset contingency with a focus on increasing the duration of the effect of
(developed by Higgings370) showed the best results interventions and improving their effectiveness
for a successful treatment episode.371 among patients with more complex presentations.377
Ling Murtaugh et al. found, in their study of 162 The is also evidence that services that target spe-
MSM methamphetamine-dependent users, that it cific groups and meet their specific needs provide
was the act of voucher redemption, rather than the effective treatment. For example, in an Australian
receipt or size of payment, that affected subsequent LGBTI-specific treatment service, clients showed
abstinence from methamphetamine. Participants reductions in methamphetamine use and improved
who delayed spending the vouchers, and those who psychosocial functioning over time.378
saved the vouchers, had worse outcomes once they
did finally redeem them. The authors recommend 10.14.2.2 Social Support and Other Interventions
that frequent purchases in incentive-based pro- Other support may also be required. Social interven-
grammes should be promoted to improve abstinence tions, such as securing stable housing, training and
outcomes.372 employment are often needed. For example, home-
Overall, studies have shown some efficacy in psy- lessness has been independently associated with the
chological treatment for methamphetamine use, but initiation of methamphetamine use among people
retention in psychological therapies of metham- who inject drugs,379,380 and a recent study found
phetamine-using patients has been an issue.373 that the loss of stable housing through residential
Some have argued that although psychosocial and eviction was associated with an increased hazard of
behavioural interventions have been the most effect- crystal methamphetamine or relapse into metham-
ive treatment for methamphetamine use, their role is phetamine use, even after adjusting for a range of
still in question. It has been argued, for example, that potential confounders including homelessness.381
CM interventions have shown benefit, but a key limi- There is increasing interest in the role of exercise
tation includes its failure to address adequately men- in the management of chronic harms associated with
tal health needs or develop relapse prevention plans stimulant use. A systematic review was to evaluate the
for after the intervention.158 There is also some evi- effectiveness of exercise for reducing anxiety and
dence that CM is not likely to have a sustained and depression, and improving fitness and quality of life
large effect on methamphetamine use.374 One RCT in adults who have previously used methampheta-
of CM to reduce methamphetamine use and sexual mine. The review suggests that overall recovery in
risk studied 217 non-treatment-seekers over 12 methamphetamine-dependent users might be
weeks and found that CM was potentially associated improved by including an effective exercise pro-
with an increase in methamphetamine use and gramme in the rehabilitation process; significant
decreases in sexual risk, but these were not statistic- improvements were found for anxiety, depression,
ally significant.376 fitness and quality of life following exercise, as com-
A systematic review and meta-analysis of mental pared to all control groups.382
health outcomes associated with methamphetamine A small number of studies have looked at electro-
use has argued that services that interact with people convulsive therapy (ECT) with patients who were
who use methamphetamine need to have the capacity unresponsive to antipsychotic medications and
216
reported improvement to psychotic symptoms, crav- Methamphetamine vaccines, which recruit the
ings, withdrawal, and mood.383,384,385 There have body’s immune system to keep the drug from enter-
also been a limited number of studies looking at ing the brain, are currently being tested in ani-
electro-acupuncture and a RCT reported significant mals, and a human clinical trial is currently
improvement to Positive and Negative Syndrome underway to test an immunologic agent called
Scale (PANSS) scores after 1 week of treatment that a monoclonal antibody, which binds to metham-
continued to improve until the end of the 4-week phetamine and neutralises it before it can exert its
trial.386 effects.89,391
A RCT of people who are dependent on metham- Over the years, in addition to new compounds,
phetamine looked at the role of electro-acupuncture a number of medications approved for other condi-
and found that it is effective in treating the metham- tions have been tested for their efficacy and safety in
phetamine withdrawal symptoms in methampheta- treating methamphetamine dependence. These have
mine, including anxiety, and depression.387 More included serotonergic agonists, dopaminergic agonists,
research is needed. monoamine agonists and mixed monoamine agonists/
Mindfulness-based relapse prevention (MBRP) antagonists.92,394,392,393,394,395,396,397,398,399,400,401,402,403,
404,405,406,407
has shown some benefit, although more research is
needed. It has been reported that MBRP can decrease As mentioned in Chapter 8, a recent systematic
craving and depressive symptoms for comorbid sub- review reported that there is currently no pharmaco-
stance use in depressive disorders.388 A RCT evaluat- therapy that has shown convincing results for the
ing the efficacy of MBRP in conjunction with treatment of amphetamine and methamphetamine
contingency management as a primary intervention dependence; this is mainly because most studies
approach for stimulant dependence found that MBRP were underpowered and had low treatment comple-
reduces negative affect and psychiatric impairment tion rates. However, there were positive signals from
and is particularly effective in reducing stimulant use several agents that warrant further investigation in
among stimulant-dependent adults with mood and larger scale studies.408
anxiety disorders.389 The systematic review that included 43 studies
also found that there are a few pharmacotherapy
10.14.3 Pharmacological Interventions candidates for the treatment of amphetamine and
methamphetamine dependence/use disorder that
for Methamphetamine Dependence demonstrate some weak positive signals, although
and Withdrawal more research is needed. The most consistent positive
The need to develop safe and effective medication for findings were shown with stimulant agonist treatment
methamphetamine dependence continues to be (dexamphetamine and methylphenidate), naltrexone
a global strategic aim. and topiramate. Less consistent benefits were shown
According to the US National Institute on Drug with bupropion, the glutamatergic agent, riluzole, and
Abuse (NIDA), one approach currently tried is to target antidepressant mirtazapine. In general, antidepres-
the activity of glial cells with a drug called AV411 sant medications (e.g. SSRIs, TCAs) have not been
(ibudilast). This has been shown to inhibit metham- effective in reducing amphetamine and metham-
phetamine self-administration in rats; it is now being phetamine use.409
studied in clinical trials to establish its safety and effect- Similarly, a study of pharmacotherapeutic agents
iveness in humans. Other approaches currently under in the treatment of methamphetamine dependence
study use the body’s immune system to neutralise the reported that no agent has demonstrated a broad
drug in the bloodstream before it reaches the brain. and strong effect in achieving methamphetamine
These approaches involve injecting a user with (anti) abstinence in Phase II trials. However, agents with
methamphetamine antibodies or with vaccines that novel therapeutic targets appear promising, with
stimulate the body to produce its own antibodies.390 more research needed.410
A clinical study is currently being conducted to estab- Similarly, another review looked at 14 different
lish the safety of an anti-methamphetamine monoclo- drugs, including antidepressants, antipsychotics, psy-
nal antibody, known as mAb7F9, in human chostimulants, anticonvulsants, and opioid antagon-
methamphetamine users.392 ists. Although there was no evidence of benefit for
psychostimulants overall, there was low strength
217
Methamphetamine
evidence from two RCTs that methylphenidate may studies was low (50.4%). Psychostimulants did not
reduce methamphetamine use. Antidepressants had reduce amphetamine use, or amphetamine craving,
no effect on abstinence or retention based on moder- and did not increase sustained abstinence. The pro-
ate to high strength evidence. Studies of anticonvul- portion of drop-outs due to adverse events was similar
sants, antipsychotics (aripiprazole), and opioid for psychostimulants and placebo. The review con-
antagonists (naltrexone) provided either low strength cluded that the evidence does not support the pre-
evidence of no effect on the outcomes of interest, or scribing of psychostimulants (at the tested doses) as
insufficient evidence to draw conclusions. Most phar- replacement therapy, although further research may
macotherapies were ineffective in treating metham- change this conclusion.418
phetamine use disorder.411 A recent systematic review of 43 RCTs examined
Another systematic review and meta-analysis also 23 pharmacotherapies for substance use disorder or
found that none of the drug classes studied in patients drug dependence due to amphetamine/metham-
with methamphetamine disorder had strong or con- phetamine, with various outcomes pertaining to use
sistent evidence of benefit on methamphetamine and associated symptoms. The review found that
abstinence, or treatment retention. The study suggests while some drugs demonstrated results that were
that methylphenidate and topiramate are promising statistically significantly better than placebo out-
drugs deserving more research.412 comes, the studies were generally small and the sam-
Similarly, another systematic review that has ples biased and study protocol completion was low.
medications evaluated for methamphetamine/ The most consistent positive findings have been dem-
amphetamine use disorder has reported that many onstrated with stimulant agonist treatment (dexam-
of its findings were insufficient to form strong conclu- phetamine and methylphenidate), naltrexone and
sions. However, there was moderate-strength evi- topiramate.416 Another systematic review has shown
dence that antidepressants had no statistically there was low-strength evidence that methylphenidate
significant effect on abstinence or retention, and low- may reduce amphetamine/methamphetamine use.417
strength evidence of no statistically significant effect The evidence on naltrexone is also not consistent.
on harms. The review also reported on low-strength One the one hand, a small double-blind placebo-
evidence that psychostimulants had no statistically controlled study on the use of N-acetyl cysteine plus
significant effect on abstinence and retention. naltrexone found no significant difference with pla-
However, methylphenidate may be more effective cebo on treatment outcomes.406 Similarly, another
than placebo in reducing use. Similarly, although the study has shown that in comparison with placebo,
evidence for anticonvulsants/muscle relaxants was extended-release naltrexone does not appear to
insufficient, the review found low-strength evidence reduce methamphetamine use or sexual risk behav-
that topiramate may be more effective than placebo iours among methamphetamine-dependent men who
for reducing methamphetamine/amphetamine use. have sex with men.418
In addition, there was low-strength evidence that A recent multisite, double-blind, two-stage, pla-
methylphenidate may reduce amphetamine/metham- cebo-controlled trial to evaluate the efficacy and
phetamine use413 and that naltrexone did not improve safety of extended-release injectable naltrexone
treatment retention. (380 mg every 3 weeks) plus oral extended-release
A trial has shown the safety and effectiveness of bupropion (450 mg per day) over a period of 12
buprenorphine and bupropion in the treatment of weeks in adults with moderate or severe metham-
methamphetamine withdrawal craving, although phetamine use disorder. The primary outcome
buprenorphine was shown to be superior compared found was that a reduction in amphetamine use
with bupropion.414 More research is needed. (defined as at least three methamphetamine-
A Cochrane review415 of the efficacy and safety of negative urine samples out of four samples obtained
psychostimulant medications for amphetamine in the last 2 weeks of each stage) was overall low, but
dependence (dexamphetamine, bupropion, methyl- was higher in those than received the bupropion/
phenidate and modafinil), in addition to psychosocial naltrexone than those who received the placebo.419
interventions, reported that no significant differences Another study has found that naltrexone may be
were found between psychostimulants and placebo especially effective in methamphetamine-dependent
for any of the studied outcomes. Overall retention in individuals with low executive function.420
218
Other trials conducted with methamphetamine there is some indication that it may reduce amounts
users have tested selegeline, ondansetron, ingested and can reduce relapse rates among those
paroxetine,397 fluoxetine421,422 and sertraline,367,399 already abstinent.395
usually accompanied by a psychosocial structured Similarly, a trial randomly assigning people to an
therapy. A placebo-controlled trial studying the active medication regimen – comprising flumazenil
selective serotonin reuptake inhibitor sertraline for (2 mg infusions on days 1, 2, 3, 22, 23), gabapentin
the treatment of methamphetamine use showed that (1,200 mg to day 40) and hydroxyzine (50 mg to day
subjects receiving sertraline did not show improve- 10) – or placebo showed that the regimen was no more
ments in depressive symptoms or craving compared effective than placebo in reducing methamphetamine
with those who did not receive it.399 It has been use, retaining patients in treatment or reducing
argued that, overall, results suggest that sertraline, craving.424 These results were different from those of
and possibly all selective serotonin reuptake inhibi- another study using the same protocol that found
tors, are ineffective and may even be contraindicated fewer positive urine tests for methamphetamine
for methamphetamine dependence.399 throughout the trial and decreased cravings.405
A number of small studies have suggested that Differences may be due to study conditions and dif-
there may be a potential for the use of mirtazapine ferent demographic characteristics of participants in
(a noradrenergic and specific serotonergic a private medical setting.427
antidepressant).11,151,423 Mirtazapine (in addition to A double-blind study of 60 subjects with bipolar or
counselling) was shown to reduce use among active major depressive disorder and methamphetamine
methamphetamine users.151 It was also shown to dependence randomised them to placebo or citicolin,
lessen the symptoms of methamphetamine with- an over-the-counter nutritional supplement
drawal (including the subjective symptoms) over 10 (2,000 mg/day), for 12 weeks. A significant between-
days of abstinence, with reductions in agitation, anx- group difference in depressive symptoms was
iety, fatigue, irritability, paranoid ideation, anhedo- observed. The study also showed significantly higher
nia, vivid dreams and suicide ideation. It also completion rates among those on citicolin than those
increased the amount of sleep.407 on placebo.321
The impact of mirtazapine, in addition to counsel- For the moment, however, psychosocial therapies
ling, on sexual behaviours that were shown by one continue to be the cornerstone of treatment, with
study is noteworthy. A 12-week double-blind trial of drug therapy regarded as an adjunct rather than
mirtazapine among 60 MSM found that most sexual a replacement for psychosocial approaches.11 There
risk behaviours decreased significantly in the mirtaza- is currently no approved pharmacotherapy for meth-
pine arm of the study in comparison with the placebo amphetamine dependence378 and no specific medica-
arm, even though both arms received HIV risk- tion to counteract the effects of methamphetamine
reduction counselling at baseline. The study also withdrawal, or prolong abstinence.425,426
found that the reduction in sexual risks was associated
with a reduction in negative test results for amphet- 10.14.4 Treatment Effectiveness, Impact,
amine use, perhaps suggesting a possible causal path-
way between the two outcomes.151 Retention and Completion
Not all studies of mirtazapine have shown its Some studies have shown that, when methampheta-
effectiveness in the management of methamphetamine users seek treatment, there is a substantial like-
mine dependence.408 One study which focused on lihood of treatment drop-out and relapse,427 although
patients with acute withdrawal symptoms showed the treatment outcomes for methamphetamine users
that it does not facilitate retention or recruitment in are not necessarily different from those of the users of
outpatient methamphetamine withdrawal other drugs.428,429 There is, though, a lack of treat-
treatment.408 ment provision.430
The use of anticonvulsants has also been investi- Although still limited in Europe, the treatment of
gated. A randomised controlled trial of 140 metham- methamphetamine use disorder can be effective in
phetamine-dependent adults prescribed topiramate leading to improvements in substance misuse, inject-
(at doses of up to 200 mg/day) suggested that this ing, health and criminal behaviour at 1 year after
medication does not promote abstinence. However, discharge from treatment.431,432
219
Methamphetamine
Treatment for methamphetamine use/dependence residential versus outpatient treatment,438 shorter

can have a positive impact on other high-risk behav- treatment duration,440 disability,430 selling
440
iours. A study of CM and CBT interventions delivered methamphetamine and intravenous use.430,439
to a group of MSM found that those who reported the Race, gender and ethnicity have also been associated
greatest decrease in methamphetamine use also with treatment success or failure, but the findings
reported the greatest and quickest reduction in have differed between studies.
depressive symptoms and high-risk sexual Similar factors were identified as affecting health-
behaviour.433 The authors suggest that lowering related quality of life (HRQOL) for those completing
methamphetamine use can have an effect on depres- treatment. A study of the HRQOL trajectories of 723
sion and sexual behaviour and that some users who people dependent on methamphetamine, resulting
respond well to treatment may show improvements in from treatment completion and continued care over
these co-occurring problems, without the need for one year, found greater improvements in mental
more intensive targeted interventions.436 health. It described ‘fairly static’ trajectories in phys-
Similar findings were reported by other studies.151 ical health status, in comparison with those who did
There is some evidence that interventions to reduce or not complete treatment or who continued to use ser-
eliminate methamphetamine use for MSM in drug treat- vices. The study showed differential patterns of health
ment settings also produce reductions in high-risk sex- improvement. Factors identified as negatively affect-
ual behaviours and resultant HIV transmission. Drug ing HRQOL included unemployment, lifetime
treatment may be an important part of an HIV/STI trauma, suicide history, interpersonal conflict, con-
prevention strategy for MSM.365 One study of metham- tinued use of methamphetamine, poly-drug use and
phetamine users found that longer treatment retention medical and psychiatric impairment.444
and greater rates of treatment completion were signifi- The study also found that higher education was
cantly related to greater reductions in risky sexual and associated with a poorer health outcome, a finding
injecting behaviours and were associated with reduc- that is not supported by the literature. The authors
tions in HIV risk three years after treatment.434 speculated that this might be because drug use among
There is a growing body of evidence on the factors highly educated subjects can lead to a lower perceived
that help predict methamphetamine treatment suc- health status, with the subjects not being able to
cess, and most particularly failure, including retention maintain previous health standards and not being
in treatment and treatment completion.430 There is able to fulfil goals they had set before drug use. The
consistent evidence that poorer outcomes are associ- study also showed poorer health outcomes for women
ated with: on methamphetamine.447
• Greater frequency of use previously The frequency of use at entry to treatment and
• More extensive history of previous early treatment responsiveness have been identified as
treatment435,436,437 predictors of treatment success. One study of 60 indi-
• Lower educational attainment,430,438 although viduals looked at whether cognitive performance can
conflicting evidence on this has been predict success in treating methamphetamine depend-
reported.438,439 ence, and considered whether cognitive performance is
• Polydrug use440
more or less predictive of treatment success than estab-
lished factors, such as frequency of use.445
• Residing in unstable accommodation441
The study found that, although a few neuro-
• Engaging in criminal behaviours442
cognitive and psychiatric variables were associated
Conversely, there is some evidence that factors asso- with treatment outcome, the frequency of meth-
ciated with remission from methamphetamine use amphetamine use at the study outset was a much
including maintaining or gaining employment and stronger predictor of outcomes. Participants who
increased levels of perceived social support were had two or fewer urine tests positive for metham-
shown to be predictive of remission.443 phetamine during the first two weeks were much
Other factors have also been associated with suc- more likely to complete treatment and achieve
cess or failure, but the evidence is either limited or abstinence in the majority of the treatment
inconsistent. These include greater craving for weeks,448 a finding that was consistent with several
methamphetamine,262 legal coercion of treatment,430 other studies.430,400,438,439,439,441
220
The authors suggest that it is possible that this There are many reasons why this may be the case.
finding was partially due to study design. A US study reported a common belief among meth-
Nonetheless, the study did show that patterns of amphetamine users that it is a ‘functional drug’, which
methamphetamine use during the initial stages of may encourage frequent and prolonged daily
treatment were able to predict the outcomes in use.83,449 Similarly, Kenny et al. reported common
terms of continued use and treatment attendance. reasons for not seeking methamphetamine treatment:
A few cognitive measures were related to treat- users did not believe that they were dependent (des-
ment outcome, but these did not allow for predic- pite meeting DSM-IV criteria for dependence); they
tion after adjustment for methamphetamine use at did not feel that regular use of methamphetamine
the beginning of the study. The authors concluded warranted formal treatment; they discounted their
that clinicians who want to identify patients at dependence; and they recognised their dependence
risk of treatment failure should use multiple but were not ready to do anything about it.450
urine tests. They also suggest that it is more plaus- There is also some evidence that treatment ser-
ible to predict treatment failure than treatment vices may not be, or be perceived to be, accessible to
success.448 methamphetamine users. An Australian study451,452
Similarly, a study of bupropion found that early suggested that the reasons for under-representation of
treatment responsiveness may be important for posi- methamphetamine users in the treatment system
tive outcomes, a finding consistent with smoking include poor orientation of services for this group,
cessation403 and with some research in cocaine lack of information about treatment options and little
treatment.403,404 Data analysis showed that the inability confidence in the effectiveness of programmes.
of users to provide at least three methamphetamine- Barriers to treatment are not only constructed by
free samples in the first two weeks of treatment was service users but also by clinical staff. A study has also
associated with a likelihood of treatment failure looked into barriers to methamphetamine treatment
exceeding 90%. The authors suggest that clinicians from the perspective of treatment providers, who saw
prescribing bupropion can predict treatment failures barriers as extensive and wide-ranging. They included
confidently within two weeks when they carry out drug the particular personality characteristics of metham-
testing three times a week, with weekly testing yielding phetamine users, complexities associated with mental
acceptable predictive power within three weeks. The health co-morbidity, waiting periods resulting in loss
ability to predict treatment failure was substantially to treatment, the binge nature of methamphetamine
more precise than the prediction of treatment success, use, lack of pharmacological options and negative
which the authors attributed partially to the overall attitudes of staff towards this patient group.453
treatment failure rates. The absence of an early Improved understanding of the ways metham-
response predicts treatment failure better than the phetamine users access other treatment services
presence of an early good response predicting treat- could be used to facilitate effective referral pathways.
ment success. The authors therefore suggest that this Studies have looked at the factors, and user character-
prediction of treatment failure is relevant to clinicians, istics, that make individuals more likely to seek
as it signals the need to change treatment modality and support.454,455 GPs have been identified as a likely
intensity.402 common starting point for patients seeking referral
for all drug-related problems.456
10.14.5 Access to Treatment Quinn et al.’s study suggests that service utilisation
People dependent on methamphetamine may not for other problems, such as mental health or other
access treatment services for many years and there is drug problems, increases the likelihood of accessing
often a delay between first use, first recognising treatment for methamphetamine use.458 They suggest
a problem with methamphetamine, and first treat- that contact with other services may increase the
ment assessment. Different studies have shown opportunity for treatment of methamphetamine mis-
a range for average length of time for the first treat- use and break down barriers to professional support,
ment. An Australian study found that methampheta- such as ignorance of the services available and stigma
mine users can wait an average of 5 years from first associated with service utilisation.457 People who use
experiencing problems to seeking treatment.447 US services for other issues are more receptive to seeking
studies have reported an average of 8448 and 9 years.83 treatment for methamphetamine misuse.458 The
221
Methamphetamine
authors also note that these findings suggest a need to high-threshold treatment services,458,461 or that many
facilitate professional support pathways for treating individuals feel that they are able to address harmful
methamphetamine users who engage in harmful use and/or dependent use without the need for intensive
patterns.458 professional intervention.360
The availability of appropriate and relevant ser- It has been suggested that elevated rates of violent
vices has been identified as enhancing service uptake. behaviour amongst people who use amphetamines
Australian studies have suggested that methampheta- and methamphetamines indicate that health services
mine injectors are more likely than those who smoke need to be equipped to manage this risk.462
or snort the drug to seek and receive treatment from
specialist services.458,458,459 It has been suggested that
there is greater availability of services for people who
10.14.6 Interventions for Mental Health
inject and fewer barriers to treatment (such as needle In a summary of clinical and policy implications of
exchanges). a recent systematic review and meta-analysis of
In comparison with other substances such as mental health problems associated with metham-
opiates, it may be important to make the treat- phetamine use, McKetin et al. (2019) have suggested
ment settings specific to methamphetamine users, that the current treatment responses, and the siloed
to accommodate the different nature of metham- arrangement of mental health and substance use
phetamine dependence and withdrawals. Although services in many countries, hinder the provision of
this may be beyond the means of many drug care for co-occurring disorders. The authors also
treatment systems and services, services can argue that the provision of treatment for co-
undertake some small changes that could have occurring mental health and substance use disorders
a large impact on user perception, such as allocat- is hindered by diagnostic issues, particularly whether
ing some time each day for methamphetamine psychosis or depression is considered to be amphet-
clients or allocating specific staff or rooms with amine-related or whether it represents a ‘primary’ or
specific methamphetamine resources.453 ‘independent’ disorder. This can lead to suboptimal
The cultural competence of services has also been management of mental health conditions in cases
identified as enhancing treatment uptake and enhan- where symptoms are thought to be amphetamine-
cing effective harm reduction.460 A study of behav- related.463
ioural psychological interventions on depression,
sexual risk behaviour and methamphetamine use 10.14.7 Aftercare and Support
among 162 MSM found that a gay-specific CBT inter-
See Section 8B.12.5.
vention reported the greatest reduction in all three
outcomes.436
Treatment readiness may also be key to accessing 10.15 Harm Reduction
support for methamphetamine problems. Quinn et al. The implications of driving under the influence of
found that two key factors were associated with seek- methamphetamine has been discussed.464 Harm
ing help for methamphetamine problems: seeking reduction is covered in Chapter 8.
help from family or peers in the year before entry It is argued that there is a need to revisit harm
into the study; and adoption of personal methods reduction approaches when applied to stimulant use,
for the reduction or cessation of methamphetamine as existing harm reduction approaches were devel-
use.458 It has been suggested that targeted interven- oped largely for opioid injectors, and they have been
tions to identify and access individuals when they first metropolitan based.465
experience readiness to change could be important.
Motivational interviewing and stepped care could be
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239
Chapter
Synthetic Cathinones
11
The natural analogue to synthetic cathinones is the (4-MEC), emerged as replacements for mephedrone,
active compound in the leaves of the khat plant (Catha methylone (3,4-methylenedioxy-N-methylcathinone)
edulis), which have been chewed for centuries in parts and MDPV (3,4 Methylenedioxypyrovalerone) when
of Africa and the Arabian Peninsula for their stimu- these came under legal controlled in 2010.12 Similarly,
lant properties.1 Synthetic cathinones are also pre- ‘second generation’ pyrovalerone-cathinones com-
scribed medications, such as bupropion, Wellbutrin®. pounds such as α-PVP, (α-pyrrolidinovalerophenone;
Synthetic cathinones form a significant proportion α-pyrrolidinopentiophenone) were developed, sharing
of novel psychoactive substances (NPS) with stimulant a very similar chemical structure with MDPV. New
effects that have appeared in the last decade or so.2,3 By pyrovalerone drugs were also identified and include
2019, the EMCDDA was monitored 138 synthetic cath- the following substances: 4F-α-PVP, α-PHP, PV8,
inones, including eight reported for the first time in 4Me-PPP, α-PBP, 4F-PV8, α-PPP, MDPHP, α-PVT,
2018.4 Police seizures of new psychoactive substances 4Cl-α-PVP, 4F-α-PHP MDPHP, and 4F-α-PVP.13
continue to be typically dominated by synthetic cath- A so-called third-generation of synthetic cathi-
inones (and synthetic cannabinoids).5 There is concern nones also began to emerge including: 3,4-DMMC
over the use of synthetic cathinones by opioid and (3,4-dimethylmethcathinone), then pentedrone (α-
stimulant injectors, as this has been linked to health methylaminovalerophenone)14 [2-(methylamino)-
and social problems in some European countries.6 1-phenylpentan-1-one], 4-methylethcathinone
Synthetic cathinones appeared on the recreational (4-MEC), butylone, ethcathinone, ethylone, 3- and
drug scene more than a decade ago. The first synthetic 4-fluoromethcathinone, methedrone, methylone,
cathinones to appear included 4-methylmethcathinone pyrovalerone, 3-MeOMC; 3-MMC; 4-BMC; 4-MEC;
(mephedrone), 3,4-methylenedioxy-N-methylcathinone 4-MeO-a-PVP; 4-MeO-PBP; 4-MeO-PV9; 4-MPD;
(methylone), and 4-methylenedioxypyrovalerone 4F-PV8; 4FPV9; 4F-PVP; a-PBT; a-PHP; a-PVT;
(MDPV).7 dibutylone; DL-4662; ethylone; MDPPP; MOPPP;
Mephedrone and its derivatives, as well as MDPV, NEB; pentedrone; PV-8, 4-CMC and alpha-PVP,
are some of the NPS that have been reported every year 4-CEC α-pyrrolidinohexanophenone (α-PHP)
since 20098 and have been detected in many parts of the Other new synthetic cathinones identified include
world. However, in more recent years, MDPV and iso-4-BMC, β-TH-naphyrone, mexedrone, and
mephedrone are no longer as prevalent as they have 4-MDMC: (1) 1-(4-bromophenyl)-1-(methylamino)
been in previous years and new generations of syn- propan-2-one (iso-4-BMC or iso-brephedrone), (2)
thetic cathinones have emerged on drug markets.9,10 2-(pyrrolidin-1- yl)-1-(5,6,7,8-tetrahydronaphthalen-
Newer generations of synthetic cathinones are 2-yl)pentan-1-one (β-TH-naphyrone), (3) 3-methoxy-
often more potent and associated with greater levels 2-(methylamino)-1-(4-methylphenyl) propan-1-one
of harms. An animal study has suggested for example (mexedrone), and (4) 2-(dimethylamino)-1-(4-methyl-
that the second generation cathinones pentylone and phenyl)propan-1-one (4-MDMC),15 4-Chlorometh-
pentedrone have abuse liability greater than that of cathinone (4-CMC, also known as clephedrone).
methylone.11 There may also have been a shift in the
use of synthetic cathinones from ‘clubbers’ to margin- 11.1 Street Names
alised populations. Street names will of course vary by country, time and
The second generation of synthetic cathinones, type of synthetic cathinones used. For example,
such as naphyrone and 4- methyl-N-ethcathinone 3-MMC, is referred to as ‘ice cream’ in Slovenia,16
240
while in the UK mephedrone is referred to as of Drugs Regulations (2003, as amended) and the
Bubble(s), Miaow, Meow Meow and Mcat.17 In Psychoactive Substances Act 2016.19
Hungary mephedrone is referred to as ‘mefedron’,
‘kati’), MDPV (‘MP’, ‘MP3’, ‘MP4’), 4-MEC (‘for-
mek’), and pentedrone (‘penta’, ‘pentakristály’,
11.3 Quality of the Research Evidence
‘kristály’).18 Our knowledge of synthetic cathinones continues to
The term ‘bath salts’ is mainly used in the US to be limited, although a number of pre-clinical, animal
refer to synthetic cathinones (often MDPV) and will and laboratory studies have been conducted in recent
appear in the American literature. years. Much of the literature on the harm associated
with the use of synthetic cathinones and the manage-
ment of those harms focuses on mephedrone and
11.2 Legal Status MDPV (often referred to in the American literature
Although the plant itself is not under international as ‘bath salts’), reflecting their higher prevalence of
control, the principal psychoactive substances that the use relative to other synthetic cathinones. We know
plant contains, cathine and cathinone, are controlled. less about the clinical effects of other synthetic cath-
Cathinone was included in Schedule I of the UN inones, especially newer ones.
Convention on Psychotropic Substances in 1988, In addition to the lack of robust research evidence,
and cathine was then included in Schedule III of this not all studies of the clinical harms have analytical
Convention. confirmation of cathinone use, reducing the ability to
Some synthetic cathinones are now under draw robust conclusions and make recommendations.
international control including 3,4- methylene- US studies generally refer to the whole group of so-
dioxypyrovalerone (MDPV), mephedrone and called ‘bath salts’. Although it is not always clear what
methylone and α-pyrrolidinovalerophenone (α- these are, they tend to include findings relating to
PVP); ethylone, pentedrone and 4-methyleth- methylenedioxypyrovalerone (MDPV) in particular,
cathinone (4-MEC) under Schedule II of the as well as mephedrone and other synthetic cathinones.
1971 Convention on Psychotropic Substances
(UNODC, 2017a).
In the US, MDPV, mephedrone and methylone
come within the realm of Schedule I of the It has been argued that because cathinones present
Controlled Substances Act 1970. In the EU, mephe- structural differences in their backbone and in the sub-
drone was submitted to control by the European stitute groups, this makes them a unique family of
Council’s decision of 2 December 2010 (2010/759/ drugs.20
EU). At national levels, other cathinone derivatives Synthetic cathinones are beta-keto phenethyla-
are caught by drug control or equivalent legislation, mines. Typically, they have an amphetamine-type
for example: analogue, which means that they are structurally
related to amphetamine, methamphetamine and
• mephedrone (Belgium, Crotia, Denmark, Estonia,
MDMA. Some synthetic cathinones are analogues of
France, Germany, Ireland, Italy, Lithuania,
pyrovalerone (3,4-methylenedioxypyrovalerone or
Norway, Romania and Sweden);
MDPV and naphyrone)21 and have a slightly different
• methylone (Denmark, Ireland, Romania and mode of action.
Sweden); Synthetic cathinones are amphetamine-like stimu-
• butylone (Denmark, Ireland, Norway, Romania lants. Like amphetamines, cathinones act as central
and Sweden); nervous system stimulants, although they are gener-
• MDPV (Denmark, Ireland, Finland and Sweden); ally less potent than amphetamine.22,23
• flephedrone (Denmark, Ireland and Romania). Synthetic cathinones are generally less able than
• Medicines’ legislation is used in Finland and the amphetamines to cross the blood–brain barrier
Netherlands to control mephedrone. In the UK because the beta-keto group causes an increase in
context, several generations/classes of synthetic polarity.24
cathinones and derivatives have been dealt with by There are considerable variations between the dif-
means of generic definitions under the 1971 Act as ferent synthetic cathinones in their chemistry, modes
Class B drugs and under Schedule 1 of the Misuse of action, potency, and toxicity.25 The most commonly
241
used are the first-generation cathinones such as these characteristics, these molecules may present
mephedrone, methylone and MDPV, which have with a high abuse potential.
been described as drugs with euphoric effects, because Box 11.1 looks at mephedrone and MDVP in more
they act through the monoamine transporters (nor- detail.
adrenaline, dopamine or serotonin transporters).
However, they do so in two ways: either as monoamine
uptake inhibitors, or as transporter substrates that Box 11.1 Mephedrone and MDVP
increase the release of these neurotransmitters.26,27
For example, mephedrone acts primarily (but not Mephedrone
exclusively) as a releasing agent of dopamine, whereas Mephedrone is an example of the fact a ‘novel’ or
‘new’ substance is not always a new invention.
MDPV is an uptake inhibitor at the same transporter.
Whereas mephedrone appeared as a recreational
In other words, mephedrone and MDPV behave in an
drug in 2007 in mainland Europe, it was synthetised
opposite manner at the level of dopamine transporter in 1929.
(DAT and NET). Like amphetamine and metham- Mephedrone is produced by replacement of the
phetamine, mephedrone is a DAT releasing agent 4-position aromatic hydrogen of cathinone with
whereas, like cocaine, MDPV is an uptake inhibitor a methyl group, and carries a similar molecular
at DAT.28 Methylone shows a pharmacological profile structure to many common street drugs, including
that more closely resembles 3,4- methylenedioxyamphetamine and MDMA.33,34
methamphetamine (MDMA).29 The ability of mephedrone to cause
A classification based on the pharmacological subjective effects resembling those of MDMA is
action of cathinones (i.e., Dopamine Transporter; likely to have contributed to its relatively
widespread use. However, its ability to cause
DAT/Serotonin Transporter SERT inhibition ratio)
dopamine release may be problematic, inasmuch
and comparability to traditional drugs of abuse, in
as in comparison with MDMA, mephedrone may
particular has been proposed.30,31 Also see:32 have a greater liability to misuse, resembling
1. Cocaine-MDMA-mixed cathinones, for example, that of dopamine releasing agents, such as
mephedrone, 4-MEC, methylone, etylone, methamphetamine.35
butylone and naphyrone. These substances are
MDPV
associated with an entactogenic, MDMA-like
Information obtained from studies carried out
effect when ingested orally, and have in vitro and in vivo in animal models suggests that
a psychostimulant cocaine-like effect when taken the psychopharmacological and behavioural profile
intranasally. observed for MDPV is similar to cocaine. However, it
2. Methamphetamine-like cathinones, for example, appears that MDPV is more potent and longer
cathinone, methcathinone, flephedrone, lasting and it has been described as having powerful
ethcathinone, and 3-FMC. cocaine-like actions.36
3. MDMA-like cathinones, for example, methedrone It has also been suggested that in comparison
and 4- trifluoromethylmethcathinone. These have to other synthetic cathinones, MDPV displays
a novel pharmacological profile in as much as it
effects broadly similar to MDMA and include NPS
is a potent uptake blocker at dopamine and
such as paramethoxymethamphetamine norepinephrine transporters.37 It has been
(PMMA), paramethoxyamphetamine, 4- suggested that the potency of MDPV at the DAT
ethylthioamphetamine. and NET and high blood–brain barrier
4. Pyrovalerone-cathinones: for example, permeability could result in high
pyrovalerone, MDPV (see Box 11.1), and α-PVP. sympathomimetic toxicity.
These molecules are non-substrate transporter Animal studies suggest that despite some of
inhibitors. All pyrovalerone-cathinones present the structural similarities and similarities in
with similar pharmacological profiles. They all behavioural effect with classical psychostimulants,
exhibit inhibitory potencies at DAT and NET MDPV shows greater potency, selectivity and
functional upregulation of DAT38 and
equal or greater than cocaine or
induces greater locomotor activation,
methamphetamine, do not induce monoamine tachycardia and hypertension than cocaine in
release, and readily cross the blood–brain barrier rats.39
(BBB) owing to their high lipophilicity. Due to
242
11.6 Prevalence and Patterns of Use
Box 11.1 (cont.) prominent, including opioid and benzodiazepine

NPS.52
A study of in vivo locomotor activity testing Widely used synthetic cathinones in the European
and assessment of cardiovascular parameters
Union are mephedrone, 3-MMC, 4-methylethcathi-
(heart rate and blood pressure) found that MPDV
none, pentedrone and pyrovalerone derivatives, such
is at least tenfold more potent than cocaine in
inducing locomotor activation, tachycardia and as MDPV and alpha-PVP.53,54
hypertension. The authors concluded that the As mentioned above, synthetic cathinones have
‘potent blockade of dopamine uptake caused by appeared on the recreational drug scene for over
MDPV predicts that the drug has a high risk for a decade. There was initially a rapid increase in the
abuse, whereas the potent blockade of use of mephedrone in 2009 in some countries55,56 and
norepinephrine uptake portends dangerous there are suggestions that in the UK and Holland, this
cardiovascular stimulation.40 was associated with the poor quality of cocaine and
Simmler et al. (2013) also argued that the ecstasy/MDMA at the time. Its popularity was also
potency of MDPV at the dopamine and enhanced by its relative low cost, availability and its
noradrenaline transporters and high blood–brain
desired effects.44,55,57
barrier permeability could not only result in high
There is a mixed picture of its availability and
sympathomimetic toxicity, but that there is also
a risk of addiction in humans.41 prevalence of use after mephedrone was
controlled.58 Studies have suggested that there was
Mephedrone and MDPV Combinations a marked general decline in the use of ‘bath salts’
Some synthetic cathinone products available appear among young people in the US after the sale of such
to contain both mephedrone and MDPV. Some have stimulants was outlawed in 2011. In the UK, the use of
argued that this combination of both is likely to be
mephedrone declined sharply in the years after it was
similar to ingestion of methamphetamine followed
placed under national control in 2010,59 and con-
by ingestion of cocaine42 – but in a more potent
fashion.43 tinues to do so.60 Some studies have suggested the
control of the drug in 2010 did not stop the spread
of its use,61,62 while others have suggested it did.63
Evidence from elsewhere shows that legal control
11.5 Clinical Uses of Synthetic may lead users to seek new drugs. For example, in
Slovenia, after the ban on mephedrone, users con-
Cathinones tinued to seek the same effects in other NPS and
Bupropion, a cathinone derivative, carries a medical were reported to have shifted to 3-MMC, methylone,
indication in the US and Europe. It is used for the 4-methylethcathinone and pentedrone, which were
treatment of depression and as a smoking cessation believed to have similar effects as mephedrone.64
aid.44 In some countries, the use of synthetic cathinones
Some synthetic cathinones were originally devel- has been particularly associated with public health cri-
oped as drug candidates, but later appeared on the sis. A study found for example that synthetic cathinones
NPS market.45,46 Others, such as pyrovalerone for were found in a majority of syringes from Budapest.
example, were developed in the late 1960s and are Synthetic cathinones in this country first appeared on
structurally related to MDPV. Pyrovalerone was the local drug market after the heroin shortage in 2011,
used in the clinical treatment of chronic fatigue and and cathinones have since presented a substantial chal-
lethargy but was later withdrawn and banned as lenge for harm reduction services. The shift towards
a narcotic substance, as a result of misuse.47,48,49,50,51 cathinones was linked to increased frequency of inject-
ing, reuse and sharing of syringes, and higher HCV
11.6 Prevalence and Patterns of Use prevalence among stimulant users. The main cathi-
Synthetic cathinones appeared as recreational drugs nones injected were pentedrone and MDPV.65
in Europe in 2004. By 2019, seizures of new psycho- In the Czech Republic, the increase in the use of
active substances in Europe were typically dominated synthetic cathinones was identified by a study as
by synthetic cathinones (as well as synthetic canna- another drug used by marginalised people. Synthetic
binoids) although more diversity can be seen in recent cathinone use was associated with poly-drug use and
years, with other groups of substances becoming more homelessness. In addition, as synthetic cathinones
243
have an inferior status among IDUs, their users face in 2009 to 13% in 2015, while cathinones, such as
a risk of stigmatisation and further marginalisation.66 MDPV, mephedrone, pentedrone and methylone,
became the main substances injected in that
11.6.1 Population Sub-groups More Likely country.73
This was reflected in patients of drug treatment
to Use Synthetic Cathinones services. In Hungary, where there was a significant
Different people will use synthetic cathinones for dif- decrease in heroin injecting, this was followed by
ferent reasons and there are geographic differences a rise in the proportion of patients of drug treatment
between the various European countries of the groups services who injected ‘amphetamine’, ‘other stimulant’
of people most likely to use synthetic cathinones. and ‘other (unclassifiable) drugs’. The proportion of
Nonetheless, the following groups have been asso- ‘other stimulant’ and ‘other drug’ injector clients
ciated with higher levels of risk of using synthetic increased in total from 1% (2008 and 2009) to 21% by
cathinones, with a shift in recent years to use by 2012. Although the authors were not able to determine
marginalised groups. the exact proportion of synthetic cathinone injectors, it
was assumed that the vast majority of clients reported
11.6.1.1 ‘Clubbers’ and People who Frequent as ‘other stimulant’ and ‘other (unclassifiable) drug’
Night-time Venues injectors were cathinone users.74
As with other club drugs, there is evidence that use of Cathinones continue to be widely available on the
mephedrone is associated with lifestyle. drug markets of many East European countries and
For example, UK population-level data showed Russia.75
that the use of mephedrone in the previous year was Problem drug users sometimes inject synthetic
around 20 times higher among those who had visited cathinones as part of poly-drug use. In Finland for
a nightclub four or more times in the past month example, the use of synthetic cathinones such as alpha-
(5.8%) than among those who had not visited PVP and MDPV, along with a primary substance, such
a nightclub in the past month (0.3%).67 as amphetamines, has been reported.76 Similarly,
a study carried out in Ireland through the analysis of
11.6.1.2 Synthetic Cathinone Use by Problem Drug urine collected from attendees of a methadone main-
Users tenance clinic, found that 14% were positive for
There is evidence that synthetic stimulants, especially mephedrone and 3% for methylone.77
cathinones, are replacing opioids in some countries Synthetic cathinones can be associated with com-
reporting heroin shortages. The motive for the transi- pulsive patterns of injecting. One qualitative Irish
tion from injecting heroin to cathinones is unclear, study of 11 attendees of low-threshold harm-
but may be linked to easy availability and perceived reduction services reported that compulsive re-
high quality of the new drugs.68 There have been injecting with excessive binge use over long periods
reports of mephedrone injecting from Romania, was common, despite the fact that respondents were
Slovenia and Ireland,69 as well as the Channel aware of the risks of injecting and of safer injecting
Islands. The practice of injecting synthetic cathinones practices. In this small cohort, 7 of the 11 were home-
is also reported by other countries in Europe, namely less, and injecting in public spaces and groin injecting
Austria, Finland, Germany, Latvia, Slovenia, Sweden were common. Mephedrone was not the first drug
and the UK.70 injected and its use appears to be an extension to
In Hungary, probably owing to the limited avail- other drugs also injected.78
ability, low purity and high prices of ‘traditional’
drugs such as heroin, amphetamines and cocaine, 11.6.1.3 Men Who Have Sex with Men and Pro-sexual
there has been a shift among street drug users from Effects of Some Cathinones
the use of heroin to mephedrone injection, potentially The use of mephedrone has been associated with men
increasing the risk of severe psychiatric symptoms.71 who have sex with men (MSM) in some countries
Dependence and high rates of cathinone injecting such as the UK, although in recent years this appears
have been reported.72 It has been shown that among to be less prevalent.
people who inject drugs, the proportion of those who Bourne et al. have shown that in the UK the use of
injected amphetamine or heroin decreased from 95% mephedrone, as well as methamphetamine, GHB/GBL
244
11.8 Desired and Unwanted Effects for Recreational Use
and ketamine, was associated with attendance of gay trifluoromethylphenylpiperazine, benzylpiperazine,

cafes, bars, pubs and clubs. Gay and bisexual men who butylone, methylone or pentylone to enhance
used any or all of these substances were more frequent stimulant and entactogenic effects;
attenders of these venues than gay and bisexual men • opiates, such as morphine or tramadol, to create
who used none of them.79 Mephedrone was one of the ‘speedball’-like effects;
drugs associated with ‘chemsex’, or the use of drugs in • GHB/GBL to enhance sexual stimulation;
a sexual context. The practice of injecting mephedrone • ketamine or zopiclone to enhance visual
has also been noted.80 hallucinations.
Factors associated with the use of cathinones in
a sexual context include its dis-inhibitory effects as
well as its pro-sexual effects (see also Section 10.7.3). 11.7 Routes of Ingestion, Dosing
There are some user reports of heightened sensuality,
disinhibition, prolonged performance in males and
and Frequency of Dosing
ability to reach climax for females; users have also Synthetic cathinones are typically misused as a fine
reported engaging in sexual behaviours when under white, off-white or yellowish powder, but some can be
the influence of mephedrone that they would not have brown in colour. Cathinones are usually used intra-
engaged in while sober.81,82,83,84,85,86 nasally or wrapped in paper and swallowed. They can
also be found as capsules and pills and can be smoked.
11.6.1.4 Polydrug Use: Use of Synthetic Cathinones as Synthetic cathinones can also be injected.
Part of a Wider Repertoire of Drugs Although broadly similar, there are some differ-
ences between them, including their half-life and dur-
Among most synthetic cathinone users, the drug is
ation of effects. Nonetheless, there are similar patterns
often taken as part of a wider repertoire of substances.
of risk associated with patterns of synthetic cathinone
Mixing cathinones with other drugs is common,87
use. The short half-life and duration of effects of some
including with alcohol,88 cannabis,89,90 cocaine,
synthetic cathinones have been reported, which
ecstasy and ketamine,91 as well as methamphetamine
means that users may redose and even binge.
and GHB/GBL.
In-depth interviews with people who have
Many users will co-ingest cathinones with other
used 3-MMC in Slovenia showed binge use spanning
substances. For example, a US study showed that
several days being a prominent feature of drug use.103
a high percentage of ‘bath salts’ or synthetic cathinone
The compulsive and repeated injecting of synthetic
users (94%) also tested positive for other common
cathinones is discussed in Section 11.6.2.
drugs such as cannabis, opiates, benzodiazepines,
Boxes 11.2 and 11.3 look in more detail at mephe-
cocaine, or amphetamines,92 a finding also made by
drone and MDPV.
numerous other studies.93,94,95,96
There is also evidence that mephedrone was used
in combination with methamphetamine and HGB by 11.8 Desired and Unwanted Effects
MSM in particular. for Recreational Use
There is evidence that some users co-ingest more
Some users reported that a cathinone-induced stimu-
than one substance not only to enhance the desired
lant effect is comparable to methylphenidate at low
effects but also to attempt to reduce the harmful
doses or to a combined effect of both amphetamine
effects. Popular combinations reported are mephe-
and cocaine at high doses.130 Others consider cathi-
drone or MDPV in combination with the following
nones to be pharmacologically similar to and as
drugs:78,84,86,97,98,99,100,101,102
potent as amphetamine, cocaine, and MDMA.131
• alcohol, propranolol or another beta-blocker to Overall, acute administration of low doses of syn-
offset tachycardia; thetic cathinones produces euphoria and increases
• cannabis, diazepam or alprazolam for anxiety and alertness. Users reported being motivated to consume
overstimulation; synthetic cathinones for their euphoric properties, out
• famotidine, omeprazole or domperidone for of curiosity, and because these drugs are inexpensive
stomach pain; and easy to obtain.132 In a study where 104 respond-
• other psychostimulants such as cocaine, ents were asked about the reasons for taking synthetic
amphetamine, modafinil, cathinones, the given reasons for use included
245
Box 11.2 Mephedrone
Mephedrone is typically sold as a white or off-white crystalline powder, with a light-yellow hue.104 Some users have
reported its distinctive unpleasant smell93 and some that their body sweat developed a ‘chemical smell’ as a result
of its use.
Mephedrone powder is often sold in small plastic bags (typically 1 g doses), but there are reports of its sale as tablets
pressed from the powder, or as capsules containing the powder. Mephedrone is water soluble. It is typically either
snorted or swallowed (usually wrapped in a cigarette paper) or added to a drink. It is also used by rubbing on the gum,
rectally, by smoking, or by injection (intramuscular and intravenous).55,85,105 Users have also reported multiple
concomitant routes of use.1,21,22,23,24,33,34,35,44,55,56,57,58,61,62,63,68,69,77,78,84,85,86,89,90,91,92,93,94,96,97,106–120
A cross-sectional anonymous online survey of mephedrone users associated with the dance music scene
suggested that the most common route of use was intra-nasally (65.9%), with women significantly more likely than
men to use the drug through snorting (76.2% and 67.2% respectively).113
Snorting is sometimes carried out through the ‘keying’ method, whereby a user will dip a key in the powder and
snort the powder off the key (it is estimated that five to eight keys would represent a 1 g dose).44 There are
suggestions that the insufflation of mephedrone is associated with significant nasal irritation, which has led some
users to switch to oral ingestion.121
Intranasal use may be associated with greater liability to misuse than oral use.113,122 A survey carried out
among 947 UK mephedrone users, reported that the amount of drug used in a typical session was
significantly larger for those snorting (mean 0.97 g, SD 0.91) than for those using it orally (mean 0.74 g, SD
0.64). Those who snorted the drug reported significantly more days of use per month (mean 4.85, SD 5.11)
than those who used it orally (mean 3.21 days, SD 3.01). Those who snorted the drug were significantly more
likely to use it more frequently than those who did not, with 59.2% having used it at least monthly over the
last 12 months.113
The onset of the desired effects of mephedrone is linked to the route of administration, being within a few
minutes through nasal insufflation or intravenous injection and 15–45 minutes following oral ingestion. The onset
of the effects following oral use can be delayed in the presence of food.123 Rectal administration has been described
by users as having a faster onset and the effects require lower doses.93
The duration of the effects is also linked to mode of use. The effects last up to 2–3 hours following nasal or oral
use, albeit with a shorter duration where ingested through nasal insufflation, but only 15–30 minutes following
intravenous use. Some users combine routes of use in a single session, for instance first snorting and then using
orally in order to achieve both a fast effect and a longer-lasting effect.117
Typically, users ingest mephedrone in staggered doses, between 0.5 g and 1 g per session. Although a UK survey of
clubbers found that approximately a quarter of mephedrone users took more than 1 g in a typical session,113 other studies
reported oral doses of 1–2 g124 or even higher.44 The same survey respondents reported that the average duration of
a single session was 10.4 hours and that there was a correlation between total amount used and the duration of
a session.113
The relatively short duration of the effects of mephedrone is associated with repeated dosing during a single
session.117 Regardless of the route of ingestion, the majority of mephedrone users will repeatedly re-dose within
a single session to maintain the desired effect, leading to ‘bingeing’.125 Cathinones are associated with compulsive
use and frequent, repeated injecting.
An animal study has reported vigorous mephedrone self-administration behaviour in rats, eliciting response
levels that appear to match, or even exceed, those seen with other drugs of misuse.126
Box 11.3 MDPV
The hydrochloride salt form of MDPV is white but has also been described as a white-tan coloured powder.
MDPV is typically found in powder form, but there are reports of tablet, capsule and liquid form. It is used nasally,
orally, and by intravenous injection; other reported routes of use include rectal insertion, smoking and
subcutaneous injection.127 There are also reports of MDPV detected in paper blotters (like LSD) and therefore buccal
or sublingual administration may also occur. Similarly, the presence of MDPV in vegetable material suggested that
this product would most probably be smoked.128
The onset of desired effects of MDPV is typically seen within 5–30 minutes, with desired effects lasting 2–7 hours
for the common routes of administration (oral and nasal).129

11.8 Desired and Unwanted Effects for Recreational Use
curiosity (79%), liking the effect (52%), mind/brain Box 11.4 (cont.)
exploration (52%), avoiding a positive test for another
drug (26%), staying awake (22%), and improved sexual behaviours which they would not engage in while
sober.138,139,140,141,142,143
experience (21%). The most commonly reported acute
A dose–response relationship between
subjective effects were stimulation and increased
mephedrone and heightened sex drive has been
energy. Fewer than one quarter reported hallucin- reported.113,132 However, the effects of mephedrone
ations, paranoia, or having an urge to act violently.133 also depend on combinations and types of drugs used,
In this study, respondents reviewed a list of 53 length of time used, sexual roles, normative risk,
potential acute subjective effects and indicated (Yes/ settings and the individual’s experiences and
No) which effects, if any, they had personally experi- expectation.134,144
enced while ‘high’ on synthetic cathinones The most Despite the desired effects of mephedrone, there
prevalent effects included a mixture of desirable and is also evidence that many users prefer other drugs
undesirable effects: increased energy (94%), fast heart with broadly similar effects to cathinones. For
beat (91%), rapid thoughts (91%), difficulty sleeping example, compared to cocaine and MDMA,
mephedrone had some less favourable effects.
(89%), rush of euphoria (88%), decreased hunger
Winstock145 reports that users ceased their ‘love
(88%), feeling more open-minded (87%), increased
affair’ with mephedrone, in part, due to its higher
sweating (86%), feeling happy (85%), dry mouth or scores for extreme agitation, headaches, tremors,
thirsty (85%), increased sex drive (79%), grinding teeth nausea and feeling depressed after use, and to
(79%), feeling loving toward others (78%), feeling closer a lesser extent paranoia and chest pain. In terms of
to others (75%), feeling that time seemed faster (66%), positive effects of using drugs, mephedrone
having hot flushes (62%), and body tension (60%).134 came second out of ten drugs for increased pleasure
Box 11.4 looks in more detail at mephedrone and from social interactions, but had more negative
MDPV. effects, which included not being able to function
normally in the days after use and negative effects
on mental health. Negative effects included its
Box 11.4 Mephedrone
impact on ability to work/study/progress; negative
The reported desired effects of mephedrone include effects on physical health; and unpleasant physical
its stimulant and sympathomimetic effects, similar to and psychological effects when intoxicated.146
those of MDMA (ecstasy) and cocaine.55,93,113,118,135,136 A survey of 900 clubbers using mephedrone
Reasons for its appeal include the fact that it is suggested that the frequency of specific unwanted
relatively non-potent and short-acting. Mephedrone effects (predetermined by the study) is as follows:
is used for both its mood-enhancing properties and excessive sweating (67.2%), headaches (50.7%),
its role as a psychomotor stimulant in social palpitations (43.4%), nausea (37%) and cold, blue
situations.113 Users report stimulant-related fingers and toes (15.3%).113 Similarly, in a Scottish
subjective effects such as euphoria, increased student survey, more than half (56%) of those who
concentration, the urge to move, talkativeness, had used mephedrone reported having at least one
reduced appetite and wakefulness. unwanted effect, at the following frequency:
Desired effects also include stimulation, mood bruxism (teeth grinding) (28.3%), paranoia (24.9%),
elevation, reduced hostility, improved mental sore nasal passages (24.4%), hot flushes (23.4%), sore
function and increased energy.55,61,86,113 At higher mouth/throat (22.9%), nose bleeds (22.4%),
doses, perceptual distortions or hallucinations and suppressed appetite (21.5%), blurred vision (21.0%),
the empathogenic properties of mephedrone have palpitations (20.5%), insomnia (19.5%),
been reported.55,61,113 hallucinations (18.0%), nausea/vomiting (17.1%) and
Synthetic cathinones can increase sexual desire blue/cold extremities (14.6%).147 Other unwanted
and sexual risk-taking behaviour. There is evidence effects include difficulties with urination, poor
that some users ingest stimulants to increase sexual concentration and aggression.
thoughts, intensify sexual desire, enhance Surveys suggest that approximately 20–56% of
sensuality, improve sexual functioning and prolong users of mephedrone have experienced adverse
sexual performance.137 effects84,141 and these are similar to those reported
Users have reported heightened sensuality, for amphetamine, methamphetamine and
disinhibition, prolonged performance for males, the MDMA.148 There is evidence that the most severe
ability to reach climax for females and sexual
247
Box 11.4 (cont.) Box 11.6 MDVP

unwanted effects may be associated with high doses Acute intoxication associated with MDPV produces
and/or prolonged use.117 typical stimulant-like effects, including increased
However, there are important individual energy, euphoria, and elevated feelings of empathy,
variations and similar doses may have significantly and sociability.
different effects and consequences in different Like other amphetamine-type substances, MDPV
individuals.149 It has been suggested that it is use is also associated with a ‘crash’ that follows use.
impossible to determine what a ‘safe’ dose is, as This typically involves negative affective states, such
negative effects may present with any dosage as depression, suicidal thoughts, anxiety, panic
consumed.150 attacks, excited delirium, bouts of violent aggression
The most common unwanted effects of towards self and others, and combativeness that
mephedrone and MDPV reported by users are resemble a severe psychotic episode.151
summarised in Boxes 11.5 and 11.6 57,77,93,113,117,130,141 For acute harms see Box 11.7 and Section 11.9.
For acute harms see Section 11.9.
α-pyrrolidinohexanophenone (α-PHP)
The long-lasting psychotic symptoms induced by
synthetic cathinones appear to be correlated with
their toxicokinetic characteristics, such as their long
Box 11.5 Some Common Unwanted Effects of half-lives.152 It has been suggested that a-PVP has
Mephedrone, as Reported by Users been associated with strong stimulation, euphoria,
and empathy at first, followed by restlessness and
Jaw clenching anxiety after about 20 minutes. Pleasant and
Reduced appetite unpleasant results alternate throughout the whole
Nasal irritation and nose bleeds duration of a-PVP action. In the last stage of action,
Nausea and vomiting users develop paranoia, anxiety, and
aggression.153,154,155,156,157,158,159,160,161,162
Discolouration of extremities and joints
Insomnia and/or nightmares
‘Head rush’
Inability to concentrate and/or to focus visually
Box 11.7 Features of Acute Mephedrone
Memory problems Toxicity
Altered conscious levels
Cardiovascular
Anxiety
Hypertension, tachycardia, chest pain, diaphoresis,
Agitation hot flushes, shortness of breath, palpitations, cardiac
Hallucinations and delusions arrest, peripheral vasoconstriction
Headaches, tremors and convulsions
Cognitive
Raised body temperature
Confusion, improved concentration, alertness,
Chest pains amnesia, cravings, empathy/feelings of closeness,
Elevated heart rate dysphoria
Dermatological
Unusual sweat odour, rash
11.9 Acute Harms ENT

Sore nasal passages, mouth/throat pain, epistaxis
11.9.1 Acute Toxicity Gastrointestinal

As mentioned above in the discussion of unwanted Nausea/vomiting, anorexia, dry mouth, abdominal
effects of synthetic cathinones, acute toxic effects of pain, sore mouth/throat
synthetic cathinones are common, with psychiatric Metabolic
and physical effects often manifesting together. (also Elevated creatinine, metabolic acidosis
see box 11.6 and 11.7)
248
11.9 Acute Harms
Box 11.7 (cont.) Box 11.8 (cont.)

