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Synthetic Cannabinoids: History, Chemistry, and Pharmacology David A. Gorelick, M.D., Ph.D., DLFAPA Professor of Psychiatry University of Maryland School of Medicine

Definition and History CB1 Synthetic cannabinoids Agonists at the cannabinoid CB1 receptor Synthetic marijuana Spice K2 Fake weed Bind more tightly than THC

THC + CB1 Subjective high Dry mouth Sedation Rapid heart rate Increased appetite (“munchies”) Conjunctival redness

First produced (research tools) Abuse was first identified Mid 2000s 1950s 2009 2015 First produced (research tools) Abuse was first identified NFLIS identified 2 different synthetic cannabinoids  Increased to 84 different compounds

The Appeal of Synthetic Cannabinoids Not detected by routine drug screening tests Conveniently purchased over the internet or in local convenience stores Perceived as legal, natural, or harmless  Cost comparable to plant cannabis Ford, B. M., Tai, S., Fantegrossi, W. E., & Prather, P. L. (2017). Synthetic pot: not your grandfather’s marijuana. Trends in pharmacological sciences, 38(3), 257-276.

Chemistry and Pharmacology 125+ different synthetic cannabinoids  8 chemical structural categories

Early Synthetic Cannabinoids Name Synthesized by JWH-018 JWH-073 John Huffman HU-208 HU-210 Hebrew University AM-694 Alexandros Makriyannis CP-47-497 Pfizer WIN55222-2 Sterling-Winthrop U.S. Drug Enforcement Administration, Diversion Control Division. (2016). Synthetic Cannabinoids and Synthetic Cathinones Reported in NFLIS, 2013–2015. Springfield, VA: U.S. Drug Enforcement Administration.

US NFLIS 2013 to 2015 AB-CHMINACA 10.89% XLR11 11.69% AB-FUBINACA 39.12% U.S. Drug Enforcement Administration, Diversion Control Division. (2016). Synthetic Cannabinoids and Synthetic Cathinones Reported in NFLIS, 2013–2015. Springfield, VA: U.S. Drug Enforcement Administration.

All known synthetic cannabinoids are illegal at the US federal level. Schedule 1 of the Controlled Substances Act U.S. Drug Enforcement Administration, Diversion Control Division. (2016). Synthetic Cannabinoids and Synthetic Cathinones Reported in NFLIS, 2013–2015. Springfield, VA: U.S. Drug Enforcement Administration.

Binds at least 100 times more tightly Partial agonist CB1 Activates receptor more strongly Full agonist CB2 No significant action Partial agonist Half-life Longer Active metabolites Ford, B. M., Tai, S., Fantegrossi, W. E., & Prather, P. L. (2017). Synthetic pot: not your grandfather’s marijuana. Trends in pharmacological sciences, 38(3), 257-276

Inactive non cannabis plant material Sold as plant material Inactive non cannabis plant material Widely varying doses of synthetic cannabinoids Different response each time Ford, B. M., Tai, S., Fantegrossi, W. E., & Prather, P. L. (2017). Synthetic pot: not your grandfather’s marijuana. Trends in pharmacological sciences, 38(3), 257-276.

Marketed as: Herbal highs Vaporized Resins Incense E-cigarettes Liquids Room deodorizer Vaping “Not for human consumption” Ford, B. M., Tai, S., Fantegrossi, W. E., & Prather, P. L. (2017). Synthetic pot: not your grandfather’s marijuana. Trends in pharmacological sciences, 38(3), 257-276.

Key Points Synthetic cannabinoids activate the cannabinoid CB1 receptor much more strongly than plant-derived THC. Intoxication and withdrawal syndromes may be more intense and longer lasting than those associated with plant cannabis. Synthetic cannabinoids are typically smoked or inhaled after vaporization, known as vaping.

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