Substance Use and the REVIEW ARTICLE


Nervous System C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Derek Stitt, MD

ABSTRACT
OBJECTIVE: This article informs and updates the practicing neurologist on the
current landscape of known neurologic injuries linked to the use of illicit
drugs, focusing on emerging agents.

LATEST DEVELOPMENTS: Synthetic opioids such as fentanyl and similar

derivatives have exploded in prevalence, becoming the leading cause of
overdose fatalities. The higher potency of synthetic opioids compared
with semisynthetic and nonsynthetic opiates poses an increased risk for
unintentional overdose when found as an adulterant in other illicit drug
supplies such as heroin. Conversely, misinformation about the risk of
symptomatic exposure to fentanyl through casual contact with the skin
and ambient air has led to misdirected fear and stigma that threatens to
impede valid harm-reduction measures for fentanyl users at risk of actual
overdose. Finally, during the COVID-19 pandemic, overdose rates and
deaths continued to climb, especially among those who use opioids and
methamphetamine.

ESSENTIAL POINTS: A variety of potential neurologic effects and injuries can

occur with illicit drug use owing to the diverse properties and mechanisms
of action of the various classes. Many high-risk agents are not detected on
standard drug screens, including so-called designer drugs, and the
practicing neurologist is best served by recognizing the clinical features of
the traditional toxidrome and other potential idiosyncratic effects of
various illicit agents.
CITE AS:
CONTINUUM (MINNEAP MINN)
2023;29(3, NEUROLOGY OF
SYSTEMIC DISEASE):923–945.
INTRODUCTION

T
oxic insults to the nervous system due to illicit drug exposure can Address correspondence to
range from mild to fatal and can present in acute, subacute, or chronic Dr Derek Stitt, 200 1st St SW,
Rochester, MN 55901,
fashion. Some agents can significantly affect individuals after one [email protected].
exposure, while other forms of neurologic injury develop after
RELATIONSHIP DISCLOSURE:
repeated or chronic exposure. Given the prevalence of illicit drug
Dr Stitt reports no disclosure.
consumption among the population, neurologists should be aware of the notable
patterns of nervous system injury that are possible from their use. Pattern UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
recognition is especially important for the clinician when it comes to the toxic USE DISCLOSURE :
effects of illicit drugs, as many prevalent agents are undetectable with standard Dr Stitt reports no disclosure.
laboratory assays, and a history of exposure may be difficult to confirm because
of a patient’s hesitancy to disclose illegal activity or because of the stigma © 2023 American Academy
associated with drug use. Most “designer drugs” are novel and consist of of Neurology.

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SUBSTANCE USE AND THE NERVOUS SYSTEM

constantly emerging synthetic compounds only detectable with techniques not

readily at the disposal of the practicing clinician, such as mass spectroscopy/
liquid chromatography. Many of these compounds are so recently created that
they have not had sufficient time to pass through the regulatory process of the
drug enforcement authorities, or some compounds escape regulation with
marketing loopholes such as being labeled as “not for human consumption.” The
drug classes discussed in this article are the following:
u Opioids
u Psychostimulants
u Sedative and hypnotic agents
u Gabapentinoids
u Marijuana and synthetic cannabinoids
u Hallucinogens
u Dissociative agents: ketamine and phencyclidine
u Anticholinergics
u Inhalants
u E-cigarettes
u Alcohol

OPIOIDS
Drugs that are agonists or partial agonists of opioid receptors have a high
potential for misuse. Common routes of administration include ingestion of pills,
inhalation of vapor, insufflation of crushed solids, or IV injection. The United
States continues to face a crisis, manifesting as a concerning upward trend in
opioid-related overdose deaths. A striking acceleration in the rate of fatal opioid
overdose occurred during the COVID-19 pandemic, and these deaths were
disproportionately observed in marginalized populations.1
Independent of the effects of the pandemic, rates of overdose have increased
in large part because of potent synthetic opioids such as fentanyl exploding in

TABLE 10-1 Commonly Used Opioids

Agonists
◆ Codeine
◆ Fentanyl and other synthetic derivatives
◆ Heroin
◆ Hydrocodone
◆ Methadone
◆ Morphine sulfate (injection)
◆ Oxycodone
◆ Tramadol
Mixed agonist/antagonist
◆ Buprenorphine

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availability. According to the Centers for Disease Control and Prevention’s KEY POINTS
National Center for Health Statistics, nationwide drug overdose deaths surpassed
● Pattern recognition is
100,000 over a 12-month time frame ending in April 2021, with more than especially important when it
75,000 of those deaths due to opioids, of which more than 60,000 were related to comes to identifying toxicity
fentanyl.2,3 TABLE 10-1 outlines some of the most used agents of the opioid class. from illicit drugs, as many
Neurologists must be able to recognize the core features of the opioid prevalent agents are
undetectable with standard
toxidrome, which is the triad of sedation, miotic pupils, and central respiratory
laboratory assays.
depression, with the latter being the typical precipitant of mortality. When
encountering an individual with an undifferentiated depressed level of ● In the setting of the
consciousness, identifying miotic pupils and a lower respiratory rate can be COVID-19 pandemic as well
potentially lifesaving, especially if the opioid reversal agent naloxone is promptly as the continued rise in
availability of potent
administered in the setting of respiratory insufficiency alongside respiratory synthetic opioids like
support. Naloxone is a competitive opioid receptor antagonist available in IV and fentanyl, overdose deaths
intranasal forms.4 As part of widespread harm reduction efforts, some state have reached new highs.
governments and private nonprofit organizations offer supplies of the intranasal
● The triad of depressed
form free of charge for distribution to the public along with opioid overdose level of consciousness,
training.5 Clinicians should be aware of naloxone’s short duration of action, miotic pupils, and
which can lead to patients who have overdosed falling back into a state of depression of respiratory
sedation and hypopnea after having been initially revived; repeat naloxone rate are the must-know
hallmarks of opioid
dosing may be required.
overdose.
In addition to the rewarding analgesia for which opioids are well-known, those
who use them often get a euphoric high. Those who self-administer opioids via ● The opioid antagonist
the most fast-acting routes, like injection, often describe a “rush” or internal naloxone administered
feeling of pleasurable warmth.6 Other commonly known clinical manifestations alongside immediate
respiratory support is the
of opioid intoxication include slowed intestinal motility leading to constipation as vital treatment for opioid
well as decreased libido. Opioid withdrawal is often characterized by users as overdose.
a severe flulike syndrome marked by myalgia, diarrhea, piloerection, rigors,
hyperthermia, and significant irritability.7 Despite the severity, opioid
withdrawal is almost never fatal and not associated with a reduced threshold
for seizures, unlike the principal drugs in the sedative and hypnotic category.
One notable exception is the significant neurophysiologic stress from withdrawal
of secondary opioid exposure that can be observed in newborns of mothers who
use, known as neonatal abstinence syndrome, which can lead to seizures.8
Synthetic opioids, namely fentanyl and fentanyl derivatives like carfentanil,
are concerning because of their exponential potency compared with their
nonsynthetic counterparts like heroin and morphine. In recent years, fentanyl
has come to replace both prescription opioids and heroin as the principal drug of
use found in the United States’ illicit supply. The genesis of this change is rooted
in cost: cartels have found that importing illegally sourced inexpensive raw
materials and using them to synthesize fentanyl compounds is more profitable
than processing heroin from opium.9 When it comes to clinical laboratory
detection of recent exposure, synthetic opioids present a challenge. While
fentanyl and a few other synthetic opioids can be detected on what are often
called targeted opioid screens available at many medical laboratories, they are not
detected on the standard urine drug screens with which most clinicians are
familiar. An additional challenge is a recently reemerging class of synthetic
opioid receptor agonists called benzimidazoles, otherwise known as nitazenes,
which appear to have a potency similar to fentanyl and contribute to the rising
number of fatal overdoses.10 Nitazenes are currently undetectable with any
clinically available assay and are often not identified until the postmortem setting

