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Synthetic cannabinoids: Acute intoxication

AUTHOR: George Sam Wang, MD
SECTION EDITORS: Michele M Burns, MD, MPH, Robert G Hendrickson, MD, FACMT, FAACT
DEPUTY EDITOR: Michael Ganetsky, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2023.

This topic last updated: Mar 08, 2023.

INTRODUCTION

This topic discusses the epidemiology, pharmacology, toxicity, clinical manifestations, and
management of acute intoxication with synthetic cannabinoids will be discussed here.

The clinical manifestations and management of toxicity from cannabis (marijuana), medical
uses of cannabinoids, and the manifestations and treatment of cannabis use disorder are
provided separately:

● (See "Cannabis (marijuana): Acute intoxication".)

● (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on

'Cannabis and cannabinoids'.)

● (See "Symptom management of multiple sclerosis in adults", section on 'Cannabinoids'.)

● (See "Assessment and management of nausea and vomiting in palliative care", section
on 'Cannabinoids and cannabis'.)

● (See "Overview of the management of epilepsy in adults", section on 'Alternative

therapies'.)

● (See "Cannabis use: Epidemiology, pharmacology, comorbidities, and adverse effects"

and "Cannabis use disorder in adults".)

BACKGROUND

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Over 60 cannabinoids are found in natural marijuana and include delta-9

tetrahydrocannabinol (THC), the most psychoactive cannabinoid, cannabidiol (CBD), and
cannabinol (CBN). Synthetic cannabinoids are chemically synthesized compounds and not
naturally occurring cannabinoids. They may have been available in Europe as early as 2004,
and were first reported in the United States in December 2008 [1]. They are now classified as
Class I controlled substances by the United States Drug Enforcement Administration and are
illegal to possess, sell, and use [2].

The synthetic compound is sold as the chemical itself, or added to herbs or other plants (eg,
Canavalia sp, Nymphaea sp, Pedicularis sp, Leonotis sp) to appear as a natural product and is
typically marketed as "incense" or "herbal remedies." They are sold under various names
including: "K2," "spice," "crazy monkey," "chill out," "spice diamond," "spice gold," "chill X" or
by its chemical nomenclature (eg, AMB-FUBINACA, JWH-018, CP 47, and many others) [1,3-7].
Adulteration of cannabis products with synthetic cannabinoids has been reported [8]. A
synthetic cannabinoid has also been discovered in counterfeit cannabidiol oil (hemp or CBD
oil) which resulted in a poisoning outbreak in Utah [9].

Despite the term “cannabinoid”, most of the chemical structures of synthetic cannabinoids
are not analogs of THC. The clinical effects can be similar to natural marijuana intoxication
but may also result in more severe life-threatening symptoms. The chemical structures of
synthetic cannabinoids consist of four building blocks: a core group (eg, indoles, indazoles), a
tail group (eg, pentyl, 5F-pentyl, halogenation), a linker group (eg, carboxamide, methanone),
and linked groups (eg, naphthyl, phenyl, valinate) [10,11]. The structures of these building
blocks determine nomenclature and are constantly being changed to avoid regulatory
oversight [10-12]. Such changes may introduce additional, and often unpredictable, toxic and
clinical effects.

EPIDEMIOLOGY

Synthetic cannabinoids are recreational drugs commonly misused in the United States and
Europe [13-15]. Synthetic cannabinoids can cause significant toxicity, including fatalities, and
continue to be associated with intermittent outbreaks of individuals warranting emergency
department care [16-23].

Synthetic cannabinoids represent a large portion of novel psychoactive substances used

around the world. In 2014, the European Drug Emergencies Network reported synthetic
cannabinoids accounted for only 3 percent of agents, which increased to 72 percent in 2019
[24]. In 2021, of the 880 new psychoactive substances monitored by the European Monitoring
Centre for Drugs and Drug Addiction, more than 220 are synthetic cannabinoids [13,25].

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Individuals who misuse synthetic cannabinoids are typically adult males [16,23]. Among
surveyed United States adolescents, 1.4 percent self-report regular use, typically as part of
polysubstance misuse [26]. In one multicenter observational study of consultations
performed by medical toxicologists, adolescents (13 to 18 years of age) accounted for about
one quarter of patients presenting to hospitals and clinics for acute synthetic cannabinoid
poisoning [27].

From 2016 to 2019, increased cannabis legalization across the United States was associated
with a decline in synthetic cannabinoid cases reported to United States regional poison
centers [23]. The decline was greatest in states with permissive cannabis laws.

TOXICITY AND PHARMACOLOGY

Many physiologic effects of synthetic cannabinoids are similar to cannabis (marijuana) and
include tachycardia, conjunctival injection (red eyes), increased appetite, nystagmus, ataxia,
and slurred speech. However, compared with cannabis, synthetic cannabinoids have a
greater potential for serious neuropsychiatric toxicity including hallucinations, delirium, and
psychosis [16,24,28-33]. Furthermore, life-threatening toxicity caused by severe agitation or
seizures is more characteristic of toxicity from synthetic cannabinoids. (See "Cannabis
(marijuana): Acute intoxication", section on 'Adolescents and adults'.)

Synthetic cannabinoids differ from naturally occurring cannabinoids in their potency and
clinical effects. They are typically added to herbals or other hallucinogenic plants and
smoked, but they also can be ingested or insufflated in pure form. Inhalation of burning
incense adulterated with a synthetic cannabinoid compound has caused mass intoxication
[12]. They can be partial or full agonists at cannabinoid receptors, and various synthetic
cannabinoids have a diversity of potency and clinical effects [1,23,24,33-36]. They are
metabolized mostly through oxidation and glucuronidation via liver cytochrome oxidase
enzymes and excreted renally [36]. Some compounds, such as the naphthoylindoles, have
reported active metabolites [37]. It is difficult to report specific toxic doses because the
compounds and content change constantly [20]. Toxicity depends upon the amount used and
the specific compound.

Synthetic cannabinoids are a chemically heterogeneic group of compounds. Similar to natural

cannabinoids, they act as agonists at cannabinoid (CB) receptors (mostly CB1), which causes
psychoactive effects [7,20]. Other receptor and enzyme involvement has yet to be elucidated
but may include serotonin and N-methyl-D-aspartate (NMDA) receptors and monoamine
oxidase inhibition [3,6,38]. Although they act on similar receptors, synthetic cannabinoids are
often more potent agonists, with reports of potencies ranging from 2 to 800 times greater
than delta-9 tetrahydrocannabinol [3]. The herbal product or plant that serves as the vehicle
for synthetic cannabinoid delivery may also have hallucinogenic properties, or may contain
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other contaminants (such as caffeine, nicotine, and tramadol) that can contribute to clinical
effects and toxicity [39].

As of 2021, over 240 known synthetic cannabinoids have been manufactured by illicit drug
laboratories and there is significant potential for novel compounds to appear in the future
[10]. Identified synthetic cannabinoids fall into many major structural groups [1,3-7,10,12,39-
41]:

● Classical cannabinoids (ie, analogues of delta-9 tetrahydrocannabinol), derived from a

dibenzopyran ring (eg, HU-210, nabilone, or dronabinol)
● Naphthoylindoles (JWH-018, 073)
● Naphthylmethylindoles
● Naphthoylpyrroles
● Naphthylmethylindenes
● Phenylacetylindoles (JWH-0259)
● Cyclohexylphenols (CP 47)

An additional category includes miscellaneous compounds, including fatty acid amides such
as oleamide, which have a similar structure to endogenous cannabinoids such as
anandamide [42]. They have various industrial uses (anti-slip agent, plastics), but their status
as an abuse agent is uncertain.

CLINICAL MANIFESTATIONS

Synthetic cannabinoids have a wide spectrum of clinical effects which occur soon after
inhalation or insufflation and can last several hours to days, depending upon the compound
and potency [16,28-32,43]. Signs of intoxication vary by the specific compound.

Clinical effects of some agents can share many characteristics of cannabis (marijuana)
intoxication, including agitation, tachycardia, conjunctival injection, nystagmus, vomiting,
ataxia, sedation, and slurred speech. However, unlike cannabis, synthetic cannabinoids have
significant potential to cause serious and life-threatening toxicity [44].

The most common clinical effects based upon approximately 2000 reports of single agent
exposure to regional poison control centers in 2010 consist of tachycardia, agitation, and
vomiting [16]. For these mild to moderate symptoms, duration is typically less than eight
hours.

However, synthetic cannabinoids have significant potential to cause more serious toxicity. As
an example, in a report from a multicenter, hospital-based registry of consultations
performed by medical toxicologists, the frequency of signs or symptoms after single agent
exposure to synthetic cannabinoids in 277 cases from 2010 to 2015 was as follows [27]:

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● Agitation, coma, toxic psychosis, or other nervous system finding (eg, seizures or
hallucinations,) - 66 percent
● Bradycardia, tachycardia, or other cardiovascular finding - 17 percent
● Rhabdomyolysis - 6 percent
● Respiratory depression - 5 percent
● Acute kidney injury - 4 percent

Neurologic findings such as severe psychomotor agitation, psychosis, seizures,

hallucinations, delirium, dystonia, and paranoia have been highlighted in several case reports
and case series [16,28-33,45,46]. In a prospective, observational study of adolescents
undergoing specialty consultation for synthetic cannabinoid or cannabis exposure, patients
with synthetic cannabinoid intoxication were more likely to demonstrate neuropsychiatric
morbidity, such as coma and seizures, than individuals with cannabis intoxication [44].
Marked motor activity from agitation or seizures may also cause hyperthermia and
rhabdomyolysis. Deaths have been reported, including sudden death after first-time use of
inhaled synthetic cannabinoids in a 17-year-old adolescent [27].

Synthetic cannabinoid intoxication in young children occurs rarely but has the potential for
severe toxicity. For example, a three-year-old child developed coma, nystagmus, hypotonia,
apnea, and bradycardia necessitating rapid sequence intubation, chest compressions,
intravenous epinephrine, and continuous vasopressor infusion after unsupervised exposure
to 5-fluoro-PICA-3,3-dimethylbutanoic acid [47]. Identification of synthetic cannabinoid
exposure was not disclosed in this case and required involvement of law enforcement and
specialized laboratory techniques to make the diagnosis.

Additional manifestations of synthetic cannabinoid intoxication that vary from earlier reports
have been described. In a report of mass exposure of 33 adults to burning incense containing
methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (AMB-
FUBINACA) with the street name AK-47 24 Karat Gold, intoxication was marked by lethargy,
blank staring, "zombie-like" groaning, and slow mechanical movements of the arms and legs
that resolved in <12 hours after exposure ceased [12].

Synthetic cannabinoids have also been associated with ischemic stroke, subarachnoid
hemorrhage, chest pain, and myocardial ischemia and infarction in adolescents and young
adults without risk factors for these events [48-52]. In addition, an outbreak of reversible
acute kidney injury occurred following regional use of a "blueberry spice" synthetic
cannabinoid [53-56]. It is unclear whether toxicity was due to the synthetic cannabinoid or an
adulterant.

Coagulopathy and serious bleeding after synthetic cannabinoid use has occurred in several
regions of the United States from adulteration with a long-acting anticoagulant rodenticide.
(See 'Life-threatening coagulopathy (brodifacoum adulteration)' below.)

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Because synthetic cannabinoids are frequently inhaled in a manner similar to cannabis

(marijuana), they have the potential to cause chest pain due to acute exacerbations of
asthma, pneumothorax, or pneumomediastinum. (See "Cannabis (marijuana): Acute
intoxication", section on 'Adolescents and adults'.)

ANCILLARY STUDIES

Patient with mild to moderate intoxication — For most mild or moderate intoxications, no
ancillary studies are typically needed.

Patient with other manifestations — Additional testing may also be indicated based upon
clinical features as follows:

Agitation or seizure — All patients with marked agitation or seizures should have prompt
measurement of blood glucose. Because of the risk for rhabdomyolysis, lactic acidosis,
stroke, intracranial hemorrhage, and acute kidney injury, patients with marked agitation or
seizures warrant the following studies:

● Serum electrolytes
● Blood urea nitrogen and creatinine
● Creatine kinase
● Venous blood gas
● Serum lactate
● Serum ethanol concentration
● Complete blood count with platelets
● Rapid urine dip for blood and, if positive, urine for myoglobin
● Rapid urine drug screen (to evaluate for co-exposure to other drugs of abuse)
● Oxygen saturation by pulse oximetry
● 12-lead electrocardiogram and continuous ECG monitoring
● Urine pregnancy test (post-menarcheal females)
● Neuroimaging (patients with seizures)

Chest pain — Patients with chest pain suggestive of myocardial ischemia or infarction
warrant a 12-lead electrocardiogram and cardiac biomarkers (eg, troponins). (See "Troponin
testing: Clinical use", section on 'Diagnosis of acute MI'.)

Chest radiograph or ultrasound may assist in the diagnosis of stable patients with chest pain
indicative of a spontaneous pneumothorax. However, patients with signs of a tension
pneumothorax should undergo decompression prior to chest radiography. Bedside
ultrasound may assist with rapid diagnosis of pneumothorax in these unstable patients. (See
"Pneumothorax in adults: Epidemiology and etiology", section on 'Epidemiology' and

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"Bedside pleural ultrasonography: Equipment, technique, and the identification of pleural

effusion and pneumothorax".)

Clinically significant bleeding — Patients with a history of recent synthetic cannabinoid

use and unexplained bleeding should undergo testing of prothrombin time (PT), international
normalized ratio (INR), and activated partial thromboplastin time (aPTT) to assess for
coagulopathy secondary to possible brodifacoum adulteration [57]. Coagulopathy from
brodifacoum poisoning is characterized by prolongation of all three tests. (See 'Life-
threatening coagulopathy (brodifacoum adulteration)' below.)

In addition, patients should undergo the following tests:

• Complete blood count with differential

• Type and screen for blood products or, if significant bleeding, type and cross match
• Urine dipstick for blood
• Plasma fibrinogen and serum fibrin degradation products
• Stool for guaiac

Other laboratory or imaging studies may also be indicated depending upon the specific
sites of bleeding (eg, electrolytes, blood urea nitrogen, serum creatinine, and
ultrasound or computed tomography [CT] of the abdomen for major genitor-urinary
bleeding; CT of the head for intracranial bleeding). (See "Anticoagulant rodenticide
poisoning: Clinical manifestations and diagnostic evaluation", section on 'Ancillary
studies'.)

Testing for synthetic cannabinoids — Rapid urine drug screens will not detect synthetic
cannabinoids because the chemical compounds and their metabolites do not cross-react with
delta-9 tetrahydrocannabinol (THC) or its metabolites, the agents that these screens are
designed to detect [58]. Confirmatory reference laboratory tests via liquid chromatography
and mass spectrometry are available but do not return in a timely manner and will not help
with immediate diagnosis or clinical care [59-66]. However, identifying synthetic cannabinoids
in blood or urine can have public health implications during outbreaks with significant clinical
toxicities. If the original product is available, it can often be examined through forensic
analytic laboratories with local authorities. However, because the chemical structures and
compounds are constantly changing, they can still be difficult to identify, even for reference
laboratories.

Drug testing for cannabinoids in patients with acute cannabis (marijuana) intoxication is
discussed separately. (See "Cannabis (marijuana): Acute intoxication", section on 'Drug testing
for cannabinoids'.)

DIAGNOSIS
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Acute intoxication with synthetic cannabinoids is a clinical diagnosis. It is typically made

based upon a history of use of "spice," "fake," or "synthetic" marijuana (or various other
names used for synthetic cannabinoids) obtained from the patient or bystanders, coupled
with consistent physical findings. Although reference laboratory testing of the patient's urine
or forensic testing of the product can provide confirmation of exposure, such studies are not
readily available, do not impact clinical care, and are typically not performed. (See 'Testing for
synthetic cannabinoids' above and 'Clinical manifestations' above.)

DIFFERENTIAL DIAGNOSIS

Patients with severe synthetic cannabinoid intoxication have features common to many other
intoxications and medical conditions, especially those that cause agitation, status epilepticus,
or acute psychosis :

● Agitation – It is important to assess for potentially dangerous organic causes of

agitation as soon as this can be done safely ( table 1). In the emergency department
(ED), drug and alcohol intoxication or withdrawal are common diagnoses in combative
adult and adolescent patients. A rapid serum glucose measurement (eg, fingerstick
glucose), pulse oximetry, and a complete set of vital signs should be obtained in all
patients. (See "Assessment and emergency management of the acutely agitated or
violent adult", section on 'Post-restraint medical evaluation' and "Emergency
department approach to acute-onset psychosis in children", section on 'Approach' and
"Assessment and emergency management of the acutely agitated or violent adult",
section on 'Etiology and differential diagnosis'.)

Known psychiatric illness is a risk factor for violent behavior, with schizophrenia (with
and without paranoia), personality disorders, mania, and psychotic depression most
often associated with violence. Psychosis, delirium, or dementia may lead to violent
behavior. (See "Assessment and emergency management of the acutely agitated or
violent adult", section on 'Etiology and differential diagnosis'.)

The mnemonic FIND ME (functional [ie, psychiatric], infectious, neurologic, drugs,

metabolic, endocrine) may be helpful to organize a diagnostic search for the etiology of
delirium and violence ( table 2). (See "Diagnosis of delirium and confusional states".)

● Seizures – Toxicological causes of seizures are extensive and include but are not limited
to the following:

• Sympathomimetics (see "Acute amphetamine and synthetic cathinone ("bath salt")

intoxication", section on 'Central and peripheral nervous system')

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• Cyclic antidepressants (see "Tricyclic antidepressant poisoning", section on 'Clinical

features')

• Anticholinergic agents (eg, antihistamines) (see "Anticholinergic poisoning", section

on 'Clinical features of overdose')

• Isoniazid (see "Isoniazid (INH) poisoning", section on 'Clinical features of acute

toxicity')

• Methylxanthines (eg, theophylline or caffeine) (see "Theophylline poisoning", section

on 'Neurologic')

• Organophosphates (see "Organophosphate and carbamate poisoning", section on

'Acute toxicity')

Toxidromes (ie, physical findings characteristic for specific toxins) can be helpful for
determining the cause of seizure for many of these agents, including
sympathomimetics, anticholinergic agents, and organophosphates ( table 3). In
addition to anticholinergic findings, cyclic antidepressants will often cause a
constellation of symptoms other than seizures, including central nervous system (CNS)
depression, hypotension, and widened QRS on ECG. (See "Tricyclic antidepressant
poisoning", section on 'Clinical features'.)

Some common medical causes of status epilepticus and differentiating features from
synthetic cannabinoid intoxication include (see "Clinical features and complications of
status epilepticus in children", section on 'Causes' and "Convulsive status epilepticus in
adults: Classification, clinical features, and diagnosis", section on 'Etiology'):

• Hypoglycemia – Low blood sugar (see "Causes of hypoglycemia in infants and

children" and "Hypoglycemia in adults without diabetes mellitus: Determining the
etiology", section on 'Ill or medicated individuals')

• Electrolyte imbalance (eg, hyponatremia or hypocalcemia) – Low serum sodium or

calcium (see "Etiology of hypocalcemia in infants and children" and "Causes of
hypotonic hyponatremia in adults" and "Etiology of hypocalcemia in adults")

• Central nervous system infection (eg, meningitis or encephalitis) – Fever and/or

meningismus

• Intracranial mass lesion – Signs of increased intracranial pressure (eg, morning

headache with vomiting, papilledema, and/or focal neurologic deficits)

• Alcohol or sedative hypnotic withdrawal – Diaphoresis, agitation, tachycardia,

hypertension, and a history of chronic ethanol consumption (see "Management of

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moderate and severe alcohol withdrawal syndromes", section on 'Minor withdrawal

symptoms' and "Benzodiazepine poisoning and withdrawal", section on
'Benzodiazepine Withdrawal')

• Traumatic brain injury (see "Severe traumatic brain injury (TBI) in children: Initial
evaluation and management", section on 'Secondary survey')

● Acute psychosis – The differential diagnosis and approach to acute psychosis in the
emergency department is provided in the tables and algorithm ( table 4 and
table 5 and algorithm 1) and is discussed in detail separately. (See "Emergency
department approach to acute-onset psychosis in children", section on 'Differential
diagnosis' and "Emergency department approach to acute-onset psychosis in children",
section on 'Approach'.)

Differentiating synthetic cannabinoid toxicity from toxicity due to other drugs of abuse can be
difficult. Mild synthetic cannabinoid toxicity can present in a fashion similar to that of natural
cannabinoid toxicity. The difference will be a negative rapid drug screen for cannabis
(marijuana) if the patient has not also used natural cannabinoids. Even if such urine drug
screens are positive for agents such as cocaine or amphetamines, co-ingestion with synthetic
cannabinoid may still exist. More severe synthetic cannabinoid intoxication can present in
similar fashion to other sympathomimetics and hallucinogenics, including cocaine,
amphetamines, lysergic acid diethylamide (LSD), phencyclidine (PCP), and other substances,
such as "bath salts" (methcathinones) [3-5].

MANAGEMENT

The management of synthetic cannabinoid intoxication is supportive and determined by the

presence and severity of specific clinical manifestations.

Mild to moderate intoxication — Mild to moderate intoxication with dysphoria can often be
managed with a dimly lit room, reassurance, and decreased stimulation. Benzodiazepines
(eg, diazepam or lorazepam) can be helpful in controlling symptoms of anxiety and have a
low side effect profile.

Severe intoxication — Severe intoxication caused by synthetic cannabinoids can be life-

threatening and warrants prompt treatment directed at the most significant findings.

Agitation and psychosis — Patients with severe agitation from synthetic cannabinoid
intoxication usually do not respond to verbal de-escalation and require sedation with
benzodiazepines (eg, midazolam or lorazepam) or other medications ( algorithm 2).
Medical personnel should take precautions to protect themselves from violent behavior
including a security presence and the application of physical restraints. (See "Assessment and

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emergency management of the acutely agitated or violent adult", section on 'Management'

and "Emergency department approach to acute-onset psychosis in children", section on
'Patient and staff safety'.)

If intoxication leads to severe psychomotor agitation or hyperthermia, large doses of

benzodiazepines may be needed for adequate sedation. Rarely, propofol infusions,
intubation, paralysis, and/or external cooling may be indicated to prevent further end organ
damage and development of rhabdomyolysis and acidosis [28-32,43].

Hyperthermia — Hyperthermia (rectal temperature >38.5°C [101°F]) may result from

synthetic cannabinoid myotonic activity, seizures, rhabdomyolysis, or a combination of the
three and should be managed aggressively with mechanical cooling measures.

Augmentation of evaporative cooling is considered the treatment modality of choice because

it is effective, noninvasive, and easily performed. The naked patient is sprayed with a mist of
lukewarm water while air is circulated with large fans. Shivering may be suppressed with
intravenous benzodiazepines, such as diazepam (0.1 mg/kg, maximum single dose 5 mg IV)
or lorazepam (0.05 to 0.1 mg/kg, maximum single dose 1 to 2 mg IV). Cold inspired oxygen,
cold gastric lavage, cooling blankets, and cold intravenous fluids may be helpful adjuncts.
(See "Severe nonexertional hyperthermia (classic heat stroke) in adults", section on 'Cooling
measures and temperature monitoring' and "Heat stroke in children", section on 'Rapid
cooling'.)

Patients with marked agitation and hyperthermia (temperature >40°C) who do not respond
rapidly to initial pharmacologic interventions warrant rapid sequence intubation (RSI)
followed by paralysis to stop heat generation from muscle activity ( table 6). The clinician
should avoid succinylcholine when performing rapid sequence intubation if hyperkalemia
due to rhabdomyolysis is present or highly suspected. (See "Rapid sequence intubation in
adults for emergency medicine and critical care" and "Methamphetamine: Acute
intoxication", section on 'Hyperthermia' and "Acute amphetamine and synthetic cathinone
("bath salt") intoxication", section on 'Hyperthermia' and "Rapid sequence intubation (RSI) in
children for emergency medicine: Medications for sedation and paralysis", section on
'Succinylcholine'.)

There is no role for antipyretic agents, such as acetaminophen or aspirin, in the management
of drug-induced hyperthermia since the underlying mechanism does not involve a change in
the hypothalamic temperature set-point. Alcohol sponge baths should also be avoided
because large amounts of alcohol may be absorbed through dilated cutaneous vessels and
produce toxicity.

Rhabdomyolysis — Hyperthermia, agitation, seizures, and muscle rigidity may lead to

muscle cell breakdown (rhabdomyolysis) with significant risk for renal failure. Patients with

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rhabdomyolysis can present with the classic triad of pigmented granular casts in the urine, a
red to brown color of the urine supernatant, and a marked elevation in serum creatine kinase
(CK) although rhabdomyolysis may occur in patients whose urine shows no visually
discernible color change. Primary treatment goals consist of (see "Prevention and treatment
of heme pigment-induced acute kidney injury (including rhabdomyolysis)"):

● Fluid repletion with isotonic saline infusion (20 to 40 mL/kg per hour up to 1 to 2 L per
hour); the emergency provider should closely monitor urine output with the goal of
maintaining a minimum urine flow of 4 mL/kg per hour in children and 200 mL per hour
in adults. Once diuresis is established with normal saline, alkalinization of the urine is
commonly employed, but its efficacy is uncertain. (See "Prevention and treatment of
heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on
'Bicarbonate in selected patients'.)

● Evaluation for significant electrolyte abnormalities (hyperkalemia, hyperphosphatemia,

and hypocalcemia); management of hyperkalemia is of particular importance.
Hypocalcemia is usually transient and calcium administration should be avoided unless
severe symptoms (eg, tetany) are present.

Seizures — Seizures caused by synthetic cannabinoids warrant initial treatment with

benzodiazepines (eg, lorazepam or diazepam), with repeat doses as necessary ( table 7). If
seizures are not controlled by appropriate doses of benzodiazepines, a second anticonvulsant
agent such as phenobarbital should be administered. Antiepileptics whose mechanism of
action relies on sodium channel blockade such as phenytoin or fosphenytoin are unlikely to
be effective in toxin-induced seizures.

Patients with seizures may warrant neuroimaging (eg, computed tomography [CT] of the
brain) to evaluate for ischemic stroke, subarachnoid hemorrhage, or intracerebral
hemorrhage if physical findings suggest a structural brain lesion (eg, focal neurologic
findings) [51,52].

Although status epilepticus is unusual following synthetic cannabinoid intoxication, patients

in status epilepticus should receive further pharmacologic therapy based upon the patient's
hemodynamic status (eg, continuous infusions of midazolam, propofol, or pentobarbital)
( algorithm 3). The administration of phenobarbital after benzodiazepines often results in
the need for airway protection with endotracheal intubation. (See "Management of
convulsive status epilepticus in children", section on 'Refractory status epilepticus' and
"Refractory status epilepticus in adults", section on 'Definition and etiology'.)

Chest pain — Chest pain in association with synthetic cannabinoid use should be managed
according to etiology as follows:

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● Acute coronary syndrome – Substernal squeezing chest pain suggestive of myocardial

ischemia or infarction occurs rarely in association with synthetic cannabinoid use but
has been described in older adolescents and young adults [67,68]. Patients complaining
of chest pain suggestive of coronary insufficiency should be evaluated for acute
coronary syndrome and treated accordingly. (See "Initial evaluation and management of
suspected acute coronary syndrome (myocardial infarction, unstable angina) in the
emergency department", section on 'Clinical presentation' and "Initial evaluation and
management of suspected acute coronary syndrome (myocardial infarction, unstable
angina) in the emergency department", section on 'Management'.)

● Air leak – Inhalation and breathholding during synthetic cannabinoid use may cause a
pneumothorax or pneumomediastinum with sharp, pleuritic chest pain and
subcutaneous crepitus. Management of a pneumothorax depends upon its size and
includes oxygen administration and, if necessary, evacuation of the air leak with needle
decompression or chest tube insertion. (See "Treatment of secondary spontaneous
pneumothorax in adults", section on 'Initial management of first event'.)

No specific treatment is necessary for uncomplicated pneumomediastinum. (See

"Spontaneous pneumomediastinum in children and adolescents", section on
'Management'.)

● Asthma exacerbation – Synthetic cannabinoid use may cause chest tightness with
bronchospasm and wheezing. Standard therapy for status asthmaticus should be
provided. (See "Acute exacerbations of asthma in adults: Home and office
management", section on 'Algorithms for assessment and treatment at home and in the
office'.)

Acute kidney injury — Acute kidney injury has been associated with use of one type of
synthetic cannabinoid in a limited outbreak. Electrolytes and renal function should be
measured in patients with severe intoxication, complaints of back pain, or urinary symptoms
such as hematuria or oliguria. Biopsies of patients with acute kidney injury caused by
synthetic cannabinoid use revealed histologic evidence for acute tubular necrosis [53-56]. It is
unclear whether the kidney injury was caused by direct toxicity, an unidentified nephrotoxin
or contaminant, or patient predisposition. Treatment for acute kidney injury should be
directed by the degree of renal dysfunction and related adverse effects such as hypertension,
azotemia, and electrolyte abnormalities in consultation with a nephrologist. Most patients
recover with supportive care. (See "Overview of the management of acute kidney injury (AKI)
in adults".)

Stroke — Synthetic cannabinoid use has been associated with ischemic and hemorrhagic
stroke in case reports [51,52]. Underlying vascular disease or other risk factors have not been
described. These patients warrant consultation with a stroke specialist in addition to

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management for ischemic stroke or hemorrhagic stroke as described separately. (See "Initial
assessment and management of acute stroke" and "Spontaneous intracerebral hemorrhage:
Acute treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage", section on
'Management and prognosis'.)

Dystonia — We suggest that patients with synthetic cannabinoid intoxication and dystonic
reactions receive short-acting benzodiazepines (lorazepam and midazolam) instead of
anticholinergic agents such as diphenhydramine. Although anticholinergic agents are useful
in the treatment of many dystonic reactions, the antimuscarinic side effects have the
potential to exacerbate agitation and delirium in patients with synthetic cannabinoid
intoxication [28].

Life-threatening coagulopathy (brodifacoum adulteration) — Patients with unexplained

coagulopathy and/or bleeding and a history of recent synthetic cannabinoid use warrant
screening for and treatment of brodifacoum poisoning in consultation with a regional poison
control center. (See 'Regional poison control centers' below.)

In 2018, there was an outbreak in Illinois involving more than 150 patients who developed
coagulopathy and bleeding diathesis from adulteration of synthetic cannabinoids with
brodifacoum (long-acting vitamin K antagonist rodenticide) [57,69-71]. A similar event was
described in Florida in 2021 [72].

The diagnosis and treatment of brodifacoum poisoning is discussed separately. (See

"Anticoagulant rodenticide poisoning: Clinical manifestations and diagnostic evaluation" and
"Anticoagulant rodenticide poisoning: Management", section on 'Coagulopathy and active
bleeding'.)

Gastrointestinal decontamination — Because inhalation is the most popular route of

exposure for synthetic cannabinoids and the onset of clinical effects is rapid and frequently
includes altered mentation, there is no role for gastrointestinal decontamination for the
treatment of synthetic cannabinoid intoxication, even in patients with oral ingestion.

DISPOSITION

Patients with mild to moderate symptoms of synthetic cannabinoid intoxication can usually
be observed and treated in the emergency department until symptoms resolve (typically four
to six hours). Screening for substance use disorder and underlying mental illness should also
be performed once the patient is no longer intoxicated. (See "Clinical assessment of
substance use disorders".)

Patients with severe agitation requiring large amounts of sedation, treatment of seizures, or
management of significant complications of intoxication (eg, hyperthermia, rhabdomyolysis,

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myocardial ischemia, pneumothorax, or acute kidney injury) warrant hospital admission to an

appropriate level of care based upon their clinical condition.

The role of brief intervention for unhealthy drug use and indications for referral to substance
abuse treatment are discussed separately. (See "Brief intervention for unhealthy alcohol and
other drug use: Efficacy, adverse effects, and administration" and "Cannabis use disorder in
adults".)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are
available at all times for consultation on patients with known or suspected poisoning, and
who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-
222-1222). In addition, some hospitals have medical toxicologists available for bedside
consultation. Whenever available, these are invaluable resources to help in the diagnosis and
management of ingestions or overdoses. Contact information for poison centers around the
world is provided separately. (See "Society guideline links: Regional poison control centers".)

Resources for substance use — The Partnership for Drug Free Kids (www.Drugfree.org)
maintains a drug guide for 40 commonly abused drugs including common slang terms.

Resources specific for synthetic cannabinoids include the following:

● European Monitoring Centre for Drugs and Drug Addiction: Synthetic cannabinoids
● National Institute of Drug Abuse (NIDA) Drug Facts: Synthetic cannabinoids
(K2/Spice)
● Synthetic cannabinoids: An overview for healthcare providers

Society guideline links — Links to society and government-sponsored guidelines from

selected countries and regions around the world are provided separately. (See "Society
guideline links: General measures for acute poisoning treatment" and "Society guideline
links: Treatment of acute poisoning caused by recreational drug or alcohol use".)

SUMMARY AND RECOMMENDATIONS

● Pharmacology – Synthetic cannabinoids are synthesized compounds used either as the

chemical itself or added to herbs or other plants to appear as a natural product. They
can be marketed as "incense" or "herbal remedies." They are sold under various names
including: "K2," "spice," "crazy monkey," "chill out," "spice diamond," "spice gold," "chill
X," or by their chemical nomenclature (eg, AMB-FUBINACA, JWH-018, CP 47, and many

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others). Synthetic cannabinoids are usually smoked or insufflated during recreational

use. (See 'Background' above and 'Toxicity and pharmacology' above.)

● Clinical manifestations – Synthetic cannabinoids have a wide spectrum of clinical

effects which can be similar to cannabis (marijuana) intoxication, such as tachycardia,
conjunctival injection, nystagmus, vomiting, ataxia, and slurred speech. However, more
serious toxicity has frequently occurred including severe psychomotor agitation, toxic
psychosis, seizures, and coma. Agitation has been complicated by hyperthermia and
rhabdomyolysis. Rarely, acute kidney injury, myocardial infarction, ischemic stroke,
subarachnoid hemorrhage, and death have been reported. (See 'Clinical manifestations'
above.)

● Ancillary studies – For most mild or moderate intoxications, no ancillary studies are
needed. All patients with marked agitation or seizures should have a rapid serum
glucose measurement (eg, fingerstick glucose). Additional testing may also be indicated
based upon clinical features. Rapid urine drug screens will not detect synthetic
cannabinoids. (See 'Ancillary studies' above and 'Testing for synthetic cannabinoids'
above.)

● Diagnosis – Acute intoxication with synthetic cannabinoids is a clinical diagnosis that is

typically made based upon a history of "K2," "Spice," or "fake"/"synthetic" marijuana use
obtained from the patient or bystanders with consistent physical findings. (See
'Diagnosis' above.)

● Differential diagnosis – Patients with severe synthetic cannabinoid intoxication often

have features common to many other intoxications and medical conditions, especially
those that cause agitation, status epilepticus, or acute psychosis. Other evaluation is
indicated based upon the primary presenting symptoms and possible diagnoses. (See
'Differential diagnosis' above.)

● Management – The management of synthetic cannabinoid intoxication is supportive

and determined by the presence and severity of specific clinical manifestations (see
'Management' above):

• Mild to moderate intoxication – Symptoms such as dysphoria can often be

managed with a dimly lit room, reassurance, and decreased stimulation.
Benzodiazepines (eg, diazepam or lorazepam) can be helpful in controlling
symptoms of anxiety and have a low side effect profile. (See 'Mild to moderate
intoxication' above.)

• Severe intoxication – Severe intoxication caused by synthetic cannabinoids can be

life-threatening and warrants prompt treatment directed at the most significant
findings (see 'Severe intoxication' above):
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- Patients with severe agitation from synthetic cannabinoid intoxication usually do

not respond to verbal de-escalation and require sedation with benzodiazepines
(eg, midazolam or lorazepam) or other medications ( algorithm 2). Medical
personnel should take precautions to protect themselves from violent behavior
including a security presence and the application of physical restraints. (See
'Agitation and psychosis' above.)

- Hyperthermia (rectal temperature >38.5°C [101°F]) may result from synthetic

cannabinoid myotonic activity, seizures, rhabdomyolysis, or a combination of the
three and should be managed aggressively with mechanical cooling measures.
(See 'Hyperthermia' above.)

- Seizures caused by synthetic cannabinoid warrant initial treatment with

benzodiazepines (eg, lorazepam or diazepam) with repeat doses as necessary
( table 7). If seizures are not controlled by appropriate doses of
benzodiazepines, a second anticonvulsant agent such as phenobarbital should
be administered. The administration of phenobarbital after benzodiazepines
often results in the need for airway protection with endotracheal intubation and
mechanical ventilation. (See 'Seizures' above.)

- Chest pain in association with cannabis use should be managed according to

etiology (eg, myocardial ischemia versus pneumomediastinum or
pneumothorax). (See 'Chest pain' above.)

- Acute kidney injury has been associated with use of one type of synthetic
cannabinoid in a limited outbreak but may also complicate rhabdomyolysis from
severe psychomotor agitation. Treatment for acute kidney injury should be
directed by the degree of renal dysfunction and related adverse effects such as
hypertension, azotemia, and electrolyte abnormalities in consultation with a
nephrologist. (See 'Acute kidney injury' above.)

• Dystonia – In a patient with a dystonic reaction in the setting of synthetic

cannabinoid intoxication, we suggest treatment with benzodiazepines (eg,
lorazepam or midazolam) instead of anticholinergic agents (eg, diphenhydramine) to
avoid exacerbation of hyperthermia (Grade 2C). (See 'Dystonia' above.)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges Stephen J Traub, MD, former section editor of the
toxicology program, for 20 years of dedicated service.

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Use of UpToDate is subject to the Terms of Use.

REFERENCES

1. Understanding the Spice Phenomenon. European Monitoring Centre for Drugs and Drug
Addiction. http://www.emcdda.europa.eu/attachements.cfm/att_80086_EN_Spice%20The
matic%20paper%20—%20final%20version.pdf (Accessed on July 01, 2014).
2. Drug Enforcement Administration, Department of Justice. Schedules of controlled
substances: temporary placement of four synthetic cannabinoids into Schedule I. Final
order. Fed Regist 2014; 79:7577.
3. Musselman ME, Hampton JP. "Not for human consumption": a review of emerging
designer drugs. Pharmacotherapy 2014; 34:745.

4. Nelson ME, Bryant SM, Aks SE. Emerging drugs of abuse. Emerg Med Clin North Am
2014; 32:1.
5. Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow…and back again? A
review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts),
kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol 2012; 8:15.

6. Wells DL, Ott CA. The "new" marijuana. Ann Pharmacother 2011; 45:414.
7. Ashton JC. Synthetic cannabinoids as drugs of abuse. Curr Drug Abuse Rev 2012; 5:158.

8. Monti MC, Zeugin J, Koch K, et al. Adulteration of low-delta-9-tetrahydrocannabinol

products with synthetic cannabinoids: Results from drug checking services. Drug Test
Anal 2022; 14:1026.
9. Kuehn B. Synthetic Cannabidiol Poisoning. JAMA 2018; 319:2264.

10. Potts AJ, Cano C, Thomas SHL, Hill SL. Synthetic cannabinoid receptor agonists:
classification and nomenclature. Clin Toxicol (Phila) 2020; 58:82.

11. Pulver B, Fischmann S, Gallegos A, Christie R. EMCDDA framework and practical guidance
for naming synthetic cannabinoids. Drug Test Anal 2023; 15:255.

12. Adams AJ, Banister SD, Irizarry L, et al. "Zombie" Outbreak Caused by the Synthetic
Cannabinoid AMB-FUBINACA in New York. N Engl J Med 2017; 376:235.
13. European Monitoring Centre for Drugs and Drug Addiction. European Drug Report: Tren
ds and Developments (2022). https://www.emcdda.europa.eu/system/files/publications/
14644/TDAT22001ENN.pdf.

14. Trecki J, Gerona RR, Schwartz MD. Synthetic Cannabinoid-Related Illnesses and Deaths. N
Engl J Med 2015; 373:103.
15. Law R, Schier J, Martin C, et al. Notes from the Field: Increase in Reported Adverse Health
Effects Related to Synthetic Cannabinoid Use - United States, January-May 2015. MMWR
Morb Mortal Wkly Rep 2015; 64:618.

https://www.uptodate.com/contents/synthetic-cannabinoids-acute-intoxication/print?search=canabinoide sintetico&source=search_result&select… 18/22

12/06/2023, 09:42 Synthetic cannabinoids: Acute intoxication - UpToDate

16. Hoyte CO, Jacob J, Monte AA, et al. A characterization of synthetic cannabinoid exposures
reported to the National Poison Data System in 2010. Ann Emerg Med 2012; 60:435.

17. Wood KE. Exposure to bath salts and synthetic tetrahydrocannabinol from 2009 to 2012
in the United States. J Pediatr 2013; 163:213.
18. Monte AA, Bronstein AC, Cao DJ, et al. An outbreak of exposure to a novel synthetic
cannabinoid. N Engl J Med 2014; 370:389.

19. Kasper AM, Ridpath AD, Arnold JK, et al. Severe Illness Associated with Reported Use of
Synthetic Cannabinoids - Mississippi, April 2015. MMWR Morb Mortal Wkly Rep 2015;
64:1121.
20. Kemp AM, Clark MS, Dobbs T, et al. Top 10 Facts You Need to Know About Synthetic
Cannabinoids: Not So Nice Spice. Am J Med 2016; 129:240.

21. Springer YP, Gerona R, Scheunemann E, et al. Increase in Adverse Reactions Associated
with Use of Synthetic Cannabinoids - Anchorage, Alaska, 2015-2016. MMWR Morb Mortal
Wkly Rep 2016; 65:1108.
22. Kasper AM, Ridpath AD, Gerona RR, et al. Severe illness associated with reported use of
synthetic cannabinoids: a public health investigation (Mississippi, 2015). Clin Toxicol
(Phila) 2019; 57:10.
23. Klein TA, Dilley JA, Graves JM, Liebelt EL. Synthetic cannabinoid poisonings and access to
the legal cannabis market: findings from US national poison centre data 2016-2019. Clin
Toxicol (Phila) 2022; 60:1024.

24. Crulli B, Dines AM, Blanco G, et al. Novel psychoactive substances-related presentations
to the emergency departments of the European drug emergencies network plus (Euro-
DEN plus) over the six-year period 2014-2019. Clin Toxicol (Phila) 2022; 60:1318.
25. European Monitoring Centre for Drugs and Drug Addiction. Synthetic cannabinoids. http
s://www.emcdda.europa.eu/topics/synthetic-cannabinoids_en.

26. Palamar JJ, Barratt MJ, Coney L, Martins SS. Synthetic Cannabinoid Use Among High
School Seniors. Pediatrics 2017; 140.
27. Riederer AM, Campleman SL, Carlson RG, et al. Acute Poisonings from Synthetic
Cannabinoids - 50 U.S. Toxicology Investigators Consortium Registry Sites, 2010-2015.
MMWR Morb Mortal Wkly Rep 2016; 65:692.
28. Cohen J, Morrison S, Greenberg J, Saidinejad M. Clinical presentation of intoxication due
to synthetic cannabinoids. Pediatrics 2012; 129:e1064.

29. Harris CR, Brown A. Synthetic cannabinoid intoxication: a case series and review. J Emerg
Med 2013; 44:360.

30. Hermanns-Clausen M, Kneisel S, Szabo B, Auwärter V. Acute toxicity due to the confirmed
consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction 2013;

https://www.uptodate.com/contents/synthetic-cannabinoids-acute-intoxication/print?search=canabinoide sintetico&source=search_result&select… 19/22

12/06/2023, 09:42 Synthetic cannabinoids: Acute intoxication - UpToDate

108:534.
31. Lapoint J, James LP, Moran CL, et al. Severe toxicity following synthetic cannabinoid
ingestion. Clin Toxicol (Phila) 2011; 49:760.
32. Winstock AR, Barratt MJ. The 12-month prevalence and nature of adverse experiences
resulting in emergency medical presentations associated with the use of synthetic
cannabinoid products. Hum Psychopharmacol 2013; 28:390.

33. Mohr ALA, Logan BK, Fogarty MF, et al. Reports of Adverse Events Associated with Use of
Novel Psychoactive Substances, 2017-2020: A Review. J Anal Toxicol 2022; 46:e116.
34. Auwärter V, Dresen S, Weinmann W, et al. 'Spice' and other herbal blends: harmless
incense or cannabinoid designer drugs? J Mass Spectrom 2009; 44:832.

35. Ammann J, McLaren JM, Gerostamoulos D, Beyer J. Detection and quantification of new
designer drugs in human blood: Part 1 - Synthetic cannabinoids. J Anal Toxicol 2012;
36:372.
36. Fantegrossi WE, Moran JH, Radominska-Pandya A, Prather PL. Distinct pharmacology and
metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying
greater toxicity? Life Sci 2014; 97:45.

37. Rajasekaran M, Brents LK, Franks LN, et al. Human metabolites of synthetic cannabinoids
JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid
type-2 receptors. Toxicol Appl Pharmacol 2013; 269:100.
38. Hindson SA, Andrews RC, Danson MJ, et al. Synthetic cannabinoid receptor agonists are
monoamine oxidase-A selective inhibitors. FEBS J 2023.

39. Dresen S, Ferreirós N, Pütz M, et al. Monitoring of herbal mixtures potentially containing
synthetic cannabinoids as psychoactive compounds. J Mass Spectrom 2010; 45:1186.
40. King A, Hill SL, Pucci M, et al. Clinical features associated with ADB-BUTINACA exposure
in patients attending emergency departments in England. Clin Toxicol (Phila) 2022;
60:1094.
41. European Monitoring Centre for Drugs and Drug Addiction. Synthetic cannabinoids drug
profile. https://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cannabinoi
ds_en.

42. De Petrocellis L, Melck D, Bisogno T, Di Marzo V. Endocannabinoids and fatty acid amides
in cancer, inflammation and related disorders. Chem Phys Lipids 2000; 108:191.
43. Kronstrand R, Roman M, Andersson M, Eklund A. Toxicological findings of synthetic
cannabinoids in recreational users. J Anal Toxicol 2013; 37:534.

