Synthetic cannabinoids (SCs) are manufactured variants of natural cannabinoids found in marijuana, potent agonists of the cannabinoid receptors (CB₁ and CB₂). They are typically modeled after delta-9-tetrahydrocannabinol (THC), which is among the most psychoactive of the cannabinoids, but their chemical structures are frequently altered in order to increase potency and circumvent regulations and law enforcement.¹ They often are sold as incense or herbal products combined with various other herbal ingredients and may be perceived as safe, legal alternatives to marijuana. However, many of these alterations result in greater toxicity, so it is important for health care providers to be aware of the toxidromes related to synthetic cannabinoid use.^2,3

SCs

There are more than 700 commonly used synonyms for synthetic cannabinoids⁴

Chill out

Chill x

Crazy monkey

Fake bake

Fake weed

Herbs

Incense

K2

Spice

Spice diamond

Spice gold

• Synthetic cannabinoids were developed in research laboratories in the 1980s and first emerged as a recreational drug around 2008.^2,3,5
• In 2015, 456 SC cases were reported in 101 participating hospitals and clinics.
• Many regions tracked by the ToxIC registry saw a doubling or tripling in SC cases from 2010 to 2015. For example, reported toxicity secondary to SC usage in the northeast region increased from ∼0.4% to 3.5%.¹
• The majority of cases occur in young men aged 20 to 30 yr as a result of intentional ingestion as a recreational drug. Adolescents 13 to 18 yr account for 27.4% of SC intoxications reported in the ToxIC sites.¹
• Prevalence is likely higher in the US than in Europe. 10.1% of U.S. high school seniors reported SC use from 2011 to 2013. Spain and France reportedly had a prevalence rate of 0.8% and 1.7%, respectively, in 2014.
• Most SC use is by males, with a rate of 93%.⁶

• Synthetic cannabinoids are manufactured experimentally, without regulation, with each variation carrying a new chemical signature. Frequently they are sold as a mixture with various herbs and other compounds. Thus physical symptoms may vary widely depending upon the route and type of substance ingested, receptor binding, and the metabolites of these compounds.³
• The majority of symptoms are mild and self-limited. However, severe toxicities are not uncommon.⁷
• Synthetic cannabinoids have much higher potency than natural marijuana, and thus greater potential for delirium, agitation, and psychosis.^3,8
• The most common symptoms across multiple studies are sinus tachycardia and neuropsychiatric symptoms (toxic psychosis, agitation, coma, central nervous system [CNS] symptoms).⁷
• Reported symptoms include:
  1. Cardiac effects: Tachycardia, palpitations, chest pain, hypotension, bradycardia, cardiac arrest^5,9
  2. Psychotic effects: Irritability, paranoia, anxiety, racing thoughts, hallucinations, delusions, psychosis, delirium, deliberate self-harm, nonsuicidal self-injury ^5,10,11
  3. Other: Conjunctival injection, nystagmus, ataxia, sedation, seizures, syncope, respiratory depression, CNS depression, coma, emesis, hyperthermia, rhabdomyolysis, acute kidney injury^2,5,10
• There have been reports of myocardial infarction, subarachnoid hemorrhages, pneumothorax, and acute ischemic strokes after ingestion. Superwarfarin adulterants of synthetic cannabinoids can lead to clinically significant coagulopathy.^4,5,12

• The majority of synthetic compounds are cannabinoid receptor 1 and 2 (CB1 and CB2) agonists. Some versions have N-nitrosodimethylamine (NDMA), serotonin, and other receptor affinity.^3,5
• Current compounds have higher cannabinoid receptor binding affinity, with resulting potency up to 800 times greater than THC.³
• Synthetic cannabinoid metabolites can have even stronger affinities for the CB1 and CB2 receptors. Binding of these metabolites may be responsible for the heightened potency and extended duration of the psychoactive effects and toxicities.^2,3,5
• Most are metabolized by glucuronidation and oxidation by liver cytochrome oxidase enzymes and renally excreted.^5,8

• Drug or alcohol intoxication
• Hypoglycemia
• Acute psychosis
• Status epilepticus or seizure disorder
• Stroke
• Toxidromes (tricyclic antidepressants, anticholinergic agents, organophosphates, sympathomimetics)

The workup is dictated by clinical symptoms and degree of toxicity.

• Mild intoxication usually does not require extensive laboratory studies.
• For severe toxicity:
  1. Serum electrolytes
  2. Blood urea nitrogen and creatinine, as there is increased risk for acute kidney injury
  3. Creatine kinase and urine myoglobin if concern for rhabdomyolysis
  4. Arterial blood gas if concern for respiratory depression
  5. Serum lactate for increased risk of lactic acidosis
  6. Drug abuse screen for contaminants or coingestions
  7. Troponin or cardiac biomarkers, as there is increased risk for myocardial infarction

Neuroimaging (CT or MRI of the brain) would be indicated if seizure, altered mental status, neurologic deficit, or concern for trauma is part of the presentation.

12-Lead electrocardiogram due to increased risk of prolonged QT and other arrhythmias

Counseling addressing psychological, substance abuse, and social issues. Education on the dangers of synthetic cannabinoid use

• Patients with mild to moderate symptoms can be observed for 6 hr in the emergency department and safely discharged after resolution of symptoms.
• Attempt to normalize any laboratory/vital sign abnormalities prior to discharge.
• Patients who remain symptomatic after this period warrant admission to an appropriate level of care, based on the severity of their symptoms.

Substance Use Disorder (Related Key Topic)

Cannabinoid Use Disorder (Related Key Topic)