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SUBSTANCE USE AND THE NERVOUS SYSTEM

in forensic laboratories. TABLE 10-2 summarizes popular recreational drugs not

detected on standard urine drug screens.
Intentional contamination, or lacing, of a different drug with fentanyl also
presents significant danger of unintentional overdose and accidental death.
Fentanyl test strips are a harm reduction measure that some people who use
drugs can obtain to check their supply if they suspect it may be undesirably
tainted.11 One major emerging theme in this realm is the so-called counterfeit pill.
These are pills sold on the street disguised to look like actual prescription pills but
contain either adulterants in combination with the namesake ingredient or 100%
adulterants without any of the namesake ingredient whatsoever. Notable
examples are counterfeit alprazolam tablets and counterfeit oxycodone M30
tablets, also known as “blues”; many of these pills contain or are mostly made up
of nonpharmaceutical fentanyl.12 Those who purchase these pills under the
impression that they contain oxycodone are at higher risk of unintentional fatal
overdose owing to the relative potency of fentanyl.
The emerging adulteration of the primary fentanyl supply adds further
complexity. In a very large portion of the current illicit opioid market, people
who use drugs are knowingly seeking fentanyl as it has surpassed heroin in
availability and distribution. However, more fatal overdoses of fentanyl
contaminated with tranquilizers and sedatives have recently emerged. “Tranq-
dope,” as it is also known, contains xylazine as an additive.13 Xylazine is an α2
agonist very similar to clonidine. It was developed as a veterinary tranquilizer. In
this instance, xylazine is added to the fentanyl supply in an attempt to extend the
high for the people who use it, owing to fentanyl’s relatively short half-life
compared with traditional heroin. However, this poses even greater danger to the
people who use it, as the effects of xylazine are not reversed with naloxone
during an overdose resuscitation, potentially leaving the patient with persistent
circulatory collapse and sedation. Similar fentanyl adulterants have recently been
discovered with novel benzodiazepine analogs like etizolam.14
Despite the validity of societal concerns about the ongoing harms of fentanyl,
unfortunately, a barrier to effective public service messaging exists regarding
assisting individuals with possible fentanyl overdose. This hindrance is caused by
widespread misinformation and false beliefs regarding the safety of casual
cutaneous contact or ambient exposure to fentanyl. It should be emphasized that
although fentanyl is very potent, just like other opioids, it requires direct passage

TABLE 10-2 Common Recreational Drugs Not Detected on Standard Toxicology Screens

◆ Inhalants (eg, nitrous oxide, paint thinner)

◆ Kratom and salvia
◆ Psychedelics (eg, psilocybin mushroom, mescaline)
◆ Synthetic cannabinoids
◆ Synthetic cathinones (“bath salts”)
◆ Synthetic opioidsa

a
Fentanyl is a synthetic opioid that can be identified on targeted opioid screens available at many hospital
laboratories.

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across an absorptive mucous membrane or IV entry to have true toxic effect. In KEY POINTS
recent years, erroneous messaging to law enforcement and first responders has
● Nonpharmaceutical
led to a pervasive misconception that touching fentanyl or even breathing near fentanyl added
fentanyl powder can lead to overdose.15 Consequently, there continue to be clandestinely to counterfeit
numerous media reports of first responders requiring treatment for fentanyl pills, mimicking prescription
exposure.16 These stories often describe a first responder coming in casual tablets like oxycodone, is
emerging as a significant
contact with fentanyl as part of their work detail and then developing sudden
source of fatal overdose and
nonspecific symptoms such as lightheadedness, syncope, limb paresthesia, and opioid-related neurologic
hyperventilation. These symptoms are falsely attributed to fentanyl toxicity by injury.
the individual and their colleagues, leading to unnecessary administration of
naloxone and sometimes unnecessary resource deployment like hazardous ● Despite the dangerous
potency of fentanyl, casual
materials crews to clean up the scene. The nonspecific symptoms mentioned in contact of fentanyl with the
these reports are of course not consistent with the clinical triad of opioid skin or ambient inhalational
overdose, suggesting pseudoneurotoxic disease in these scenarios. exposure does not cause
Pseudoneurotoxic disease refers to a neurologic symptom or symptoms ascribed toxicity or overdose.
to toxic injury that are either coincident in onset or worsening of an unrelated ● Misinformation about the
illness or psychogenic in etiology.17 risk of fentanyl toxicity
Widely distributed news media broadcasts of these stories inevitably cause a through casual contact has
portion of the public to adopt these misconceptions, which could hinder harm become widespread, which
could deter members of the
reduction efforts by deterring the good Samaritan response from people who
public from coming to the
could otherwise come to the aid of those facing death or serious injury from actual aid of those experiencing
fentanyl overdose. As trusted members of the medical community, neurologists actual fentanyl overdose.
can provide another respected voice to combat these misinformed sentiments.
While opioids are classically known to cause death or severely disabling ● Selective brain insults
separate from typical
neurologic injury via hypoxic-ischemic brain insult due to unreversed overdose, hypoxic-ischemic cerebral
other less conventional types of neurologic injuries are possible. A toxic injury are sometimes
spongiform leukoencephalopathy is a recognized central nervous system (CNS) observed with opioid misuse
insult possible with opioid exposure.18-20 The most well-described presentation is or overdose, both in the
acute or more prolonged
associated with recurrent exposure to black tar heroin vapor, inhaled through a setting.
pipe after firing the tar from underneath a piece of aluminum foil, referred to by
those who use as “chasing the dragon.” These patients can develop abulia, ● A diffuse toxic
cerebellar dysfunction, parkinsonism, and eventually spasticity with other upper leukoencephalopathy may
be seen with recurrent
motor neuron deficits that progress over a matter of weeks. MRI typically reveals
heroin vapor exposure.
a high burden of diffuse symmetric T2 hyperintensity in the white matter that
preferentially involves the posterior cerebrum and cerebellum. However, a more ● Opioid intoxication may
acute fatal spongiform leukoencephalopathy can also occur after opioid be associated with a rare,
overdose, including with prescription forms.20 FIGURE 10-1 depicts the MRI, distinct syndrome
characterized by lesions of
gross pathology, and histopathology images from one such case.21 the bilateral cerebellar
The diffuse cerebral and cerebellar injuries that have been reported after cortex, hippocampi, and
opioid intoxication exist on a spectrum with regard to the brain regions basal ganglia known as
most involved. In contrast to the white matter injury, a lesser-reported gray cerebellar, hippocampal,
and basal nuclei transient
matter–predominant insult can be seen in the setting of acute opioid intoxication, edema with restricted
exhibiting variations within a spectrum of radiographic features characterized diffusion (CHANTER)
by cerebellar, hippocampal, and basal nuclei transient edema with restricted syndrome.
diffusion (CHANTER) syndrome (CASE 10-1),22 whereas a mixed picture of
cerebellar white matter and basal ganglia lesions has been described with
oxycodone overdose.23 It is the author’s opinion that any opioid, either
prescription or nonpharmaceutical, via any route of administration, should be
considered as a possible cause for these severe types of idiosyncratic diffuse brain
injury, especially if exposure is excessive. With the exception of reversal with

