Synthesis of Smokable Synthetic Cannabinoids ('Spice') for Human Study

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DESCRIPTION (provided by applicant): Abuse of synthetic cannabinoids ('Spice') as an alternative to cannabis is increasing rapidly. Despite their widespread use, the risks of these products are unknown. Based upon the pharmacology of the primary constituents of Spice, JWH-018 and JWH-073, the synthetic cannabinoids pose a greater risk for substance use disorder than cannabis. The proposed studies are critical in order to conduct subsequent human laboratory studies to address the physiological risks and behavioral effects of these widely-abused compounds by providing agents appropriate for research in humans. The proposed study will provide techniques, methods and models for future research with this class of compounds and can be extended to other chemical classes of cannabinoids that may emerge. Aim 1: JWH Synthesis: Although the JWH compounds are widely available on the illicit market, none are manufactured according to standards required for controlled human laboratory investigation. Therefore, we will synthesize JWH-018 and JWH-073 using cGMP for human pharmaceuticals. The purity and integrity of synthesized compounds will be verified by an independent FDA-registered laboratory. Aim 2: Cigarette Preparation: We will develop procedures for standardizing synthetic cannabinoid cigarette production. Cigarettes of various JWH-018 and JWH-073 concentrations will be prepared using NIDA placebo cannabis plant matter. To verify the effectiveness of the method in producing consistent, concentration-specific JWH-018 and JWH-073 cigarettes, cigarettes will be analyzed using high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) (Teske et al., 2012). Aim 3: Determine the optimal conditions required for reliable in vitro detection of JWH-018 and JWH-073 and respective metabolites in human plasma using HPLC/MS/MS. Human plasma will be spiked with increasing concentrations of the parent compounds and metabolites and stored at varying temperatures (-80, -20, or 4¿ C) and duration (24 hr. - 4 wks.). Stability of the compounds and metabolites will be assessed as a function of time and temperature. Impact. The proposed study will accomplish the first steps needed to address the immediate, significant public health concern of the rapid rise in synthetic cannabinoid abuse, and is possible because of our substantial expertise in synthesizing compounds of particular