JWH-018 and JWH-073 are two prevalent synthetic cannabinoids (SCBs) that are abused as marijuana substitutes in the “herbal incense” products commonly known as “K2”. Use of K2 has an apparently higher prevalence of severe adverse effects compared to use of marijuana, including seizures, hallucinations, and psychosis. Almost nothing is known about the human pharmacology of JWH-018 and JWH-073; therefore, the mechanism(s) of adverse effects produced by these SCBs is unknown. We first hypothesized that major urinary metabolites retain pharmacological activity, enabling them to contribute to these adverse effects. K2 is usually a blend of multiple SCBs, including JWH-018+JWH-073. Synergistic drug-drug interactions of multiple, similarly-acting drugs would be predicted to more readily produce adverse effects than abuse of a single drug; therefore, we also hypothesized that JWH-018 and JWH-073 have synergistic drug-drug interactions.
Ten of 12 metabolites examined retain physiologically significant Cannabinoid 1 Receptor (CB1R) affinity (Ki=2.7-224 nM), and exhibit CB1R intrinsic activity ranging from neutral antagonism to full agonism. Further in vitro analysis demonstrates that one metabolite, JWH-073-M4, acts as a competitive neutral CB1R antagonist. This metabolite partially blocks JWH-018-induced hypothermia, but not locomotor suppression, catalepsy or analgesia, in mice. Two metabolites identified as CB1R agonists by in vitro studies also exhibit cannabinoid agonist activity in vivo by robustly suppressing locomotor activity and decreasing core temperature in mice.
Further studies demonstrate that concurrent administration of JWH-018 and JWH-073 produces synergistic effects in Δ9-THC discrimination, a tail-immersion assay for analgesia in mice, and competition receptor binding at CB1Rs employing mouse brain homogenates. JWH-018+JWH-073 elicited sub-additive effects on food-maintained operant behavior, and additive hypothermic effects in mice and additive CB1R-mediated adenylyl cyclase inhibition in Neuro2A wild-type cells.
Results from this dissertation indicate that several major urinary metabolites of JWH-018 and JWH-073 retain pharmacological activity and thus may contribute to the observed effects of K2 use. Synergistic effects that occur when JWH-018 and JWH-073 are combined may also contribute to K2 abuse and toxicity. Future studies will be required to determine mechanisms of drug-drug interactions and whether interactions and active metabolites contribute the effects of K2 in humans.
|Advisor:||Prather, Paul L.|
|Commitee:||Budney, Alan J., Fantegrossi, William E., Gottschall, Paul E., Radominska-Pandya, Anna|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 74/09(E), Dissertation Abstracts International|
|Subjects:||Behavioral psychology, Pharmacology|
|Keywords:||Cannabinoid 1 receptor, Drug interactions, Emerging drugs of abuse, Synthetic cannabinoids|
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