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SUBSTANCE USE AND THE NERVOUS SYSTEM

KEY POINT

● Various patterns of
myelopathy have been
reported in association with
opioid intoxication,
including anterior horn
cell–predominant injury
suggestive of spinal cord
infarction, inflammatory
myelitis, and tractopathy.

FIGURE 10-1
Acute fatal spongiform leukoencephalopathy after methadone overdose. A, Axial fluid-
attenuated inversion recovery (FLAIR) sequence MRI shows diffuse and dramatic hyperintensity
in the cerebral white matter sparing the subcortical U-fibers. B, Coronal brain section at
autopsy showing subtotal hemispheric white matter damage. C, Hematoxylin and eosin (H&E)
stain showing diffuse spongiform changes in the white matter with subcortical U-fiber sparing.
Reprinted with permission from Stitt D and Kumar N, Continuum (Minneap Minn).21 © 2020 American
Academy of Neurology.

naloxone in the setting of acute opioid overdose and removal of exposure to the
offending agent, treatment is supportive. Prognostication is difficult because
wide-ranging outcomes have been observed, including full recovery, survival
with long-term disability, and death.24
While the brain is at risk for serious insult associated with opioids, the spinal
cord and even the peripheral nervous system are potential targets as well. Various
presentations of myelopathy are associated with heroin exposure,25 including
acute paraparesis in the setting of heroin insufflation with features suggestive of
spinal cord ischemia such as selective anterior horn cell T2 hyperintensity on
MRI.26 A more progressive course resembling subacute combined degeneration
with lateral and posterior column involvement has also been reported.27
Additionally, a myelitis with an inflammatory CSF has been observed in
subsequent exposure to heroin after a period of abstinence, which may reflect a
hypersensitivity mechanism, but without improvement after a trial of steroids
and plasma exchange.28 Regardless of the pattern of spinal cord injury,
significant residual deficits were the norm, despite removal of the opioid
exposure. Isolated reports of idiopathic brachial plexopathy have been described
in association with repeated heroin injection.29

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 A 51-year-old woman was found unresponsive by her family. Her CASE 10-1
respirations were shallow per emergency medical services, and she was
intubated for airway protection. Naloxone was administered by
emergency medical services
without response. After
transport to the emergency
department, an initial
neurologic examination by
the on-call neurologist found
the patient to be in a coma
with preserved brainstem
reflexes, diffuse limb
hypertonia, and extensor
posturing to stimuli. Urine
drug screen in the emergency
department was negative.
Law enforcement later
identified M30 counterfeit
oxycodone pills at the
scene. Brain MRI was
obtained once the patient
was stabilized in the intensive
care unit, demonstrating
bilateral symmetric diffusion
restriction and T2
hyperintensity with
edematous appearance
primarily in the cerebellar
cortex, interior temporal FIGURE 10-2
lobes, and basal ganglia MRI of the patient in CASE 10-1 presenting with
(FIGURE 10-2). The patient cerebellar, hippocampal, and basal nuclei transient
edema with restricted diffusion (CHANTER)
eventually became responsive syndrome after exposure to counterfeit pills
after a few weeks but containing fentanyl. From top to bottom,
remained severely disabled. diffusion-weighted sequences (left) and
Diffusion restriction resolved T2 fluid-attenuated inversion recovery (FLAIR)
sequences (right) show bilateral symmetric
on subsequent imaging, but diffusion restriction with corresponding edematous
T2 signal abnormalities T2 hyperintensity in the cerebellar cortex (A),
persisted. interior temporal lobes (B), and basal ganglia (C).

This case is an example of cerebellar, hippocampal, and basal nuclei COMMENT

transient edema with restricted diffusion (CHANTER) syndrome in the
setting of acute fentanyl intoxication. These patients most often present
with stupor or coma. The radiographic pattern on MRI is distinct from
conventional hypoxic ischemic injury, which almost invariably involves
the cerebral cortex and thalami, which are spared in patients with
CHANTER syndrome. Obstructive hydrocephalus from cerebellar swelling
is an additional complication that can occur.

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SUBSTANCE USE AND THE NERVOUS SYSTEM

Another miscellaneous effect of opioids that the neurologist should be aware

of is myoclonus. Opioid-induced myoclonus is usually nonfocal and may not be
accompanied by altered consciousness from the drug. It is more likely to occur in
those taking opioids with acute kidney injury.30 Finally, opioids should be
considered a possible culprit for otherwise unexplained acute ophthalmoparesis
in patients receiving high-dose analgesia when more pressing or conventional
etiologies have been ruled out, such as posterior circulation ischemia. The ocular
misalignment can be reversed with naloxone.31

