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Synthetic Cannabinoids: Epidemiology, Clinical Manifestations, and Practical Diagnostic Aspects David A. Gorelick, M.D., Ph.D., DLFAPA Professor of Psychiatry University of Maryland School of Medicine

Epidemiology 2017 Global Drug Survey Lifetime use 5.8% 77.8% Past-year use 1.1% 60% Global Drug Survey 2017. Available at https://www.globaldrugsurvey.com/wp- content/themes/globaldrugsurvey/results/GDS2017_key-findings-report_final.pdf. Accessed 02/20/2018.   United Nations Office on Drugs and Crime, World Drug Report 2017. United Nations publication, Sales No. E.17.XI.6). Available at https://www.unodc.org/wdr2017/index.html. Accessed 02/20/2018.

Survey: US High School Seniors 2014-2015 Current use of synthetic cannabinoids 2.9% Use on at least 3 different days 49.7% Global Drug Survey 2017. Available at https://www.globaldrugsurvey.com/wp- content/themes/globaldrugsurvey/results/GDS2017_key-findings-report_final.pdf. Accessed 02/20/2018.   United Nations Office on Drugs and Crime, World Drug Report 2017. United Nations publication, Sales No. E.17.XI.6). Available at https://www.unodc.org/wdr2017/index.html. Accessed 02/20/2018.

Trends in Synthetic Cannabinoid Use 2011-2012 2016 Prevalence of past-year use in 12th graders 12% 4% Synthetic cannabinoid users also use plant cannabis. 

Clinical Manifestations Little high-quality data on their human safety or toxicity  More associated with serious medical and psychiatric problems than plant cannabis Winstock, A., Lynskey, M., Borschmann, R., & Waldron, J. (2015). Risk of emergency medical treatment following consumption of cannabis or synthetic cannabinoids in a large global sample. Journal of Psychopharmacology, 29(6), 698-703.

2017 Global Drug Survey X 5 Current/past-year synthetic cannabis users Sought emergency medical treatment 3.2% 0.6%

Retrospective Case Series: Results Psychotic symptoms 77.1% 55.5% Agitation 57.1% 27.3% Psychotic disorder diagnosis 82.8% 49.8% Mood disorder diagnosis 17.1% 45.5% Winstock, A., Lynskey, M., Borschmann, R., & Waldron, J. (2015). Risk of emergency medical treatment following consumption of cannabis or synthetic cannabinoids in a large global sample. Journal of Psychopharmacology, 29(6), 698-703.

Synthetic Cannabinoid Intoxication and Withdrawal More intense Longer lasting Pharmacologic differences between synthetic cannabinoids and plant-derived cannabis  Plant cannabis contains cannabidiol, which counteracts the effects of THC.

Synthetic Cannabinoids Effects Desired subjective effects Undesired effects Synthetic Cannabinoids Effects Anxiety Euphoria Increased appetite Sedation Dizziness Relaxation Conjunctival redness Tachycardia Monte, A. A., Calello, D. P., Gerona, R. R., Hamad, E., Campleman, S. L., Brent, J., ... & ACMT Toxicology Investigators Consortium. (2017). Characteristics and treatment of patients with clinical illness due to synthetic cannabinoid inhalation reported by medical toxicologists: a ToxIC Database study. Journal of Medical Toxicology, 13(2), 146-152.  Müller, H. H., Kornhuber, J., & Sperling, W. (2016). The behavioral profile of spice and synthetic cannabinoids in humans. Brain research bulletin, 126, 3-7.   Tait, R. J., Caldicott, D., Mountain, D., Hill, S. L., & Lenton, S. (2016). A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clinical Toxicology, 54(1), 1-13.

More Intense Effects + CB1 Stupor Prolonged psychosis Increased muscle tone Muscle pain

Life-Threatening Medical Complications Nausea and vomiting Hypertension Seizures Cardiac arrhythmias Rhabdomyolysis Hyperventilation Acute myocardial infarction Acute renal failure Apnea Monte, A. A., Calello, D. P., Gerona, R. R., Hamad, E., Campleman, S. L., Brent, J., ... & ACMT Toxicology Investigators Consortium. (2017). Characteristics and treatment of patients with clinical illness due to synthetic cannabinoid inhalation reported by medical toxicologists: a ToxIC Database study. Journal of Medical Toxicology, 13(2), 146-152.  Müller, H. H., Kornhuber, J., & Sperling, W. (2016). The behavioral profile of spice and synthetic cannabinoids in humans. Brain research bulletin, 126, 3-7.   Tait, R. J., Caldicott, D., Mountain, D., Hill, S. L., & Lenton, S. (2016). A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clinical Toxicology, 54(1), 1-13.

