title: Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences.
abstract: 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 CB2receptors, were more efficacious than (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) in stimulating CB1receptor-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.
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.) bft@rti.org jwiley@rti.org.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Thomas
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lefever
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Cortes
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Megan
authors.initials: M
authors.lastname: Grabenauer
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Kovach
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Anderson O
authors.initials: AO
authors.lastname: Cox
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Purvi R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Pollard
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Julie A
authors.initials: JA
authors.lastname: Marusich
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Richard C
authors.initials: RC
authors.lastname: Kevin
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.).
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gamage
authors.affiliation: RTI International, Research Triangle Park, North Carolina (B.F.T., T.W.L., R.A.C., M.G., A.L.K., A.O.C, P.R.P, J.A.M, T.F.G, J.L.W.); Howard Associates, LLC, Research Triangle Park, North Carolina (G.T.P.); and School of Psychology, The University of Sydney, NSW, Australia (R.C.K.) bft@rti.org jwiley@rti.org.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D015198:Designer Drugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006358:Hot Temperature / Q000009:adverse effects*; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009281:Naphthalenes / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*
chemical_list: C588309:CNR2 protein, human; D002186:Cannabinoids; D015198:Designer Drugs; D007211:Indoles; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol; C552597:1-pentyl-3-(1-naphthoyl)indole