PSYCHOSTIMULANTS
Psychostimulants may be the drug class with the most extensive list of clinically
relevant agents to review. Despite the large number of agents in the category,
their common pharmacologic properties and overlapping adverse effects allow a
simplified approach to their associated toxidromes. TABLE 10-3 lists commonly
misused psychostimulants. Many of the agents in this class share the common
chemical backbone known as phenylethylamine. Despite the seemingly endless
number of specific compounds derived from this original structure, they all share
similar pharmacologic effects of promoting neurotransmission of dopamine,
serotonin, and norepinephrine in the CNS, each to different degrees.32 In general,
this common effect leads to a very desirable euphoric high for the people who
use it that can eventually yield strong addiction with recurrent exposure.
The comedown, or withdrawal, from psychostimulants in those who have
developed dependence can lead to a feeling of depression, severe fatigue, and
hunger (as opposed to the anorexia characteristic of the high). Withdrawal is not
life-threatening but is extremely unpleasant. Patients with psychostimulant
overdose present with hyperactive encephalopathy and can be complicated by
psychosis, cardiac arrhythmia, seizures, dilated pupils, hyperthermia,
and rhabdomyolysis.
Cocaine is possibly the most historically prolific drug in this class. The
Erythroxylum coca plant, indigenous to South America, is harvested and
processed to refine cocaine. The hydrochloride powder form is the most popular

TABLE 10-3 Psychostimulants With Misuse Potential

◆ Amphetamine
◆ Cathinone
◆ Cocaine
◆ Dextroamphetamine
◆ Ephedrine
◆ Methamphetamine
◆ Methcathinone
◆ Methylenedioxymethamphetamine (MDMA, “ecstasy”)
◆ Methylphenidate
◆ Phentermine
◆ Pseudoephedrine
◆ Synthetic cathinones (“bath salts”)

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and is consumed mostly by nasal insufflation. It can be further processed into an KEY POINTS
alkaloidal form, creating a solid, or “rock,” known as “crack,” which is consumed
● Opioids are commonly
by smoking. This yields a rapid-onset, intense high with significant risk to evolve associated with diffuse
into addiction. Methamphetamine, or “meth,” is the drug in this class that is new-onset myoclonus,
currently of the greatest public health concern. Even before the accelerations often in a dose-dependent
from the COVID-19 pandemic, US methamphetamine-associated overdose manner, and are more likely
to occur in those with
deaths tripled from 2015 to 2019.33 A further alarming observation has been the
renal failure.
increasing use of methamphetamine and opioids concurrently, and the two
epidemics appear to have merged in some populations of people who use drugs.34 ● Psychostimulants
Methamphetamine is most often consumed by either smoking or putting it into a promote dopamine,
solution for IV injection. serotonin, and
noradrenergic transmission
3,4-Methylenedioxymethamphetamine (MDMA) (ie, “ecstasy,” and more in the central nervous
recently referred to as “molly,” “X,” or “E”) is a prolific party drug. People who system. This explains the
use it find it favorable for its effects of enhancing their social experience. They euphoric high they produce
often describe a sense of warmth, alertness, disinhibition, a sense of and their use potential.
interpersonal connection to those in their presence, and enhanced sexual ● Methamphetamine
experiences. MDMA is somewhat chemically novel in this class in that it has a overdose deaths have
structural similarity to serotonin, which correlates with its additional dramatically increased in
hallucinogenic potential similar to lysergic acid diethylamide (LSD) as well as its recent years, tripling in
the United States from
ability to cause serotonin syndrome.35
2015 to 2019.
Cathinones are stimulants that occur naturally in the khat plant (Catha edulis),
which is native to Africa and the Arabian Peninsula. Cathinones can be ● Concurrent misuse of
consumed directly for a euphoric effect that is like that of methamphetamine. methamphetamine and
However, the synthetic cathinones, or “bath salts,” have created a public health opioids is on the rise and
may represent a “merged
concern in the Western hemisphere. These are an ever-changing list of epidemic” in some
compounds with new chemical agents being introduced on the market to replace populations.
the older compounds that have fallen under regulation, but they all have the
cathinone chemical backbone and thus have similar clinical effects and risks. ● The chemical structure of
3,4-methylenedioxymeth-
Many of these compounds would be considered designer drugs, whereby they amphetamine is similar to
can be legally purchased online or in smoke shops or convenience stores as they serotonin, which
are either too new to have undergone designation as a scheduled substance or are contributes to its additional
exploiting regulatory loopholes like being labeled as “not for human hallucinogenic potential as
well as its risk for causing
consumption.” Bath salts are consumed via a wide variety of routes: ingestion,
serotonin syndrome.
insufflation, inhalation, or injection. Severe intoxication with bath salts tends to
have core features of agitation, tachycardia, and hallucination. Intoxication with ● Synthetic cathinones, or
these drugs can have even more extreme presentations including paranoia, “bath salts,” are designer
self-mutilating behavior, and severe agitation with violent tendencies.36 drugs with high misuse
potential. Severe
Numerous neurologic injuries have been known to occur in association with intoxication can present
various drugs in the psychostimulant class. All drugs in the class lower the seizure with violent agitation, self-
threshold; however, cocaine has been observed to have an effect known as kindling, mutilation, tachycardia, and
whereby recurrent seizures can continue to be provoked despite subsequent seizures.
exposure to smaller or nonescalating doses.37 CASE 10-2 illustrates an interesting
neuropsychiatric complication of chronic cocaine use. MDMA use has been
associated with acute dystonic reactions and seizures with or without hyponatremia
owing to the syndrome of inappropriate secretion of antidiuretic hormone
(SIADH) or polydipsia effect.38 Anecdotally, a toxic leukoencephalopathy primarily
affecting the deep white matter has also been observed with MDMA use.39
In the setting of unregulated production of these drugs, impurities introduced
during the synthetic process and manufacturing of these agents have also been
associated with neurotoxic injury. Levamisole, an anthelminthic compound used

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SUBSTANCE USE AND THE NERVOUS SYSTEM

as a cutting agent for cocaine, can lead to an inflammatory demyelinating

leukoencephalopathy.41 FIGURE 10-4 shows the MRI from one of these reported
cases. Multiple cases of nonlevodopa-responsive parkinsonism have resulted
from neurotoxicity from the manganese added during the self-preparation of
injectable methcathinone, a type of synthetic cathinone popular in Eastern
Europe.42 As with other etiologies of manganese neurotoxicity, MRI in these
patients shows bilateral T1 hyperintensity in the globus pallidus bilaterally.43
Because of the vasoactive nature of the monoamine neurotransmission
promoted by these stimulants, essentially all agents in the class increase the risk
for ischemic and hemorrhagic cerebrovascular complications. Mechanisms for
stroke provoked by these agents could include severe hypertension, vasospasm,
vasoconstriction (including reversible cerebral vasoconstriction syndrome), or
vasculitis. Methamphetamine possibly poses the biggest cerebrovascular risk of
the class and tends to be associated with intracranial hemorrhage more than
ischemic stroke.44 However, bath salts are known to be associated with stroke in

CASE 10-2 A 62-year-old man was admitted to the hospital after presenting to the
emergency department with concerns about cutaneous parasitic
infection. The patient reported
seeing “tubular” organisms erupting
from his skin, and examination
showed multifocal cutaneous
lesions. FIGURE 10-3 shows the diffuse
foci of cutaneous erosion.
Dermatology was consulted and
deemed the lesions to be
inconsistent with parasitic infection
and most consistent with
excoriations due to scratching. The
patient had a prior history of
systemic and neurologic
autoimmunity in the form of lupus
and myasthenia gravis, respectively.
Neurology was then consulted with
the question of possible autoimmune
encephalitis presenting with delusion
of parasitic infection. Neurologic FIGURE 10-3
examination, including mental status A photo of the patient in CASE 10-2
shows multifocal excoriations due to
assessment, was completely normal scratching in a patient with hallucinosis
outside of the single delusion. Urine of cutaneous parasites in the setting of
drug screen was positive for cocaine. cocaine use, also known as “coke bugs.”

COMMENT This is a case of hallucinosis of cutaneous infestation in the setting of

cocaine use, referred to informally as “coke bugs.”40 The skin erosions
healed, and the patient’s hallucinations resolved after cocaine exposure
was no longer present.

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 younger patients (younger than KEY POINTS
50) and those with a paucity of
● The impurities added
other cerebrovascular risk during preparation of
factors.45 Like heroin, methcathinone (bath salts)
methamphetamine has been and cocaine can cause
reported in association with serious neurologic injury,
FIGURE 10-4
including manganese
Brain MRI in a patient with levamisole-induced spinal cord infarction.46 neurotoxicity causing
demyelinating leukoencephalopathy. A, T1 Finally, the misuse of popular parkinsonism and
sequence with multifocal round hypointense
stimulants used to treat attention levamisole causing central
lesions in the white matter. B, The same lesions
deficit hyperactivity disorder nervous system
displaying hyperintensity on T2 sequences. C, The
inflammatory
same lesions are also ring enhancing or partially (ADHD) and narcolepsy, such as
demyelination, respectively.
ring enhancing on postgadolinium sequences. amphetamine/dextroamphetamine
Reprinted with permission from Yan R, et al, Exp Ther
and methylphenidate, among ● All drugs in the
Med.41 © 2013 Spandidos Publications.
teenagers and young adults is psychostimulant class
prevalent.47 Whether or not this theoretically lower the
seizure threshold and
misuse definitively leads to increase the risk for stroke
increased occurrence of seizures or other sinister neurotoxicity in this population and intracranial
is unclear. However, one large study did observe a slightly increased risk of hemorrhage.
seizures in the first 30 days after the initiation of methylphenidate in children
● Pharmaceutical use of
being treated for ADHD,48 so it would be reasonable for the neurologist to ask barbiturates has declined in
about cognitive-enhancing stimulant use when taking a history for a patient with recent decades owing to
seizures of unknown provocation. their increased potential for
misuse, dependence, and
withdrawal.
SEDATIVES AND HYPNOTICS
Benzodiazepines, barbiturates, and a few other miscellaneous sedatives make
up the principal drugs in this class. Commonly prescribed benzodiazepines
include diazepam, clonazepam, lorazepam, and alprazolam. Common
pharmaceutical barbiturates include phenobarbital, pentobarbital, and
butalbital. Several of these agents are familiar to neurologists given their use for
sedation in the critical care setting and their utility in aborting status epilepticus.
However, nonpharmaceutical misuse of benzodiazepines is common. This
includes misuse and sale of prescription benzodiazepines, like alprazolam,
sometimes known as “Xanny bars,” given the rectangular shape of the
name-brand Xanax tablet. Additionally, as previously mentioned, novel illicit
benzodiazepines are in circulation and have been found as adulterants in
fentanyl supplies.14 This class of drugs induces sedation via agonist effects of the
γ-aminobutyric acid A (GABAA) receptor in the CNS, thus facilitating inhibitory
neurotransmission. Pharmaceutical use of barbiturates has declined in recent
decades owing to their increased potential for misuse, dependence,
and withdrawal.
Mild to moderate intoxication with these agents commonly produces euphoria
with superimposed drowsiness. Amnesia of recent events is common and
dose-dependent. Conversely, benzodiazepine exposure can cause idiopathic
paradoxical reactions, which can appear similar to a hyperactive delirium. Both
barbiturates and benzodiazepines carry significant risk of morbidity and
mortality in untreated overdose, which can lead to life-threatening respiratory
depression and coma.
These agents can produce significant physical dependence and risk for
harmful withdrawal with abrupt discontinuation. Because these agents share a
common mechanism of action with ethanol, withdrawal from benzodiazepines

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SUBSTANCE USE AND THE NERVOUS SYSTEM

and barbiturates can have a similar clinical phenotype to alcohol withdrawal.

This includes diaphoresis, agitation, hallucinations, tachycardia, and most
concerning, status epilepticus. Those with chronic use of benzodiazepines and
barbiturates should not be abruptly discontinued but rather tapered off these
agents, including butalbital, which some patients still take chronically for
headache. Long-term use of these agents is discouraged as it can contribute to
cognitive impairment.49
Miscellaneous drugs to note in this category are γ-hydroxybutyric acid (GHB)
and flunitrazepam (“roofies”), which are notorious for their use in sexual assault.
These are also GABA-mediated (GABA-ergic) agents that require individually
ordered hospital laboratory assays to detect and will not be detected on a
standard urine drug screen panel. They can be covertly added to an individual’s
alcoholic beverage. Then, through potentiating the effect of the alcohol and the
agent’s own strong sedative properties, the drug causes initial euphoria leading to
stupor or coma, but has a rapid offset, returning the person to the fully alert state.
During the individual’s period of depressed consciousness, they are highly
vulnerable to assault by the perpetrator and have amnesia of recent events after
awakening.50 The agent can only be detected if the individual seeks medical
evaluation and the correct assay is ordered.

GABAPENTINOIDS
Gabapentin and pregabalin are familiar medications to neurologists, mainly for
their use in treating neuropathic pain. The agents are modulators of
neurotransmission via presynaptic voltage-gated calcium channels.51 However,
these medications continue to have prevalent misuse. When taken alone,
each agent can produce its own desirable, euphoric high, although its potential
for addiction as a solitary agent of misuse has yet to be definitively established.
Sometimes referred to as “gabbies,” evidence exists of a growing trend of
these agents being misused alongside opioids with the goal of prolonging and
potentiating the high.52 These medications are considered controlled substances
in some US states. Neurologists should exercise caution when titrating
gabapentinoids in those concurrently taking opioids given the risk of
oversedation.

