TY - JOUR T1 - Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 162 LP - 171 DO - 10.1124/jpet.116.238717 VL - 361 IS - 1 AU - Brian F. Thomas AU - Timothy W. Lefever AU - Ricardo A. Cortes AU - Megan Grabenauer AU - Alexander L. Kovach AU - Anderson O. Cox AU - Purvi R. Patel AU - Gerald T. Pollard AU - Julie A. Marusich AU - Richard C. Kevin AU - Thomas F. Gamage AU - Jenny L. Wiley Y1 - 2017/04/01 UR - http://jpet.aspetjournals.org/content/361/1/162.abstract N2 - 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. ER -