Neurological/Psychiatric/Psychological The health burden caused by MDPV includes
Anxiety, panic, depression, irritability, lack of serious intoxications requiring intensive care
motivation, anhedonia, sexual arousal, sociability, treatment and fatalities.234,235,236,237,238 In addition,
euphoria, insomnia, bruxism, headache, dizziness/ it has been argued adverse effects do not only
light-headedness, tinnitus, seizures, nystagmus, concern acute toxicity but also chronic toxicity.239
mydriasis, blurred vision, numbness, blue/cold There are also acute and longer-term problems
extremities, fever, paraesthesias, visual and auditory associated with the injecting of MDPV240 and other
hallucinations, paranoid delusions, intensification of cathinones, as will be discussed in the next section.
sensory experiences, reduced consciousness, agitation,
aggression, short-term psychosis, short-term mania
α-pyrrolidinohexanophenone (α-PHP)
Musculoskeletal Symptoms of intoxication with α-PVP include
Increase in muscle tone, trismus hypertension, tachycardia, agitation, psychosis,
visual and/or auditory hallucinations, and potentially
Respiratory death as a result of heart
Dyspnoea failure.241,242,243,244,245,246,247,248,249,250
Serotonin Syndrome
Synthetic cathinone exposure has also resulted in
many cases of seizures in the paediatric population.229
Synthetic cathinones produce sympathomimetic
clinical effects consistent with stimulant
intoxication.163–179 Cardiovascular effects (tachycardia,
Box 11.8 MDPV Acute Harms hypertension) and hallucinations are the most common
medical complications of synthetic cathinone use.180
There is some evidence from animal studies on the Case reports and case series relating to
acute adverse effects and the potential for toxicity hospital presentations with acute mephedrone
associated with MDPV (both dose- and time-
toxicity85,97,114,181,182 describe sympathomimetic clinical
dependent), can cause cardiovascular stimulation
features114 and clinical effects consistent with stimulant
and hyperpyrexia (particularly at increased ambient
temperature). It has been suggested that the intoxication.183 Triangulation of data from a number of
stimulant effects of MDPV appear to be intermediate sources presents a picture of mephedrone acute toxicity
between the stimulant effects of cocaine and (Box 11.6) that is consistent with that seen with the use
methamphetamine.230 MDPV acts as a dopamine of other sympathomimetic recreational drugs, such as
reuptake inhibitor; it is more potent than cocaine.231 amphetamine, cocaine and MDMA.184
Data from a small number of cases in Europe, People with synthetic cathinone poisoning will
along with information from user self-reports, suggest present to hospital with psychiatric, neurological,
that individuals typically present to emergency gastrointestinal, cardiovascular and muscular
services with stimulant features including agitation/ symptoms,185 with cardiac, psychiatric and neuro-
aggression, psychosis, delirium, tachycardia,
logical symptoms the most common reported effects
hypertension and convulsions; there are also reports of
that require medical care.175,186,187
more severe toxicity including hyperpyrexia,
rhabdomyolysis, acute kidney injury and stroke.232 Synthetic cathinones can be associated with sero-
A study looking at the medical records and tonin syndrome, especially if other serotonergic illicit
clinical data of 193 MDPV-positive cases found that drugs or medications are also used.188,189 The use of
the main clinical manifestations reported in patients synthetic cathinones has been associated with
testing positive for MDPV included agitation, hyperthermia, similar to that linked to MDMA
tachycardia (100/min), and hypertension (systolic use.190,191,192 (See Chapter 8 and Section 9.14 on sero-
blood pressure 140 mmHg), which were observed in tonin syndrome.)
130 (69%), 106 (56%), and 65 (34%) cases, A range of adverse effects are associated with syn-
respectively. Other symptoms included thetic cathinones toxicity. Case reports have described
hallucinations (16%), delirium (15%), hyperthermia
for example mephedrone-induced euvolaemic hypoos-
(10%), and rhabdomyolysis (8%).233
motic hyponatraemia with encephalopathy and raised
249
intracranial pressure;176 posterior reversible encephal- In the UK, a report of a case series of 72 patients with
opathy syndrome (PRES);193 spontaneous subcutaneous self-reported acute mephedrone toxicity indicated
emphysema associated with mephedrone use, which did that the most common symptoms on presentation to
not require airway support;194 and a case report of hospital, or before, were: agitation (38.9%); tachycar-
methaemoglobinaemia, a serious complication caused dia (36.1%); palpitations (25.0%); vomiting (13.9%);
by a number of oxidising drugs.195 A case of prolonged clinically significant hypertension (13.9%); chest pain
hypoglycaemia associated with the use of synthetic cath- (12.5%); severe tachycardia (8.3%); headaches (7.2%);
inones has also been reported.196 self-limiting pre-hospital seizures (6.9%).96
A case report highlighted the potential danger of
mephedrone to people with diabetes. A patient with
type 1 diabetes developed ketoacidosis following self- 11.9.2 Harms from High-risk Injecting
reported mephedrone use. Cathinone compounds
may directly increase the risk of diabetic ketoacidosis
and Sexual Behaviour
by stimulating the central nervous system. They may Synthetic cathinones can be associated with frequent
also indirectly impair an individual’s ability to man- and compulsive injecting, increasing the risk of blood-
age diabetes through changes in cognitive function borne infections as well as systemic and bacterial
and behaviour.197 infections.
As with other ‘traditional’ psychostimulants, syn- Injecting synthetic cathinones has been
thetic cathinones appear to be linked to neurocogni- a challenge for some countries, notably Hungary and
tive dysfunction and cytotoxicity (toxicity to cells), Romania, where it seems to be widespread among
which are dependent on drug type, dose, frequency, injecting drug users.251,252,253,254
and time after use.198 Synthetic cathinones may be The injection of synthetic cathinones has been
associated with enhanced neurotoxicity in compari- linked with increased transmission of HIV and hepa-
son to traditional stimulants.199–215 There is emerging titis C in many countries in Europe, including
evidence that when intoxicated, mephedrone use can Hungary, Ireland and the UK; in Greece and
impair working memory acutely119 and a case report Romania, the injection of these substances was iden-
of catatonia.216 tified in 2012 as a possible factor linked to outbreaks
A wide spectrum of psychiatric effects of synthetic of HIV infection.255
cathinones has been described. As with other stimu- The limited research describing this practice
lants, these affect in particular, but not exclusively, strongly suggests its potential for unpleasant side-
people with mental health co-morbidities. The most effects. Intravenous users of mephedrone report para-
commonly reported are agitation, insomnia, impaired citosis (leading to scratching and gouging of the skin
concentration, transient paranoid and perceptual dis- of the face, neck and arms in particular), paranoia,
turbances, anxiety, temporary mood disturbances, suicidal ideation and severe insomnia, especially after
andalso delirium.217,218,219 Repeated use of synthetic prolonged use.117
cathinones is associated with paranoia and In a small qualitative Irish study, participants
hallucinations.220 reported unwanted effects which included intense
Psychosis and suicidality have also been paranoia, violent behaviour and aggression, and the
reported,221,222,223 with studies on ‘bath salts’ describ- emergence of Parkinson-type symptoms, in the form
ing psychotic symptoms and ‘bath-salt’-induced of spasm, ‘wobbling’ and permanent numbness in the
psychosis,224,225,226,227 similar to other cathinones, extremities. Injectors also report intense burning sen-
such as pentedrone.228 sations at injection sites, limb abscesses, and vein
It is not possible to quantify accurately how com- clotting, damage and recession. These result from
mon these presentations are. A US case series of 35 drug toxicity, crystallisation of the drug when diluted
patients presenting at an emergency department and syringe flushing practices. They also report multi-
with toxicity relating to synthetic cathinones drug and serial drug injecting. Heroin is used in an
reported that: attempt to manage the intense ‘rush’ and avoid an
unpleasant come-down from mephedrone.78
• 91% had neurological symptoms;
As with other club drugs, mephedrone use has
• 77% had cardiovascular symptoms;
been linked to high-risk sexual behaviours among
• 49% had psychological symptoms.177 heterosexual men and men who have sex with
250
11.10 Management of Acute Harms
men.86,137 There is some anecdotal evidence of There are numerous reports of deaths where
mephedrone injecting among MSM in London synthetic cathinones were implicated. This includes,
(referred to as ‘slamming’), sometimes in combin- but is not limited to, deaths where mephedrone was
ation with methamphetamine and injecting behav- implicated,250 as well as MDPV,264 alpha-PVP,265
iours that put users at high risk of HIV and N-ethylpentylone,266 α-propyloaminopentiophe-
hepatitis.110 none,267 n-Ethyl pentylone (NEP),268 α-pyrrolidino-
heptiophenone (PV8)269 and pentedrone and
a-pyrrolidinovalerophenone.270
11.9.3 Acute Withdrawal It has been shown by one study on deaths where
For withdrawal see Section 11.12.2. mephedrone was implicated that most deaths occurred
when more than one substance was ingested, and espe-
11.9.4 Poly-drug Use and Drug Interaction cially when alcohol was one of these.250 Nonetheless, in
The co-ingestion of other substances alongside syn- a small number of cases, death was directly related to
thetic cathinones appears to increase harm. mephedrone on its own, which confirms the concerns
For example, the reports of many mephedrone- regarding the acute toxicity potential of the drug
associated deaths in the UK indicate poly-drug use.256 itself.250 In the same study, Schifanno et al. found that
Alcohol in particular may potentiate the effects of factors associated with mephedrone-associated death
mephedrone.257,258 were young age (mean age 29 years), male and previous
A two-patient case study found that large quan- history of substance misuse.250
tities of alcohol ingested with mephedrone may lead
to serious cardiac arrhythmias.259 The co-ingestion of 11.10 Management of Acute Harms
two stimulants is likely to increase mephedrone tox-
icity, as well as its potential harm,90 including the risk
of serotonin syndrome or toxicity (see Chapter 8 and
11.10.1 Identification and Assessment
Section 9.14 ). of Mephedrone Toxicity
An animal study found that mephedrone Toxicological screening is not usually carried out
enhances the neurotoxicity of methamphetamine, for patients presenting to emergency departments
amphetamine and MDMA, substances that are com- with harms associated with synthetic cathinones
monly used alongside mephedrone.260 There is also because the results are typically not available in
one reported death resulting from a combination of time to inform the patient’s management. It is
GHB and mephedrone, albeit with no analytical con- recommended that diagnosis is made on clinical
firmation of the substances used.261 assessment, with other causes of presentation
As CYP2D6 and CYP3A4 may be involved in excluded and recognition of the associated clinical
mephedrone metabolism, inhibitors of these meta- toxidrome.
bolic enzymes could increase the systemic exposure It is not possible to determine accurately the num-
to mephedrone and lead to increased toxicity. In bers of presentations to hospital associated with mephe-
terms of HIV treatment medications, among the anti- drone toxicity or indeed admissions resulting from the
retroviral drugs, these would be ritonavir (a CYP3A4 use of any recreational drug, not least because presenta-
inhibitor at low boosting doses) and cobicistat (a tions with acute toxicity are assigned a wide variety of
CYP3A4 and CYP2D6 inhibitor). The role of ritona- primary codes, which are likely to relate to symptoms
vir’s inducing effect on glucuronidation and its rather than cause.271 In addition, synthetic cathinones
impact on mephedrone exposure remains unclear. are also often used as part of a wider repertoire of drug
Care should also be given to the prescribing of use and thus effects may be due to other substances.117
medications with serotonergic effects. Two case series of presentations to an emergency
department (ED) for acute mephedrone toxicity provide
11.9.5 Mortality some insight. In a study of 89 cases in the ED of
Deaths associated with a range of synthetic cathinones Aberdeen Royal Infirmary, self-reports suggested that
have been reported. The medical literature presents 33% had ingested mephedrone only, 30% mephedrone
numerous fatal case reports associated with the range and alcohol, and 35% co-ingestion of other
of synthetic cathinones.262,263 substances.272
251
11.10.2 Management of Acute Toxicity ward; the other 15.3% were admitted to hospital, with
11.1% admitted for observation/management on
There are no large robust studies that have looked at
a general internal medicine ward, and 4.2% required
the management of acute synthetic cathinone intoxi-
admission to intensive care. Overall, 13.9% required
cation, but there is consistency from case series and
benzodiazepines (oral or intravenous) for ongoing
reports that treatment should consist of symptom-
agitation at, or after, presentation to the hospital. All
directed supportive care. It has been argued that,
but one patient were discharged with no long-term
given the similarities with cocaine and amphetamine,
sequelae at the time of discharge. The length of stay
management strategies similar to those recommended
following presentation ranged from 0.3 to 30 hours (a
for intoxication with those drugs might be useful.180
mean of 6.7 hours, SD 7.3 hours).96
Symptom-directed supportive care for acute
stimulant intoxication may include the management
of agitation, convulsions, metabolic acidosis, hyper- 11.10.4 Management of Acute
tension, hypothermia and rhabdomyolysis. The man- Withdrawal
agement of serotonin syndrome may also be See section 11.12.2.
indicated.
It also suggests that agitated adults be sedated with
an initial dose of oral or intravenous diazepam (0.1–
11.11 Harms Associated with Chronic
0.3 mg/kg body weight). Larger doses may be Use
required.
For agitation and psychiatric symptoms associated 11.11.1 Dependence
with mephedrone, the use of benzodiazepine is com-
There is some evidence that mephedrone has
monly reported. Case reports described the use of
a dependence potential. It has been argued that the
antidepressants, hypnotic-sedatives including mida-
ability of mephedrone to cause striatal dopamine
zolam, lorazepam, diazepam, and etomidate given
release may be problematic inasmuch as, in compari-
for agitation.273 One report described lorazepam as
son with MDMA, mephedrone may have an enhanced
effective for agitation and various sympathomimetic
liability to misuse, more resembling that of dopa-
features of mephedrone use.114
mine-releasing agents such as methamphetamine.35
Case studies have reported the use of propofol,
One animal study suggests that the dopaminergic
haloperidol, as well as quetiapine and other anti-
effects of mephedrone may contribute to its addictive
psychotics for paranoid ideation, agitation and
potential.277
anxiety.90,274 Antipsychotics should be used cau-
It has been suggested that, because of the similar-
tiously with synthetic cathinone intoxication, as they
ity of synthetic cathinones to amphetamine, they
increase seizure activity275 and decrease heat
carry a similar risk of dependence, with chronic use
dissipation.
leading to dependence and a cycle of bingeing and
periods of recovery associated with depression.44
11.10.3 Treatment Outcome Cases of dependence have been reported.86,278 In
A study looking into pharmacological treatment in a Scottish school survey, 17.6% of those who had
acute hospital settings of 201 analytically confirmed used mephedrone reported ‘addiction/dependency’
MDPV-positive patients reported that medication symptoms relating to their use of mephedrone.141
used primarily included benzodiazepines, haloperidol Similarly, a survey of 797 clubbers who had used
and propofol (n = 16; 8%). Only seven (4%) patients mephedrone reported that it was ‘as or more addict-
required intubation. The number of days in hospital ive’ than cocaine.113 In another survey, 50% of
care was 1 day for 76 (40%) patients, 2 days for 79 1,500mephedrone users considered it to be
(42%) patients, and 3 days for 21 (11%) patients.276 addictive.84
People who present to hospitals generally make MDPV is also associated with a risk of harmful and
a good recovery. The majority (84.7%) of the 72 dependent use,279 with associated health care utilisation
patients presenting to hospital with acute toxicity and social costs.280 It has also been shown that the regular
described in one case series96 were discharged either use of α-PVP may lead to dependence, tolerance and
directly from the ED or from a short-stay observation withdrawal syndrome.281,282,283,284,285,286,287,288,289,290
252
Box 11.9 ICD-11 6C47.2 Synthetic Cathinone difficulties, feelings of fear and anxiety, irritability,
Dependence292 tiredness, insomnia, and, in some cases, cravings fol-
lowed in response to compulsive drug use.294,295
Synthetic cathinone dependence is a disorder of
regulation of synthetic cathinone use arising from
repeated or continuous use of synthetic cathinones. 11.11.2 Withdrawal
The characteristic feature is a strong internal drive to Reports have been published of craving for mephe-
use synthetic cathinones, which is manifested by drone and of withdrawal.55,93,141 There are users’
impaired ability to control use, increasing priority reports that the development of cravings for mephe-
given to use over other activities and persistence of drone may be linked to increased frequency of use.113
use despite harm or negative consequences. A survey of users also suggested that those who
These experiences are often accompanied by
ingested the drug through nasal insufflation were
a subjective sensation of urge or craving to use
more likely than those who used it orally to rate it as
synthetic cathinones. Physiological features of
dependence may also be present, including more addictive than cocaine,113 possibly reflecting the
tolerance to the effects of synthetic cathinones, more rapid onset and shorter duration of desired
withdrawal symptoms following cessation or effects of mephedrone when it is used nasally.
reduction in use of synthetic cathinones, or repeated Craving for mephedrone has been described as
use of synthetic cathinones or pharmacologically stronger than for ecstasy.57
similar substances to prevent or alleviate withdrawal Studies have shown that unpleasant physical and
symptoms. The features of dependence are usually mental symptoms may be experienced when going
evident over a period of at least 12 months but the through withdrawal from synthetic cathinones. They
diagnosis may be made if synthetic cathinone use is have not described a physical withdrawal syndrome
continuous (daily or almost daily) for at least 1
following the abrupt stopping of chronic use of syn-
month.
thetic cathinones, but psychological dependency is
possible. Reported symptoms include anxiety and
depression, craving, anhedonia, anergia and insomnia
α-PVP appears to give rise to extreme craving and risk of associated with mephedrone, methcathinone and
binge consumption and it seems that it has abuse liability MDPV for example.296
and possibly a dependency potential in humans.291 A study of 100 users suggested that the most
Diagnostic criteria for dependence on synthetic frequent effects related to withdrawal after a session
cathinones have been described by IDC-11 (see of mephedrone use were tiredness, insomnia, nasal
Box 11.9). congestion and impaired concentration. Other with-
There is increasing evidence that mephedrone drawal symptoms include depression, anxiety,
causes a strong and repeated compulsion to increased appetite, irritability, unusual sweat odours
use,57,141 that tolerance to mephedrone develops and urge or craving to use.86
quickly and that users tend to consume higher There may be some differences between the vari-
doses more frequently. Subjective reports of crav- ous synthetic cathinones, but more research is needed.
ing suggest that mephedrone may have a greater For example, Van Hout (2014) noted that 4-MEC
potential for repetitive and compulsive use than users did not report withdrawal symptoms akin to
MDMA,57,84,141 although these observations are those of mephedrone.297 Mephedrone was described
made on the basis of self-reports. Emerging evi- by a frequent and heavy user in a case report as
dence on the subjective effects of mephedrone sug- providing a more intense initial euphoria and
gests that its ingestion is associated with ‘wanting a more severe withdrawal syndrome than MDPV.298
more’,57,86,119 and this was shown to be elevated In this case report, the user, who also reported
significantly when users were sober but anticipated a history of opiate and methamphetamine use,
use in the near future.119 reported mephedrone withdrawal as the most
The development of substance use disorder symp- unpleasant drug withdrawal he had experienced. He
toms associated with synthetic cathinones, such as reported that discontinuation of mephedrone resulted
tolerance, have been described,293 as well as within agitation and dysphoria within a few hours, which
drawal after repeated use. The withdrawal symptoms was more severe than that of cocaine or metham-
reported include depression, concentration phetamine, and which was accompanied by an
253
increase in muscle tone, the alleviation of which in a case report of dependence on mephedrone (diag-
required constant movement.293 He reported that nosis based on ICD-10 criteria) and where depend-
only methamphetamine gave some degree of relief to ence had led to psychotic symptoms. Another case
the withdrawal.293 report described a patient prescribed antidepressants
for residual symptoms of depressed mood, anhedonia
11.11.3 Other Harms and hopelessness present in all his periods of
abstinence.293 A further case report described
11.11.3.1 Risk of Systemic and Viral Infections a pharmacological intervention for MPDV with-
drawal involving risperidone, which was effective for
Like other club drugs, the impact of mephedrone on
symptoms of disorganisation, delusions and
sexual behaviour can affect the transmission of blood-
hallucinations.301
borne viruses and sexually transmitted infections.137
Moreover, mephedrone is associated with compulsive
and frequent injecting, making its users at particular 11.12.3 Aftercare and Support
risk of the acquisition and transmission of blood- As is the case with many people who use drugs in
borne viruses. To this are added the risks specifically general, some people who use synthetic cathionones
linked to the injection of mephedrone, which can will sometimes use harm reduction strategies to min-
include limb abscesses and vein clotting, damage imise risk. For example, 3-MMC users in Slovenia
and recession. This places injectors at risk of septicae- report obtaining information beforehand, using
mia, endocarditis, deep-vein thrombosis and other their own injecting equipment and paraphernalia
complications. and using only small quantities of unknown
substances.302
11.12 Management of Harms Related
to Chronic Use and Dependence 11.12.4 Public Health and Harm
Reduction
11.12.1 Clinical Management of Chronic Winstock et al. recommend as harm reduction116:
• Avoiding using regularly to prevent developing
Use and Dependence tolerance;
See Chapter 8 on the identification and assessment of • Not using with stimulants or large amounts of
dependence on ATS in general (Section 8.10.1), which alcohol and/or other depressants;
apply to mephedrone, as does the guidance on psy-
• Not injecting;
chosocial and pharmacological support and interven-
• Avoiding dehydration;
tion (Chapter 2 and Section 8.10.3).
• Avoiding overheating.
See also Chapter 8.
11.12.2 Management of Withdrawal
Psychosocial interventions constitute the main inter-
ventions for dependence on synthetic cathinones, as
11.12.5 Public Safety: Driving
with other stimulants as discussed in Chapter 2. Mephedrone can affect driving inasmuch as it can
Ongoing psychological support may be required, produce poor concentration, hallucinations and
including for the prevention of relapse.117 psychosis.303
There are no recognised pharmacological regi-
mens for the management of synthetic cathinone
withdrawal, as with other stimulants (also see References
Chapter 8, Section 8.14.3.2). Some have suggested 1. Warfa N, Klein A, Bhui K, Leavey G, Craig T, Alfred
bupropion,299,300 but more research is needed. Stansfeld S. Khat use and mental illness: a critical review. Soc
Sci Med 2007;65(2):309–318.
Nonetheless, patients may require medical treat-
ment for their symptoms on discontinuation. Reports 2. World Drug Report 2019 (United Nations publication, Sales
No. E.19.XI.9)
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265
Part IV Drugs with Primarily Hallucinogenic Effects
Chapter
Hallucinogenic Drugs
12
12.1 Introduction receptor agonists, and therefore ultimately produce
altered perceptions of reality and synaesthesia.7,8
Hallucinogens are drugs that distort the way a user
They have been traditionally classified by either their
perceives time, motion, colour, sounds and self.
primary mechanism of action or by chemical groups,
The varied perceptual distortions caused by such
including:
drugs do not strictly correspond to clinical definitions
of ‘hallucinations’ (perceptions in the absence of exter- • tryptamines (e.g., psilocin and N,
nal stimuli that are experienced as if they were real, as N-dimethyltryptamine/ DMT);
seen in psychoses and delirium).1,2 Therefore, alterna- • ergolines (lysergic acid diethylamide/LSD); and
tive terms, such as ‘illusions’, ‘pseudo-hallucinations’ • phenethylamines (e.g., mescaline, 2CB series).9
and ‘perceptual distortions’ have also been employed.3 In recent years, new drugs with primarily hallucino-
Some authors have suggested that the term ‘psy- genic effects from all of these chemical groups have
chedelic’ should replace terms like ‘classical hallu- been synthesised and have emerged in the recreational
cinogen’ to describe drugs such as LSD and drug market, with claims to be the next-generation
psilocybin,4 but it has also been argued that this designer drugs, or with claims to replace or to be the
term carries disadvantages because of its cultural con- ‘legal’ alternatives of existing hallucinogenic drugs
notations of a style of music and art associated with such as LSD, for example.
Western counter-culture in the 1960s. These include, for example, the tryptamines
Other terms used for drugs with hallucinogenic alpha-methyltryptamine (AMT); 5-methoxy-N,
effects include ‘psychomimetic’, a term previously N-dimethyltryptamine (5-MeO-DMT) and 5-meth-
used to emphasise effects that resemble the symptoms oxy-N,N-diisopropyltryptamine (5-MeO-DIPT)10
of psychosis, and the term ‘entheogen’, which empha- and new phenethylamines, including the 2C-
sises the mystical-type experiences the drugs are said series and its structural analogues, such as
to promote. However, these terms have also been N-benzylphenethylamines (NBOMes).11 For more
criticised, as they highlight only a single aspect of information see Table 12.1.
a much broader range of hallucinogenic effects.5 As with other novel psychoactive substances (NPS),
Based on their mechanism of action in the human new generations of hallucinogenics have emerged over
central nervous system, hallucinogenic drugs in gen- time,12 in some cases exhibiting much potency and
eral can be divided into two main groups: classic potentially increased adverse effects. For example, 2C-B
hallucinogens and dissociative or anaesthetic appeared on the drug market in the mid-1980s and its
hallucinogens,6 with the latter including ketamine more recent derivative 2-(4-bromo-2,5-dimethoxyphe-
and its analogues discussed in Chapter 6. nyl)- N-(2-methoxybenzyl)ethanamine (25B-NBOMe)
This chapter will use the term ‘hallucinogen’ to is highly potent even at microgram-level doses.13
refer only to the classic hallucinogens: drugs with Similarly, other NPS such as bromo-dragonfly are par-
a mechanism of action mediated primarily by agon- ticularly potent and long-lasting.14
ism of the 5HT2A serotonin receptor. LSD (N,
N-diethyl-D-lysergamide) and psilocybin are the 12.2 Legal Status
prototypical and most prevalent drugs of this class. The status of control for different hallucinogens,
Classic or serotonergic hallucinogens fall into sev- including NPS with hallucinogenic effects, varies:
eral chemically related groups. They act as serotonin most of the common hallucinogens are controlled
267
Part IV Drugs with Primarily Hallucinogenic Effects
Chapter
12
12.1 Introduction receptor agonists, and therefore ultimately produce
altered perceptions of reality and synaesthesia.7,8
Hallucinogens are drugs that distort the way a user
They have been traditionally classified by either their
perceives time, motion, colour, sounds and self.
primary mechanism of action or by chemical groups,
The varied perceptual distortions caused by such
including:
drugs do not strictly correspond to clinical definitions
of ‘hallucinations’ (perceptions in the absence of exter- • tryptamines (e.g., psilocin and N,
nal stimuli that are experienced as if they were real, as N-dimethyltryptamine/ DMT);
seen in psychoses and delirium).1,2 Therefore, alterna- • ergolines (lysergic acid diethylamide/LSD); and
tive terms, such as ‘illusions’, ‘pseudo-hallucinations’ • phenethylamines (e.g., mescaline, 2CB series).9
and ‘perceptual distortions’ have also been employed.3 In recent years, new drugs with primarily hallucino-
Some authors have suggested that the term ‘psy- genic effects from all of these chemical groups have
chedelic’ should replace terms like ‘classical hallu- been synthesised and have emerged in the recreational
cinogen’ to describe drugs such as LSD and drug market, with claims to be the next-generation
psilocybin,4 but it has also been argued that this designer drugs, or with claims to replace or to be the
term carries disadvantages because of its cultural con- ‘legal’ alternatives of existing hallucinogenic drugs
notations of a style of music and art associated with such as LSD, for example.
Western counter-culture in the 1960s. These include, for example, the tryptamines
Other terms used for drugs with hallucinogenic alpha-methyltryptamine (AMT); 5-methoxy-N,
effects include ‘psychomimetic’, a term previously N-dimethyltryptamine (5-MeO-DMT) and 5-meth-
used to emphasise effects that resemble the symptoms oxy-N,N-diisopropyltryptamine (5-MeO-DIPT)10
of psychosis, and the term ‘entheogen’, which empha- and new phenethylamines, including the 2C-
sises the mystical-type experiences the drugs are said series and its structural analogues, such as
to promote. However, these terms have also been N-benzylphenethylamines (NBOMes).11 For more
criticised, as they highlight only a single aspect of information see Table 12.1.
a much broader range of hallucinogenic effects.5 As with other novel psychoactive substances (NPS),
Based on their mechanism of action in the human new generations of hallucinogenics have emerged over
central nervous system, hallucinogenic drugs in gen- time,12 in some cases exhibiting much potency and
eral can be divided into two main groups: classic potentially increased adverse effects. For example, 2C-B
hallucinogens and dissociative or anaesthetic appeared on the drug market in the mid-1980s and its
hallucinogens,6 with the latter including ketamine more recent derivative 2-(4-bromo-2,5-dimethoxyphe-
and its analogues discussed in Chapter 6. nyl)- N-(2-methoxybenzyl)ethanamine (25B-NBOMe)
This chapter will use the term ‘hallucinogen’ to is highly potent even at microgram-level doses.13
refer only to the classic hallucinogens: drugs with Similarly, other NPS such as bromo-dragonfly are par-
a mechanism of action mediated primarily by agon- ticularly potent and long-lasting.14
ism of the 5HT2A serotonin receptor. LSD (N,
N-diethyl-D-lysergamide) and psilocybin are the 12.2 Legal Status
prototypical and most prevalent drugs of this class. The status of control for different hallucinogens,
Classic or serotonergic hallucinogens fall into sev- including NPS with hallucinogenic effects, varies:
eral chemically related groups. They act as serotonin most of the common hallucinogens are controlled
267
Table 12.1 Hallucinogenic drugs used for recreational purposes
Lysergamides
• (6aR,9 R)-N,N-diethyl-7-methyl4,6,6a,7,8,9-hexahydroindolo-[4,3-fg]quinoline-9-carboxamide (N,N-diethyl-D-lysergamide)
LSD27
• (8β)-9,10-didehydro-6-methylergoline-8-carboxamide LSA (ergine)
• (6aR,9 R)-4-acetyl-N,Ndiethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide9 (1-acetyl-N,
N-diethyllysergamide) ALD-5228
• (6aR,9 R)-N,N-diethyl-7-ethyl4,6,6a,7,8,9-hexahydroindolo-[4,3-fg]quinoline-9-carboxamide (6-ethyl-6-nor-lysergic
aciddiethylamide) ETH-LAD28
• (8β)-N,N-Diethyl-6-propyl-9,10-didehydroergoline-8-carboxamide(6-propyl- 6-nor- Lysergic acid diethylamide) PRO-LAD28
• 6-allyl-6-nor-lysergic acid diethylamide AL-LAD28
• (8β)-8-{[(2S,4S)-2,4-Dimethylazetidin-1-yl]carbonyl}-6-methyl-9,10-didehydroergoline (lysergic acid 2,4-dimethylazetidide)
LSZ28
Lysergamide NPS Summary

Some novel LSD derivatives have recently reached the market, such as those listed above. They produce effects resembling those of
LSD, having similar pharmacological action at 5-HT2A-receptors, but possessing different potencies, onset and duration of effects.29
For example, LSZ was synthesised as an analogue of LSD. We know little about it, but it was found that the S isomer of LSZ was slightly
more potent than LSD itself and showed greater binding affinity to 5-HTA receptors in rats.30
A more recent NPS is 1-P-LSD (1-propionyl-d-lysergic acid diethylamide hemitartrate),31 which seems to have been developed as an
alternative to LSZ, after it was banned. 1PLSD is also believed to be slightly more potent than its parent drug and more potent than
LSZ.32
Tryptamines
Tryptamine NPS include
• O-phosphoryl-4-hydroxy-N,Ndimethyltryptamine 4-hydroxy-N,N-dimethyltryptamine Psilocybin
• N,N-dimethyltryptamine DMT
• alpha-methyltryptamine αMT ‘AMT’28
• N,N-diallyl-5-methoxytryptamine 5-MeO-DALT
• N,N-diisopropyltryptamine DiPT (sometimes known as‘Foxy’)
• 5-methoxy-N,N-diisopropyltryptamine 5-MeO-DiPT (sometimes known as‘Foxy Methoxy’)
Tryptamine NPS Summary

Tryptamines are hallucinogenic drugs that act primarily as agonists of the serotonergic receptor 5-HT2A, but their action may also be
modulated by interactions with other targets, including other 5-HT receptors, monoamine transporters, and trace amine-associated
receptors.33
Tryptamines require low doses to produce changes in perception, mood, and thought. The effects of tryptamine NPS are
expected to be similar to those of the legally controlled tryptamines, such as psilocybin or DMT. However, information
available suggests that there may be significant differences with traditional drugs as well as among the various tryptamine
NPS.
For example, 5-methoxy group, such as in 5-MeOAMT, 5-MeO-AMT and α-MT seem to have d increased potency, compared to
psilocybin and DMT which produce hallucinogenic effects with relatively low potency.34
A study of the receptor interaction profiles of the tryptamine NPS (DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT) also
suggested that hallucinogenic effects are similar to classic serotonergic hallucinogens, but that they also possessed MDMA-like
psychoactive properties.35
Some NPS, such as 5-MeO-AMT, also have structural similarity to the amphetamines. 5-MeO-AMT produces a strong binding activity at
5-HT1A and 5- HT2A receptors, whilst inhibiting monoamines’ reuptake. It is associated with a range of sympathomimetic effects.36
AMT and AET have also been found to possess central stimulant as well as hallucinogenic properties.37
Phenethylamines
The classic hallucinogenic phenethylamine is 3,4,5-trimethoxyphenethylamine, which is also known as Mescaline.
Phenethylamine NPS include:
• 2C Series, and their derivatives 2C-B has various close analogues; bk-2C-B, and 25B-NBOMe. The same selection of analogues may
exist for the rest of the 2C series, e.g. 2C-E, 2C-I, 2C-T-7.
• Hallucinogenic amphetamines, DOx series and their derivatives DOM, DOI, DOB, TMA-2.
• Tetrahydrodifranyl compounds 10 2C-B-FLY, ‘bromodragonfly’. They are called ‘FLY’ because their molecular structure resembles
the insect.17
Phenethylamines Summary
Phenethylamines include a wide range of natural or synthetic substances which have psychostimulant, empathogenic and
hallucinogenic effects. They include several potent hallucinogenics that exert their effects through interactions with the serotonergic
5- hydroxytryptamine 2 (5-HT2) receptor site.
268
Table 12.1 (cont.)