44. Anderson SAR, Oprescu AM, Calello DP, et al. Neuropsychiatric Sequelae in Adolescents
With Acute Synthetic Cannabinoid Toxicity. Pediatrics 2019; 144.

https://www.uptodate.com/contents/synthetic-cannabinoids-acute-intoxication/print?search=canabinoide sintetico&source=search_result&select… 20/22

12/06/2023, 09:42 Synthetic cannabinoids: Acute intoxication - UpToDate

45. Seywright A, Torrance HJ, Wylie FM, et al. Analysis and clinical findings of cases positive
for the novel synthetic cannabinoid receptor agonist MDMB-CHMICA. Clin Toxicol (Phila)
2016; 54:632.

46. Hill SL, Najafi J, Dunn M, et al. Clinical toxicity following analytically confirmed use of the
synthetic cannabinoid receptor agonist MDMB-CHMICA. A report from the Identification
Of Novel psychoActive substances (IONA) study. Clin Toxicol (Phila) 2016; 54:638.
47. Ruiz-Maldonado TM, Dorey A, Christensen ED, Campbell KA. Near-Fatal Spice Intoxication
of a Toddler. Pediatrics 2021; 148.

48. Mir A, Obafemi A, Young A, Kane C. Myocardial infarction associated with use of the
synthetic cannabinoid K2. Pediatrics 2011; 128:e1622.
49. Young AC, Schwarz E, Medina G, et al. Cardiotoxicity associated with the synthetic
cannabinoid, K9, with laboratory confirmation. Am J Emerg Med 2012; 30:1320.e5.
50. Clark BC, Georgekutty J, Berul CI. Myocardial Ischemia Secondary to Synthetic
Cannabinoid (K2) Use in Pediatric Patients. J Pediatr 2015; 167:757.
51. Rose DZ, Guerrero WR, Mokin MV, et al. Hemorrhagic stroke following use of the
synthetic marijuana "spice". Neurology 2015; 85:1177.
52. Freeman MJ, Rose DZ, Myers MA, et al. Ischemic stroke after use of the synthetic
marijuana "spice". Neurology 2013; 81:2090.

53. Bhanushali GK, Jain G, Fatima H, et al. AKI associated with synthetic cannabinoids: a case
series. Clin J Am Soc Nephrol 2013; 8:523.

54. Centers for Disease Control and Prevention (CDC). Acute kidney injury associated with
synthetic cannabinoid use--multiple states, 2012. MMWR Morb Mortal Wkly Rep 2013;
62:93.

55. Thornton SL, Wood C, Friesen MW, Gerona RR. Synthetic cannabinoid use associated with
acute kidney injury. Clin Toxicol (Phila) 2013; 51:189.
56. Buser GL, Gerona RR, Horowitz BZ, et al. Acute kidney injury associated with smoking
synthetic cannabinoid. Clin Toxicol (Phila) 2014; 52:664.

57. Outbreak alert: Potential life-threatening vitamin K-dependent antagonist coagulopathy

associated with synthetic cannabinoids use. Centers for Disease Control and Prevention.
April 5, 2018. https://content.govdelivery.com/accounts/USCDC/bulletins/1e6dac3.
58. Arntson A, Ofsa B, Lancaster D, et al. Validation of a novel immunoassay for the
detection of synthetic cannabinoids and metabolites in urine specimens. J Anal Toxicol
2013; 37:284.

59. Hutter M, Broecker S, Kneisel S, Auwärter V. Identification of the major urinary

metabolites in man of seven synthetic cannabinoids of the aminoalkylindole type

https://www.uptodate.com/contents/synthetic-cannabinoids-acute-intoxication/print?search=canabinoide sintetico&source=search_result&select… 21/22

12/06/2023, 09:42 Synthetic cannabinoids: Acute intoxication - UpToDate

present as adulterants in 'herbal mixtures' using LC-MS/MS techniques. J Mass Spectrom

2012; 47:54.
60. Moran CL, Le VH, Chimalakonda KC, et al. Quantitative measurement of JWH-018 and
JWH-073 metabolites excreted in human urine. Anal Chem 2011; 83:4228.

61. Penn HJ, Langman LJ, Unold D, et al. Detection of synthetic cannabinoids in herbal
incense products. Clin Biochem 2011; 44:1163.
62. Sobolevsky T, Prasolov I, Rodchenkov G. Detection of JWH-018 metabolites in smoking
mixture post-administration urine. Forensic Sci Int 2010; 200:141.

63. Freijo TD Jr, Harris SE, Kala SV. A rapid quantitative method for the analysis of synthetic
cannabinoids by liquid chromatography-tandem mass spectrometry. J Anal Toxicol 2014;
38:466.
64. Giorgetti A, Barone R, Pelletti G, et al. Development and validation of a rapid LC-MS/MS
method for the detection of 182 novel psychoactive substances in whole blood. Drug
Test Anal 2022; 14:202.
65. Namera A, Kawamura M, Nakamoto A, et al. Comprehensive review of the detection
methods for synthetic cannabinoids and cathinones. Forensic Toxicol 2015; 33:175.
66. United Nations Office on Drugs and Crime. Recommended methods for the identification
and analysis of synthetic cannabinoid receptor agonists in seized materials. https://www.
unodc.org/documents/scientific/STNAR48_Synthetic_Cannabinoids_ENG.pdf.
67. Caldicott DG, Holmes J, Roberts-Thomson KC, Mahar L. Keep off the grass: marijuana use
and acute cardiovascular events. Eur J Emerg Med 2005; 12:236.
68. Deharo P, Massoure PL, Fourcade L. Exercise-induced acute coronary syndrome in a 24-
year-old man with massive cannabis consumption. Acta Cardiol 2013; 68:425.
69. Moritz E, Austin C, Wahl M, et al. Notes from the Field: Outbreak of Severe Illness Linked
to the Vitamin K Antagonist Brodifacoum and Use of Synthetic Cannabinoids - Illinois,
March-April 2018. MMWR Morb Mortal Wkly Rep 2018; 67:607.

70. Kelkar AH, Smith NA, Martial A, et al. An Outbreak of Synthetic Cannabinoid-Associated
Coagulopathy in Illinois. N Engl J Med 2018; 379:1216.
71. Connors JM. Hemorrhagic Highs from Synthetic Cannabinoids - A New Epidemic. N Engl J
Med 2018; 379:1275.
72. Coble N, Mulay P, Funk A, et al. Notes from the Field: Coagulopathy Associated with
Brodifacoum Poisoning - Florida, December 2021. MMWR Morb Mortal Wkly Rep 2022;
71:1288.
Topic 97100 Version 40.0

https://www.uptodate.com/contents/synthetic-cannabinoids-acute-intoxication/print?search=canabinoide sintetico&source=search_result&select… 22/22