Version May 2024
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 "Symptom management of multiple sclerosis in adults", section on 'Cannabinoids'.)
●(See "Overview of the management of epilepsy in adults", section on 'Alternative therapies'.)
●(See "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects" and "Cannabis use disorder: Clinical features, screening, diagnosis, and treatment".)
BACKGROUND — 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].
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 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]:
●Agitation, coma, toxic psychosis, or other nervous system finding (eg, seizures, 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 [16,28-33,45-47]. 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 [48]. 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 [49-53]. In addition, an outbreak of reversible acute kidney injury occurred following regional use of a "blueberry spice" synthetic cannabinoid [54-57]. 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.)
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 "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 [58]. 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 [59]. 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 [60-67]. 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 — 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".)
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".)
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')
•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 moderate and severe alcohol withdrawal syndromes", section on 'Minor withdrawal symptoms' and "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 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 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) [52,53].
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:
●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 [68,69]. 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 [54-57]. 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 [52,53]. Underlying vascular disease or other risk factors have not been described. These patients warrant consultation with a stroke specialist in addition to 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) [58,70-72]. Similar events were described in Florida in 2021 and Israel in 2021 to 2022 [73,74].
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 "Substance use disorders: Clinical assessment".)
Patients with severe agitation requiring large amounts of sedation, treatment of seizures, or management of significant complications of intoxication (eg, hyperthermia, rhabdomyolysis, 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: Clinical features, screening, diagnosis, and treatment".)
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 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):
-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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