Benzofurans, which are phenethylamines structurally related to MDMA and MDA (3,4-methylenedioxyamphetamine), include several
compounds, e.g.: 6- APB (6-(2-aminopropyl) benzofuran; aka ‘BenzoFury’); 5-APB (s (5-(2- aminopropyl)benzofuran); 6-APDB
(6-(2-Aminopropyl)-2,3-dihydrobenzofuran; aka ‘4-Desoxy-MDA’); 5-APDB (5-(2-Aminopropyl)-2,3-dihydrobenzofuran; aka ‘3-Desoxy-
MDA’); etc. They are typically ingested, since nasal insufflation may be painful.38
Phenethylamine NPS derivatives include ‘Bromodragonfly’, NBOMe derivatives; indanes; benzofurans; and the class of 2C- molecules
such (2C-B), (2C-I); (2C-E).
It has been shown that substances such as Bromo-Dragonfly (aka ‘DOB-Dragonfly’/‘3C-Bromo-Dragonfly’ displays a high affinity for
5-HT2A, 5-HT2B, and 5-HT2C receptors and effects include long-standing hallucinations, mood elevation, paranoid ideation,
confusion, anxiety and flashbacks.39
The 2C-series, 2C drugs are a subfamily of substituted phenethylamines, with hallucinogenic and psychostimulant properties.40 Over the
last decade 2C-B has gained popularity among electronic music party goers as the replacement of choice for MDMA and LSD, either
alone or combined.41,42,43
Preclinical studies have demonstrated that 2C-drugs inhibit the norepinephrine (NE) and serotonin transporters (NET and SERT,
respectively) with very low potency in comparison to amphetamines.
Like other hallucinogenic phenethylamines, 2C-series is a partial agonist of 5HT2A, 5HT2B, and 5HT2C receptors, although some studies
have reported it may act as a 5HT2A full antagonist.44 They also display low-affinity binding to D2 receptors and a low inhibitory
activity to monoamine transporters.45 In addition to 5-HT2A effects, some 2C agents can inhibit the reuptake of dopamine,
norepinephrine, and serotonin.46
All 2C compounds are capable of producing clinical effects at doses as low as 50 μg. Affinity for these receptors generally correlates with
the hallucinogenic properties of the drug.47
It appears that NBOMe compounds, which are derivatives of the 2C series, exhibit even higher 5-HT2A potency than the parent 2C class,
and there is some evidence from in-vitro receptor studies that NBOMe compounds act as potent full agonists at the 5-HT2A and
5-HT2C receptors.48,49 Their higher 5-HT2A receptor affinity, compared to the 2C- derivatives, is associated with hallucinations and
delusions.50
NBOMe are pharmacologically active at very low, sub-milligram, doses.51,52 It has been suggested that NBOMe are similar to classic
hallucinogens like LSD, although they do not possess LSD’s affinity for 5-HT1A receptors.53 Their potency is reportedly in the same
range as that for LSD.54
NBOMEs also possess sympathomimetic properties, which may be linked to their activity at adrenergic receptors.55 They also have
affinity for dopaminergic, and histaminergic receptors, as well as monoamine transporters.56,57
under the Convention on Psychotropic Substances of these skeletons for them to be more usefully con-
1971, although some NPS synthetic hallucinogens are sidered a distinct class of hallucinogenic.2 Some
not currently under international control.15 hallucinogenic NPS, such as the ‘Fly’ series, are less
easy to classify, because they are fairly distant struc-
12.3 Quality of Research Evidence tural analogues of their phenethylamine parent
compound.17
The international evidence on the clinical manage-
The common denominator in the pharmacol-
ment of the harms related to the use of hallucino-
ogy of true hallucinogenic drugs is agonism or
gens remains limited. The bulk of it focuses on
partial agonism of 5-HT2 serotonin receptors,2
LSD and psilocybin, although research on the clin-
particularly 5-HT2A and/or other 5-HT2
ical management of harms of even these sub-
receptors.18 This activity is of central importance
stances is limited. Very little has been published
to their characteristic hallucinogenic effects.18
about other hallucinogenic drugs, with evidence
Hallucinogenic drugs interact with an array of
limited to case reports and series of patients with
other sites too, contributing to the psychophar-
acute toxicity.
macological and behavioural effects.18,19,20
A recent study looking at the hallucinogenic drug
12.4 Brief Summary of Pharmacology DMT, a tryptamine, suggests that it may be an
Structurally, most hallucinogens can be roughly div- endogenous ligand for the sigma-1 receptor in
ided into tryptamines, phenethylamines and lyserga- humans. This suggests the need to look beyond
mides (LSD-like structures), as shown in table 12.1 the serotonin system for a complete understanding
below.2,16 LSD and other lysergamides share of the pharmacology of tryptamines.21
a complex molecular structure with both tryptamine Understanding of hallucinogenic drugs is still
and phenethylamine backbones. However, lyserga- very limited. It is assumed that qualitative differ-
mide structures are sufficiently elaborated from ences in the subjective phenomenology of the drugs
269
may relate to their individual affinity profiles.19 In and MEM are highly selective for 5-HT2
a recent study, psilocybin, the prototypical hallu- receptors.19
cinogenic tryptamine, has been shown to reduce
apparent activity in hub regions, and to uncouple
synchronised activity in the posterior cingulate cor-
12.5 Clinical Uses
tex and the medial prefrontal cortex.22 This sup- There are currently no hallucinogenic drugs that are
pression of orderly and regulated patterns of licensed for clinical use, and many of the compounds,
activity between different brain areas has been including LSD and psilocybin, are restricted as
interpreted as allowing for the relatively uncon- Schedule 1 substances.
strained patterns of cognition, with abnormal inte- Some research on the clinical use of hallucino-
gration of sensory information, that seem to gens was carried out in the 1950s, 1960s and
characterise the ‘psychedelic state’.22 More research 1970s. A meta-analysis of early randomised con-
is needed. trolled trials of LSD for alcoholism showed that
The structure–activity relationships of hallucino- a single application of LSD in a variety of treat-
gens are complex, and differ between the various ment modalities reduced alcohol intake or main-
drugs. This means that hallucinogen NPS appearing tained abstinence at rates which compare
on the market may be structurally similar to other favourably to mainstream treatment with naltrex-
NPS, or to other well-known hallucinogenic drugs, but one and acamprosate.58
may have different levels of potency, effects, duration of Some clinical research involving the adminis-
effects and risks. tration of classical hallucinogens is currently tak-
For example, the phenethylamines 2C-B and ing place.59,60,61,62 This includes small pilot studies
bk-2C-B 28 differ only by the addition of looking at the utility of LSD63 and psilocybin64 for
a ketone group, but some reports suggest that the treating anxiety associated with life-threatening
latter drug has a significantly longer duration of diseases. Psilocybin has also been trialled in nine
effect, with the peak lasting in some instances for people with obsessive-compulsive disorder, all of
10 to 14 hours.23 The duration of the effects of whom experienced improvement in symptoms,
5-methoxy-N,N-diisopropyltryptamine (5-MeO- mostly short-lived, but with one experiencing full,
DiPT, foxy methoxy) is seven times greater than lasting remission.65 Another trial has been
that for N,N-diisopropyltryptamine (DiPT or approved for testing psilocybin in treatment-
‘Foxy’).24 resistant depression.
Bromo-dragonfly is a distant derivative from the There is increasing interest in, and studies of,
core phenethylamine structure, with a potency similar therapeutic use of hallucinogens in a controlled
to that of LSD, but has a far longer duration of effect setting,59–62,66 including for treatment-resistant
(1–3 days) and apparently has greater toxicity.17 In depression67,68,69,70,71 anxiety and depression in
terms of acute toxicity, within the 2C family, 2-CB has life-threatening illnesses4,72,73,74,75,76 and in pal-
not been associated with any fatalities, whereas there liative care77 and as a treatment for alcohol
are reports from the US of deaths in which 2C-T-7 has dependence,78 smoking cessation.79 The need for
been implicated.25 more research on the role of classic hallucinogens
Some hallucinogens have strong stimulant in the treatment of addictions has been
effects. For example, αMT is a tryptamine, with emphasised.80,81 It is argued that clinical research
a methyl group in the alpha position, just like an has shown them to be safe when appropriate
amphetamine, and has marked stimulant effects, precautions are taken.82 Research is at an early
seen in clinical observations.26 On the other stage and more evidence is needed before recom-
hand, some phenethylamines, which are amphet- mendations can be made.
amine-type substances, are also hallucinogenic
drugs. These include ring-substituted substances, 12.6 Prevalence and Patterns of Use
such as the ‘2C series’ and the ‘D series’ (e.g. At a global level, the 2019 World Drug Report has
DOI, DOC), and benzodifurans (e.g. bromo- suggested that the quantities of substances with
dragonfly, 2C-B-Fly). Similarly, the phenethyla- hallucinogenic properties (other than ketamine)
mines DOB(2,5-dimethoxy-4-bromoamphetamine) seized globally have been fluctuating over time,
270
12.7 Routes of Ingestion and Frequency of Dosing
but have shown an upward trend in recent years. 12.7 Routes of Ingestion
This is in line with some information suggesting
an increase in use of such substances in recent and Frequency of Dosing
years.83 There are very marked differences between the vari-
In Europe, information on the prevalence of ous hallucinogenic drugs in terms of potency and
the use of hallucinogens relates mainly to ‘trad- type, onset and duration of effects.
itional’ rather than NPS hallucinogens. Available
data suggest that the overall prevalence of LSD and 12.7.1 Potency
hallucinogenic mushroom use has been generally The potency of a hallucinogenic substance appears to
low and stable for a number of years. Among be broadly, but not entirely, a function of its affinity
young adults (15–34 years), national surveys report for the 5-HT2A receptor.2,18 Substances with lower
last year prevalence estimates of less than 1% for affinity for the receptor, and lower potency, include
both substances in 2017 or the most recent year mescaline2 (typical oral dose approximately 0.25 g).
the survey was conducted. Exceptions are preva- LSD has a high affinity, and is the most commonly
lence estimates of Finland (1.9%) and used potent hallucinogenic substance (a typical dose
the Netherlands (1.6%) for hallucinogenic mush- may be 75–150 µg90).
rooms, and Norway (1.1%) and Finland (1.3%) for Over the years, very potent new hallucinogenic sub-
LSD.84 stances have emerged on the recreational market, such
Although limited, there is some increasing interest as the NBOMe series and bromo-dragonfly.91 The latter,
among some people in ‘micro-dosing’ hallucinogen. for example, has been described by users (on drug user
This is discussed in Box 12.1. websites) as ‘just too powerful’, due to its duration as
well as potency.17 This may have contributed to the fact
that some new drugs, such as bromo-dragonfly,
appeared on the market but then disappeared quickly.17
Box 12.1 Micro-dosing
For more information on NPS properties and dif-
‘Micro-dosing’ is a term used for a pattern of using ferences see Table 12.1.
hallucinogens that has been growing in popularity
and visibility.85 It refers to the use of a dose of 12.7.2 Onset of Effects and Duration
hallucinogenic drug that is too small to cause
intoxication or significant alteration of There are significant differences between hallucinogenic
consciousness. The intention is that micro-dosing substances in terms of the speed of the onset of effects
affects mood, health and cognition in positive ways, after ingestion, ranging from a few moments to hours.
while allowing the user to carry on with everyday The duration of the effect of hallucinogens also
activities.86 differs widely and can range from between minutes
People involved in miro-dosing argue that taking and days, depending on the substance used.
small amounts of psilocybin mushrooms, LSD or • Very short effects (e.g. DMT).92,93 Vaporised
mescaline enhances cognitive function, perception
DMT is an example of a very short-acting drug
and creativity and adds a new dimension to what
could be considered ‘illegal cognitive enhancement’.
with rapid onset.94 DMT’s effects appear in under
This reflects a new desired effect of hallucinogenic a minute and may peak within 5 minutes, with
drugs.87 minimal adverse after-effects (come-down).93,95
There is currently little evidence to draw upon Similarly, 5-MeO-DMT is associated with
regarding the benefits and harms of micro-dosing, experiences similar in intensity to those caused by
although studies are proposed.88 psilocybin, but with a much shorter duration of
The micro-dosing phenomenon has been action (half-life 12–19 minutes).96
spread most recently by the Internet, where • Intermediate duration of effects, (e.g. 2C-B, with
discussion fora enable users to share experiences effects lasting 2–3 hours97)
and exchange information in ways that make new
• Long duration of effects (e.g. LSD and mescaline
practices accessible for others. Its growing
visibility has been reflected in substantial recent are longer-acting hallucinogens and a duration of
media coverage.89 8–12 hours is common.98 LSZ has a duration of
271
action lasting from 7–10 hours. After effects can be 1970s; doses of above 100 µg/tab were then typical,
felt for up to 3 hours.99,100 but, by 2003, 30–40 µg/tab was more usual.109
• Very long duration of effects. Including DOM
and others in the DOx series, ibogaine, 2C-P and
bromo-dragonfly, have effects which have been
12.7.3 Modes of Ingestion
reported to last a day or longer, and in some cases Hallucinogens are typically ingested orally, or sublin-
can lead to exhaustion.17,98,101,102,103 AMT’s gually/buccally, often through small blotter paper
desired effects peak in 3–4 hours and last up to 12– portions or ‘tabs’, which are held in the mouth to
24 hours,104 1-P-LSD duration of action lasts up to allow absorption through the oral mucosa. Other
12 hours, with after-effects lasting up to 24 less common routes of administration include insuf-
hours.105 Bromo-dragonfly is a distant derivative flation, smoking, rectally and by injection26 (see also
from the core phenethylamine structure, with Boxes 12.2, 12.3 and 12.4).
a potency similar to that of LSD, but has a far As with other drugs, the route of administration of
longer duration of effect (1–3 days) and apparently hallucinogens may have an impact on effects, their
has greater toxicity.17 onset and duration. User reports suggest, for example,
that the effects of 25I-NBOMe last 6–8 hours when the
There are also differences between the onset of the
drug is taken sublingually or buccally, but only 4–6
effect of the various hallucinogenic drugs, including
hours when it is insufflated.
NPS. For example, onset of action of the tryptamine
DMT occur almost immediately whereas in the case of
the NPS, AET occurs within 30–90 minutes.106 User
reports suggest that maximal effects following inges- 12.7.4 Frequency of Use
tion of bromo-dragonfly may not be reached for up to Overall, bingeing is not reported with hallucinogen
6 hours after ingestion,107 posing a risk that users re- drugs, partly because once the effects begin to fade,
dose because of a mistaken belief that the first dose has subsequent doses usually do not produce further psy-
had no effect. choactive effects (tachyphylaxis)2 (see Section 12.13.1
The purity and quantity of the active compounds on dependence).
in a single dose and the reliability of hallucinogenic
drugs (in terms of being the drug users think they are
buying) varies between product and batches, contrib- Box 12.2 Tryptamines
uting risk to dose estimation. As with other drugs,
users will not know the strength of the product they Tryptamine derivatives are usually available as
are taking, or may not be ingesting the substance they capsules, tablets, powder and liquid formulations
and may be ingested, snorted, smoked or
intended to use, or think they are taking.
injected.110
Hallucinogen NPS have, on some occasions, been
NBOMe-containing products are usually
sold as LSD.108 available as tablets, capsules, powder, liquid, spray,
Some drugs can be more ‘reliable’ than others at and blotters. They are usually taken sublingually/
particular times and in different locations. For orally or via nasal insufflation.111 Injection
example, in a Spanish study, 99% of samples purport- (intravenous and intramuscular), rectal and smoking
ing to be 2C-B actually contained 2C-B (average for routes have also been reported.112,113
the four-year study period), a high reliability com- Salvia extracts and DMT are usually vaporised or
pared with 66.8% for MDMA, 86.3% for amphet- smoked. As DMT is inactive after oral administration
amines, 87.4% for cocaine, and 92.2% for unless combined with monoamine oxidase
ketamine.97 Similarly, there are differences between inhibitors (MAOIs), it is usually smoked, snorted, or
injected.114 However, it is interesting to note that
different batches for the same product; for example,
capsules, known as pharmahuasca, have become
bromo-dragonfly appears to come in batches of dif-
available containing DMT together with some
ferent potency.17 MAOIs, such as synthetic harmaline, or plant-based
Changes in the drugs’ strength and potency MAOIs such as Harmala alkaloids. The MAOIs inhibit
over time have also been documented. LSD ‘tabs’ the otherwise rapid metabolisation of DMT and,
in 2003 contained significantly less LSD on average thus, allow for the hallucinogenic effects when the
than in the early years of use, in the 1960s and drug is taken orally.115
272
12.8 Desired Effects of Recreational Use
Box 12.3 Ergoline NPS The use of hallucinogens was strongly linked
with higher expansion motive and lower degree of
LSZ and 1P-LSD have been marketed in the form coping, social and conformity motives by
of blotters containing usually 150 micrograms of Benschop et al. 2020.130 Desired effects of hallu-
the substance which is placed under the tongue cinogens include euphoria, mild stimulation,
in a similar fashion to LSD. 1P-LSD is also enhanced appreciation of music and lights, visually
available in tablet or ampoule forms.116 appealing distortions, intensification of sensual or
sexual feelings, altered sense of time and place,
and a sense of shared and heightened significance
of the situation. In a survey where 22,000 people
Box 12.4 Phenethylamines in different parts of the world ranked drugs in
terms of pleasure and pain, drug-using respond-
2CB was in some countries, such as Spain for ents placed LSD and magic mushrooms as
example, initially sold as powder, but tablets the second and third most pleasurable drugs, fol-
(including small pills) were later developed.117
lowing MDMA.131
In the US, drugs of the 2C family first
A study that developed a cross-culturally valid
appeared on the US market in 2010 and are
frequently sold as ‘LSD’ on blotter paper, standardised tool to identify the reasons of NPS use
although tablets and liquid preparations are also in six European countries reported that the use of
available.118 psychedelics (hallucinogenics) was linked with
a high score on the expansion motive. The author
argued that this result may be explained by the phar-
macodynamical properties and subjective effects of
12.7.5 Poly-drug Use psychedelics.132
Reports from users and the work of researchers,
Hallucinogens are sometimes combined with other
such as the Shulgins, strongly suggest that each drug
drugs, in poly-drug repertoires, particularly with
has distinct characteristics, and that there are qualita-
stimulant drugs.119 In a Spanish study of 52 users of
tive differences between the different drugs, with
2C-B, 83% reported that they had taken it simultan-
variability in multiple sensory and emotional
eously with other drugs, most commonly with
dimensions.101,129
MDMA (69%), alcohol (43%) or cannabis
Overall, the effects of hallucinogenic phenethy-
(40%).97 Reported combinations with bromo-
lamines include euphoria, increased sociability,
dragonfly include: alcohol, prescribed drugs such as
visual/auditory/olfactory/tactile perceptual disturb-
alprazolam, cannabis, cocaine, amphetamine, LSD,
ances, empathy, depersonalisation, dissociation
and legal highs, including salvia and kratom.17,120
and derealisation.133
Some combinations have their own user names.
It has been reported for example that 2C-B pro-
For instance, LSD or magic mushrooms taken with
duces constellations of psychedelic-psychostimulant-
ecstasy is called candyflipping and hippyflipping
like effects.134 2C-B has been described as inducing
respectively.121 It has even been suggested that the
‘perceptual enhancement’ and euphoria, but these are
popularity of these combinations may have contrib-
milder than those of classical hallucinogens such as
uted to a resurgence of LSD use, following the increas-
LSD and the drug lacks the potent hallucinogenic
ing popularity and use of MDMA.122
effects of LSD.135 This has contributed to its associ-
ation with ‘clubbing’. While it elicits perceptual modi-
12.8 Desired Effects of Recreational fications that are similar to other hallucinogens, the
Use lower impairment and higher pleasurable effects make
it comparable with MDMA.136 2C-B has proved
Hallucinogens are a diverse group of drugs that alter and
popular as a dance drug, and has sometimes appeared
distort perception, producing sensory distortions, most
in tablets sold as ecstasy.137 In the Spanish study of 52
notably visual, and also modify thought and mood.123
users of 2C-B, 60% reported that typical settings of
DiPT is atypical because (at least according to anecdotal
2C-B use were recreational environments (clubs, par-
reports) it produces predominately auditory perceptual
ties, raves), followed by home use with friends (54%),
changes.124,125,126,127,128,129
273
at home with partner (37%) or in the countryside fora as an energetic experience similar to that pro-
(20%).97 duced by MDMA. At higher doses the experience is
The main clinical effects of tryptamines in general more similar to that of LSD. In addition, and even
are visual hallucinations, alterations in sensory per- when the same substance is used at similar doses, any
ception, intensification of colours, distortion of body two experiences by the same individual user may be
image, depersonalisation, marked mood lability, strikingly dissimilar qualitatively.148
euphoria, relaxation, entactogenic properties, and Unlike most other drugs, the effects of hallucino-
anxiety.138 For example, AMT possesses central gens are highly variable, producing different effects in
stimulant and hallucinogenic properties. Its effects different people at different times. Non-
include euphoria, distortion of colour/shapes and vis- pharmacological variables such as expectations, per-
ual hallucinations.139 sonality, environment and emotional state appear to
Users have also reported a variety of moderate-to- have a much greater influence on the effects of hallu-
strong mystical experiences associated with trypta- cinogens than with other drugs.149 Compared with
mines (e.g. awe or awesomeness, amazement, loss of the more predictable and replicable effects of stimu-
time and space, and difficulty putting experience into lants and depressants, the desired and actual effects of
words), with fewer experiencing more challenging hallucinogenic drugs are highly context-dependent
experiences (e.g. fear, anxiousness).140,141,142,143 and user-specific.20,48
Some tryptamines, such as DMT, produce strong The use of hallucinogenic drugs for self-
hallucinogenic LSD-like effects, powerful entheogenic medication has been reported. The ‘therapeutic’
or ‘spiritual’ experiences, euphoria and intense visual effects of hallucinogens have been noted by people
hallucinations, especially when DMT is ingested at who use them, with a study showing that a large
high concentrations.144,145 A recent small study on proportion of respondents reported that 5-MeO-
DMT reported significant increases in phenomeno- DMT use contributed to improvements in symptoms
logical features associated with near death experience related to several psychiatric conditions, including
following DMT administration compared to anxiety, depression, substance use problems, and
placebo.146 post-traumatic stress disorder, suggesting that
People who use ergoline or LSD-like NPS, such as 5-MeO-DMT may have psychotherapeutic effects
of LSZ or 1P-LSD, reported mostly similar effects to under optimal conditions.150 It has been argued that
those of LSD, with experiences such as internal– the therapeutic potential of tryptamines appears to be
external visual hallucinations, loss of ego, empathy, due, at least in part, to their ability to occasion mys-
euphoria, increased tactile sensation and perception tical experiences, which has been demonstrated to
alteration. Users also sometimes reported ‘self- have lasting beneficial effects.151
realisation’ or ‘spiritual’ experiences whilst tripping. LSD and psilocybin are both reportedly used by
Overall, most reports of LSZ or 1P-LSD are positive, some sufferers of cluster headaches,152 and are anec-
with users often reporting a more positive outlook dotally effective in aborting clusters and also reducing
on life afterwards and an agreeable experience they headache frequency in the long term.153 A non-
are willing to repeat.147 hallucinogenic analogue of LSD has been tested on
Self-described ‘psychonauts’ use a wide range of a small number of people with apparent success,
hallucinogens and may experiment with newly emer- although the trial was neither blinded nor
ging psychoactive substances, potent substances and randomised.154
with drug combinations. The emphasis of use is on
seeking novelty and extremes of experience and 12.9 Unwanted Acute Effects
sometimes a spiritual experience. Users may push The hallucinogenic experience, even when positive, is
boundaries in terms of potency of the substance often experienced as emotionally and physically
and dose. The Internet plays an important role in draining.155 Unwanted psychological effects are com-
providing a platform for sharing experience and mon to many hallucinogens and include what is
information. referred to as a ‘bad trip’, characterised by anxiety,
However, as with other substances, the effects of fear/panic, dysphoria and/or paranoia.
hallucinogens are dose-dependent. For example, at Distressing effects can be sensory (e.g. frightening
lower doses, 2CB is described by users on discussion perceptions), somatic (e.g. distressing awareness of
274
12.10 Acute Harms
physiological processes), personal (e.g. troubling when the user assumes that s/he has taken LSD and
thoughts or feelings) or even metaphysical (e.g. feel- that the effects should have dissipated.
ings about evil forces).5,156,157,158,159 In very rare cases,
this may escalate to dangerous behaviour; for 12.10 Acute Harms
example, fear and paranoid delusions may lead to
It is common to see psychological effects of hallucino-
erratic behaviour and potential aggression against
gens without marked physiological symptoms, espe-
self and others.5,158
cially from the use of LSD and magic mushrooms,
Adverse psychological reactions can occur at
which are of low intrinsic toxicity, unless a very large
typical doses, and may feature feelings of loss of
dose is ingested.166
control, disturbing perceptions and attacks of anx-
However, this is not true of all hallucinogenic
iety, agitation and panic, which can be severe.123
NPS. Among hallucinogenic NPS, the patterns of sys-
A patient’s mental state may switch rapidly
temic toxicity vary across the drug class and type.
between severe anxiety and relative normality and
Some hallucinogens will have a potential to cause
back again.160
toxicity with stimulant features (e.g. αMT88); others
Even when a user is not experiencing a ‘bad
drugs may more typically evoke symptoms of sero-
trip’, unwanted effects can include confusion, dis-
tonin syndrome (e.g 5-MeO-DiPT30).
orientation, anxiety and unwanted thoughts, emo-
For example, the highly potent phenethylamine
tions and memories.161 Other unwanted physical
hallucinogens, ‘NBOMes’, were found to be toxic
effects can include nausea, diarrhoea or non-
and have been associated with several fatalities.167
specific gastric discomfort,148 heaviness or tingling,
Similarly, other hallucinogenic NPS, such as bromo-
feelings of heat and cold, trembling and
dragonfly and other ‘Fly’ drugs, the DOx family, the
weakness.129,101,161 They also include dizziness,
NBOMe series and AMT, have much narrower thera-
weakness, tremors, drowsiness, paraesthesia,
peutic ratios and a very different safety ratio, and so
blurred vision, dilated pupils and increased tendon
carry greater risk of acute toxicity and death.108,168
reflexes.5 Sub-acute effects may include headache,
which for psilocybin has been shown by an experi-
mental study to be dose-dependent.162 Halluci-
12.10.1 Features of Toxicity
nogens can also moderately increase pulse rate Reported overall features of acute toxicity linked
and systolic and diastolic blood pressure.5 mainly to the use of controlled hallucinogenic drugs
However, it has been noted that physical effects are listed in Box 12.5. For specific information on NPS
vary and are ‘unimpressive even at doses yielding hallucinogens harms by group see Boxes12.2 to 12.4.
powerful psychological effects’.5
Adverse effects related to hallucinogen NPS are in
some cases linked to the fact that they are mis-sold to Box 12.5 Reported Features of Acute Toxicity
people on the illicit markets as ‘traditional’ substances Linked to the Use of Hallucinogenic Drugs
such as LDS, or as so-called legal alternatives for these
CNS, Neurobehavioural and Psychiatric
traditional substances. For example, people in a series
of ten cases in New Zealand were sold or given Dilated pupils, mydriasis (common, psilocybin169)
25BNBOMe as ‘Synthetic LSD’, ‘synthetic speed’ and Sensory distortions, visual hallucinations, auditory
‘2C-B’. Other studies also show that NBOMes also illusions, synaesthesia,27,170 tactile hallucinations,
appear to be commonly sold as LSD,163,164 substitut- e.g. formication171
ing LSD with a more potent and potentially lethal Affect lability, euphoria172
drug. Dysphoria158
If people who use these substances think they are Acute panic27
using a less potent drug, then the risk of inadvertently Paranoia, ideas of reference27,170
overdosing is compounded. As the minimum psycho- De-personalisation27,170,173
active dose of NBOMes is very small in comparison to Anxiety27,170
LSD, the risk of measurement error is high.165 The Disorientation174
very long duration of some hallucinogen NPS, dis-
Dissociation174
cussed in Section 12.4, also poses a risk, especially
275
Box 12.5 (cont.) Box 12.6 Ergoline NPS

24,48
Agitation Overdose with LSD is rare, but may cause collapse,
Aggression, combativeness24 coma, vomiting, respiratory arrest and hyperthermia.
Delirium, depression, suicidal ideation, attempted Platelet dysfunction may occur causing mild,
suicide175 generalised bleeding tendency and polymorph
Psychosis, delusions, hallucinations176,177 leukocytosis.159,180 Rhabdomyolysis has been
reported.181 Sympathomimetic toxicity has been
Seizures26
reported after ingestion of LSD.182
Confusion58,178 Tachycardia, tachypnoea, agitation,
Ataxia27,170 hyperpyrexia and hypertension have been reported
‘Bizarre behaviour’58 following ingestion of bromo-dragonfly, a drug with
Lightheadedness27,173 a potency similar to LSD, but a far longer duration
(1–3 days) and apparently greater toxicity.17 The
Headaches27 vasoconstriction that has been observed in cases of
Paraethesias,174 abnormal sensations of heat and bromo-dragonfly toxicity has appeared resistant to
cold, chills27 treatment with ACE inhibitors, nitroprusside,
Restlessness, excitement24,178 prostacyclin analogues, glyceryltrinitrate or calcium
Cardiovascular channel blockers.91
LSD has a safety ratio (the ratio of the typical
Tachycardia24,27
effective dose to the lethal dose) of around 1:1000,
Hypertension27 making accidental overdoses rare.183
Musculoskeletal There is little evidence that the NPS LSZ and 1P-
LSD are linked with cases of acute toxicity cases or
Myalgias27
hospitalisation.184 An overview of harms that looked
Twitching173 at the views of users on Internet forums reported
Muscle tension and jaw clenching24 that both LSZ and 1P-LSD were deemed by users to
Shaking179 have no addictive potential and very low toxicity.185
Respiratory tachypnoea24,173 More research is needed.
Metabolic acidosis24
Gastrointestinal/Urological
Gastrointestinal symptoms may be more common
after consumption of natural unrefined products Box 12.7 Hallucinogenic Phenethylamine NPS
containing hallucinogens such as ayahuasca,148 Harms
mushrooms and cacti, in comparison with refined
chemical substances such as LSD Nausea, Although classic 2C drugs are considered
vomiting58,174 (psilocybin common)169 physiologically relatively safe, several incidences,
Diarrhoea148,174 including sympathomimetic toxicity, psychosis, and
Renal death, have been reported.186,187,188 Severe and life-
threatening effects have been associated with the
Acute kidney injury/acute kidney failure27
ingestion of NBOMes189,190 and bromo-dragonfly.17
Other Symptoms Their adverse effects may include nausea,
Hyperthermia,24,27 pyrexia174 vomiting, headache, panic/severe agitation,
Hypoglycaemia aggressiveness, seizures, insomnia, muscle rigidity/
rhabdomyolysis with renal failure, tremors and
Rhabdomyolysis24
cardiopulmonary arrest. Several fatalities have been
Flushing,173 sweating179 reported following the intake of NBOMe
compounds.191
Adverse effects of substances in the 2C family
include headache, dysphoria, hallucinations,
12.10.2 Physiological Adverse Effects mydriasis, seizures, severe agitation, and apnoea.192
Clinical symptoms of patients with 2C or NBOMe
The adverse effects of hallucinogenic NPS are listed in toxicity are typically those of serotonergic and
Boxes 12.6, 12.7 and 12.8.
276
12.10 Acute Harms
Box 12.7 (cont.) Box 12.7 (cont.)

sympathomimetic excess. These include 5-APB 6-APDB (‘4-Desoxy-MDA’); 5-APDB; aka
tachycardia, hypertension, nausea, vomiting, ‘3-Desoxy-MDA’).210 Their intake may be
dizziness, hallucination, agitation, and confusion. associated with stimulant, empathogenic and
Hyperthermia and seizures may occur and acute hallucinogenic effects. Adverse effects may
kidney injury and rhabdomyolysis have been include: dry mouth, nausea, jaw/teeth clenching,
reported. NBOMe in particular has been associated insomnia, diarrhoea, light hypersensitivity, hot
with a high level of toxicity. flushes, headache, drowsiness, panic attacks/
It has been suggested that the diagnosis of NBOMe anxiety, depression, severe paranoia and
intoxication can be difficult.193 Associated clinical psychosis. An unpleasant ‘come-down’, lasting
features include internal preoccupation, violent several days, has been reported. Several deaths
agitation and hallucinations. Serotonergic effects such related to 5- and 6-APB have been identified.211
as mydriasis, sweating, agitation, tachycardia Benzofurans have been associated with
hypertension, hyperreflexia, increased muscle tone and stimulant, entactogenic and hallucinogenic
clonus can be present but difficult to distinguish from effects.212 Adverse effects may include: dry
sympathomimetic excess.194,195,196 The most common mouth, nausea, jaw/teeth clenching, insomnia,
adverse clinical effects reported to a poison centre by diarrhoea, light hypersensitivity, hot flushes,
users were tachycardia, agitation, hallucinations, headache, drowsiness, panic attacks/anxiety,
hypertension and confusion.197 depression, severe paranoia and psychosis. The
A higher incidence of hallucination and delirium use of benzofuran has been associated with an
has been reported for the NBOMe drugs compared unpleasant ‘come-down’, lasting several days.213
with the parent 2C compounds.198,199,200 Symptoms of Several deaths related to 5- and 6-APB have been
NBOMe toxicity include nausea, vomiting, headache, reported.214
panic/severe agitation, aggressiveness, seizures, Bromo-dragonfly has also been linked to
insomnia, muscle rigidity/rhabdomyolysis with renal a number of related acute intoxications with
failure, tremors and cardiopulmonary arrest.201 convulsions, respiratory problems, liver and kidney
A review of 51 cases of NBOMe toxicity showed failure and severe vasoconstriction. Fatalities have
that rhabdomyolysis is a relatively common been described.215 It has been shown that
complication of severe NBOMe toxicity, an effect substances such as ‘DOB-Dragonfly’/’3C-Bromo-
that may be linked to NBOMe-induced seizures, Dragonfly’ displays a high affinity for 5-HT2A,
hyperthermia and vasoconstriction.202 5-HT2B, and 5-HT2C receptors and effects include
In a case series of ten patients, 25B-NBOMe long-standing hallucinations, mood elevation,
intoxication caused hallucinations with violent paranoid ideation, confusion, anxiety and
agitation. Serotonergic and sympathetic signs were flashbacks.216
observed; mydriasis, tachycardia, hypertension and
hyperthermia. These effects were also similar to
those described in other reports involving other
analogues in the class; 25I-NBOMe and
25CNBOMe.203 25B-NBOMe appears to cause similar Box 12.8 Tryptamine NPS
physiological and psychoactive effects compared to
Hallucinogens, particularly when taken in combination
25I and 25C NBOMe analogues.204.205,206,207
with other serotonergic drugs such as MDMA and SSRI
Seizures are frequently reported after 25I-
antidepressants, may contribute to serotonin
NBOMe and 25BNBOMe use. In a retrospective
syndrome, which may be life-threatening (see
review of 148 cases of NBOMe use (mostly 25I-
Chapter 8 and Section 9.14.3). Drugs with the potential
NBOMe), 8.8% had associated seizures.208 Poklis
to cause serotonin toxicity, for example 5-MeO-DiPT,
et al. reported a case of 25B-NBOMe intoxication that
may mimic the toxicity profile of MDMA.24
went into status epilepticus. Lorazepam IV and
Other adverse effects of tryptamine include
a phenytoin infusion were required to terminate
agitation, tachyarrhythmias, hyperpyrexia,
seizure activity.209
serotoninergic and neurotoxicity. Deaths have been
Benzofurans, are phenethylamines structurally
reported.217,218 Our knowledge of the adverse
related to MDMA and MDA
effects of the specific drugs remains limited, but
(3,4-methylenedioxyamphetamine) and include
research has shown the following for example:
several compounds, 6-APB (aka ‘BenzoFury’);
277
Box 12.8 (cont.) Hallucinogens are rarely a cause of substance-

induced psychosis, where the drug triggers a psychotic
• AET adverse effects may include: facial flushing,
headache, gastrointestinal disorders, irritability, episode that may persist hours, days or even weeks after
insomnia and at times, hyperthermia and agitated the acute intoxication should have run its course.229
delirium.219 Nonetheless, psychotic symptoms in the context of
• DET adverse effects include anxiety, tremors, LSD use have been reported, as well as in the context
nausea/vomiting, mydriasis, disinhibition, visual of hallucinogenic NPS, for example 2C-T-4.230 It has
distortions and increased blood pressure.220 been suggested that salvia231 can trigger psychosis in
• 5-MeO-AMT presents with a range of people with existing psychotic illnesses or
sympathomimetic effects.221,222 predispositions,20 although there are also reports of the
• 5-MeODIPT (aka ‘foxy/‘foxy methoxy’/5MEO), appearance of psychosis de novo.232 There are a few case
adverse effects include disinhibition, nausea, reports of psilocybin mushrooms causing an exacerba-
vomiting, mydriasis, auditory and visual tion of psychosis.233 Similarly, it was also reported that
hallucinations, formication, tachycardia, there was greater psychotic response to LSD in persons
hypertension, echolalia, paranoia, restlessness/ with a genetic predisposition to schizophrenia.234
agitation and muscle tension, colour/shapes,
Overall, the evidence suggests that individuals
auditory and visual hallucinations, muscle tension
who suffer from prolonged hallucinogen-induced
and tremors.223,224
psychosis may have pre-morbid mental illness. It is
not known whether the onset of psychosis in these
individuals represents a psychotic reaction that would
not have occurred in the absence of use of hallucino-
gens, or whether it represents an earlier onset of
12.10.3 Psychological and Psychiatric Effects psychosis that would have occurred anyway.5,158
As mentioned previously, the most common cause of Psychoses, apparently triggered by hallucinogens,
hospital presentations related to hallucinogens27,225 is have been reported in a small number of cases associ-
what people sometimes refer to as ‘bad trips’.27 ated with violence and homicide. However, these have
A typical distressing hallucinogenic experience is also been reported in subjects with pre-existing psy-
distinct from delirious or dissociative states. On typical chiatric conditions.177,232
recreational doses, it is usual for people to maintain 12.10.3.2 Excited Delirium
insight into the cause of their experiences, but the
dread of permanent madness or of death is not LSD has been involved in a small number of fatalities
unusual.226 Hallucinogenic drugs may provoke distress- attributed to ‘excited delirium’, more commonly asso-
ing thoughts and reflection on personal problems and ciated with cocaine.235 Excited delirium has also been
past experiences and traumas.5 They can profoundly associated with 5-MeO-DALT236 and αMT.179 It has
exaggerate existing or underlying negative moods.225 been argued that, in some instances, fatalities attrib-
Some studies have identified factors that may contribute uted to excited delirium may reflect underlying seroto-
to the onset of paranoid delusions and psychosis, which nergic and/or sympathomimetic toxicity.237 Excited
include depressed emotional state at the time of taking delirium is often associated with the use of force and
the drug and doing so among strangers.177 restraint, including cases where hallucinogens were
implicated; the mechanism of death can be positional
12.10.3.1 Psychosis asphyxia or sudden cardiac arrest.235,238
As mentioned above, the term ‘psychosis’ has been
used in the literature to describe typical hallucino- 12.10.4 Trauma and Self-injury
genic intoxications.227 Intoxication with hallucinogenic drugs can lead to
A study using data from the large representative accidental injury and death, including from traffic acci-
sample of the US National Survey on Drug Use and dents, falls or hypothermia.235,239 There are a few case
Health found that the use of hallucinogenic drugs reports of self-injury associated with the use of hallu-
appears not to be causally linked to the de novo cinogenic NPS and a case report of a fatality following
development of chronic disorders of mental health AMT consumption.179 Unusual self-injurious acts have
such as schizophrenia or depression.228 also been recorded following hallucinogen use with or
278
12.12 Clinical Management of Acute Toxicity
without co-intoxicants.240 These include at least two The management of phenethylamine derivatives,
cases of severe ocular self-injury,240 a case of self- such as 2-CB, which acts as a serotonin agonist, will
castration after LSD consumption,241 and two cases of need to consider the effects and harms relating to the
self-inflicted stab wounds following consumption of use of amphetamine-type substances, as well as the
magic mushrooms.242 potential risks of serotonin syndrome. As with other
Hallucinogen NPS can also be associated with stimulants, some recommend that in the event of
trauma and accidents. For example, the effects of cardiac arrest, CPR should be continued for at least
LSZ or 1P-LSD have been reported to significantly 1 hour and stopped only after discussion with a senior
alter cognitive functions enough to endanger the clinician. Prolonged resuscitation for cardiac arrest is
user if in a potentially unsafe situation in that state, recommended following poisoning, as recovery with
such as walking on roads.243 good neurological outcome may occur.
It has been recommended, for example, that the
12.11 Mortality management of 2C intoxication is supportive and
should focus on control of agitation and a close moni-
Deaths directly attributed to acute toxicity linked to
toring of the patient’s core temperature is prudent, as
the use of the most prevalent drugs (LSD and magic
serotonergic and sympathomimetic effects can lead to
mushrooms) are uncommon, but some have been
hyperthermia. It is suggested that benzodiazepines and
reported.158,244
IV fluids can be used to successfully treat tachycardia,
Hallucinogenic drugs have been implicated with acci-
agitation, hypertension, and hyperthermia in most
dents secondary to intoxication, such as traffic accidents
cases of phenylethylamine toxicity, although active
and falls.245 There are also several reports of suicides
cooling measures should be considered if hyperthermia
during or following LSD intoxication, although studies
is severe or unresponsive to other measures.252,253,254
have not necessarily implied causality.158,180 There are
The literature on NBOMe intoxication management
also reports of fatalities following ingestion of ibogaine,
is limited, but suggests symptomatic management with
or products containing mixed iboga alkaloids.246
intravenous fluids, benzodiazepines and mechanical
Hallucinogen NPS have also been associated with
ventilator support when indicated.255,256,257 The clin-
a small number of deaths. αMT has been linked to
ician should also keep in mind that a patient presenting
reported tryptamine-related deaths.28 5-MeO-
with hallucinatory symptoms after ingesting what is
DALT,247 DOC,248 25C-NBOMe and 25H-NBOMe
thought to be LSD or drugs in the 2C family may, in
consumption have also been implicated.249,250
fact, suffer from NBOMe poisoning.
The management of patients with mild to moder-
12.12 Clinical Management of Acute ate NBOMe intoxication is often focused on control-
Toxicity ling agitation and preventing physical harm.258 Many
The management of acute toxicity resulting from the users get injuries arising from their agitation.259,260,261
use of hallucinogens will in part depend on the hallu- Patients with only minor agitation may be managed
cinogenic substance consumed. It has been suggested without pharmaceutical intervention, by providing
that monitoring and supportive treatment is all that is a quiet, non-stimulating environment and close
required for the majority of patients,123 including monitoring. More severely agitated patients require
airway management. TOXBASE® recommends that physical restraints to prevent self-harm; rapid
all patients be observed for at least 4 hours after pharmacological sedation with benzodiazepines
exposure. Asymptomatic patients can then be dis- should be commenced concurrently.262
charged with advice to return if symptoms develop. In Gee et al.’s case series (ten patients) it is sug-
Some products sold as LSD may in fact contain gested that large doses of benzodiazepines may be
potent hallucinogens with far narrower therapeutic required to overcome agitation, tachycardia and
ratios,108 such as NBOMes, with a greater potential hypertension. Hyperthermia may be present due to
to cause acute toxicity. It has therefore been suggested serotonergic and adrenergic excess. Fuelled by agita-
that emergency room staff monitor patients present- tion, core temperature may rise precipitously. Large
ing following ingestion of ‘LSD’ with the greater doses of benzodiazepines have generally been
intensity and supportive care necessary for the man- reported as first line treatment, with additional early
agement of NBOMe intoxications.251 paralysis and active cooling if required.263
279
For up-to-date information consult local protocol,

12.13.1 Dependence
national guidance and national and regional poisons The use of LSD or other classic hallucinogens does not
information services. appear to lead to dependence. Typically, there is no
persistent and compulsive pattern of use20,268 and the
use of hallucinogens is not associated with any recog-
nised withdrawal syndrome. There are currently no
12.12.1 Management of Adverse reports of hallucinogen NPS causing physiological
Psychological Effects, Agitation dependence.61,265,269,270,271
and Drug-induced Psychosis Hallucinogens do not appear to show classic pat-
terns of tolerance,270 but, on the contrary, are associ-
A number of studies have looked at the management
ated with tachyphylaxis.2 This means that sensitivity
of adverse reactions and the following have been
to the effects of LSD and other hallucinogens appears
shown to be beneficial:
to be strongly attenuated for a period after use. It may
• Attempts to ‘talk the patient down’. therefore prove difficult for a user to achieve desired
Sympathetic,27 non-judgemental264 reassurance, effects from LSD if taken two days in a row, or indeed
support and observation were often sufficient.5 to get a desired effect from other hallucinogens.1,2
Where possible, the patient should be placed in DMT consumed by vaporisation (usually called
a well-lit room with minimal disturbance.20,27 ‘smoking’ by users) appears to be an exception to
Patients may be prone to mistrust and paranoid this rule, having both an unusually brief duration of
ideation, and early efforts in empathising, action and a proportionately brief duration of
expressing understanding of their fears and tachyphylaxis.272 Anecdotal evidence confirms that
establishing confidence have been shown to be this enables users to have the desired effects multiple
beneficial.27,160 Finding a more peaceful corner or times a day if they want to.273 According to the
room may prove worthwhile,123 as the typical authors of one survey, this, added to DMT’s fewer
clinical environment (with medical equipment unwanted effects and less of a ‘come-down’ than
and white coats) has been shown to be a predictor LSD or mushrooms, gives it a higher potential for
of adverse anxious reactions in participants in misuse.93 However, the same survey did not find an
psychedelic research.149 increased desire to use.93
• Benzodiazepines, particularly diazepam or
lorazepam,27,123 have been reported by some
studies to be first-line choice if pharmacological 12.13.2 Hallucinogen Persisting
interventions are needed and in cases of Perceptual Disorder (HPPD)
agitation.5,20,265 ‘Flashbacks’ and hallucinogen persisting perception
• Antipsychotics should be considered as a second disorder (HPPD) have been associated with use of
line if benzodiazepines do not produce adequate classic hallucinogens in particular, but also with other
sedation.264 substances ranging from cannabis to MDMA.
• In cases of severe agitation or ‘excited delirium’, Hallucinogen NPS may also be linked to
physical restraint should be avoided, as this is HPPD,274,275,276,277,278,279,280,281,282,283 as well as other
associated with sudden cardiovascular collapse.266 types of NPS, including synthetic cannabinoids.284,285
It has been argued that HPPD is a poorly under-
12.13 Harms Associated with Chronic stood aspect of hallucinogen consumption and is the
total or partial recurrence of perceptual disturbances
Use that appeared during previous hallucinogenic ‘trips’
There is no evidence that ‘classical’ hallucinogens
or intoxications and re-emerged without recent
such as LSD or psilocybin have potential neurotoxic
use.286 Some have argued that it is an understudied
effects, as for example MDMA does in high doses.5
mental disorder that has a complex and unpredictable
A brain imaging study comparing hallucinogen users
nature with overlapping psychiatric, psychological,
with ecstasy users found evidence for serotonergic
and neurological symptoms.287 It is also frequently
neurotoxicity only among the latter.267
unrecognised in clinical practice.288
280
Although knowledge of HPPD remains very or stroke,292 and is often associated with migraine
limited, symptoms of this disorder can persist for and tinnitus.296
months or years after the use of hallucinogens.289 Others attribute a directly causal effect through
For some, this long-term change to vision and hearing neurotoxicity caused by the drug (e.g. ‘destruction of
is much less problematic than for others,290,291 for inhibitory serotonergic interneurons’123). Some have
whom it can cause substantial morbidity.289 argued that serotonergic neurological damage under-
The concept of HPPD remains contested. It is lies HPPD, resulting in imbalances of excitation and
described in DSM-5 (F16.983), but is not identified inhibition in brain regions responsible for early visual
as such nor mentioned in ICD-11. ICD-11 also does processing.297 However, these models based on
not mention the concept of ‘flashbacks’ as associated neurological disorders have also been questioned in
with hallucinogenic drugs, in contrast to ICD-10, light of reports of HPPD involving a single use of
which does. a typical dose of a hallucinogen, while many users
A number of people have challenged the value of with a much higher frequency and dose of use do
the concept of ‘flashbacks’.289 Indeed, it has been not present with these symptoms.289
argued that the distinction between ‘flashback’ and
HPPD remains unclear and requires further investi- 12.13.2.1 HPPD Definitions
gation. Some have even argued that the concept of Halpern et al. (2016) have described HPPD as a re-
‘flashback’ is not a useful diagnostic entity, has been experiencing of some perceptual distortions induced
defined in very many different ways and is ‘essentially while intoxicated and suggested that this can cause
valueless’.289 In the literature, there is sometimes functional impairment and anxiety.298 HPPD is
a distinction between the two, with ‘flashbacks’ gener- described in the Diagnostic and Statistical Manual of
ally used to describe intermittent, infrequent experi- Mental Disorders (DSM-V), as discussed in Box 12.9.
ences, in contrast to the more persistent experiences
of HPPD.292 ‘Flashbacks’ are generally transient and
often pleasant, in contrast to HPPD, which is chronic
and can be highly debilitating.293
Box 12.9 HPPD in DSM-5
Transient ‘flashback’ phenomena appear largely
absent from the more recent clinical literature, in The concept of HPPD was first introduced in DSM-3,
which the chronic visual distortions critical for based on the work of Abraham on habitual LSD
a diagnosis of HPPD predominate. These are com- users.299 More recently, the diagnostic criteria of
monly associated with co-morbid psychiatric symp- HPPD as defined by DSM-5 (292.89 F16.983) are as
toms, particularly anxiety, somatisation, panic and follows:
affective disorders.228,289,293 • Following cessation of use of a hallucinogen, the
In fact, the notion of HPPD itself has been con- re-experiencing of one or more of the perceptual
tested. It been suggested that there may not be symptoms that were experienced while
a common aetiology to the diverse phenomena intoxicated with the hallucinogen (e.g. geometric
described as HPPD and ‘flashbacks’ in the hallucinations, false perceptions of movement in
literature,289,294 with diverse interpretations having the peripheral visual fields, flashes of colours,
intensified colours, trails of images of moving
been made. It has been suggested that some cases
objects, positive afterimages, halos around
may be explained in terms of a heightened awareness objects, macropsia, and micropsia).
of and concern about ordinary visual phenomena,289
• The symptoms listed in the previous criterion
which is supported by the high rates of anxiety, cause clinically significant distress or impairment
obsessive compulsive disorder, somatisation, hypo- in social, occupational, or other important areas of
chondria and paranoia seen in many such patients. functioning.
Visual symptoms like ‘visual snow’, ‘floaters’, pali- • The symptoms are not due to a general medical
nopsia (after-images) and trails are all common in condition (e.g. anatomical lesions and infections of
the healthy general population,228,289 may not depend the brain, visual epilepsies) and are not better
on the effect of psychotropic substances on the accounted for by another mental disorder (e.g.
brain,295 or may be symptoms of psychosis, seizure delirium, dementia, schizophrenia) or
disorders, persistent migraine aura without headache, hypnopompic hallucinations.
281
In contrast with genuine psychosis, there is no disorder, bipolar disorder and schizophrenia spec-
paranoid misinterpretation of the perceptions in trum disorders. However, onset of HPPD is not neces-
people who suffer from HPPD.293 Studies on HPPD sarily accompanied by any prominent additional
have recommended that other conditions be ruled out psychiatric disorder, and is an independent condition.
before a diagnosis of HPPD is made, including post- Although not fully understood, reported triggers
traumatic stress disorder (PTSD), depersonalisation include existing mental disorders such as anxiety,
and derealisation associated with severe anxiety and mood and sleep disturbance, entering a dark environ-
depression, as well as other hallucinogen-induced dis- ment, pregnancy and post-partum states, flashing car
orders recognised by DSM, such as hallucinogen- or neon lights, exposure to noise, and exercise.313,314
induced psychosis and mood or anxiety disorders.289 Triggers including emotional (e.g. tension and anx-
HPPD is both rare and unpredictable.292 Estimates iety), environmental (e.g. flickering lights), behav-
of the proportion of users who have experienced flash- ioural (e.g. sexual activity) and biological (e.g. use of
backs on one or more occasions after hallucinogen use other substances) triggers.315,316,317 Among the many
vary widely, from 5% to 50%.300,301 However, many of triggers able to precipitate the symptoms of those with
these studies were conducted before the development existing HPPD, the use of natural and synthetic can-
of the DSM-3 diagnostic criteria for HPPD and are nabinoids appears to be frequent.318
therefore difficult to interpret.289 More recently, a 2003 The analysis of the literature on HPPD suggests
review of the literature concluded that ‘it seems classification into two major subtypes of hallucino-
inescapable that at least some individuals who have genic substance-use related to recurring perceptual
used LSD, in particular, experience persistent percep- disturbances have been identified and reported:
tual abnormalities reminiscent of acute intoxication, HPPD type I, also described and named as benign
not better attributable to another medical or psychi- Flashback, or Flashback type I; and HPPD type II.319,320
atric condition, and persisting for weeks or months It has been noted that the distinction between
after last hallucinogen exposure’.289 Current prevalence HPPD type I and HPPD type II has not yet been
estimates are unknown, but DSM-5 suggests 4.2%.302 made in DSM-5 and is still debated. HPPD type I is
The exact causes of HPPD are not known. The consistent with the diagnostic definition in ICD-10,
condition is more often seen in individuals with while HPPD type II better matches the DMS-5
a history of psychological problems or substance criteria.321
misuse,303 but can arise in anyone, even after a single • HPPD type I or brief flashbacks. HPPD type
exposure.304 HPPD is mainly associated with LSD use, I is short-term, reversible and benign. HPPD
but it has also been reported after use of other psyche- type I is typically associated with ‘auras’,
delic drugs, including mushrooms,305 mescaline289 and minor feelings of self-detachment, mild
5-MeO-DIPT.306 Other substances may trigger HPPD, bewilderment, and mild depersonalisation and
including cannabis,307 alcohol and MDMA.308 HPPD derealisation. Although it can provoke
or flashbacks have also been reported in people who unpleasant feelings, it is not associated with
have taken pharmaceutical drugs such as risperidone,309 significant concern, distress, and impairment
topiramate,310 trazodone, mirtazapine, nefazodone293 in individual, familial, social, occupational, or
and SSRIs311 and it has been suggested recently that other important areas of functioning. 20,21 The
hallucinogen use is not actually a necessary condition impairment is mild and the prognosis is
for this multifactorial syndrome.293 usually good.322,323,324,325,326,327
It has also been suggested that HPPD is in most • HPPD type II is suggested to have a chronic,
cases due to a subtle over-activation of predominantly relapsing and remitting course with fluctuating
neural visual pathways after the use of hallucinogens. symptoms lasting months or even years, while
Factors that may predict vulnerability to HPPD HPPD type II visual disturbances are generally
include individual or family histories of anxiety, pre- unpleasant, long-term, slowly reversible or
drug use complaints of tinnitus, eye floaters, and irreversible, intruding, distressing, disabling, and
concentration problems.312 pervasive reoccurrences.328 It has a long-term,
HPPD also appears to be associated with the co- irreversible or slowly reversible and pervasive
occurrence of depressive and anxiety traits and with course The impairment of HPPD type II is severe
severe mental illnesses such as major depressive with visual distortions and dissociative effects
282
causing significant distress and the prognosis is adaptation to the dark takes significantly longer com-
worse than for HPPD type I. Significant pared with the general population.352,353,354
impairment in social, occupational, or other
important areas of functioning is usually observed 12.13.2.3 Treatment of HPPD
in HPPD type II, but not HPPD type I.329,330 Some A survey using a web-based questionnaire reported
of the patients fail to adapt and live with these that although symptoms of HPPD were common,
long-lasting recurrent ‘trips’, and may require only a few found them distressing enough or impair-
long-term support.331,332,333, 334,335 ing enough to consider treatment, with constant
A study explored differences in triggers between indi- symptoms increasing the likelihood of seeking treat-
viduals with HPPD type I and HPPD type II percep- ment. Even when these symptoms were constant, they
tual disturbances following LSD use and found that were not always considered problematic.292
individuals in the HPPD type II group initiated LSD Another study has found similarly that individuals
use at an earlier age in comparison to those in the in the HPPD type I group reported longer overall
HPPD type I group and used it more frequently than persistence of perceptual disorders than those in
those with HPPD type I. In addition, in this sample, type II. However, this may be partially due to post-
the mean age of subjects with HPPD type II was poning psychiatric treatment, as flashback-type per-
younger than among those with HPPD type I.336 ceptual disorders commonly do not cause
Individuals in the HPPD type II group reported sig- psychological distress and impaired function.355
nificantly higher rates of lifetime use of synthetic There is no established treatment for HPPD and
cannabinoids, inhalants, and stimulants.337 research is very limited. Some cases of HPPD are
reported to have improved with the use of
sunglasses,299 psychotherapy299 and behaviour
12.13.2.2 Features, Symptoms and Increased Risks
modification.356
from HPPD It has been argued that the fact that distinct
The symptoms of HPPD can include a range of substances, with completely different mechanisms
ongoing disturbances, although visual disturbances of action, might lead or precipitate the genesis of
appear most common. In contrast with psychosis, HPPD, therefore suggesting a multifaceted aeti-
there is rarely persecutory misinterpretation of the ology. Thus, it is accordingly conceivable that
perceptions in people who suffer from different medications could be useful and helpful
HPPD.338,339,340,341,342,343,344,345,346,347,348 in the treatment of different subtypes of
Visual disturbances, which tend to be more prom- HPPD.357
inent in HPPD, may be episodic or nearly continuous Treatment outcomes have been reported from
and must cause significant distress or impairment as a number of pharmacological interventions, but the
specified in DSM-V type II, described in multifactorial nature of the disorder, and the promin-
Section 12.13.2.1. There seems to be no strong correl- ence of co-morbidities, suggest the need for highly
ation between HPPD and frequency of use of hallu- individualised treatment, with stress reduction,
cinogens, with reported instances of HPPD in reduction of or abstinence from substance use
individuals with minimal exposure to hallucinogens.349 (including alcohol and perhaps caffeine) and treat-
Common visual features include geometrical hallu- ment of co-morbid disorders.293
cinations, flashes or intensification of colour, move- Pharmacological interventions for HPPD have
ments, particularly in the peripheral vision, after been used but many of the studies (especially older
images (palinopsia), visual trails and haloes.350 ones) had methodological limitations. These inter-
Intensification of colour, flashing colours, geometric ventions have included several classes of antidepres-
imagery and visual ‘snow’ appear to be common and sants, anxiolytics and antipsychotics, a COMT
resistant symptoms. Other visual symptoms can include inhibitor, naltrexone, levodopa, clonidine,
teleopsia, pelopsia, macropsia, micropsia and false per- lamotrigine293 and citalopram.358
ception of movement of images in the peripheral field. Over the years, there have been reports of treatment
Dissociative symptoms including depersonalisation and and positive outcomes using haloperidol,359
derealisation are also consistently associated with diphenylhydantoin,360 trifluoperazine,361 barbitur-
HPPD.351 Moreover, some HPPD subjects report that ates,299 benzodiazepines,299,362,363 carbamazepine,364
283
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Part V Synthetic Cannabinoid Receptor Agonists
Chapter
Synthetic Cannabinoid Receptor Agonists
13
13.1 Introduction to Synthetic street dealers, similar to those used for natural
cannabis.
Cannabinoid Receptor Agonists Brands names appear and disappear and include,
Synthetic cannabinoid receptor agonists (SCRAs), but are not limited to, Spice, Black Mamba or K2.
also referred to as synthetic cannabinoids, or synthetic Products of the same ‘brand’ do not necessarily con-
cannabimimetics, are a large group of smokeable tain the same type of SCRA. What particular brands
drugs initially sold as legal alternatives to cannabis. contain is likely to vary, and certainly brand names
They have a strong effect on the endocannabinoid are not reliable indicators of what is consumed.
system. More than 200 different SCRA compounds Analytical tests have shown that the cannabinoid con-
were available in Europe at the end of 2020. stituents and dosage can vary greatly both between
Synthetic cannabinoid receptors play an import- products and between batches of the same brand.
ant part in the novel psychoactive substances (NPS) There may even be differences within the same pack-
market. Although the number of newly synthesised age, if for example the SCRA has been sprayed
SCRA has decreased in comparison to previous unevenly on the herbal product. There is also evidence
years, SCRAs (and synthetic stimulants) continue that some products contain a combination of different
to be the largest total number of substances reported SCRA compounds.
to EMCDDA and UNODC.1,2 Although they first
appeared in Europe, they are now part of the drugs 13.3 Legal Status
market throughout the world.3 It has been argued
Synthetic cannabinoid receptor agonists (SCRAs) are
that the number of synthetic cannabinoids, their
not under international control through UN drug
chemical diversity and the speed of their emergence
control conventions.
make this group of compounds particularly challen-
However, in Europe, SCRAs are controlled in
ging in terms of detection, monitoring, and
Denmark, Germany, Estonia, France, Ireland, Italy,
responding.4
Latvia, Lithuania, Luxembourg, Austria, Poland,
Romania, Sweden and the UK.6
13.2 Street Names
A variety of street names are used for SCRAs. The 13.4 Quality of the Research Evidence
term ‘Spice’, which is the brand name of one the most
Although it is increasing, the research evidence on
common SCRA products sold in Europe, is often used
SCRAs, especially on clinical harms and their man-
as a generic term for all synthetic cannabinoids. They
agement, continues to be limited to case reports and
are often referred to as ‘K2’ in the US, and ‘Kronic’in
case series, as well as retrospective studies, human and
Australia and New Zealand.5
animal laboratory studies, surveys and interviews with
A wide range of branded herbal products contain-
SCRA users. Longitudinal studies and randomised
ing synthetic cannabinoids has been available on the
controlled trials are rare.
market, containing different SCRAs, with different
levels of potency (see also Box 3.1). Herbal products
are often marked ‘not for human consumption’ and 13.5 Brief Summary of Pharmacology
sometimes presented in attractive and colourful pack- Synthetic cannabinoid receptor agonists have
aging. Where they have been controlled, SCRAs are been developed since the discovery of delta-
increasingly being sold in plain plastic packets by 9-tetrahydrocannabinol (Δ9-THC or THC)
299
Part V Synthetic Cannabinoid Receptor Agonists
Chapter
13
13.1 Introduction to Synthetic street dealers, similar to those used for natural
cannabis.
Cannabinoid Receptor Agonists Brands names appear and disappear and include,
Synthetic cannabinoid receptor agonists (SCRAs), but are not limited to, Spice, Black Mamba or K2.
also referred to as synthetic cannabinoids, or synthetic Products of the same ‘brand’ do not necessarily con-
cannabimimetics, are a large group of smokeable tain the same type of SCRA. What particular brands
drugs initially sold as legal alternatives to cannabis. contain is likely to vary, and certainly brand names
They have a strong effect on the endocannabinoid are not reliable indicators of what is consumed.
system. More than 200 different SCRA compounds Analytical tests have shown that the cannabinoid con-
were available in Europe at the end of 2020. stituents and dosage can vary greatly both between
Synthetic cannabinoid receptors play an import- products and between batches of the same brand.
ant part in the novel psychoactive substances (NPS) There may even be differences within the same pack-
market. Although the number of newly synthesised age, if for example the SCRA has been sprayed
SCRA has decreased in comparison to previous unevenly on the herbal product. There is also evidence
years, SCRAs (and synthetic stimulants) continue that some products contain a combination of different
to be the largest total number of substances reported SCRA compounds.
to EMCDDA and UNODC.1,2 Although they first
appeared in Europe, they are now part of the drugs 13.3 Legal Status
market throughout the world.3 It has been argued
Synthetic cannabinoid receptor agonists (SCRAs) are
that the number of synthetic cannabinoids, their
not under international control through UN drug
chemical diversity and the speed of their emergence
control conventions.
make this group of compounds particularly challen-
However, in Europe, SCRAs are controlled in
ging in terms of detection, monitoring, and
Denmark, Germany, Estonia, France, Ireland, Italy,
responding.4
Latvia, Lithuania, Luxembourg, Austria, Poland,
Romania, Sweden and the UK.6
13.2 Street Names
A variety of street names are used for SCRAs. The 13.4 Quality of the Research Evidence
term ‘Spice’, which is the brand name of one the most
Although it is increasing, the research evidence on
common SCRA products sold in Europe, is often used
SCRAs, especially on clinical harms and their man-
as a generic term for all synthetic cannabinoids. They
agement, continues to be limited to case reports and
are often referred to as ‘K2’ in the US, and ‘Kronic’in
case series, as well as retrospective studies, human and
Australia and New Zealand.5
animal laboratory studies, surveys and interviews with
A wide range of branded herbal products contain-
SCRA users. Longitudinal studies and randomised
ing synthetic cannabinoids has been available on the
controlled trials are rare.
market, containing different SCRAs, with different
levels of potency (see also Box 3.1). Herbal products
are often marked ‘not for human consumption’ and 13.5 Brief Summary of Pharmacology
sometimes presented in attractive and colourful pack- Synthetic cannabinoid receptor agonists have
aging. Where they have been controlled, SCRAs are been developed since the discovery of delta-
increasingly being sold in plain plastic packets by 9-tetrahydrocannabinol (Δ9-THC or THC)
299
cannabinoids. They are a large and chemically agonists that have been detected globally. A total of 209
diverse group of molecules with some functional new synthetic cannabinoids have been detected in
similarity to THC and other phytocannabinoids, Europe since 2008, including 11 reported for the first
with 14 recognisable chemical families of syn- time in 2020. SCRAs fall into seven major structural
thetic cannabinoids.7 groups: naphthoylindoles (e.g. JWH-018, JWH-073
Overall, SCRAs produce effects that have similar- and JWH-398); naphthylmethylindoles; naphthoylpyr-
ities to THC, although they are not the same.8,9,10 roles; naphthylmethylindenes; phenylacetylindoles (i.e.
Both SCRAs and phytocannabinoids (natural canna- benzoylindoles, e.g. JWH-250); cyclohexylphenols (e.g.
bis) bind CB1 and CB2 receptors.11 However, SCRAs CP 47,497 and homologues of CP 47,497) and classical
can range from those with potency similar to THC to cannabinoids (e.g. HU-210).
those that are significantly greater.12 And in general, Synthetic cannabinoid receptor agonists overall
SCRAs have a much higher affinity for those receptors have a complex molecular structure, consisting of
than natural cannabinoids and produce a stronger four pharmacophore components which are referred
effect.13 Structure–activity relationship analyses to as the ‘core’, ‘tail’, ‘linker’ and ‘linked’ groups. It is
reveal that SCRA compounds may indeed exhibit suggested that this structural complexity offers mul-
higher potency. In fact, SCRAs are full agonists on tiple opportunities for chemical modification to evade
the endocannabinoid system, while THC is only drug control legislation based on chemical structure,
a partial agonist.14,15 and this explains the large numbers of individual
The second most prevalent cannabinoid in natural- products that have been detected.23
grown cannabis is cannabidiol (CBD). This is absent in The large structural heterogeneity of the different
SCRAs.16 CBD seems to possess anxiolytic, anti- SCRA compounds means that some are more potent
psychotic and anti-craving properties.17,18 These effects than others. There are differences in terms of metab-
of CBD in cannabis cannot be found in SCRAs.16 It has olism, toxicity and duration of effects. Generally
been suggested that the presence of CBD reduces the speaking, the greater the affinity to the CB1 receptor,
risk of THC-induced psychosis in natural cannabis. As the higher is the pharmacological activity and psycho-
SCRAs do not contain CBD, their risk of causing active effect of the agonist compound.
psychosis is argued to be greater.19 The JWH series of SCRAs were at first the most
Synthetic cannabinoid receptor agonists were ini- commonly used in Europe.24,25 Their chemical struc-
tially synthesised for biomedical research purposes,20 ture is markedly different from THC. In comparison
by scientists investigating the mode of action of can- with THC, the JWH class has a much greater affinity
nabinoids on signalling pathways in the body or as for and full agonism on cannabinoid receptors.26,27
therapeutic agents.21 This includes the analogues to The CP compounds are another commonly used
THC (the classical cannabinoid) which were devel- group of cannabinoid receptor agonists and also lack
oped by Raphael Mechoulam at the Hebrew the classical cannabinoid structure. CP-47,497, often
University (the ‘HU’ compounds) in the 1960s and found in herbal products, is up to 28 times more
include HU-210, which is structurally similar to potent than THC.28,29 The HU compounds are struc-
Δ9-THC, but more potent, and difficult to synthesise. turally similar to THC but are 100–800 times more
The cyclohexylphenols (‘CPs’), referred to as non- potent.30 Benzoylindoles are a fourth group and they
classical cannabinoids, were developed by Pfizer in the include AM-694 and RCS-4, which have also been
1970s. In the 1990s, John W. Huffman developed the detected in herbal blends.31,32
‘JWH’ series of synthetic cannabinoids which evolved As mentioned in Chapter 1, with time, new gen-
from a computational melding of the chemical struc- erations and formulations of drugs were developed
tural features of Δ9-THC with previously developed as NPS. Often, they were more potent than earlier
aminoalkylindoles.22 Other indole-derived cannabin- forms and may be associated with greater harms.
oids detected in products for recreational use are There is evidence that the evolution of the synthetic
those synthesised by Alexandros Makriyannis (the cannabinoid drug market may be focused toward
‘AM’ compounds).9 compounds with increased potency.33 In
Today, products derived from these and other more January 2009, Germany banned the production,
recently synthetised SCRAs are sold on the drugs mar- sale, acquisition and possession of the two specific
ket. There are currently over 200 cannabinoid receptor psychoactive synthetic chemicals (CP 47,497-C8 and
300
13.6 What Are Synthetic Cannabinoid Products?
JWH-018). Within 4 weeks of this legal control, late 2007, to ‘ambivalent opinion’ in late 2008/early
samples of ‘Spice’ obtained throughout Germany 2009, to finally becoming thereafter what the authors
demonstrated replacement of those two recently refer to as ‘communal rejection’, mainly because the
banned compounds with JWH-073, a then unregu- number of negative effects overweighed the number
lated chemical homologue.26,34 A study by the of positive effects over time.40 More recently, another
Poisons Information Centre in Freiburg, Germany, study of posts by users on Internet forums suggests
undertaken between September 2008 and that the proportion of negative effects linked to
February 2011, reported that, after January 2010, SCRAs mentioned has increased over time, suggesting
when JWH-073 and JWH-019 were added to the that recent generations of SCRAs generate more
list of scheduled substances, there was an increase harms.41
in emergency presentations associated with the
extremely potent synthetic cannabinoids JWH-122 13.6 What Are Synthetic Cannabinoid
and JWH-210. The authors commented that in early
cases (i.e. patients presenting after taking JWH-018), Products?
symptoms were generally mild, but later presenta- In the pure state, SCRAs are either solids or oils. Most
tions, mainly due to the highly potent agonists JWH- synthetic cannabinoids are produced in China and
081, JWH-122 or JWH-210, involved much more exported, usually in powder form, using wrong dec-
severe symptoms.35 larations, such as ‘polyphosphate’, ‘maleic acid’,
Elsewhere too, producers of these products have ‘fluorescent whitening agent’ or ‘ethyl vanillin’3. See
been quick to adapt to changes in legislation by using also Box 13.1.
similar compounds that are yet to be controlled.3
Slight modifications are made to banned compounds
and new derivatives continue to emerge as older ones Box 13.1 Production of SCRA products
are regulated. Chemists have synthesised similar com-
pounds easily by the addition of a halogen, alkyl, Once in Europe, the retail products are assembled by
alkoxy or other substitutes to one of the aromatic lacing inert herbal products with synthetic
cannabinoids. Commonly used herbal bases for the
ring systems, or by making small changes in the length
active chemical ingredients are damiana (Turnera
and configuration of the alkyl chain, for example.3
diffusa) and lamiaceae herbs, such as Mellissa,
New formulations belonging to chemically diverse Mentha and Thymus. The synthetic chemicals are
families, such as for example naphthoylpyrroles mixed with or sprayed onto the herbs, typically on an
(including JWH-307 and JWH-030), the adamantyl- industrial scale, often using equipment like cement
indoles/indazoles (e.g. APICA and APINACA), and mixers and liquid solvents, such as acetone or
the dicarboxamide-indazoles (e.g. AB-PINACA and methanol, to dissolve the powders. They are then
AB-FUBINACA) have been developed.36 dried and packaged for sale.21
The so-called third generation SCRAs, such as Pure compounds (not sprayed on inert herbal
MDMB-CHMICA, FUBIMINA, FUBIMINA ana- products) are also available for sale on websites,
logues, AB-PINACA and 5F-ADB, for example, have which users can mix with their own herbal
mixture.42,43 This practice of selling products as pure
been particularly associated with altered mental
powders may increase the risk of overdose, in
states, including what was described as ‘zombie-like’
comparison to the ready-to-use herbal smoking
behaviours.37 They have also been associated with mixtures.44 There are reports from countries such as
adverse effects, which can be severe and life- the UK that SCRAs are sometimes sprayed on letters
threatening.38 or photos and smuggled into prisons for use by
People who have used MDMB-CHMICA, for inmates.45,46
example, have described a spectrum of effects that It has also been reported that SCRAs have been
are consistent with other synthetic cannabinoids, but found in products that look like cannabis resin, as
there was a high prevalence of adverse effects; users well as in samples of herbal cannabis. This may be to
and even suppliers have warned of its high potency.39 strengthen the potency of weak cannabis or to
Similarly, a qualitative analysis of Norwegian web reduce the ‘harvest time’ and increase production
rates by improving the poor potency of immature
forum data showed how the opinion of forum users
plants.
gradually changed from an ‘initial attractiveness’ in
301
Box 13.1 (cont.) Other substances identified in SCRA products

include fatty acids and their esters (linoleic acid, palm-
The unpredictability of the content and of the itic acid), amide fatty acids (oleamide, palmitoyletha-
potency of a SCRA product compounds to their
nolamide), plant-derived substances (eugenol, thymol
potential harms. SCRA composition and dose
and flavours like acetyl vanillin), preservatives (benzyl
within a single SCRA package, or in a production
lot of SCRA products, are often unpredictable and benzoate) and additives (alpha-tocopherol).69,70 SCRA
variable, and place SCRA users at a significant products may also contain high quantities of tocoph-
health risk.47,48,49 erol (vitamin E), possibly to mask analysis of the active
For instance, in one analysis, the JWH-018 cannabinoids.71 They are often contaminated with the
content ranged from 6.8 mg/g to 44.4 mg/g within beta2 -adrenergic agonist clenbuterol,72 thus providing
a single product.50 Another study looked at the a basis for sympathomimetic-like effects (tremor,
purity of JWH-018 and JWH-073 from three online tachycardia, anxiety) often described in intoxicated
suppliers. Purity was determined using high- patients presenting to emergency departments.73,74
performance liquid chromatography with ultraviolet Although the herbal blend that contains the SCRA
detection, and compared against validated
is most likely to be an inert product, the pharmacol-
standards obtained from a traditional research
ogy and toxicology of the plant material in these
chemical supplier. The study found that products
bought online were of comparable purity to blends is unclear.75 The herbal material, which is
validated standards, even though the products used as a basis for the smoking of these mixtures,
varied from each other in colour, texture and may contain toxicologically relevant substances like
odour.51 On the other hand, other studies found that pesticides.58
the cannabinoid constituents and dosage vary
greatly between products and batches.52,53,54,55 13.7 Clinical and Other Legitimate
Even within the same package, the uneven spraying
of the inert herb may give rise to what are known as Uses of Synthetic Cannabinoids
‘hot spots’, with some of the product being stronger Synthetic cannabinoids have been developed for the
than the rest.56 past 40 years as potential pharmaceutical agents,
In addition, one of the factors associated with often for pain management76 or nausea. Those cur-
SCRA-related harms is that SCRA products often
rently used include nabilone (Cesamet®), for the
contain multiple SCRA compounds.57,58,59 In
treatment of anorexia and for its antiemetic proper-
Japan, Kikura-Hanajiri et al.60 detected an average
of 2.6 different SCRAs per product. The most ties in cancer patients. Dronabinol (Marinol®) and
detected in one mixture by the authors was ten nabiximol (Sativex®) and the cannabidiol Epidiolex®
different SCRAs. Some SCRAs (JWH-018, JWH073, are used in the management of multiple sclerosis
AM-2201, APICA and ADB-PINACA) have active and pain3,77 and the treatment of seizures associated
metabolites that possess high affinity and full with two rare and severe forms of epilepsy.
agonist effect on both the CB1 and CB2 receptor. SCRA products are different from medicinal can-
These metabolites may predispose users to nabis products, which are derived from natural prod-
severe adverse effects when combined with other ucts. They are not synthetic versions of natural
SCRAs.61 cannabis.
Synthetic cannabinoid receptor agonists have
also been detected in mixtures containing other
NPS, such as stimulants, hallucinogens and 13.8 Prevalence and Patterns of Use
sedatives/hypnotics or have been detected in what Herbal products containing SCRA first appeared
appear to be ‘ecstasy’ tablets or capsules. It has been around 2004.75 The first SCRA detected in Europe as
reported that SCRAs have been detected in mixtures a so-called legal high was JWH-018, which was
containing other psychoactive herbs and plants,62 detected in Germany and Austria in late 2008.21 It
but also in medications including benzodiazepines,
has been noted that the popularity of these drugs
such as phenazepam, opioid analgesics,63
increased significantly around 2008, as a result of
benzocaine,64 and diphenidine,21,65,66 as well as
other drugs including tryptamines,65,67 numerous media reports that called them a ‘legal’
phenethylamines/NBOMe compounds,68 alternative to cannabis.3
cathinones, benzocaine64 and diphenidine.21,65,66 Although SCRA are one of the largest groups of
NPS,78,79,80 their overall prevalence of use by the
302
13.10 Desired and Undesired Effects for Recreational SCRA Use
general population in Europe is relatively low.81,82 For also been described.64 There are also reports that SCRAs
example, in their most recent surveys, last year esti- can be ingested as an infusion, although this is rare.3
mates of the use of synthetic cannabinoids among 15- The onset of the action of SCRAs is usually within
to 34-year-olds ranged from 0.1% in the Netherlands minutes of smoking, like cannabis, because of the
to 1.5% in Latvia.83 instant absorption via the lungs and redistribution into
Although the prevalence of SCRA use is generally the brain and other organs, within minutes of use. This
low in Europe, it has gained popularity among more seems to be true for the new generation SCRAs, whereby
marginalised social groups, such as homeless and prison for example the onset of effect of 5F-AKB-48 is reported
populations.84 Use in these populations has been identi- to be between 2 and 15 minutes when smoked.99 There
fied as a concern.85 For example, a UK survey of eight is a delay of absorption following oral consumption.3
prisons reported the prevalence of ‘spice’ use within the The length of the effect of SCRAs varies. It has
previous month had increased from 10% in 2015 to 33% been reported that within 10 minutes of inhaling a 0.3
in 2016, with 46% of those users using almost daily.86,87 g dose, users demonstrate mild to moderate cognitive
In the US, a study found that people who reported using impairment, as well as changes in perception and
SCRAs were more likely to have experienced past-12- mood. Effects gradually diminish over 6 hours.28
month homelessness, higher rates of probation/parole Although there are no controlled studies in humans,
involvement and incarceration.88 there are reports that the duration of action for JWH-
It also appears that people who have used syn- 018 is 1–2 hours, that the effects of 5F-AKB-48 last 1–
thetic cannabinoids were more likely to have also 2 hours,100 and for CP 47,497 it is 6–8 hours.28
used natural cannabis. A study of college students in Compared with THC, the effects seem to be shorter
the Netherlands has shown that people who have used for JWH-018 and longer for CP-47,497 (and its C8
natural cannabis were more than seven times more homologues, the effects of which last 5–6 hours).
likely than those who had not to have used SCRAs.89 As many of the SCRA products are much more
Overall, there is evidence that poly-drug use is com- potent than THC, it has been postulated that the
mon among SCRA users. A study of young people in psychoactive dose may be less than 1 mg.76,101 Apart
treatment for SCRA use found that those using these from high potency, some of these substances could
drugs were also more likely to use a range of other have long half-lives and active metabolites,102 poten-
substances.76 Similarly, among non-treatment-seekers, tially leading to a prolonged psychoactive effect.21 It
an Internet survey of 168 users in 13 countries found has been noted that naive users in particular mis-
that lifetime use included: alcohol (92%), cannabis takenly equate the safety and dosing profile of natural
(84%), tobacco (66%), hallucinogens (37%), prescrip- cannabis to that of SCRA herbal products.75
tion opioids (34%), MDMA (29%), benzodiazepines
(23%), amphetamines (22%), cocaine (17%), Salvia divi- 13.10 Desired and Undesired Effects
norum (17%), heroin (7%), inhalants (7%), dissociative
anaesthetics (6%), methamphetamine (3%) and miscel- for Recreational SCRA Use
laneous other drugs (mephadrone, dextromethorphan, One of the main reasons for the misuse of SCRAs is the
kratom; 12%).90 Poly-substance use with SCRAs, espe- difficulty detecting consumption by analysis of bio-
cially alcohol and cannabis, has been described in case logical samples for THC, such as clinic-based urine
reports and series, online surveys and toxicology retro- drug testing kits. The non-detectability of SCRAs
spective reviews.91,92,93,94,95,96 Poly-drug use of other makes them attractive for persons undergoing regular
NPS together with SCRAs has been described too.97,98 drug tests (e.g. patients of forensic or withdrawal clin-
ics, people obliged to undergo workplace drug testing,
13.9 Routes of Ingestion and driving license re-granting candidates, those work-
ing in law enforcement, fire-fighting, the armed
and Frequency of Dosing forces,103 prisoners or clients on probation, mining
Based on user reports and on the dosage forms of prod- workers, and athletes).16 Laboratory techniques have
ucts, the primary route of administration of SCRAs is been developed to detect an increasing number of
inhalation, either by smoking the ‘herbal mixture’ as SCRA compounds, but these are currently not widely
a joint, or by utilising a vaporiser, ‘bong’ or pipe.58 Both available to frontline clinical staff. They will also not
oral consumption and snorting of the compounds have detect every newly emerging compound.
303
Other reported motivations to use SCRAs centre on Castellanos et al. suggested that the effects cluster
their availability, low pricing and in some cases in four areas: cognitive impairment; behavioural dis-
a perception of safety.104 SCRA are also popular in turbances; changes in mood; and sensory and percep-
some countries among homeless people and particularly tual changes.76 Although they are related to THC
rough sleepers, as well as prison inmates because of their (found in natural cannabis), SCRAs are five times
sedating effects and high potency, as seen in box 13.2 more likely to be associated with hallucinations.114
below In one Internet survey of 168 SCRA adult users from
The desired effects of SCRAs are similar to those of a number of countries, the majority of respondents
cannabis intoxication90: relaxation, altered conscious- (87%) reported having a positive experience after the
ness, disinhibition, a state of ‘being energised’ and use of Spice, although 40% also reported negative or
euphoric90,92, 105 and other factors mentioned previously, unwanted effects. The quantities of SCRA products con-
such as availability, affordability and the fact that it is not sumed did not vary significantly between those who had
detected by many commonly used urine drug negative effects and those who did not. In addition, 11%
tests.8,106,107 reported that multiple use of the same brand of SCRA
An Australian survey of 316 SCRA users reported product results in variable and unpredictable effects.90
reasons for first use include curiosity (50%), legal status A study of 11 adolescents aged 15–19 who had used
(before its control) (39%), availability (23%), recre- SCRA found that all the subjects reported a feeling of
ational effects (20%), therapeutic effects (9%), non- euphoria but nine (82%) also reported negative mood
detection in standard drug screening assays (8%) and changes, four irritability and three anxiety. All 11
to aid the reduction or cessation of cannabis use (5%).91 respondents reported difficulties with memory, one
described auditory perceptual disorders, five visual per-
ceptual disorders and two described paranoid
Box 13.2 SCRA Use among Homeless People thoughts.92
and Prisoners Reported subjective and physiological effects of
SCRA products can vary greatly.10,115 There are some
In some European countries, there is a relatively high reports of sedation, while other users have reported
use of SCRAs among vulnerable populations agitation, sickness, hot flushes, burning eyes, mydriasis
including the street homeless and among prisoners.
and xerostomia (dryness in the mouth). The most
The appeal of SCRAs to vulnerable groups
appears to be that they are cheap and potent
commonly reported unwanted physical effects are nau-
intoxicants.108 SCRAs are sought by homeless sea and vomiting.28,116 There are some reports that the
people and rough sleepers for their ability to detach frequency of hallucinations is greater than for canna-
those under the drug’s influence from reality and bis. For example, in a survey of 168 users by Vandrey
their environment. However, because they et al., 28% reported hallucinations following SCRA
frequently result in rapid intoxication, individuals use, which the authors describe as greater than what
under the influence of SCRAs are vulnerable to would be expected for cannabis consumption.90
crime, particularly theft, robbery and exploitation.109 In a study of university students in the US, com-
Research carried out in British prisons has shown mon reasons for use were legality, not appearing on
that SCRAs are very widely available and that drug tests, and availability, not that students enjoyed
prevalence of SCRA use is significantly higher than
using synthetic cannabinoids or thought they were
among the general population despite being sold at
much higher value inside custodial settings than on
safe to use.117
the street.110 Similar findings have been reported in In the Australian survey of 316 SCRA users, more
prison and probation services in Sweden.101 than two-thirds (68%) reported at least one side-effect
The most commonly reported motives for SCRA during their last session of use, including decreased
use in prison were boredom and escapism; other motor coordination (39%), fast or irregular heartbeat
reasons include relaxation and addiction and less (33%), dissociation (22%), dizziness (20%), paranoia
detectable smell compared to cannabis.111 It has (18%) and psychosis (4%). Four respondents reported
been reported that prisoners use SCRA to ‘clear their seeking help. More side-effects were reported by
mind’, ‘manipulate time’, and ‘escape the basic males, respondents aged 18–25 years, those who had
confines of prison life,112 and that ‘boredom’ is used water pipes and those who had concurrently
a reason for consumption and that Spice ‘kills time’
used alcohol.91
and ‘makes prison life more bearable.’113
304
13.12 Acute Harms
Despite indicating that the effects of SCRAs are 13.11 Mortality

broadly similar to those of cannabis, 54% of respond-
A number of deaths have been related to SCRA inges-
ents to an Internet survey reported that SCRAs pro-
tion, either on their own or in combination, in analyt-
duce subjective effects unique and discernible from
ically confirmed reports.119–127 and include but are not
other licit or illicit drugs.90 Similarly, findings from
limited to completed suicides following a SCRA
the Global Drug Survey also suggest that, when prod-
intake.120,128,129 Death associated with newer gener-
ucts are smoked, users are able to differentiate between
ations of SCRAs have been documented in a number
the effects of natural versus synthetic cannabis.5
of countries (including 5F-ADB 5F-AMB, AMB-
Respondents to the Global Drug Survey reported
FUBINACA and AB-CHMINACA).130,131,132,133,134
a strong preference for natural over synthetic cannabis
In a recent Australian study of 55 SCRA-related
(it was preferred by 93% of users), with natural cannabis
deaths, the mean age of the deceased was 37.2 years
rated as giving greater pleasurable effects while leaving
and 91.1% were male. Causes of death comprised of
the user able to function better. SCRAs were given sig-
accidental toxicity (38.2%), accidental toxicity/cardio-
nificantly higher scores for self-reported hangover effects
vascular disease (9.1%), natural disease (20.0%), suicide
and other negative effects compared to scores given for
(10.9%) and traumatic accident (10.9%). The most com-
natural cannabis. The survey also found that natural
mon clinical presentation was sudden collapse (25.5%).
cannabis was used more frequently and more recently
Cardiovascular disease was prominent, including severe
than SCRAs. Only a small minority of users seem to have
atherosclerosis (20.0%), myocardial replacement fibro-
fully substituted natural for synthetic cannabis.5
sis (18.0%), cardiomegaly (12.0%).135
Similarly, in a US study of 500 clients enrolled in
a residential drug recovery programme, almost two-
thirds (68.4%) of clients reported lifetime SCRA use. 13.12 Acute Harms
Individuals reporting SCRA use also showed exten-
sive substance use histories and favoured heroin, 13.12.1 Acute Toxicity
opioids, and amphetamines compared with SCRAs. It has been suggested that synthetic cannabinoid intoxi-
Only 5.2% of the SCRA-using group stated that cation appears to be a distinct and novel clinical
SCRAs were a preferred substance, and only 11.8% entity136, with differences between SCRA and natural
reported that they would try SCRAs again, indicating cannabis discussed in Box 13.3. Overall, SCRAs are
that SCRAs are not a preferred drug.118
Box 13.3 SCRA: Differences with Natural Cannabis and THC
Synthetic cannabinoids receptor agonists are not synthetic versions of the substances occurring in herbal cannabis
(THC). Both SCRAs and natural cannabis bind CB1 and CB2 receptors. However, SCRAs have a much higher affinity
for CB1 receptors than natural cannabinoids, produce a stronger effect and may have higher potency.
Overall, the adverse side effects induced by SCRAs in general may be more severe and occur more frequently
than those induced by natural cannabis.142,143,144,145,146,147 Unlike natural cannabis, SCRAs are associated with
serious adverse effects, including cardiotoxicity, nephrotoxicity and death.148 SCRA overdoses appear to be
associated with significantly pronounced neurotoxicity and cardiotoxicity, compared with natural cannabis.149
Similarly, studies have shown that SCRA use is associated with increased mental health symptoms compared to
natural cannabis use150 and that the severity of psychiatric symptoms has been observed to be greater for SCRA
users than that of natural cannabis user.151 Similarly, in a clinical population, differences between natural cannabis
and SCRA users were observed, which indicated an association of SCRA use with increased psychotic problems,
agitation, and longer hospitalisations.152,153
It seems that the risk of requiring medical attention following use of SCRA is greater than that for natural
cannabis consumption. For example, a study carried out among Dutch students showed that approximately 17% of
those who had ever used SCRAs said they considered or did go to the emergency room while using synthetic
cannabinoids.154 Similarly, a number of other user surveys also suggest higher need for emergency medical care by
those using SCRAs in comparison to natural cannabis.155,156
However, there is also evidence that these episodes of medical care appeared to largely require only
symptomatic or supportive care157 and were of short duration.158,159 A systematic review of adverse events found
305
Box 13.3 (cont.)

that typically events requiring hospitalisation were not severe, only required symptomatic or supportive care and
were of short duration. Nonetheless, the review also reported that a number of deaths have been attributed either
directly or indirectly to SCRA consumption, as well as a number of other adverse effects, including a significant
number with persistent effects such as new onset psychosis with no family history of psychosis.160
It is important to remember that SCRAs are not a single drug as discussed previously (see Section13.5). There are
over 200 different SCRA molecules which can produce a wide range of physiological and psychiatric adverse effects
that can vary in duration and severity.161 More recent formulations and new generations of SCRAs are typically more
potent that earlier SCRAs and seem to be associated with greater harms.66,162,163
It has been suggested that early reports on SCRA acute harms noted a similar pattern of toxicity to cannabis.
These include typical neuropsychiatric and cardiovascular effects – drowsiness, paranoia, delusion, hallucination,
impaired cognition/memory as well as tachycardia and hypotension.164,165 Later reports have suggested that SCRAs
have additional toxicity including acute kidney injury, sympathomimetic (stimulant) toxicity and seizures.166,167
An analysis of US National Poison System data showed that with new generations of SCRAs appearing, clinical
toxicity from SCRA use changed significantly between 2010 and 2015, with an increasing proportion of patients
experiencing prolonged adverse effects each year, leading to increasing hospitalisation.168
It seems that even in the case of new generation SCRA acute intoxication and hospitalisation, most of the single-
substance SCRAs were associated with self-limited symptoms and required supportive care. Nonetheless, the study
also found that SCRA-associated clinical toxicity had changing since 2010. Each year, larger proportions of patients
experienced more severe and prolonged adverse effects resulting in higher utilisation of healthcare resources (e.g.
emergency department presentation, hospitalisation and therapeutic interventions),169 and although SCRA toxicity
only rarely results in death, the number of deaths increased each year. The authors argue that it is possible to
speculate that this trend may be due to the higher potency of new SCRAs.170
During 2015, US poison control centres fielded 1,501 cases regarding SCRAs and reported that 11% of cases
were noted to have a major adverse event. Males or those more than 30 years old were more likely to have a severe
outcome. In these case clusters, intensive care unit (ICU) admission rates were from 8% to 27%.171
New generations and new formulations of SCRAs brought with them new harms. For example, acute kidney
injury (AKI) related to synthetic cannabinoid use was first described in the US in 2012, even though SCRAs have been
on the market since the 2000s. It was therefore argued that a new SCRA metabolite, likely introduced in 2012,
seemed to be associated with AKI,172 leading to the identification of XLR-11.173 Similarly, ADB-FUBINACA and AB-
CHMINACA were also identified through outbreak investigations of severe delirium in some US states.174,175,176
Report of ‘zombie-like’ features of ABM-FUBINACA exposure suggest that the clinical effects of SCRA exposure
appears to be changing with the introduction of new SCRA compounds.177 Some SCRAs have specific effects which
have not been reported for others. For example, 5F-AKB-48 has been associated with paranoia, intense anxiety and
an unpalatable taste in the mouth like ‘burned plastic’.178
more potent, unpredictable and toxic than natural can- A major health problem arises from the fact that
nabis. It is agreed that it cannot be assumed that the mixtures differ with regard to their active
risks associated with the use of SCRAs will be compar- ingredients.58 As a consequence, it is not possible
able to those of THC, as SCRAs appear to have greater for the consumer to estimate the dose at all accur-
potential to cause harm. ately. Two cigarettes or ‘joints’, prepared from the
There is a wide range of adverse health effects same mixture, could contain significantly different
reported following the consumption of SCRAs, with amounts of the drug, and this raises the risk of
unpredictable effects ranging from profound sedation harm.
to intense agitation and psychosis.137 As mentioned In addition, SCRA products also often contain
above, like the users of other NPS and illicit drugs, people more than one form or type of SCRA and these can
who use SCRAs are not able to know exactly what it is interact in unpredictable ways.138,139,140
they are consuming. The lack of quality control leads to Furthermore, variability is due to the differences
batch-to-batch differences in SCRA concentrations in between the particular SCRA compounds, but could
different products.3 The amount and type of SCRA also be related to individual susceptibility to the effect
may vary, within and between products,76 and some of the drug or the dose, or it may be multifactorial.141
may contain more than intended.11,34,69 It has been suggested that the effects of SCRAs are
306
13.12 Acute Harms
greater in individuals with less previous exposure to regarding the emergence of ‘third generation’ synthetic
cannabis, and especially those who are drug naïve.35 cannabinoids and their increasing market
Harms associated with adulterants found in availability.192
SCRAs have also been reported. It has been noted Similarly, a case series of seven male patients with
that the rationale for using adulterants, such as brodi- analytically confirmed MDMB-CHMICA toxicity also
facoum (BDF), in SCRA products may be associated found that clinical features common to all seven pres-
with attempts to enhance the psychoactive effects of entations were heart rate disturbances (tachycardia/
the drug, keeping the user high for a longer period of bradycardia), as well as reduced level of consciousness
time because of lipid storage, hepatic metabolism and and mydriasis. Tonic–clonic seizures and agitation
slow release.179 were reported in one individual with no other co-
Studies have reported a range of symptoms asso- ingestants. Respiratory depression was reported with
ciated with the various adulterants in SCRAs. This all three presentations of lone MDMB-CHMICA
includes suggestions that superwarfarin adulterants intoxication.193 Analytically confirmed exposure to
of synthetic cannabinoids can lead to clinically signifi- MDMB-CHMICA was associated with acidosis
cant coagulopathy,180 or that rat poison adulterants in (often of respiratory origin), reduced level of con-
SCRAs may be linked to haematuria.181,182,183 sciousness, mydriasis, heart rate disturbances and
convulsions.194 PB-22 has also been associated with
13.12.2 Features of Acute Intoxication seizures.195 The overall features of acute SCRA tox-
icity are listed in Box 13.4.
Adverse effects of intoxication have been reported.184
Overall, SCRAs can cause minor and moderate 13.12.2.1 Cognitive Effects and Effects on Mental
adverse effects similar to those of cannabis intoxica-
Health
tion, including tachycardia, nausea, somnolence, hal-
lucinations, paranoia, xerostomia, and injected A number of studies have reported cognitive changes
conjunctivae (hyperaemia). associated with SCRA use, including difficulty in
SCRAs are, also associated with more severe thinking clearly, confusion, sedation and somno-
adverse effects and complications, such as renal injur- lence, disorganisation, thought blocking, or non-
ies, aggressiveness, cerebral ischaemia and myocardial sensical speech or alogia, memory changes/
infarction.185 The use of SCRAs has been associated problems, increased focus and internal
with sympathomimetic effects such as mydriasis, unrest.74,90,92,107,229,230,231,232,233 Studies have also
hypertension and tachycardia.186 reported a variety of behavioural disturbances,
Common symptoms reported in outbreak clusters including a change of activity from decreased activity
of adverse effects of SCRAs reported by the literature to excitability, agitation and restlessness. Aggression
include lethargy, agitation, intermittent lethargy and has been reported in a small number of
agitation, aggressive behaviour, confusion, tachycar- subjects.74,92,94,107,234,235,239,240 Psychomotor retard-
dia, hypokalaemia, hyperglycaemia, vomiting and ation and nightmares were reported in one
tonic-clonic seizures.187,188,189,190,191 study.93,238
A UK study of a series of 179 people with acute A study has suggested impaired cognitive function
recreational drug toxicity presenting to hospital emer- in chronic users of SCRAs compared with recreational
gency departments identified synthetic cannabinoids in users of cannabis and non-users. Impairments in
18 (10%) patients. The most frequently observed clin- working and long-term memories and response
ical features were cardiovascular (tachycardia, (n=5, inhibition were observed among SCRA users com-
28%), chest pain, (n=1, 6%)); neurological (seizures, pared with recreational cannabis and non-cannabis
(n=4, 22%), coma, (n=1, 6%)); and neuro-psychiatric users. No difference was found in cognitive perform-
(agitation, (n=4, 22%), psychosis, (n=1, 6%)); there was ance between recreational cannabis and non-cannabis
one case of elevated body temperature (n=1, 6%) that users. Additionally, synthetic cannabis users showed
was also associated with the co-ingestion of serotoner- higher depressive and anxiety symptoms than the
gic agents. The fluorinated analogues of the users of natural cannabis and non-users.236
SCRAnAKB-48 and PB-22 were most commonly seen A controlled study found that acute SCRA intoxi-
in this study and the authors argue that the data are cation can potentially result in impaired motor func-
reflective of the increasing concern in the UK tioning, attention and response inhibition, but does
307
Box 13.4 Features of SCRA Toxicity
SCRA overdoses have significantly pronounced neurotoxicity and cardiotoxicity compared with natural cannabis.196
Unlike their predecessors, some novel SCRAs may be associated with significant central nervous system depression and
bradycardia. Commonly identified compounds such as CID and alkyl SCRA derivatives, such as INACA compounds and
XLR-11, tend to be full agonists at the cannabinoid receptor and are presumably more potent.197 At least some SCRAs
could lead to severe or even life-threatening intoxication when taken in sufficiently larger doses, particularly so in the
case of compounds that act as full agonists at the CB1 receptor, such as HU-210, CP-55,940 or WIN-55,212–2.198,199
• SCRAs have been linked to sympathomimetic effects such as mydriasis, hypertension, tachycardia200 seizures,
diaphoresis, agitation and combativeness.
• Serotonin syndrome – SCRAs fall into the major structural groups, based on their chemical structure.3,201 Many of
the compounds incorporate indole-derived moieties, as components of the structure or as substituents.202
Indoles are groups structurally similar to serotonin, and so are active on 5-HT receptors.203 It has been argued that
ingestion of indole SCRA compounds may be associated with particularly high levels of activation of serotonin
receptors.204,205 Furthermore, it has been suggested that, at high doses, SCRA compounds may also possess some
monoamine oxidase inhibitory properties.206 This element may further increase the risk of serotonin syndrome in
SCRA users (for serotonin syndrome see Chapter 8 and Section 9.14).
SCRA toxicity is characterised by the following features, listed in Box 13.5.
Box 13.5 Features of SCRA Toxicity

Features of SCRA toxicity include35,106,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228
Neurological, cognitive and psychiatric effects
• Severe anxiety, agitation, aggressiveness, mood disturbance and suicidal thoughts, thought disorganisation,
perceptual changes, persecutory thinking, delusions, auditory and visual hallucinations.
• Numbness, tingling, light-headedness, dizziness, pallor, tinnitus, diaphoresis, tremor, impaired motor performance,
somnolence, syncope, nystagmus and convulsions, reduced levels of consciousness, catatonia, coma.
• Short-term memory and cognitive deficits, confusion, amnesia.
Cardiovascular and cerebral effects
• Tachycardia, hypertension, hypotension, hypokalaemia, chest pain, palpitations, myocardial ischaemia,
myocardial infarction, ischaemic stroke.
Neuromuscular and musculoskeletal effects
• Hypertonia, myoclonus, tonic-clonic seizures, myalgia, rhabdomyolysis.
Renal effects
• Acute kidney injury (aetiology unknown)
Other effects
• Hyperglycaemia, hypoglycaemia, respiratory acidosis, cold extremities, dyspnoea, mydriasis, nausea, vomiting,
loss of sight and speech
Serotonin syndrome
• Some SCRAs have been linked to serotonin syndrome.
not have an effect on other executive functions such as Studies have reported changes in mood and affect
spatial memory and information processing.237 associated with SCRAs. There are reports of subjective
SCRAs are also associated with adverse effects on feelings of euphoric mood associated with
mental health and are linked to psychotic symptoms. intoxication,90,92 but reports of users experiencing
308
13.12 Acute Harms
negative mood changes are more common and typify psychosis in otherwise healthy people with no history
intoxication associated with SCRA rather than canna- of psychosis. This will be discussed in Section 13.13, on
bis use.76 There are also reports of inappropriate or the harms of chronic SCRA use.
uncontrollable laughter,90,238 anger and sadness,92 SCRA use may lead to psychotic symptoms in
with an odd/flat affect.93 individuals with no past psychiatric history, or in the
Sensory and perceptual changes include paranoid absence of a personal or family history of psychosis.
thinking,90,92,94,107,241,242,239 delusions93,94,107,240,240 and There are reports of SCRA-associated acute tran-
auditory and visual hallucinations.90,93,107,242–244,241 sient psychosis,35,95,243 as well as reports that some
Other problems associated with SCRA use include com- individuals may experience psychosis that persists for
bativeness, irritability,92,239,249 thought disorgani- weeks after the acute intoxication.93,248,249,252
sation,241,248 anxiety and panic attacks,92,239,249 A small number of reports has described the asso-
depression and suicidal thoughts,93,94,140,242,243 as well ciation between the use of SCRAs and hallucinogen
as self-harm, agitation and aggressive behaviour.244 In persisting perception disorder (HPPD).263,264,265
addition, SCRA use has been associated with increased There is also some evidence that one of the triggers
levels of violence.245 able to precipitate the symptoms of those with exist-
It has been argued that there has been an increase of ing HPPD, is the use of natural and synthetic
case reports of individuals with no pre-existing mental cannabinoids.266
health conditions experiencing acute psychotic reactions,
as well as anxiety,244 suicidality, and other adverse psy- 13.12.4 Physiological Effects
chological reactions resulting from SCRA
use246,247,248,249 and compared to natural cannabis users 13.12.4.1 Cardiovascular
and non-users.250,251 In some cases, these have resolved
SCRAs have been reported to be two or three times
quickly with minimal intervention, but in others, there
more likely to be associated with sympathomimetic
have been persistent difficulties.252,253,254,255,256
effects such as tachycardia and hypertension than
natural cannabis.73,74,267
13.12.3 Psychotic Symptoms SCRAs are cardio-toxic, with increased risks posed
by new generations of SCRAs. MDMB-CHMICA for
and SCRA-induced Psychosis example has also been associated with serious cardio-
The use of SCRA has been associated with psychosis and vascular toxicity, particularly sudden cardiac deaths
psychosis linked to SCRA has been associated with more in young people.268,269,270,271,272,273
agitation than would be expected from cannabis SCRAs can be linked to severe cardiovascular
alone.73,247,249,257 It has also been argued by some that events and pathologies.274 The consumption of
there is a greater risk of psychosis with SCRA than with SCRAs increases the risk of myocardial
cannabis.258 This is due to a combination of factors infarction.237,275 Case reports and case series have
which may include the absence of cannabidiol (CBD), described a range of cardiovascular problems, includ-
a naturally occurring product in cannabis which may ing bradycardia, chest pain and cardiac
have antipsychotic properties.249 The impact of the ischaemia,74,247,250,276 and cerebrovascular accident
absence of CBD has been described in relation to natural (CVA) associated with the use of synthetic
cannabis with low cannabidiol content, such as cannabinoid.277
‘skunk’.259
Studies have shown that SCRA use is significantly 13.12.4.2 Neurological
associated with psychotic symptoms and there is an SCRAs have neurotoxic properties. Some neuro-
association between SCRA use with a wide range of logical and neuromuscular effects linked to the use
positive and negative psychotic symptoms and higher of SCRAs have also been reported and include
levels of positive psychotic symptoms than natural tremors,238,239,244 numbness,92,238,244 tingling,244
cannabis users.260,261,262 lightheadedness,90,250 and dizziness.90 Also reported
There is some evidence that SCRAs may precipitate are pallor,239,244 tinnitus,90 excessive sweating,238
psychosis in vulnerable individuals,35,73,240,241,247,249 diaphoresis,242 and unresponsiveness.73
including those with a history of psychosis.93,94,240–243, SCRAs may be associated with lowering the seiz-
249,252
There is also some evidence of new-onset ure threshold in susceptible individuals.278 Although
309
seizures or convulsions associated with the use of 13.12.4.4 Other