MARIJUANA AND SYNTHETIC CANNABINOIDS

Delta-9 tetrahydrocannabinol (THC) is the principal psychoactive cannabinoid
compound found in the cannabis or marijuana plant. Traditionally, smoking

TABLE 10-4 Popular Hallucinogenic Agents

◆ Dimethyl-tryptamine (DMT)
◆ Ibotenic acid/muscimol
◆ Kratom
◆ Lysergic acid diethylamide (LSD)
◆ Mescaline
◆ Psilocybin
◆ Salvia divinorum

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the plant leads people to feel a high characterized by increased jocularity, KEY POINTS
relaxation, increased appetite, and an altered sense of perception and passage
● Patients chronically using
of time. Some experience a more extreme toxidrome where they can develop benzodiazepines and
paranoia, dysphoria, and even psychotic intrusions.53 Physical withdrawal barbiturates should be
is not thought to be a risk, but psychological dependence is observed and, in tapered off the medication
the setting of new abstinence, can precipitate strong cravings. In recent years, a instead of abruptly
discontinuing medication to
higher proportion of those who use the drug consumes it through ingestion avoid a potentially severe
of THC-infused foods known as “edibles,” coinciding with numerous US states withdrawal syndrome that
legalizing cannabis. Delta-8 THC is an isomer that is less potent than its can include seizures.
delta-9 counterpart and is found in smaller quantities in cannabis plants.
● Novel benzodiazepines
However, it is refined and sold legally in multiple US states where delta-9
have been found as
THC is still illegal. Despite its reduced relative potency, high-dose exposure has adulterants to the
been reported to cause an acute encephalopathy.54 Because of cross-reactivity, nonpharmaceutical fentanyl
delta-8 THC exposure can lead to a positive urine drug screen for delta-9 THC. supply on a regional basis,
further complicating
The early 21st century saw the introduction and proliferation of synthetic
overdose intervention.
cannabinoids. These are compounds that function as full agonists of the
cannabinoid receptors in the CNS, thus yielding a higher potency than naturally ● Misuse of gabapentin
derived THC.55 These are designer drugs, not detected on standard urine drug and pregabalin to potentiate
screens, and commonly consumed by spraying the compound in liquid form onto and prolong the effects of
illicit opioids is a growing
herb leaves and smoking. They can be legally purchased as “herbal trend.
incense—not for human consumption.” They can also be consumed via
electronic cigarettes (e-cigarettes). Compared with traditional marijuana, ● Synthetic cannabinoids
synthetic cannabinoids are more likely to cause neuropsychiatric effects like are more potent than natural
cannabis and can produce
agitation, paranoia, delusions, and psychosis. Neurologists should know that
more stimulantlike effects,
synthetic cannabinoids pose a high risk of precipitating seizures.56,57 Intracranial including severe agitation
hemorrhage has been reported after use of synthetic cannabinoids adulterated and psychosis.
with the rodenticidal anticoagulant brodifacoum.58
Both natural and synthetic cannabis use have been associated with various ● Seizures are a known and
concerning risk with the use
cerebrovascular complications in those older than the age of 50 or without a high of synthetic cannabinoids.
burden of other stroke risk factors. Marijuana has been tied to ischemic stroke in
the setting of multifocal cerebral vasoconstriction and is a listed risk factor for ● Marijuana use is not
reversible cerebral vasoconstriction syndrome (RCVS).59,60 Synthetic totally risk free
neurologically. It increases
cannabinoid exposure has also been associated with ischemic and hemorrhagic the risk of cerebrovascular
stroke.61,62 Finally, neurologists consulted regarding a neurogenic source for complications, and people
intractable nausea and vomiting should inquire about chronic cannabis exposure. who use it chronically are at
Cannabinoid hyperemesis syndrome is a well-described complication of chronic risk for cannabinoid
hyperemesis syndrome.
natural or synthetic cannabinoid use that has the near-pathognomic feature of
relief of nausea through hot water bathing.63,64 ● Hallucinogens induce
psychotropic effects of
HALLUCINOGENS altered perception by
While hallucinations can be one of the effects of several other classes of drugs, potentiating central
serotonergic activity.
hallucinogens (colloquially called psychedelics) have the primary ability to alter
sensory perception and produce frank hallucinations. TABLE 10-4 lists popular
drugs in this category. Those who use hallucinogens describe a heightened
sensation of sounds, smells, and colors. Agents in this category share a common
mechanism for their toxidrome: potentiation of central serotoninergic activity.
As such, hallucinogens increase the risk of serotonin syndrome when combined
with prescription pharmaceuticals such as those used for treating depression.65
Most of these drugs are consumed orally. Those who use the drugs commonly
experience nausea or vomiting before developing the psychedelic effects. The

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SUBSTANCE USE AND THE NERVOUS SYSTEM

highs, or “trips,” for these agents can be unpredictable for some, whereby they
have a “bad trip” with perceptual alterations that induce fear or panic.
Severe intoxications are not thought to be life-threatening, and patients who
overdose and present for medical attention are best treated supportively with
calming techniques and sometimes medication to relieve agitation if the risk
of injury is possible. Physical withdrawal is not well-recognized for this
drug class.
LSD is a powerful synthetic hallucinogen. Its prevalence has declined since the
1960s and 1970s, but evidence suggests an increase in usage from 2015 through
2018, including among those who used other illicit nonhallucinogenic drugs.66
Most agents in the hallucinogen class can cause flashbacks, but LSD is
particularly notorious for this. Flashbacks are instances where a person who
previously used a hallucinogen experiences an unprovoked recurrence of a
previous hallucination or other symptom of a prior hallucinogen intoxication.
This can occur long after the previous use, sometimes days or months after taking
the drug. Flashbacks are more likely to occur with those who have been
chronically exposed but are still possible after taking the drug just once. Patients
whose recurrent flashbacks are disabling enough to cause functional impairment
are deemed to have hallucinogenic persisting perception disorder.67 Given
that LSD is an ergot derivative, it presents a theoretical risk in those with
concurrent cardiovascular and stroke risk factors, much like the migraine
drugs with similar vasoactive properties.
While LSD is synthetic, many other drugs in this class occur naturally. These
include various psychedelics like psilocybin and psilocin from mushroom species
(“shrooms”), mescaline from the peyote cactus (synthetic versions also exist),
and dimethyltryptamine (“DMT,” or “Ayahuasca” derived from Amazonian
region plants). The potential pharmaceutical use of psychedelics for the
treatment of depression, anxiety, and substance use disorders is a focus of
ongoing research and discussion.68
This class of drugs also contains some slightly atypical agents such as kratom
and salvia. Kratom (Mitragyna speciosa) is a tropical tree with leaves that are
ground into powder and consumed orally by being stirred into liquid, making
teas, or via capsules. The active compounds in the leaves are mitragynine and
7-hydroxymitragynine. These compounds do have some weak opioid activity
and thus kratom is an exception in this category in that chronic use may be
associated with a withdrawal syndrome.69 It is legal in most parts of the United
States and can be purchased at gas stations and smoke shops. Salvia divinorum is a
type of sage plant containing the psychoactive compound salvinorin A, which
can act as an agonist at the kappa opioid receptor but interestingly yields a
psychoactive high that can include visions of geometric figures,
anthropomorphic objects, and body distortions that are often only minutes in
duration.70,71 It is a drug considered also to be a “legal high” and can be purchased
by similar avenues as kratom. Salvia is commonly sold in leaf or seed form and is
then smoked or chewed to achieve intoxication.

DISSOCIATIVE AGENTS: PHENCYCLIDINE AND KETAMINE

Phencyclidine (also called “PCP” or “angel dust”) and ketamine are both
dissociative agents that share similar chemical properties in that they both cause
significant blockade of the N-methyl-D-aspartate (NMDA) receptor and can
produce profound acute psychotic presentations.72-74 Intoxication effects can be

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unpredictable from individual to individual. The dissociative aspect refers to the KEY POINTS
user’s out-of-body experience. Effects can range from violent agitation to
● Hallucinogen use,
significant psychomotor retardation, or even coma, which should not be especially chronic use, can
surprising given ketamine’s well-known utility as an anesthetic agent. Lower lead to flashbacks, whereby
doses of exposure often lead to mild euphoria or tactile sensory distortions. the effects of the drug recur
These agents should be considered as a potential chemical precipitant of a sometimes days or weeks
after the last exposure.
new-onset, undifferentiated schizophrenic presentation, including
hallucinosis, delusions, or catatonia.72 Ketamine also continues to be used as a ● Kratom and salvia are
“club drug,” much like those in other classes such as MDMA, GHB, and plant-derived hallucinogens
flunitrazepam. Despite its lower prevalence in recent decades, PCP still with some opioid agonist
appears on most standard urine drug screens, but ketamine requires an activity, albeit milder than
actual opioid compounds,
individual assay that is available in most hospital laboratories. Illicit routes of but can be purchased legally
administration of these agents are variable but often are ingestion, in many areas.
insufflation, or sometimes injection or smoking.
● Dissociative drugs like
phencyclidine (PCP) or
ANTICHOLINERGICS ketamine can have a wide
Neurologists should be familiar with the anticholinergic toxidrome characterized spectrum of presentations
by dilated pupils, tachycardia, encephalopathy, flushing, and urinary retention. with intoxication ranging
Severe cases can lead to seizures, myoclonus, or even coma. Those who use these from mild euphoria with
tactile sensory distortions,
drugs for nonpharmaceutical purposes typically seek them for their euphoric
to acute psychosis with or
sedative properties. Agents of misuse in the category include conventional without violent agitation,
pharmaceutical agents like diphenhydramine, which has both antihistamine and to coma.
anticholinergic activity.75 Plant products like jimson weed (a plant containing
atropine and scopolamine compounds) have been sources of misuse in the past ● The anticholinergic
toxidrome is marked by
via oral consumption.76 mydriasis, tachycardia,
Anticholinergic misuse of prescription antiemetics, particularly encephalopathy, and urinary
promethazine, has emerged in the 21st century. Known as “purple drank,” retention.
“sizzurp,” or “lean,” these are liquid concoctions with codeine cough syrup as the
● Treatment of
base but often are combined with promethazine, followed by artificial flavors anticholinergic overdose is
and often lemon-lime soda to improve the taste. The sedative effect of with IV physostigmine, given
promethazine potentiates the effect of the opioid, which can result in death its central nervous system
from respiratory depression and lack of airway security.77,78 Regarding isolated penetrance compared with
other acetylcholinesterase
anticholinergic toxicity, if the toxidrome is recognized, overdose can be treated
inhibitors.
with IV physostigmine, which is an acetylcholinesterase inhibitor with
CNS penetrance.79 ● Most misused inhalants
are volatile hydrocarbons
INHALANTS that yield short euphoric
highs.
Numerous industrial and household chemicals are volatile and have fumes that
can be intentionally inhaled to achieve an intoxicated state. Those who engage in ● Toluene, an industrial
recreational use of inhalants often compare the high to that of conventional solvent and thinner,
drunkenness from alcohol ingestion. Intoxication from inhalants is often short can cause a
leukoencephalopathy
duration, within a range of a few hours or less. The euphoria and drunkenness that can present as a
can be followed by a depressed, let-down feeling. Chemically, the typical white matter dementia or
backbone of most inhalants is an aliphatic or aromatic halogenated hydrocarbon. cerebellar and visual
Extreme levels of exposure can lead to seizures or hallucinations. Those who deficit syndrome.
chronically use develop very strong cravings. However, a clear physical
withdrawal syndrome has not been recognized. TABLE 10-5 lists some commonly
used inhalants.
A spectrum of neurologic injury results from inhalant use. Toluene is a widely
employed solvent that is used by inhalation (ie, huffing). Chronic toluene

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SUBSTANCE USE AND THE NERVOUS SYSTEM

exposure has been well described as associated with a toxic leukoencephalopathy

that can present as a white matter dementia.80 In some it can also present with
cerebellar signs and decreased visual acuity. MRI can show diffuse T2
hyperintensity in the cerebral and posterior fossa white matter, with
corresponding thalamic hypointensity (FIGURE 10-5).81
n-Hexane is another industrial solvent, and glue sniffing is one well-known
means of its recreational exposure. Chronic n-hexane use has been associated
with an axonal sensorimotor peripheral neuropathy with significant motor
impairment that can even progress for a period of time after discontinuing the
drug, a toxic neuropathic phenomenon known as coasting.82
Nitrous oxide is also a misused inhalant. Known to clinicians and dentists for
its use as a procedural sedative, it can also be found in canned aerosol food
products and other pressurized canisters. Inhaling nitrous oxide from these
canisters to achieve a high is known as doing “whip-its.” Repetitive exposure
over time leads to a functional vitamin B12 deficiency resulting from oxidation of
cobalamin by nitrous oxide. A clinical phenotype of classic subacute combined
degeneration can result; refer to the article “Neurologic Manifestations of
Gastrointestinal and Nutritional Disorders” by T. Scott Diesing, MD, FHM,83 in
this issue of Continuum. CASE 10-3 is an illustrative example with typical
imaging findings.84

E-CIGARETTES
Considerable attention has been paid to the dangers of e-cigarettes (ie,
“vaping,”) given the recent explosion in usage, especially by younger individuals.
From a neurologic standpoint, reports of seizures occurring after exposure
to e-cigarettes prompted a statement on this issue by the US Food and
Drug Administration (FDA) in 2019.85 However, a definitive correlation has

