Synthetic cannabinoids are manufactured clandestinely with little quality control and are distributed as herbal “spice” for smoking or as bulk compound for mixing with a solvent and inhalation via electronic vaporizers. Intoxication with synthetic cannabinoids has been associated with seizure, excited delirium, coma, kidney damage, and other disorders. The chemical alterations produced by heating these structurally novel compounds for consumption are largely unknown. Here, we show that heating synthetic cannabinoids containing tetramethylcyclopropyl-ring substituents produced thermal degradants with pharmacological activity that varied considerably from their parent compounds. Moreover, these degradants were formed under conditions simulating smoking. Some products of combustion retained high affinity at the cannabinoid 1 (CB1) and CB2 receptors, were more efficacious than (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) in stimulating CB1 receptor–mediated guanosine 5′-O-(3-thiotriphosphate) (GTPγS) binding, and were potent in producing Δ9-tetrahydrocannabinol–like effects in laboratory animals, whereas other compounds had low affinity and efficacy and were devoid of cannabimimetic activity. Degradants that retained affinity and efficacy also substituted in drug discrimination tests for the prototypical synthetic cannabinoid 1-pentyl-3-(1-naphthoyl)indole (JWH-018), and are likely to produce psychotropic effects in humans. Hence, it is important to take into consideration the actual chemical exposures that occur during use of synthetic cannabinoid formulations to better comprehend the relationships between dose and effect.
- Received November 1, 2016.
- Accepted January 12, 2017.
↵1 Current affiliation: Proteomics and Metabolomics Shared Resource, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, North Carolina.
The research described in this manuscript was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01DA-040460 and R01DA-003672] and the National Institute of Justice, Office of Justice Programs, U.S. Department of Justice [Contract 2012-R2-CX-K001]. None of the funding agencies had any other role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. The opinions, findings, and conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect those of the Department of Justice or the National Institutes of Health.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics