Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences

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PROJECT SUMMARY Synthetic cannabinoids (SC) produce psychological effects resembling those of 9-tetrahydrocannabinol (THC) but are usually more potent and efficacious. Notably, the use of these substance is often associated with greater toxicity. Clusters of severe adverse reactions and death have been reported internationally, including in the U.S. and New Zealand. The global nature of SC abuse argues for an international approach to addressing the problem. To this end, one overall goal of this project is to strengthen a nascent international collaboration initiated among laboratories in the U.S. (RTI International) and New Zealand (University of Otago). Through this collaborative and multi-disciplinary effort, we will determine molecular and pharmacokinetic mechanisms that may underlie differences in the in vivo effects of chemically diverse SC related to their abuse potential and to their toxicological effects in peripheral systems. A foundational hypothesis for this proposed work is that the both the behavioral effects and the toxicological effects associated with SC use are related to their differential interactions with the endogenous cannabinoid system, as compared to THC and other partial CB1 receptor agonists. This hypothesis will be evaluated through systematic study of the SAR of SC and the mechanisms underlying their central and peripheral actions (i.e., their molecular fingerprints). This work will enhance ability to predict which new compounds are likely to have toxicological effects when – or before – they appear and will provide a scientific basis for evaluation of potential health concerns associated with use of these compounds. This research also will increase knowledge of the structure-activity relationships at cannabinoid receptors, resulting in deepened understanding of endocannabinoid system functioning.