(natural) cannabis seem to be unusual, there are Xerostomia, hyperglycaemia and hypokalaemia have
some reports associated with SCRA use. These include been described in case reports.28,74,247 Nystagmus,
a case report which describes a patient presenting to conjunctival injection and mydriasis were reported
hospital with seizures after consuming a large quan- in a small number of cases.28,247 The loss of eyesight
tity of analytically confirmed SCRA powder and alco- and speech has been reported.296
hol, and reports of generalised convulsions occurring Other reported harms linked to the use of SCRAs
after SCRA use.279,280,281,282,283 include case reports of hyperthermia,297 diffuse alveo-
Out of the 1,898 exposures to SCRA reported to lar haemorrhage,298 and hypokalaemia.21
the US National Poison Data System between Delirium, severe rhabdomyolysis, acute kidney
January 2010 and October 2010, 52 cases of seizures injury, and hyperthermia are common in patients
were reported; the majority (43) were single episodes, with synthetic cannabinoid intoxication.299
although two patients developed status epilepticus.
The majority of all 1,898 patients had minimal symp-
toms but the study identified 34 cases in which there
13.12.5 Multi-organ Failure
were life-threatening effects associated with exposure, Reports of multiple organ failure and hepatic failure
and more than half of these involved seizures.284 in particular, associated with SCRA toxicity are rare.
In a study on toxicity linked to MDMB-CHMICA, A recent case series described six patients displaying
the development of seizures and deep unconscious- similar symptoms and sequelae resulting from mul-
ness were common features.285 Similarly, some new tiple organ failure secondary to SCRA use.300 In this
generation SCRAs have been associated with delayed series the majority or 5/6 patients presented with
onset seizures.286 acute kidney injury; 4/6 required continuous renal
A prospective observational study of patients replacement therapy. Five of six patients experienced
with suspected synthetic cannabinoids toxicity fever and myocardial injury, as evidenced by
treated in emergency departments in Germany a troponin elevation (3/6Seizures occurred in half of
reported analytically confirmed intake of AB- patients (3/6 patients). Two patients required emer-
CHMINACA or MDMB-CHMICA in 45 patients gent fasciotomies of the bilateral lower extremities for
(age range: 12–48 years), of which the majority acute compartment syndrome. Two patients devel-
were male (40) and in 21 presentations more oped fulminant hepatic failure that necessitated liver
than one synthetic cannabinoid was present. The transplant evaluation, one requiring Molecular
majority of the clinical features described were Adsorbent Recirculating System (MARS) therapy as
neurological/neuro-psychiatric, with reporting of a bridge to successful transplant, while the patient
somnolence (25 patients), disorientation (19), hal- without it did not survive.
lucinations (16), generalised seizures (13), aggres-
sive behaviour (11), psychosis (6), syncope (6), 13.12.6 Presentations for Treatment
muscle weakness/loss of control (5), amnesia (5) for Acute Intoxication
and dysarthria (2).287
Although the prevalence of use of SCRA is generally
13.12.4.3 Renal and Gastrointestinal low at population levels, it has been noted that the risk
of requiring medical attention following use of SCRA
Gastrointestinal effects of SCRAs include nausea90,238
appears to be greater than that for natural cannabis
and vomiting.90,238,244 Acute kidney injury (AKI)
consumption.301
associated with SCRA use has also been
A systematic review of adverse events found that
described.106,288,289,290,291,292 Even without prolonged
typically events associated with acute SCRA toxicity
agitation, AKI has been noted with some specific
were not severe. They generally only required symp-
compounds, such as the 16 cases of AKI from XLR-
tomatic or supportive care and were of short
11.293 SCRAs have also been linked to thrombotic
duration.302 Similarly, in a study of 1,898 exposures
microangiopathy (TMA) secondary to synthetic
to SCRA reported to the US National Poison Data
cannabinoids.294 A recent case series has reported
System between January and October 2010, the
a case of SCRA-associated acute liver failure requiring
majority of cases had self-limited signs and symp-
organ transplantation.295
toms. Only 7.3% of symptomatic exposures were
310
13.12 Acute Harms
coded by a poison centre specialist as potentially life- days. One patient with diabetes mellitus developed
threatening.286 pronounced hyperglycaemia.307
Overall, the most frequently reported effects were A retrospective review of cases presenting to an
tachycardia (37.7%), hypertension (8.1%), chest pain emergency department during a three-month period,
(4.7%), syncope (2.1%), hypotension (1.3%) and with chief complaint of SCRA use before arrival,
bradycardia (1.3%). Reported central nervous system reported that most such patients can be discharged
effects included agitation/irritability (23.4%), drowsi- after a period of observation (an average of 2.8
ness/lethargy (13.5%), confusion (12%), hallucin- hours).140
ations or delusions (9.4%), dizziness (7.3%) and The psychotomimetic effects of synthetic canna-
respiratory depression (>1%). Although the majority binoids, even following a moderate dose, have been
of cases had self-limiting symptoms, the study identi- reported.308 The use of SCRAs has been linked to
fied 34 cases in which there were life-threatening major adverse consequences, including a significant
effects associated with exposure; more than half were number with persistent effects including new on-set
seizures, which were reported in 3.8% of cases.286 As psychosis with no family history of psychosis.309
shown above, some people will present to hospitals An Australian study of patients hospitalised in an
with harms which can be severe and a number of acute psychiatric ward for problems associated with
deaths have been attributed either directly or indir- SCRA use found that they represented 13% of all
ectly to SCRA consumption.303 admissions on the ward (17 patients with 21 admis-
In the US, the rise in the use of SCRA was mir- sions). For four patients, this was their first hospital-
rored by a rise in the incidence of SCRA-related health isation and these patients presented with new
problems. For example, a report on monthly calls to psychotic symptoms; nine had a recurrence of a pre-
all poison centres, which are tracked by the National existing disorder. Symptoms included psychotic
Poison Data System, reported that adverse health symptoms, affective symptoms, disturbances and/or
effects or concerns about possible adverse health intense suicidal ideation/behaviour. The mean length
effects related to synthetic cannabinoid use increased of admission was 8.5 days, with significantly longer
330%, from 349 cases in January 2015 to 1,501 cases in duration for those presenting with psychotic symp-
April 2015.3,304 toms (13.1 days versus 4.4 days).310
A study of consecutive patients presenting to hos- It has also been noted that among patients with
pital emergency departments with SCRA toxicity psychiatric illness, the use of SCRAs may increase the
reported that the most common clinical features at number of nights spent in hospital and the need to ask
presentation were seizures and agitation.305 Others specifically about SCRAs has been highlighted.311
also reported that the most commonly reported
adverse health effects reported by this study during 13.12.7 Increasing SCRA Harms with New
this period were agitation (35.3%), tachycardia
(29.0%), drowsiness or lethargy (26.3%), vomiting Generations
(16.4%), and confusion (4.2%). Among 2,961 calls The evolution of clinical effects appears to be linked to
for which a medical outcome was reported, 11.3% of the identification of new SCRA compounds,312 such
callers had a major adverse effect; 47.5% had as increased risk of nephrotoxicity, for example (dis-
a moderate effect). Just over one-third (37.0%) had cussed in the following). It also appeared that in
a minor effect and (3.7%) had no effect. A total of 15 comparison to older generation SCRAs, such as
(0.5%) deaths were reported.306 JWH-018, newer generations, for example AB-
A case report of 21 patients presenting to an emer- CHMINACA MDMB-CHMICA, were associated
gency department with analytically confirmed SCRA with a higher prevalence of certain neuropsychiatric
use presents a broadly similar picture. The most fre- symptoms, more severe poisoning and duration of
quent clinical symptoms were tachycardia (12 cases), symptoms.313 This was reflected in an increase in
nausea/vomiting (11), somnolence (9) and hypergly- hospitalisation. US study of hospitalisation resulting
caemia (9). Less frequent symptoms were hypokal- from toxicity from synthetic cannabinoid receptor
aemia (4), syncope (4), dyspnoea (3), aggressive agonist exposure in the US increased significantly
behaviour (3), amnesia (2), diplopia (2) and seizures between 2010 and 2015.314 The study also identified
(2). Acute psychosis in one individual lasted for 5 that SCRA-associated clinical toxicity has been
311
changing since 2010. Each year, larger proportions of 13.13.2 Clinical Management of Acute
patients experienced more severe and prolonged
adverse effects resulting in higher utilisation of Toxicity
healthcare resources (e.g. emergency department Synthetic cannabinoid receptor agonists do not give
presentation, hospitalisation and therapeutic a positive result on routine urine screening tests for
interventions). metabolites of delta-9-tetrahydrocannabinol
Data from this study has shown that SCRA tox- (THC).247,328 Although there are currently specific
icity rarely results in death; however, the number of mass spectrometry tests for a number of SCRAs,
deaths increased each year. The authors speculate that these are currently not widely available to frontline
this trend may be due to the higher potency of new clinical staff. Moreover, the forensic chemical detec-
SCRAs. With increasing occurrence of bradycardia, tion of SCRA remains complex,71 not least because
hypotension, coma and respiratory depression, SCRA of continuously emerging compounds and the lack
toxicity may lead to higher fatality in the future, of reference samples in laboratories to identify
especially in the setting of polysubstance abuse.315 them.
Distribution of new SCRAs has been associated with It has been argued that given the diversity of
outbreaks of severe adverse effects. For example, in the available SCRA compounds, the constantly changing
US in 2012, an outbreak of acute kidney injury in composition even within brands, difficulties with
Wyoming and Oregon led to the discovery of XLR-11, detection and the limited available evidence, making
a previously unreported SCRA.316 ADB-FUBINACA specific clinical recommendations is currently
and AB-CHMINACA were also identified through out- problematic.329
break investigations of severe delirium in Georgia and It is suggested that people present to emergency
Florida.317,318 departments as a result of behavioural issues (agita-
Similarly, very low concentration MDMB- tion, psychosis, anxiety) or symptoms associated with
CHMICA have been reported in fatal cases and severely acute critical illness. These can include seizure, (them-
ill patients.319,320,321,322,323 Other new generation drugs selves potentially associated with rhabdomyolysis and
were associated with significant analytically confirmed hyperthermia), acute kidney injury and myocardial
toxicity include 5F-AKB-48 and 5F-PB-22.324 ischaemia and infarction.330,331
Symptoms of SCRA intoxication may be self-
13.12.8 Acute Withdrawal limiting and resolve spontaneously.76,286 Case reports
suggest that, in emergency departments, hydration
For withdrawal, see Section 13.14.
and monitoring may be enough for patients with
mild to moderate intoxication.74,239,241,243,332
13.13 Management of Acute Harms It seems that the majority of the single-substance
SCRA exposures resulted in self-limited symptoms
13.13.1 Identification and Assessment and required supportive care.333 The majority of
SCRAs cannot be detected by the screening tests for mild intoxications may only require symptomatic
phytocannabinoid delta-9-transtetrahydrocannabinol treatment and generally do not require hospital
(THC). Although laboratory techniques have been admission. For example, a nine-month study of the
developed to detect some compounds,116,325,326,327 National Poison Data System that reported 1,898
there are currently no widely available tests. In add- SCRA exposures found that the majority had self-
ition, more than one SCRA can be found within the limited signs and symptoms and received only symp-
same mixture or product, and the regular appearance tomatic treatment.286
of new compounds poses another challenge.16 SCRAs can have sedating effects on users, but
It has therefore been recommended that clinicians Armenian at al. (2017) have argued that clinically it
need to rely on clinical skills to detect SCRA use. This is best to characterise SCRAs as stimulants, since they
includes specifically asking about SCRA use, being lead to tachycardia, hypertension, hyperthermia, dia-
aware of the physiological effects, such as conjunctival phoresis, generalised tonic-clonic seizures, agitation,
injection, and having a high index of suspicion in the and delirium, similar to other CNS stimulant
context of unexplained deterioration despite drugs.334 If agitation and seizures are uncontrolled
a negative urine screen.248 they can lead to hyperthermia and rhabdomyolysis,
312
which can cause end-organ damage to the brain, kid- cases. Out of those, clinical effect lasted less than 8
neys, liver and coagulation system.335,336,337 hours in 78.4% of cases, between 8 and 24 hours in
The management of SCRA toxicity is symptomatic 16.6% and more than 24 hours in 4.9% of cases.286
and supportive, as no antidotes exist.106 Supportive
treatment is dependent on a patient’s specific presen- For up-to-date information and clinical guidance
tation. Treatment is primarily symptomatic, with air- please also refer to national and regional poison
way protection and control of agitated delirium being information services as well as national guidance and
the key initial steps in caring for the intoxicated local protocols.
patient.338 Intravenous fluids may be required to
treat electrolyte and fluid disturbances.339
It is argued that severe intoxications, involving
seizures, severe agitation or mental health disturb-
13.14 Harms Associated with Chronic
ances, arrhythmias and significant chest pain, should Use
be admitted to hospital for further investigation.340 In
cases of acute SCRA intoxication, it has been sug-
gested that an electrocardiogram should be per-
13.14.1 Dependence, Tolerance
formed, because misusers may present with and Withdrawal Symptoms
vomiting and associated hypokalaemia.341 The evidence remains limited, but it seems that
In a small case series of patients with psychosis SCRAs have the potential for misuse and
presentations to acute psychiatric settings, the clinical dependence.343 There is increasing evidence that the
presentations were characterised by an acute onset of chronic use of SCRAs may be associated with
agitation and aggressive behaviour. The symptoms tolerance.76 Tolerance may develop more quickly for
decreased in intensity and frequency in no less than SCRAs than for natural cannabis and the quicker
72 hours. The management of acute intoxications development of tolerance may contribute to the
included treating the symptoms with benzodiazepines higher dependence potential in comparison to natural
and antipsychotic medications. In addition, vital cannabis.238,344
parameters were monitored and nursing observations Although the evidence is currently limited, SCRAs
were increased. These measures led to rapid and suc- may have greater dependence liability than natural
cessful resolutions of symptoms and reduced the need cannabis and this may develop more quickly.
for transfer to more intensive care settings. Withdrawal symptoms have been reported to be the
Furthermore, they promoted more rapid step-down primary reason given by daily users for their con-
and recovery in the community.342 tinued use.345
Benzodiazepines may be of benefit to patients who Abrupt discontinuation of prolonged daily SCRA
present with symptoms of anxiety, panic and use is associated with withdrawal symptoms, which can
agitation.74,94,107,239 Antipsychotic medication may be severe and prolonged. Symptoms include craving,
be indicated for some patients, especially those who lack of appetite, irritability, sleep disruptions, drug
present with agitation or aggression, when the patient craving, insomnia, nocturnal nightmares, profuse dia-
has a history of psychotic disorders, and when the phoresis, headache, severe anxiety, nausea and vomit-
psychotic symptoms do not remit spontaneously or ing, diarrhoea and loss of appetite. They can also
with supportive care.93,94,249,252 include in severe cases tremor and reoccurring seizures
Only a few specific interventions have been and cardiovascular and respiratory risks (tachycardia,
described. Intravenous benzodiazepines have been chest pain, palpitations, dyspnoea) and suicidal
reported for the management of seizures and moni- ideation.238,248,346–356 It has been suggested that the
tored observation for cases of SCRA-related magnitude of withdrawal may correspond to quantity
psychosis.73 One study reported that the most com- of use.
mon intervention for patients with a single-agent There may be a link between the severity of with-
SCRA exposure was the administration of intraven- drawal symptoms and the quantity of SCRA used
ous fluids (25.3%), followed by benzodiazepine (16%), daily. A study found for example a link between
supplemental oxygen (5.8%) and anti-emetics (4.7%). amount smoked and whether the patient required
The duration of clinical effect was recorded in 907 outpatient care, inpatient care or complex care, with
313
intensity of care increasing with amount of SCRA For example, three patients who presented to an
used daily.357 emergency department with persistent psychosis,
which did not resolve within 24–48 hours, required
13.14.2 Other Harms of Chronic Use at least 2 weeks of hospitalisation. Two of the patients
were treated with haloperidol and one with risperi-
Knowledge of the long-term effects of the use of
done and although the patients demonstrated
SCRAs is still limited. Although no experimental
improvements, in no cases had symptoms resolved
data are available, it is expected that these SCRAs, as
completely upon discharge.94
lipophilic compounds, have high volumes of distribu-
tion. It is therefore likely that chronic use of them can
lead to accumulation of the substances themselves 13.15 Management of Harms Related
and/or their metabolites in fat-containing compart- to Chronic Use
ments in the body.3 There is also speculation that
It has been argued the onset and severity of SCRA
some of these products, and particularly the ami-
withdrawal symptoms reflect greater CB1 receptor
noalkylindoles carrying a naphthyl moiety, may have
efficacy and pharmacokinetic differences relative to
carcinogenic potential.358
THC. As such, it has been argued that managing and
There may also be gastrointestinal effects, treating SCRA withdrawal poses a unique clinical
which range from mild symptoms, such as challenge. Withdrawal symptoms range from mild,
abdominal pain and vomiting, to more severe
requiring only outpatient care, to severe, warranting
ones such as intestinal ischaemia. One case report
inpatient care and continuous monitoring.362
suggests that frequent habitual smoking of SCRAs
It has been suggested that many adverse effects
can cause cannabinoid hyperemesis syndrome,
associated with acute intoxication are identical to
which is mediated by cannabinoid receptors.359
some withdrawal symptoms and consequently, they
Xerostomia28,90 has been reported, as well as lac-
are treated similarly.
tic or metabolic acidosis.28,247 Patients who present with irritability, agitation,
Case reports have described multiple-organ- anxiety, and seizures associated with intoxication or
failure-associated symptoms of acute SCRA
withdrawal363,364,365 are generally administered
toxicity.360 There is one case report of pulmonary
benzodiazepines as a firstline treatment. In cases
infiltrates associated with chronic SCRA use.361
where patients did not respond to benzodiazepines,
Psychosis has also been reported among frequent
there are reports of neuroleptics being administered
users. One study describes new-onset psychosis in
for acute psychosis and agitation366,367 and psychotic
otherwise healthy young men.93 A case series
symptoms.368 Some have argued that the use
reported on ten patients admitted in the context of of second-generation antipsychotics may be
SCRA use, none of whom had a history of psychosis. a rational approach as they may present with lower
All of the patients reported smoking SCRAs on more
risk of increase in cravings369 and a more significant
than one occasion (ranging from four uses over
antagonism at 5-HT2A receptors.370 There are reports
a three-week period to daily use for a year and
of the prescribing of quetiapine371,372 for example.
a half). The onset of psychotic symptoms varied
The administration of antipsychotics with antidepres-
from after the fourth use to after more than a year
sants has also been described in cases of concurrent
of use. Presentations were characterised by paranoid
depression.233
delusions, ideas of reference and a disorganised, One case report has described the use of naltrex-
confused mental state. It was noted that a distinct, one, which appeared to reduce SCRA cravings associ-
though waxing and waning, stuporous appearance
ated with detoxification.373
was often present for weeks after last SCRA use. The
Anti-emetics have been administered for hyper-
mood of patients was described as generally flat,
emesis although are not always effective.374,375
with most patients reporting significant depressive
symptoms and 40% describing suicidal ideation.
Hospitalisation generally lasted 6–10 days. 13.15.1 Clinical Management
Although psychotic symptoms did remit in most of Dependence and Chronic Use
patients, 30% were noted to have persistent psych- In comparison with natural cannabis, SCRAs show
osis at eight-month follow-up.93 a potential need for more intensive management.376
314
13.15 Management of Harms Related to Chronic Use
Patients with SCRA withdrawal symptoms often Update 6 June 2017. Available at: www.emcdda.europa.eu/sys
require intense medical support and admission to tem/files/publications/2753/POD_Synthetic%20cannabin
oids_0.pdf [last accessed 26 April 2022].
inpatient detoxification.377,378,379
Psychosocial interventions remain the most effect- 5. Winstock AR, Barratt MJ. Synthetic cannabis: a comparison of
patterns of use and effect profile with natural cannabis in
ive treatment for the management of harmful patterns
a large global sample. Drug Alcohol Depend 2013;131(1–
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Psychotherapeutic strategies to reduce use and/
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328
Chapter
Conclusion
14
This is the first textbook to undertake a comprehensive, entation and these can be broadly considered as
in-depth review of the literature relating to novel psy- stimulant, sedative/dissociative and hallucinogenic.
choactive substances (NPS) and club drug harms and Using this approach, we hope that clinicians will be
their clinical management. The book builds on the able to assess and manage unfamiliar substances using
work of the NEPTUNE project, which has been review- familiar approaches, delivering what may well be life-
ing the evidence on this fast-moving area for the last saving clinical interventions. We strongly suggest that
decade. Some predicted that NPS would be a short- all health professionals who support people who use
lived phenomenon; however, drug markets continue to drugs need to develop the skills to assess emerging
rapidly evolve with new, and typically more harmful, drugs and manage their harms. This will include
substances appearing with alarming frequency. The health staff working in drugs services, mental health,
increased role of the Internet and social media plat- acute care settings, sexual health services and other
forms to sell drugs, including NPS and club drugs, is areas in contact with populations with a high preva-
a further example of the pace of change. lence of drug use. To achieve this, appropriate train-
At the time of writing, the range of substances ing and standardised clinical competencies will be
available on drug markets has never been wider. needed and these should be integrated into core cur-
While NPS have not replaced existing illegal drugs, ricula. We see this as an essential next step.
they are now established throughout drug markets This book has rightly focused on clinical harms
both in terms of substances that people seek to use, and their management; however, NPS continue to
as well as substances that are used to adulterate other present severe challenges to researchers and policy
drugs, including counterfeit medications, with some- makers. The policy challenge extends from public
times catastrophic results. The mortality resulting health to law enforcement and currently there is
from adulteration of illegal drugs with opioid NPS a limited evidence base to guide decision making.
such as fentanyl analogues, is a devastating example. Researchers have a crucial role in improving the
Given the large number of new substances and the understanding of emerging drugs, their harms, the
constantly evolving drug market, we have attempted populations most at risk and potential new treat-
to future proof this book by suggesting that health ments. Funding for further research is a priority.
professionals approach unfamiliar NPS and club NPS and club drugs will present challenges to
drugs by considering the primary psychoactive effect clinicians, researchers and policy makers for the fore-
of the substance. The psychoactive effect should be seeable future and we hope that this book will play
based upon the clinical signs and symptoms at pres- a part in the developing response.
329
Chapter
Conclusion
14
This is the first textbook to undertake a comprehensive, entation and these can be broadly considered as
in-depth review of the literature relating to novel psy- stimulant, sedative/dissociative and hallucinogenic.
choactive substances (NPS) and club drug harms and Using this approach, we hope that clinicians will be
their clinical management. The book builds on the able to assess and manage unfamiliar substances using
work of the NEPTUNE project, which has been review- familiar approaches, delivering what may well be life-
ing the evidence on this fast-moving area for the last saving clinical interventions. We strongly suggest that
decade. Some predicted that NPS would be a short- all health professionals who support people who use
lived phenomenon; however, drug markets continue to drugs need to develop the skills to assess emerging
rapidly evolve with new, and typically more harmful, drugs and manage their harms. This will include
substances appearing with alarming frequency. The health staff working in drugs services, mental health,
increased role of the Internet and social media plat- acute care settings, sexual health services and other
forms to sell drugs, including NPS and club drugs, is areas in contact with populations with a high preva-
a further example of the pace of change. lence of drug use. To achieve this, appropriate train-
At the time of writing, the range of substances ing and standardised clinical competencies will be
available on drug markets has never been wider. needed and these should be integrated into core cur-
While NPS have not replaced existing illegal drugs, ricula. We see this as an essential next step.
they are now established throughout drug markets This book has rightly focused on clinical harms
both in terms of substances that people seek to use, and their management; however, NPS continue to
as well as substances that are used to adulterate other present severe challenges to researchers and policy
drugs, including counterfeit medications, with some- makers. The policy challenge extends from public
times catastrophic results. The mortality resulting health to law enforcement and currently there is
from adulteration of illegal drugs with opioid NPS a limited evidence base to guide decision making.
such as fentanyl analogues, is a devastating example. Researchers have a crucial role in improving the
Given the large number of new substances and the understanding of emerging drugs, their harms, the
constantly evolving drug market, we have attempted populations most at risk and potential new treat-
to future proof this book by suggesting that health ments. Funding for further research is a priority.
professionals approach unfamiliar NPS and club NPS and club drugs will present challenges to
drugs by considering the primary psychoactive effect clinicians, researchers and policy makers for the fore-
of the substance. The psychoactive effect should be seeable future and we hope that this book will play
based upon the clinical signs and symptoms at pres- a part in the developing response.
329
Index
acceptance and commitment therapy MDMA. arylcyclohexylamines, see also

(ACT), 32 medical and other legitimate uses, ketamine; methoxetamine
acetylfentanyl, 79–80, 84 146 (MXE), 102, 109, 111
acrylfentanyl, 79, 84 prevalence in northern and eastern attention deficit hyperactivity disorder,
acute kidney injury, SCRA-related, 310 Europe, 144 203, see ADHD (attention
acute toxicity, factors linked to, 9 amphetamine-type stimulants (ATS), deficit hyperactivity
ADHD (attention deficit hyperactivity 146 disorder).
disorder) acute toxicity, 148 autistic adults, MDMA-assisted
amphetamine dependence and, 154 diagnosis and assessment, 151 psychotherapy study, 170
amphetamine treatment, 146 poly-drug use, 158 AV411 (ibudilast), 217
methamphetamine treatment, 203 serotonin syndrome, 149–150,
agitation, benzodiazepine treatment, 153, 158 behavioural couples therapy (BCT),
51, 152, 181, 252, 254, 313, symptoms/features, 148–149 effectiveness in treatment of
314 chronic harms drug misuse, 32
akathisia, serotonin syndrome and, 151 dependence and withdrawal, 153 benzodiazepine, treatment, agitation,
alcohol diagnosis and assessment, 51, 152, 181, 252, 254, 313,
co-ingestion 154 314
amphetamine-type stimulants, stepped care, 155–156 benzodiazepine misuse
158 management, 154 outcomes associated with
benzodiazepines, 67, 68, 70 physical and psychiatric/ concomitant opioid use, 68
cathinones, 245, 251 psychological harms, poor outcomes associated with,
fentanyl, 84 153–154 67
GHB/GBL, 41, 43, 44, 45, 53 effects, desired, 147 reasons for, 67–68
deaths related to, 40, 43 harm reduction advice, 158 benzodiazepines, 65
hallucinogens, 273 high-risk injecting and sexual acute harms, 68
ketamine, 109–111, 117, 119 behaviours, 147–148 acute toxicity
MDMA, 171, 174, 273 mortality, 148 clinical management, 70
risks of, 179 pharmacology, 146 symptoms/features, 68
mephedrone, 251 prevalence and patterns of use, and aggressive behaviours, 70
deaths related to, 251 147 availability to purchase, 66
nitrous oxide, 134 public health and safety, 158 clinical uses
opioids, 84 routes/modes of ingestion and agitation treatment, 51, 152, 181,
SCRAs, 304, 310 dosing frequency, 147 254, 313, 314
lifetime use, 303 similarity to MDMA, 144 efficacy, 65
effects of masked by WHO definition, 146 GHB/GBL withdrawal syndrome
methamphetamine, 210 antipsychotic medications treatment, 50, 51
HPPD triggered by, 282 amphetamines and, 157–158 hallucinogen intoxication
MDMA, research on the use of for benzofuran compounds and, 188 management, 279, 280
alcohol use disorder, 170 GHB/GBL and, 40, 51 HPPD intervention, 283
relapse prevention approach, 32 hallucinogens and, 280 ketamine toxicity treatment, 111
similarities in patterns of use with ketamine and, 117 ketamine withdrawal
NPS, 23 methamphetamines and, 211, 214, management, 117
Alcoholics Anonymous (AA), 31 216 methoxetamine toxicity
amphetamines, 144 SCRAs and, 313, 314 treatment, 112
drug interaction with opiates, 84 synthetic cathinones and, 252 SCRA intoxication management,
effects on dopamine, 143 anxiety, self-medication 313
empathogenic effects, 165 GHB/GBL, 40 SCRA withdrawal treatment, 314
see also entactogenic/ ketamine, 106 serotonin syndrome treatment,
empathogenic effects, nitrous oxide, 133 152
330
Index
synthetic cathinone intoxication modes and patterns of use, 188 cannabis, co-ingestion
treatment, 252 pharmacology, 187, 277 GHB/GBL, 39
synthetic cathinone withdrawal N-Benzylphenethylamines. hallucinogens, 273
management, 254 N-Benzylpiperazin (BZP), 144 methamphetamine, risks, 210
dependence and withdrawal, 70–71 beta-keto (bk) amphetamines, 144 cardiac disease, risks of nitrous oxide
management, 71–72 bingeing behaviour use, 134
management, Cochrane review, hallucinogens, 272 carfentanyl, 79, 87
72 ketamine, 112 catatonia, 109
symptoms/features, 70–71 bipolar disorder, benzodiazepines and, cathinone/cathine, legal status, 241
treatment, 71 71 cathinones, 6
effects of, 68 blood–brain barrier permeability empathogenic effects, 165
emergence as recreational drugs, 66 amphetamine-type stimulants, 146 synthetic, see synthetic cathinones.
fatal toxicity index, 9 fentanyl, 80 CBD (cannabidiol), 300, 309
half-life, 66 GHB/GBL, 38 chemsex
half-life and duration of effects, 66 MDPV, 243 association with risk and adverse
and high-risk sexual behaviours, methamphetamine, 202 effects, 8
69–70 nitrous oxide, 131 concept of, 8, 209
legal status, 65, 66 synthetic cathinones, 242 deaths associated with, 40
mental health co-morbidity, 71 Bluelight, 8 drugs typically used, 8, 38–39, 40,
methamphetamine come-down bodybuilding, use of GHB in, 38 208
management, 206 brachycardia, co-use of substances mephedrone, 7
misuse of as worldwide public health and, 179 methamphetamine, 208, 209
concern, 65 brief interventions NPS use, 7, 30
modes of use, 66–67 extended, 29 role of in problematic GHB use,
mortality, 69 WHO manual, 27 40
most common, 66 British Association for club drugs
pharmacology, 65–66 Psychopharmacology, 3 concept and background, 1
poly-drug use, 67 bromo-dragonfly definition, 4–6
population groups most likely to adverse effects, 276 overall use, 7
misuse, 67–68 co-ingestion combinations, 273 users and contexts of use, 7
potency, 66 effects, onset and duration, 272 ‘clubbers’
comparison of NPS with toxicity, 275 mephedrone use, 244
traditional benzodiazepines, adverse effects, 277 methamphetamine use, 204
69 buprenorphine, 85, 88 cluster headaches, therapeutic
prevalence and patterns of use, 67 treatment of amphetamine and potential of LSD and
reasons for benzodiazepine misuse, methamphetamine psilocybin, 274
67–68 dependence with, 218 cobicistat, 44, 102, 210, 251
reported adverse effects, 69 bupropion cocaine
reported hospital presentations and clinical uses, 243 co-ingestion risks
overdoses, 69 synthetic cathinones contained in, MDMA, 179
research evidence, 65 240 methamphetamine, 210
risks, 68–69 treatment of amphetamine and dopamine reuptake action, 143
co-ingestion with ketamine, 110 methamphetamine drug interaction with fentanyl, 84
street names, 65 dependence with, 157, 217, fentanyls found in products sold as,
targeting of at long-term/ 218, 221 81
problematic drug users, 23 1,4-butanediol, 37 prevalence in western and southern
testing, 70 GHB conversion process, 37 Europe, 144
benzofurans high anion gap metabolic acidosis Cochrane reviews
acute toxicity, 188 associated with intoxication, amphetamine
management, 189 42 dependence treatment, 218
chronic harms, management, 189 industrial use, 38 psychosis treatment, 154, 158
clinical uses, 188 metabolism blocked by ethanol and benzodiazepine discontinuation, 72
derivatives, 187 fomepizole, 38 CBT and CM approaches, 29
effects butane, 134 methamphetamine, 202
adverse, 277 psychosocial interventions
desired, 188 caffeine cocaine and psychostimulant
empathogenic, 165 adulteration of MDMA with, amphetamine disorders, 215
unwanted, 188 166–167, 171 stimulant use, 155
fatal toxicity index, 9 risks of co-intoxication with codeine, methamphetamine and, 210
harm reduction advice, 189 MDMA, 179 cognitive behavioural therapy (CBT)
331
Index
for amphetamine-type stimulant- club drug and NPS-associated, synthetic cathinones and, 242–243,
use disorders, 156 limited data, 12 249, 252
benzodiazepine dependence GHB/GBL-associated, 40 driving
treatment, 72 hallucinogen-associated, 279 ketamine and, 119
effectiveness of interventions based ketamine-associated, 110 methamphetamine and, 222
on, 29 MDMA-associated, 173–174 SCRA use and, 315
high-risk sexual behaviour methamphetamine-associated, 206 drug acquisition, new markets for, 8–9
interventions, 220, 222 methoxetamine-associated, 110 drug dependence treatment, best
methamphetamine and, 212, 215 nitrous oxide-associated, 133 practice principles, 13
relapse prevention treatment, 32 opioid-associated, 92 drug testing for club drugs and NPS,
SMART groups, 31 benzodiazepines commonly limitations of, 11–12
structured drug treatment, evidence implicated in, 68 drug treatment services
for, 29 PMMA-associated, 177 indicators for referral, 25
substance-misusing MSM, 31 SCRA-associated, 305 as setting for higher-intensity PSIs,
third-wave models, 32 synthetic cathinone-associated, 251 25
cognitive-behavioural therapy (CBT) deep-vein thrombosis, injecting risk, Drugs Forum, 8
high-risk sexual behaviours, 220 145, 254
relapse prevention treatment, 32 delta-9-tetrahydrocannabinol, 299, 312 Early Warning Advisory on New
coma/loss of consciousness, 41 depression Psychoactive Substances
Commission on Narcotic Drugs, 6 ketamine (UNODC), 1
communication about drugs by users, role of in treatment, 101, 103, 116 ecstasy
8–9 self-medication with, 106 co-ingestion with GHB/GBL, 39
community reinforcement approach methoxetamine, potential as see also MDMA (ecstasy).
(CRA), 22, 29, 32, 155 treatment for, 103 effects/harms of club drugs and NPS,
structured drug treatment, evidence detoxification, CBT-based relapse 9–12
for, 29 prevention treatment new generations of substances, 11
contingency management (CM) following, 32 toxicity and other acute harms, 9–10
concept, 32 dexamphetamine, treatment of unpredictability, 10–11
effectiveness of interventions based amphetamine and electro-acupuncture,
on, 29 methamphetamine methamphetamine and, 217
methamphetamine, dependence and dependence with, 157, 217 electroconvulsive therapy (ECT),
withdrawal, 216 dextromethorphan (DXM), 101, 105, psychosis and, 216
methamphetamine and, 215, 216 179 emergency department admissions/
structured drug treatment, evidence diabetic ketoacidosis (DKA), presentations
for, 29 ketamine, chronic harms, amphetamine users, 154
control of NPS, legal, changes in, 6 115 butane mistaken for nitrous oxide,
counterfeit medications, risks of using, diabetics 134
69 mephedrone, potential danger to chemsex and, 208
cultural competence, role of in service people with, 250 chest pain after methamphetamine
engagement and uptake, 23, risks of ketamine use, 115 use, 207
40, 222 risks of MDMA use, 179 GHB users, 41
CYP2B6 inhibitors, ketamine and, 102 risks of synthetic cathinone use, 250 ketamine users, 107–109, 111
CYP2D6 inhibitors dialectical behaviour therapy (DBT), MDMA users, 174, 180
examples of, 210 32 methamphetamine users, 207,
GHB and, 44 diphenidine, 101, 102 210–211, 213
mephedrone and, 251 acute toxicity, 110 NPS and drug-related presentations,
methamphetamine and, 210 dissociative drugs, 101–102, see also 12
CYP3A4 inhibitors ketamine; methoxetamine psychosis, 154, 314
GHB and, 44 (MXE); nitrous oxide (Nb SCRA users, 302, 310, 312, 314
ketamine and, 102 2O), synthetic cathinone users, 250, 252
mephedrone and, 251 dopamine clinical assessment, 251
CYP450 inhibitors, ketamine and, 115 amphetamines and, 153 emergency departments, as setting for
cyproheptadine, serotonin syndrome amphetamine-type stimulants and, lower-intensity PSIs, 25
management, 180 153 endocarditis, injecting risk, 145, 207,
ketamine and, 102, 112 254
‘date rape’, GHB implicated in, 38 MDMA and, 168, 178 entactogenic/empathogenic effects
death methamphetamine and, 213 definition, 165
amphetamine-type stimulants, 148 methoxetamine and, 102, 202 difficulty of replicating, 165
benzodiazepines, 69 methoxphenidine and, 110 MDMA, 165
increase in mortality risk, 67 stimulants and, 143, 144 pharmacology, 169
332
Index
role of serotonin, 143 ocfentanil, 83 gamma-hydroxyvaleric acid (GHV), 37

substances which produce, 165, 166, overdose gamma-valerolactone (GVL), 37, 38
245 atypical characteristics, 82 gender differences
epilepsy, risks of nitrous oxide use, 134 management, 87 MDMA
erectile dysfunction, 172, 204 pharmacology, 79–80 adverse effects, 175, 177
ergolines poly-drug use, 84–85 fatalities, 177
adverse effects, 276 risks of, 82, 84 nitrous oxide effects, debate around,
routes/modes of ingestion and position on the illegal drug market, 133
dosing frequency, 273 79 stimulants, responses to, 157
Erowid, 8 potency, 81, 84 GHB/GBL
European Drug Emergencies Network public health risks, 82, 88 accidental overdoses, 41
(Euro-DEN), 12 research evidence, 79 acute harms, poly-drug use and drug
‘excited delirium’ risk of acute toxicity and overdose, interactions, 44
clinical management, 280 78 acute toxicity, 40–44
fatalities, 278 testing limitations, 85 cardiovascular effects, 43
hallucinogens, 278 toxicity comparison with heroin, 84 CNS and respiratory effects, 43
exercise withdrawal symptoms, 88 diagnosis and assessment, 45
methamphetamine use and, 216 festival attendees, adoption of dosing neurological and psychiatric
potential for treatment of substance related harm reduction effects, 42
use disorder, 156 strategies by, 14 symptoms/features, 42–44
exogenous obesity, methamphetamine flashbacks, hallucinogen related, see treatment outcome, 46
treatment, 203 also hallucinogen persisting treatment outcome, London
perception disorder (HPPD), study, 46
facilitating access to mutual aid 280–281 vomiting, 43–44
(FAMA), 31 4-fluoroamphetamine (4FA), 167 association with sexual assault, 53
fentanyl fluoxetine chronic harms, 47–53
estimated lethal dose, 81 MDMA and, 179 dependence and withdrawal,
legal status, 78 methamphetamine and, 210 47–49
fentanyl NPS formal psychological treatment see also GHB/GBL, withdrawal
acute toxicity, 9 benefits for service users completing syndrome.
see also fentanyls. detoxification, 31 for men who have sex with men,
fentanyl-induced respiratory muscle competences required, 30 49
rigidity (FIRMR), 82 formulation-based approach, 30 research recommendations, 49
treatment, 86 higher-intensity PSIs, 29–31, 156 clinical and other uses, 38
fentanyls multiple-model perspective, 30 demographic and socio-economic
acetylfentanyl, 83 FRAMES model of PSI, 27 perspective, 39
acrylfentanyl, 83 example, 28–29 drugs commonly co-ingested with,
acute hams, 81–84 39
acute toxicity, naloxone treatment, gamma-aminobutyric acid (GABA), effects, desired and unwanted, 39–40
85 37, 65 fatal toxicity index, 9
clinical settings, 85–86 gamma-butyrolactone (GBL) half-life, 41
community settings, 86–87 industrial use, 38 high-risk sexual behaviours, 40, 49
butyrylfentanyl, 83 see also GHB/GBL. legal status, 37
carfentanyl, 83 gamma-hydroxybutyrate (GHB) methamphetamine come-down
chronic harms, 87–88 association with high-risk sexual management with, 206
dangers of, 80, 82–84 behaviours, 39, 40 mortality, 40
dependence and withdrawal, 87–88 dose-dependent effects, 41 overdose
management, 88–89 half-life, 37 clinical management, 45–46
effects hazard profile, 41 harm reduction measures, 46
adverse, 81–84 implication in crime, Hungarian pharmacology, summary, 37–38
desired, 81 study, 38 prevalence and patterns of use,
long-term, 88 implication in ‘date rape’ and sexual 38–39
examples, 83 assaults, 38, 40 psychosocial interventions, 50
non-pharmaceutical fentanyl precursors, 37 public health and safety, 53
analogues, 79 risks of co-ingestion with recreational use, 37
4-fluorobutyrylfentanyl, 83 methamphetamine, 210 research evidence, 37
furanylfentanyl, 83 role in alcohol and opiate routes/modes of ingestion and
legal status, 78 detoxification, 38 dosing frequency, 39
methylfentanyls, 83 see also GHB/GBL. withdrawal syndrome, 47–49
mode and patterns of use, 80–81 gamma-hydroxyvaleric (GHV), 38 acute, 44, 46
333
Index
clinical management, 50–52 onset and duration, 271–272 derivation, 31