TABLE 10-5 Common Sources for Inhalant Misuse

◆ Aerosols
◆ Anesthetics (eg, dental surgical supply, whipped cream dispensers, or “whip-its”)
◆ Cleaning fluids, spot removers
◆ Fire-extinguishing agents
◆ Furniture polish
◆ Glues, cement, rubber patching
◆ Lighter fluid
◆ Marker pens
◆ Mothballs (p-dichlorobenzene)
◆ Nail polish remover
◆ Natural gas
◆ Paints, enamels, paint thinners
◆ Petroleum (eg, gasoline, naphtha gas, benzene)
◆ Room deodorizers (eg, amyl nitrite, butyl nitrite, isobutyl nitrite)

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 yet to be established and thus remains KEY POINTS
somewhat of a controversy requiring
● n-Hexane misuse is
further study.86 associated with a potentially
Given the well-known association severe peripheral
between stroke and smoking traditional neuropathy with motor
leaf tobacco, the risk of stroke in young impairment that can persist
and even temporarily
adults who vape has been investigated, and worsen after abstinence.
there does not appear to be an increased
risk of stroke unless there is a concurrent ● Nitrous oxide misuse can
history of combustible tobacco use.87 lead to a functional vitamin
B12 deficiency and a
presentation
ALCOHOL indistinguishable from
FIGURE 10-5 Alcohol, specifically ethanol, is the most subacute combined
Fluid-attenuated inversion recovery familiar drug of use in Western society, degeneration.
(FLAIR) MRI sequence in a patient with given its widespread legality, marketing,
chronic toluene thinner toxicity ● The increased risk of
and cultural insertion. The toxidrome is seizure due to “vaping” or
showing T2 hyperintensity diffusely in
the cerebral white matter with T2 very recognizable, not just by clinicians, e-cigarette use has yet to be
hypointensity in the thalami. but by the public as well. It includes confirmed; however, there
Reprinted with permission from Uchino A, disinhibition, jocularity, ataxia does not appear to be an
et al, Eur Radiol.81 © 2001 Springer-Verlag. increased risk for stroke in
(especially of gait and speech), young adults who vape
dose-dependent sleepiness, and nausea or unless they also have used
vomiting. Ethanol has GABA-ergic CNS traditional combustible
depressant effects, so severe toxicity can be fatal owing to respiratory tobacco leaf.
suppression and coma. The person who uses may be prevented from
progressing to this level of severity because of the nuisance symptoms of
moderately severe intoxication discouraging further consumption. Sporadic
but heavy use of ethanol produces the postintoxication hangover, with which
many are familiar. However, chronic alcohol use can put patients at risk for
the severe withdrawal syndrome delirium tremens. This condition often
begins 48 to 72 hours after the last ethanol consumption and is marked by
tachycardia, agitation, hyperthermia, hallucinations, and generalized
seizures. Careful use of benzodiazepines is the most traditional staple of
treatment to replace the relative decrease in GABA-ergic activity. Alcoholic
hallucinosis is sometimes confused with delirium tremens but is a separate
entity that refers to hallucinations in the first 12 to 24 hours of abstinence after
chronic use that resolves by day 2.88
Many different patterns of primary and secondary nervous system injury can
occur with chronic alcohol use. This includes cerebellar degeneration (classically
affecting the cerebellar vermis), peripheral neuropathy, and cognitive
impairment that can persist despite cessation in those who previously used
heavily. Most neurologists in hospital practice are likely to encounter a patient
with hepatic encephalopathy caused by alcoholic cirrhosis. Chronic alcohol use
predisposes patients to nutritional deficiencies that lead to secondary nervous
system injury (thiamine and vitamin B6 and B12 deficiencies).89,90 Chronic
alcohol use disorder with malnutrition is also a classic association with the rare
diagnosis of Marchiafava-Bignami disease, whereby there is selective necrosis
of the corpus callosum and adjacent white matter. Since thiamine deficiency
has the same risk factors and can have clinical overlap, aggressive vitamin B1
supplementation is recommended in this clinical scenario as well.91 Finally, in
illicit homemade production of alcohol, particularly in areas where its lawful sale

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SUBSTANCE USE AND THE NERVOUS SYSTEM

CASE 10-3 A 22-year-old man presented to the emergency department after

experiencing 2 weeks of progressive foot paresthesia followed by hand
paresthesia. He reported that he first noticed a subtle imbalance, but it
continued to worsen, and at the time of presentation he required
assistance to walk. Neurologic examination revealed mild toe extensor
weakness and decreased vibratory sensation and proprioception in the
distal lower extremities greater than the upper extremities. Muscle
stretch reflexes were slightly reduced in the upper extremities and
absent in the lower extremities. He had a very wide-based gait with a
positive Romberg sign and pseudoathetosis of the outstretched fingers
with his eyes closed.
His brain MRI and CSF profile were normal. His cervical spine MRI
showed a T2-hyperintense, longitudinally extensive cord lesion
(FIGURE 10-6).84 His vitamin B12 level was low at 183 ng/L, and his
methylmalonic acid level was very elevated at 7.10 nmol/mL.

COMMENT This is a case of myeloneuropathy resulting from functional vitamin B12

deficiency secondary to repeat exposure to nitrous oxide. The imaging and
clinical syndrome are essentially identical to that of the prototypical
subacute combined degeneration of the spinal cord. He had no risk factors
for vitamin B12 malabsorption, and the patient later described frequently
inhaling “whip-its” to get high over the previous year. He improved in the
ensuing weeks after cessation of the inhalant misuse and aggressive
supplementation with vitamin B12 intramuscular injections.

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FIGURE 10-6
Cervical spine MRI of the patient in
CASE 10-3 with repeated voluntary
nitrous oxide exposure via “whip-its.”
A, Sagittal view shows a longitudinally
extensive cord lesion with
T2 hyperintensity. B, Axial view
shows a T2 hyperintense lesion in
the posterior columns. C, Axial
postgadolinium sequence shows
contrast enhancement in the
posterior cord.

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SUBSTANCE USE AND THE NERVOUS SYSTEM

is prohibited, methanol contamination during the production process can cause

blindness due to optic neuropathy.92

CONCLUSION
Substance use has the potential for a huge spectrum of neurotoxicity, ranging
from mildly bothersome symptoms to neurologic devastation and death.
Currently, synthetic opioid overdoses, followed by methamphetamine use, pose
the greatest threat to public health. Given that some of the recreational drugs
with the highest potential for neurologic injury do not show up on standard drug
screens, the clinician must be able to recognize the toxidromes and correlate the
history with ancillary data to confirm the diagnosis of illicit drug effect. Bilateral,
symmetric abnormalities on MRI should cue the clinician to consider a toxic
(or metabolic) pathology.

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