Cannabinoid intoxication syndrome Diagnosis of Intoxication Cannabinoid intoxication syndrome Collateral informants History Drug samples Paraphernalia Packaging Monte, A. A., Calello, D. P., Gerona, R. R., Hamad, E., Campleman, S. L., Brent, J., ... & ACMT Toxicology Investigators Consortium. (2017). Characteristics and treatment of patients with clinical illness due to synthetic cannabinoid inhalation reported by medical toxicologists: a ToxIC Database study. Journal of Medical Toxicology, 13(2), 146-152.    Tait, R. J., Caldicott, D., Mountain, D., Hill, S. L., & Lenton, S. (2016). A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clinical Toxicology, 54(1), 1-13.

Diagnosis is often made by exclusion. Confirmed by sophisticated and expensive assay methods Results are delayed several days False negative results possible due to novel chemical structures Monte, A. A., Calello, D. P., Gerona, R. R., Hamad, E., Campleman, S. L., Brent, J., ... & ACMT Toxicology Investigators Consortium. (2017). Characteristics and treatment of patients with clinical illness due to synthetic cannabinoid inhalation reported by medical toxicologists: a ToxIC Database study. Journal of Medical Toxicology, 13(2), 146-152.    Tait, R. J., Caldicott, D., Mountain, D., Hill, S. L., & Lenton, S. (2016). A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clinical Toxicology, 54(1), 1-13.

Clinical Manifestations Warranting a High Index of Suspicion (1) Conjunctival redness (2) Sudden onset of otherwise unexplained psychosis (3) Sudden onset of otherwise unexplained cognitive impairment, such as disorientation or disorganized speech Monte, A. A., Calello, D. P., Gerona, R. R., Hamad, E., Campleman, S. L., Brent, J., ... & ACMT Toxicology Investigators Consortium. (2017). Characteristics and treatment of patients with clinical illness due to synthetic cannabinoid inhalation reported by medical toxicologists: a ToxIC Database study. Journal of Medical Toxicology, 13(2), 146-152.    Tait, R. J., Caldicott, D., Mountain, D., Hill, S. L., & Lenton, S. (2016). A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clinical Toxicology, 54(1), 1-13.

Clinical Manifestations Warranting a High Index of Suspicion (4) Sudden onset of otherwise unexplained kidney, neurological (seizure), or cardiovascular problems, such as chest pain, tachycardia, arrhythmia, or hypertension (5) Typical signs and symptoms of cannabis intoxication when the drug test is negative for THC or cannabis Monte, A. A., Calello, D. P., Gerona, R. R., Hamad, E., Campleman, S. L., Brent, J., ... & ACMT Toxicology Investigators Consortium. (2017). Characteristics and treatment of patients with clinical illness due to synthetic cannabinoid inhalation reported by medical toxicologists: a ToxIC Database study. Journal of Medical Toxicology, 13(2), 146-152.    Tait, R. J., Caldicott, D., Mountain, D., Hill, S. L., & Lenton, S. (2016). A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clinical Toxicology, 54(1), 1-13.

Synthetic Cannabinoid Brand Names No distinctive cannabis odor Spice and K2 Black Mamba Bliss Bombay Blue Genie Joker Kush Kronic Zohai ~ 700 different brand names identified Image: http://mediad.publicbroadcasting.net/p/waer/files/styles/medium/public/201807/synthetic_cannabinoids_600x338.jpg

Useful Resources US Drug Enforcement Administration (DEA) www.dea.gov US National Institute on Drug Abuse (NIDA) www.drugabuse.gov

Physical and neurological Clinical laboratory testing Complete blood count Review of systems Electrolytes Blood chemistry Medical evaluation 12-lead electrocardiogram Physical and neurological examination Imaging (e.g., brain imaging)  Monte, A. A., Calello, D. P., Gerona, R. R., Hamad, E., Campleman, S. L., Brent, J., ... & ACMT Toxicology Investigators Consortium. (2017). Characteristics and treatment of patients with clinical illness due to synthetic cannabinoid inhalation reported by medical toxicologists: a ToxIC Database study. Journal of Medical Toxicology, 13(2), 146-152.    Tait, R. J., Caldicott, D., Mountain, D., Hill, S. L., & Lenton, S. (2016). A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clinical Toxicology, 54(1), 1-13.

Key Points The diagnosis is often made by history and/or presence of typical cannabis intoxication signs, such as conjunctival redness, in the absence of a drug test positive for THC.  Synthetic cannabinoids are not detected by routine drug screening tests. Diagnosis is suggested by sudden onset of unexplained psychosis; cognitive impairment; or kidney, neurological, or cardiovascular problems.

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