medications, 51 unwanted, 274–275 formal psychological treatment,
self-medication/detoxification, harms associated with newer 29–31, 156
51 generations of, 11 residential treatment, 31
identification and assessment, 50 legal status, 267–269 settings for delivery, 25–26
medically assisted detoxification, pharmacology, 269–270 structured drug treatment, 27–29
52 lysergamides, 268 see also lower-intensity PSIs
supporting recovery, 52–53 phenethylamines, 268–269 high-risk behaviours
predictors, 47 tryptamines, 268 fentanyl use and, 88
rapid onset and duration, 47 poly-drug use, 273 ketamine injecting related, 118
symptoms, 38, 47, 48–49 potency, 271 misuse of benzodiazepines
persistence, 49 prevalence and patterns of use, associated with, 67
psychiatric symptoms, 49 270–271 synthetic cathinone related, 254
variations and unpredictability, 48 micro-dosing, 271 see also high-risk sexual behaviours;
Glasgow Coma Scale, 107 research evidence, 269 injecting
Global Drug Survey routes/modes of ingestion and high-risk sexual behaviours
on ketamine, 103 dosing frequency, 271–273 amphetamine dependence and, 154
on nitrous oxide, 131 ergolines, 273 amphetamine-type stimulant use
see also World Drug Report. phenethylamines, 273 and, 147–148
gonorrhoea, 40 tryptamines, 272 benzodiazepine NPS and, 69–70
grapefruit juice, co-ingestion with self-medication uses, 274 CM and CBT interventions study for
fentanyl, 84 terminology, 267 methamphetamine users,
therapeutic effects, 274 220
hallucinogen persisting perception haloperidol GHB use and, 39, 40
disorder (HPPD), 280–281 MDMA and, 179, 181 GHB/GBL use by MSM and, 40, 49
benzodiazepine intervention, 283 methamphetamine and, 210 substance misuse and, 12
cannabinoids and, 309 harm reduction measures/advice HIV infection
comparison of type I and type II, adoption by festival attendees, 14 amphetamine dependence and risk
282–283 amphetamine-type stimulants, 158 of, 154
contested nature, 281 benzofurans, 189 GHB/GBL
definitions, 281, 283 club drug and NPS use, 13–14 and ART, 44–45
diagnosis and assessment, 281, 282 GHB/GBL overdose, 46 relationship with, 40
symptoms/features, 283 ketamine, 119 injecting and risk of, 145
treatment, 283–284 MDMA, 186–187 methamphetamine and, 208–209,
hallucinogens methamphetamine, 222 215
acute toxicity, 275–280 nitrous oxide, 137 potential transmission as public
adverse effects SCRAs, 315 health risk, 53
ergolines, 276 synthetic cathinones, 254 prevalence in MSM who use
phenethylamines, 276–277 hepatitis C methamphetamine, 204
physiological, 276–278 cognitive impairment and, 215 synthetic cathinone injection and,
psychological/psychiatric, 278 injecting risk 250
clinical management, 280 amphetamine-type stimulants, HIV services, as setting for lower-
psychosis, 278 148 intensity PSIs, 25
trauma and self-injury, 278 fentanyls, 88 homelessness
tryptamines, 277–278 synthetic cathinones, 145, 250 methamphetamine use and, 216
clinical management, 279–280 methamphetamine use, association SCRA use associated with, 8, 304
mortality, 279 with, 208, 213 5-HT2A receptors
symptoms/features, 275–279 heroin effects of MDMA, 168
chemical groups, 267 comparison of fentanyl with, 81 hallucinogens and, 271
chronic harms, 280–284 overdose, 81, 87 ketamine activation, 102
brain imaging studies, 280 toxicity, 84 second-generation antipsychotics
dependence and withdrawal, 280 fentanyls sold as replacement for in and, 314
HPPD, 280–284 European countries, 80–81 5-HT2A antagonists, 152
see also hallucinogen persisting methamphetamine come-down
perception disorder (HPPD). management, 206 injecting
psychosocial interventions, 284 high anion gap metabolic acidosis amphetamine-type stimulants
clinical uses, research on, 270 (HAGMA), associated with injection, risks associated
effects GHB/GBL and 1,4-BD with, 147–148
adverse, 276–279 intoxication, 42 deep-vein thrombosis risk, 145, 254
desired, 273–274 higher-intensity PSIs endocarditis risk, 145, 207, 254
334
Index
fentanyl, risks associated with, 88 acute, 108 serotonin syndrome, 149, 152
and HIV infection, synthetic desired, 105–106 hyperpyrexia/hyperthermia,
cathinone, 250 half-life, 102, 113 175–177
HIV infection risk, 145, 250 harm reduction advice, 119 clinical management, 180
ketamine, high-risk behaviours, high risk sexual and injecting hyponatraemia, 177–178
103–104, 118 behaviours and, 103–104, gender differences, 177
methamphetamine, high-risk 118 intracranial haemorrhage, 179
behaviours, 204, 208, injecting, infection risk, 118 liver failure, 179
209–210 ‘keying’, 104 poly-drug use, 171, 175, 178,
stimulants legal status, 102 179–180, 186–187
evidence of increase in, 144 medical uses, 101, 103 serotonin syndrome, 149, 152
harms associated with, 145 treatment of depression, 101, 103, psychiatric presentations, 178
synthetic cathinones 116 clinical management, 181
high-risk behaviours, 243, monitoring recommendations, 103 pulmonary harms, 178–179
250–251 pharmacology, 102–103 serotonin syndrome, 149, 152
HIV and hepatitis C infection, poly-drug use, 106–107, 109 clinical management, 180
145, 250 prevalence and patterns of use, suicidal ideation and suicide,
risk of infection, 254 103–104 178
International Association of Forensic public health and safety, 118–119 symptoms/features, 175–176
Toxicologists (TIAFT), 10 research evidence, 102 adulteration with PMMA, 173–174
The International Association of risk of accidents and assaults, 119 alternatives and variations, 166–167
Forensic Toxicologists routes/modes of ingestion and analogues and NPS with similar
(TIAFT), 10 dosing frequency, 104 effects, 165
International Drug Control self-medication uses, 106 chronic harms, 181
Conventions, 6 street names, 102 cognitive deficits, 182
International Standards for Treatment ketamine bladder, 114 dependence and withdrawal,
of Drug Use Disorders, 13 ‘keying’, 104, 246 183–185
Internet, role in the sale of drugs, 8–9 khat, 240 treatment, 185–186
depression, treatment, 186
ketamine legal control of NPS, changes in, 6 heart disease, 185
acute toxicity, 106–107 ‘legal highs’, 5 management, 185–186
clinical management, 111–112 ketamine and PCP analogues, 105 neurotoxicity, 181–182
diagnosis and assessment, 111 LGBT (lesbian, gay, bisexual and poly-drug use and, 183
mortality, 110 transgender) populations, psychiatric harms, 183
poly-drug use, 109 use of club drugs and NPS, 8 sleep problems, 185
symptoms/features, 107–108 loss of consciousness/coma, 41 vascular problems, 185
analogues and derivatives of lower-intensity PSIs clinical use, 169–170
ketamine and PCP, 107 brief interventions, 26–27 effects
chronic harms, 112–116 FRAMES model desired, 172
cognitive impairment, 115–116 example of, 28–29 unwanted, 173
depression, 116 brief interventions, FRAMES model gender differences, 175, 177
diabetic ketoacidosis (DKA), 115 framework, 27 empathogenic effects, 165
diagnosis and assessment, 116 settings for delivery, 25 fentanyls found in products sold as,
gastrointestinal toxicity, 114–115 typical elements, 26 81
interaction with antiretroviral see also higher-intensity PSIs. half-life, 169
medications, 115 LSD (lysergic acid diethylamide) hallucinogen co-ingestion, 273
memory impairment, 115–116 clinical trials, 270 harm reduction measures, 186–187
neurological effects, 116 nitrous oxide interaction, 134 increase in average dose and
psychological support, 117 safety ratio, 276 strength, 167–168
social harms, 116 lysergamides, pharmacology, 268 legal status, 168
urinary tract damage, 113–114 mortality, 173–174
management, 117–118 mapping tools, enhancing outcomes of pharmacology, 168, 169
see also ketamine bladder. drug treatment with, 29 prevalence and patterns of
dependence and withdrawal, MDMA (ecstasy), 165 recreational use, 170–171
112–113 acute toxicity, 174–175 public health considerations,
aftercare and support, 117 cardiac dysfunction, 178 186–187
pharmacological interventions, clinical management, 180–181 research evidence, 168
117 diabetic ketoacidosis, 179 routes/modes of ingestion and
withdrawal symptoms, 113 drug interactions, 179–180, dosing frequency, 171
effects 186–187 see also benzofurans.
335
Index
MDPV (3,4- comparison with benzofurans, 188 psychosocial interventions,

methylenedioxypyrovalerone), dependence potential, 252 215–217
240 driving and, 254 social interventions, 216–217
acute toxicity, 249 effects treatment completion and
effects, desired and unwanted, 248 desired, 247 effectiveness, 219–221
legal status, 241 unwanted, 247–248 withdrawal symptoms, 212
pharmacology, 242–243 emergence as a club drug, 170 drug interactions, 210
routes/modes of ingestion and legal status, 243 effects
dosing frequency, 246 motives for using, 7 desired, 205
street names, 241 pharmacology, 242 unwanted, 205–206
memory impairment potential danger to people with half-life, 205
benzodiazepine-associated, 68 diabetes, 250 harm reduction measures, 222
ketamine-associated, 107, 115–116 routes/modes of ingestion and high-risk behaviours
MDMA-associated, 173 dosing frequency, 246 injecting, 208
methamphetamine-associated, 211 street names, 241 sexual, 204–205, 208–209
SCRA-associated, 306, 307 withdrawal symptoms, 253 legal status, 202
men who have sex with men (MSM) methadone, 88 mortality, 206
amphetamine-type stimulant use, methamphetamine and, 210 pharmacology, 202–203
148 methamphetamine poly-drug use, 210
benzodiazepine misuse, 68 acute harms, 206 prevalence and patterns of use,
CM and CBT interventions for cardiovascular and respiratory, 203–205
methamphetamine 206–207 ‘clubbers’, 204
dependence, 216, 220 emergency hospital admissions, men who have sex with men,
frequent use of NPS by, 30 210–211 204–205
GHB and HIV antiretroviral hyperthermia, 207 population subgroups, 204–205
therapy, 44–45 management, 211 problem drug users, 204
GHB/GBL use, 38 psychological, 208 pro-sexual effects, 148
and potential high-risk sexual psychosis, treatment, 211 research evidence, 202
behaviour, 40, 49 renal and liver failure, 208 routes/modes of ingestion and
healthcare recommendations, 40 rhabdomyolysis, 207 dosing frequency, 205
ketamine use, 104, 106 symptoms/features of acute street names, 202
mephedrone toxicity, 206 methoxetamine (MXE), 101
injecting behaviours, 250 chronic harms acute toxicity
use, 7 blood related, 213 clinical management, 111–112
methamphetamine, high-risk brain imaging studies, 202, 215 mortality, 110
behaviours cardiovascular, 212–213 symptoms, 109
injecting, 204, 208 cognitive, 215 adulterants typically found in, 105
sexual, 204–205, 208–209 co-morbidities with HIV, 215 driving accidents associated with,
methamphetamine use dependence and withdrawal, see 119
and high-risk behaviours, methamphetamine, effects
204–205, 208–209 dependence and withdrawal. desired, 106
prevalence and patterns of, dermatological, 213 unwanted, 106
204–205 mental health/psychological introduced as alternative to
prevalence of drug use, 12 effects, 213–215 ketamine, 101
STIs, methamphetamine and GHB/ interventions, 222 legal status, 102
GBL use, 40 neurological, 213 pharmaceutical potential, 103
synthetic cathinone use, 244–245 ophthalmological, 213 pharmacology, 102–103
mental health Pott puffy tumour, 213 routes/modes of ingestion and
benzodiazepines and, 71 psychiatric, 203 dosing frequency, 104–105
methamphetamine and, 213–215, pulmonary and respiratory, 213 street names, 102
222 clinical and other legitimate uses, urinary tract issues, 114
nitrous oxide and, 135–136 203 withdrawal symptoms, 113
mental health services, as setting for dependence and withdrawal, 211, methoxphenidine (MXP), 101, 102
lower-intensity PSIs, 25 212 acute toxicity, 110
4-MeO-PCP (methoxydine), 101–102, access to treatment, 221–222 3-methoxy-PCP (3-MeO-PCP), 101,
105, 109, 112 aftercare and support, 222 105
mephedrone contingency management, 216 acute toxicity, 109
acute toxicity, 249 diagnosis and assessment, 215 half-life, 109
diagnosis and assessment, 251 pharmacological interventions, methoxydine (4-MeO-PCP), 101–102,
symptoms/features, 248–249, 250 217, 219 105, 109, 112
336
Index
2-methoxydiphenidine (2-MXP), 110 toxicity treatment, 85–87 desired, 132–133

4-methoxyphencyclidine, 111 opioid overdose management, 90 gender differences debate,
3,4-methylenedioxy- opioids 133
N-methylamphetamine, 165 overdose treatment, 85 unwanted, 133
see also MDMA (ecstasy). role in preventing deaths harm reduction measures, 137
3,4-methylenedioxy- associated with, 85 industrial applications, 131
N-methylcathinone. potential for inhibition of nitrous likely cause of dissociative effects,
methylfentanyls, 80, 88 oxide analgesic effects, 131 131
4-methylmethcathinone respiratory depression management, mental health harms, 135–136
4-methyl-N-ethcathinone (4-MEC), 86 mortality, 133
240, 241, 242 ‘take-home’ programmes (THN), 87 occupational exposure, concerns
street names, 241 naltrexone, 157 around, 131, 132
methylphenidate amphetamine dependence treatment pharmacology, 131
amphetamine dependence treatment RCT, 157 poly-drug use and drug interactions,
RCTs, 157 treatment of amphetamine and 134
clinical uses, 147 methamphetamine prevalence and patterns of
treatment of amphetamine and dependence with, 217, 218 recreational use, 131–132
methamphetamine treatment of ketamine withdrawal, psychosocial and pharmacological
dependence with, 217–218 117 support, 136
4-methylthioamphetamine (4-MTA), treatment of SCRA withdrawal, 314 public health considerations,
169 naphyrone, 240, 241 136–137
micro-dosing narcolepsy research evidence, 131
definition, 271 methamphetamine treatment, 203 risk of confusion with other gases,
hallucinogens, 271 treatment with amphetamines, 146 134
mindfulness-based interventions treatment with sodium salt of GHB, routes/modes of ingestion and
(MBIs), 32 38 dosing frequency, 132
mirtazapine, treatment of Narcotics Anonymous (NA), 31 street names, 131, 135
amphetamine and NBOMes (N-Benzylphenethylamines), N-methyl-D-aspartate (NMDA),
methamphetamine toxicity antagonists, 101–102, 109,
dependence with, 217, 219 clinical management, 279 131
mislabelling of NPS, potential for symptoms, 277 non-pharmaceutical fentanyls (NPF),
harm, 11 NEPTUNE guidance 79
Misuse of Drugs Act (UK), 65 aims and guidance development, noradrenaline, effects of stimulant
moclobemide, 179 1–2 agents on, 143
modafinil, amphetamine dependence development process, 3–4 novel psychoactive substances (NPS)
treatment RCTs, 157 literature review, 3 changes in legal control, 6
monoamine oxidase inhibitors objectives, 1–2 classifying, 3–4
(MAOIs), association with reasons behind, 2 concept and background, 1
serotonin syndrome, 150, substances and drug groups covered, definition, 5–6
152 3–4 groupings, 5
morphine, comparison of fentanyl target audience, 2 growth and spread, 6–7
with, 79, 81 update, 3 manufacture, 6
mortality neuroleptic malignant syndrome, motives for using, 7
amphetamine-type stimulants, 148 comparison with serotonin number of unique new substances
GHB/GBL, 40 syndrome, 152 reported, 5–6
methamphetamine, 206 new markets for drug acquisition, 8–9 population groups most likely to use,
PMMA, 177 night-time economy, club drugs and 7–8
synthetic cathinones, 251 NPS use, 8 producers’ awareness of legal
motivational interviewing nitrous oxide (Nb 2O), 131–137 frameworks, 5
effectiveness as substance use acute toxicity, 133–134 targeting of at long-term/
intervention, 27 symptoms and features, 134 problematic drug users, 8, 23,
in structured drug treatment, 29 chronic harms, vitamin B12 78
in WHO manual on brief deficiency, 131, 134, 135, 136 users and contexts of use, 7
interventions, 27 management, 136 Novel Psychoactive Treatment UK
mutual aid, tradition of in the clinical and other legitimate uses, Network (NEPTUNE), aims
substance misuse field, 31 131 and guidance development,
clinical management, 135 see NEPTUNE guidance.
naloxone dependence and withdrawal, 135
fentanyl diagnosis and assessment, 135 ocfentanil, 79, 84
overdose management, 87 effects opioid crisis, in North America, 78
337
Index
opioid medications, evidence of MDMA and, 179 ketamine, 106–107, 109

misuse, 78 methamphetamine and, 210 related high-risk behaviours, 118
opioid overdose patterns of NPS use, parallels with MDMA, 171, 175, 179–180, 183,
symptoms, 81 patterns of alcohol use, 23 186–187
WHO guidelines, 85 pentedrone psychosis, 178
opioid related mortality, abuse liability, 240 nitrous oxide, risk of death, 133
benzodiazepines commonly street names, 241 serotonin syndrome and, 149, 150,
implicated in, 68 pentylone, 240, 245 152
opioids phenazepam, 66, 69, 302 synthetic cathinones, 245
acute intoxication, management, 90 half-life, 66 poly-drug use and drug interactions
adverse effects of intoxication, 89 street names, 65 GHB/GBL, 44
availability and mode of use, 89 phencyclidine (PCP), 101 GHB/GBL, HIV antiretroviral
chemical structures, 89 phenethylamines, 148 therapy, 44–45
chronic effects and dependence, 92 acute toxicity, clinical management, MDMA, 179–180, 186–187
comparison with other NPS types, 279–280 serotonin syndrome, 149, 152
78 adverse effects, 276–277 methamphetamine, 210
dependence, management, 92 empathogenic effects, 165 nitrous oxide, 134
desired effects, 89 pharmacology, 146, 268–269 opioids, 84–85
detected on Europe’s drug market, routes/modes of ingestion and synthetic cathinones, 251
78 dosing frequency, 273 polysubstance use, 312, see poly-drug
fentanyls, see fentanyls. see also methamphetamine. use.
global public health threat, 78 α-PHP (α-pyrrolidinohexanophenone), population groups most likely to use
intoxication, characteristics, 81 240, 248 NPS
mortality, 92 acute toxicity, 249 ‘clubbers’ and night-time economy
non-fentanyl opioid NPS, 89 pipradrols/piperidines, 144, 165 users, 7–8
pharmacology, 89 placenta permeability, GHB/GBL, 38 homeless people and prison inmates,
poly-drug use and drug interactions, PMA (paramethoxyamphetamine) 8
84–85 acute toxicity, 174 LGBT+ population, 8
reported to the EU Early Warning adulteration of MDMA with, 173, men who have sex with men, 8
System, 79 174 poly-drug users, 7
research evidence, 79 deaths associated with, 174 problem/long-term drug users, 8
targeting of at long-term/ risks of co-ingestion, 179 ‘psychonauts’, 8
problematic drug users, 78 toxicity, 148 young people, 7
overdose PMK (piperonyl methyl ketone), 170 post-traumatic stress disorder (PTSD),
amphetamine-associated, 148 PMK (piperonyl methyl ketone), 169, see PTSD (post-
benzodiazepine-associated, 69 PMK-glycidate, 170 traumatic stress disorder).
fentanyl-associated, 82 PMMA (p- Pott puffy tumour (PPT),
comparison with heroin, 81, 84, 87 methoxymethamphetamine) methamphetamine and, 213
management with naloxone, 87 acute toxicity, 174 pregnancy, GHB/GBL detoxification
GHB/GBL-associated, 41 adulteration of MDMA with, during, 50
clinical management, 45–46 173–174 Priestley, Joseph, 131
harm reduction measures, 46 mortality, 177 primary care
naloxone and, 85, 87, 90 risks of co-ingestion, 179 as setting for lower-intensity PSIs, 25
opioid-associated, 81 serotonin syndrome, 177 WHO manual on brief
management with naloxone, 85, toxicity, 148 interventions, 27
90 poisons centres, 2, 277 prison populations
symptoms, 81 Poland, 81 use of NPS, 8
risk of, see risk of overdose. poly-drug use use of SCRAs, 304
SCRA-associated, 305, 308 acute toxicity risk increased by, 9 problem drug users
2-oxo-PCE, 110, 111 amphetamine-type stimulants, 158 methamphetamine, prevalence and
oxytocin, 169, 172 association with fatalities, 12 patterns of use, 204
association with serotonin methamphetamine use, 204
paranoia, 248 syndrome, 149, 150 synthetic cathinone use, 244
Parkinson’s disease association with sexual risk targeting of NPS at, 8, 23, 78
MDMA and relief from symptoms behaviours, 70 prolactin, 169, 172
of, 170 benzodiazepine misuse in context of, psilocybin, clinical trials, 270
methamphetamine users’ risk of 67 psychonauts, use and understanding of
developing, 213 fentanyls, 84–85 NPS, 8
Parkinson-type symptoms, 250 risks of, 82, 84 psychosis
paroxetine hallucinogens, 273 amphetamine-associated, 154
338
Index
management, 157–158 quinidine, 180 phenethylamine, 276

benzofuran-associated, 188 PMA/PMMA, 174
GHB/GBL-associated, 42 recovery capital model, of substance SCRA, 306, 307, 308, 309, 310, 311,
ketamine-associated, 116 misuse intervention, 24 312, 313, 314
MDMA-associated, 178 relapse prevention serotonin syndrome, 150
MDPV-associated, 249 CBT approach, 32 self-medication
methamphetamine-associated, 205, mindfulness-based approach, 156, hallucinogens, 274
208, 210, 213, 214 217 ketamine, 106
treatment, 211 residential treatment, indications for, serotonin, effects of stimulant agents
phenethylamine-associated, 276 31 on, 143
α-PHP-associated, 249 respiratory depression, reversing with serotonin syndrome
SCRA-associated, 306, 307, 309, 310, naloxone, 86 amphetamine-type stimulants-
311 responses to club drug and NPS use associated, 149–150, 153,
synthetic cathinone-associated, 250 adaptation of programmes for 158
psychosocial interventions (PSIs) ‘established’ or ‘traditional’ poly-drug use and, 158
adjustments to existing protocols, drugs, 23 comparison with neuroleptic
23 harm reduction strategies, 13–14 malignant syndrome, 152
available research, 22 hospital emergency departments, 12 diagnosis, 151–152
EMCDDA principles, 22 screening, identification and fentanyl-associated, 84
evidence on effectiveness of, 22 management of drug harms, hallucinogen-associated, 275, 277
evidence-based models, 32 13 5-HT2A antagonists treatment, 152
motivational interviewing, 32 sexual health services, 12 management, 151–153
network and environmental substance misuse treatment services, MAOI-associated, 150, 152
therapies, 32 13 MAOIs and, 150, 152
GHB/GBL, 50 rhabdomyolysis, benzodiazepine MDMA, 149, 152, 177
higher-intensity PSIs overdose and, 68 MDMA-associated
derivation, 31 riluzole, treatment of amphetamine clinical management, 180
residential treatment, 31 and methamphetamine fatal, 173, 177
settings for delivery, 25–26 dependence with, 217 methamphetamine co-ingestion
structured drug treatment, risk of overdose and, 210
27–29 fentanyls, 82, 84 phenethylamine-associated, 279
identification of NPS use and increased by injecting, 10, 82, 84, 88 poly-drug use and, 149, 150, 152
severity, 23–25 increased by repeated risk of convulsions, 152
indicators for referral, 25 administration of a drug, 9 see also seizures.
lower-intensity PSIs MDMA, 169 SCRA-associated, 308
brief interventions, 26–27 PMA and PMMA mistaken for symptoms/features, 149–150, 187
example of FRAMES model, MDMA, 169 synthetic cathinone-associated, 249,
28–29 SCRAs, 301 252
framework, 27 ritonavir, 44, 84, 102, 180, 210, 251 therapeutic drugs, 150
settings for delivery, 25 treatment, 152
typical elements, 26 safrole, 170 serotoninergic agents, risks of using
methamphetamine dependence and schizophrenia, amphetamine-induced fentanyl with, 84
withdrawal, 215–217 psychosis and, 154 sertraline, treatment of amphetamine
minimum recommended levels in seizures and methamphetamine
selected settings, 26 amphetamine, 148–149 dependence with, 219
mutual aid, 31 anti-psychotic medication, 157 sexual assault
residential treatment, 31 benzodiazepine, 69, 71 GHB implicated in, 38
social re-integration, 32 GHB/GBL, 44, 48 GHB/GBL’s association with, 53
psychosocial interventions, hallucinogenic drugs, 276, 277 ketamine use and the risk of, 119
methamphetamine, ketamine, 108 sexual behaviours, high risk, 30, see
dependence and withdrawal, MDMA and drugs with similar high-risk sexual behaviours.
215–217 effects, 173, 174–176, 177 sexual health services
psychotherapy, MDMA-facilitated, mephedrone and other synthetic prevalence of drug use among
169–170 cathinones, 249 patients of, 12
PTSD (post-traumatic stress disorder), methamphetamine, 206, 213 as setting for higher-intensity PSIs,
169–170, 282 methoxphenidine, 110 26
MDMA treatment, 281 nitrous oxide, 134 as setting for lower-intensity PSIs, 25
therapeutic effects of hallucinogens, opioid NPS, 91 sexualised drug use, effectiveness of
274 paediatric, exposure to synthetic combined interventions,
pyrovalerone, 243 cathinones and, 249 30–31
339
Index
sexually transmitted infections (STIs), phenazepam, 65 unwanted, 304–305

association with SCRAs, 299 fatal toxicity index, 9
methamphetamine and synthetic cathinones, 240 harms associated with newer
GHB/GBL use, 40 STRIDA Project, 110 generations of, 11
sildenafil (Viagra), 39, 204, 209 structured drug treatment, minimum legal status, 299, 301
Single Convention on Narcotic Drugs requirements, 29 mortality, 305
(1961), 5 substance misuse treatment services, pharmacology, 299–301
‘skunk’, 309 responses to club drug and prevalence and patterns of use,
‘slamming’, 251 NPS use, 13 302–303
SMART groups, 31 substituted phenylethylamines, 144 public safety considerations and
social behaviour network therapy suicidal ideation and suicide, MDMA- harm reduction measures,
(SBNT), 32 associated, 178 315
social media, acquisition of drugs and suicidal ideation/thoughts research evidence, 299
NPS through, 9 association with benzodiazepine use routes/modes of ingestion and
social re-integration, 32 in opioid use disorders, 68 dosing frequency, 303
sodium oxybate, treatment of MDMA-associated, 178 street names, 299
narcolepsy, 38 mephedrone-associated, 250 targeting of at long-term/
‘speedballing’, 84 suicide problematic drug users,
SSRIs (selective serotonin reuptake amphetamine dependence and, 154 23
inhibitors), association with attempted, methoxetamine- use by homeless people and prison
serotonin syndrome, 150 associated, 109 inmates, 304
stepped care approach, principles, 23 benzodiazepine as risk factor, 71 synthetic cannabinoids
stimulants GHB-associated, 40 HPPD and, 280
dependence, 155–158 LSD-associated, 279 similarity to benzodiazepine NPS,
aftercare and support, 158 methamphetamine-associated, 206, 66, 280
amphetamine-induced psychosis, 208, 210 see also synthetic cannabinoid
management, 157–158 symptom rebound, benzodiazepine- receptor agonists (SCRAs).
characteristic features, 155 associated, 70 synthetic cathinones, 144, 240
pharmacological interventions, synthetic cannabinoid receptor acute harms, 249, 251
157 agonists (SCRAs) high-risk injecting and sexual
psychosocial interventions, acute harms, 305–313 behaviour, 250–251
155–157 adulterant-associated, 307 mortality, 251
psychosocial interventions, cardiovascular, 309 poly-drug use and drug
Cochrane review, 155 diagnosis and assessment, 312 interaction, 251
stepped care for amphetamine- gastrointestinal/renal, 310 toxicity, 248–249
type stimulants users, multiple organ failure, 310 acute toxicity
155–156 neurological, 308, 309–310 diagnosis and assessment, 251
gender differences in responses to, physiological, 309–310 management, 252
157 presentations for treatment for MDPV, 249
injecting acute intoxication, 310–312 mephedrone, 248–249
harms associated with, 145 psychological, 307–309 α-PHP, 249
increase in, 144 psychosis, 309 symptoms/features, 249–250
pharmacology, 143 toxicity treatment outcome, 252
prevalence and patterns of use, 147 clinical management, 312–313 chronic harms
prevalence and types of NPS symptoms/features of, 305–308 clinical management, 254
globally, 144 association with homeless people dependence and withdrawal,
regional variations, 147 and with prison populations, 252–254
stimulant NPS in Europe, 143–145 8 clinical management, 254
see also amphetamine-type available products, 301–302 risk of infection, 254
stimulants (ATS). chronic harms, 313–315 clinical uses, 243
street names dependence and withdrawal, comparability to traditional drugs of
benzodiazepines, 65 313–314 abuse, 242
ketamine, 102 clinical management, 314 effects
MDPV, 241 support and aftercare, 315 desired, 245–247
4-MEC, 241 management, 314–315 MDPV, 248
mephedrone, 241 other, 314 mephedrone, 247–248
methamphetamine, 202 clinical and other legitimate uses, α-PHP, 248
methoxetamine, 102 302 unwanted, 247
nitrous oxide, 131, 135 effects empathogenic effects, 165
pentedrone, 241 desired, 303–304 half-life, 245
340
Index
harms associated with newer mephedrone; mephedrone; urological/urinary problems

generations of, 11 pentedrone. GHB/GBL-associated, 42
high-risk injecting behaviour, 243, synthetic opioids ketamine-associated, 107, 113–114
250–251 reported rise in deaths related to, 78 management, 117–118
legal status, 241 worldwide public health risk, 78 opioid-associated, 81
natural analogue, 240 see also fentanyls; opioids.
pharmacology, 241–243 Viagra, 39, 204, 209
combination products, 243 tachyphylaxis, hallucinogens, 272, vitamin B12 deficiency, nitrous
MDPV, 242–243 280 oxide-associated, 131, 134,
mephedrone, 242 testing for club drugs and NPS, 135, 136
prescribed medications containing, limitations of, 11–12 management, 136
240 THC (tetrahydrocannabinol), 300
prevalence and patterns of thioridazine, 179 ‘wooden chest’, fentanyl-associated, 82
recreational use, 243–245 topiramate, treatment of amphetamine World Drug Report
men who have sex with men and methamphetamine on non-medical use of
(MSM), 244–245 dependence with, 217–218, benzodiazepines, 67
poly-drug use, 245 219 on number of NPS present on the
population sub-groups, 244–245 toxicity, definition, 9 market, 6
public health crisis associations, 243 tramadol, 84, 150, 245 on stimulants, 147
public safety and harm reduction trauma informed interventions, need on targeting of new psychoactive
measures, 254 for research, 23 substances at long-term/
pyrovalerones, 240 tremor problematic drug users, 78
research evidence, 241 benzodiazepine treatment for, World Health Organization (WHO),
routes/modes of ingestion and 152 manual on brief
dosing frequency, 245–246 serotonin syndrome and, 151 interventions, 27
MDPV, 246 see also seizures.
mephedrone, 246 tryptamines, 144 young people, use of club drugs and
second and third generations, 240 adverse effects, 277–278 NPS, 7
street names, 240 pharmacology, 268
see also bupropion; MDPV (3,4- routes/modes of ingestion and ‘zombie’-like behaviours associated
methylenedioxypyrovalerone); dosing frequency, 272 with SCRA, 301, 306
341

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Part I Introduction and Background 8B Amphetamine-type Stimulants: An

Figure 1.1 Categorising substances by their primary psychoactive eﬀects

Table 1.1 Proximal mechanisms of drug eﬀects

Drug Primary (proximal) target Brain eﬀect

1.6.1 Overall Drug Use 1.6.3 Population Groups Most Likely

Detection Assessment Brief Complex Complex

25. Peters FT, Martinez-Ramirez JA. Analytical toxicology of 39. www.unodc.org/LSS/announcement/Details/4977098d-62f0-4

2 and Novel Psychoactive Substances

2.1 Introduction Box 2.1 European Monitoring Centre for Drugs

Lower-intensity PSI Higher-intensity PSI

Figure 2.1 Stepped care PSI for problematic NPS use

• Current injecting of any substance;

• Ask permission to give information

• Provide relevant information in

• Elicit service user’s view or interest in

Figure 2.2 A proposed framework for brief advice and information

Box 2.4 Example of a Brief Intervention Based on the FRAMES Model

Box 2.4 (cont.)

3 and Gamma-Butyrolactone (GBL)

3.1 Introduction 3.4 Brief Summary of Pharmacology

3 and Gamma-Butyrolactone (GBL)

3.1 Introduction 3.4 Brief Summary of Pharmacology

Box 3.1 Reported Neurological and Psychiatric Eﬀects

Box 3.2 Cardiovascular Eﬀects

Box 3.3 Central Nervous System and Respiratory Eﬀects

• Dose-related respiratory depression 87,88,97,98,107,110,113,114,117,119,120,123,130,134,135,149

to a US emergency department study82 and in more A double-blind, placebo-controlled, cross-over vol-

3.12.2.2 Onset and Duration of Withdrawal Syndrome

Box 3.4 GHB Withdrawal Symptoms

Other Reported Symptoms

• Abdominal pain (less common)223

Box 3.5 Medications Used to Manage Acute GHB/GBL Withdrawal

Benzodiazepines are safe and eﬀective in managing most cases

A number of studies have examined the high

CIWA-Ar protocol. J Formos Med Assoc gamma-hydroxybutyrate (GHB)-dependent patients:

4.1 Introduction controlled under the Misuse of Drugs Act by the

• Sleep disorders There is also evidence that benzodiazepines have

symptom-oriented and pragmatic. Reduction regimens

NeuroToxicology 2019;73:8–16. https://doi.org/10.1016/j European Union. BMC Psychiatry 2016;16:274. https://doi.org

5 Substances (Fentanyl and Non-fentanyl)

5.1 Introduction NPS. The appearance and increase in the number of

Table 5.1 Fentanyl toxicity

Fentanyl toxicity Fentanyl severe toxicity Diﬀerences between heroin

Box 5.2 Example of Fentanyl Novel Psychoactive Substances

5.11 Management of Acute Toxicity 5.12 Clinical Settings

Table 5.2 World Health Organization recommendations

Recommendation Strength Quality

Source: WHO, 2014

Table 5.3 Non-fentanyl opioid novel psychoactive substances: brief pharmacology

Table 5.4 Availability and Mode of Use

AH-7921 U-47700 MT-45

Table 5.5 Desired eﬀects of three novel synthetic opioids

AH-7921 U-47700 MT-45