WC Booher^1,2, K Lanier¹, K Doenges¹, J Manke¹, M Armstrong¹, L Saba^1, N Reisdorph¹, RA Radcliffe^1,2

Oral consumption of Cannabis carries many of the same well-documented negative consequences associated with smoking Cannabis, along with additional health concerns specific to oral ingestion. It is essential to gain a deeper understanding of the factors contributing to the health risks of oral consumption, including individual differences in how people metabolize delta-9-tetrahydrocannabinol (∆9-THC), which is likely influenced by genetic factors. We hypothesized that genetically distinct mouse strains would exhibit variations in metabolism of ∆9-THC. To test this hypothesis, we administered 10 or 15 mg/kg ∆9-THC via oral gavage to four mouse strains (A/J, C57BL/6J, CAST/EiJ, and NZO/HILtJ) that are among the founders of two well-characterized experimental genetic mouse populations, the Collaborative Cross recombinant inbred strains and the Diversity Outbred heterogenous stock mice. Blood was collected at 60-, 90-, and 240-minutes post administration and plasma levels of ∆9-THC and its primary metabolites were measured using mass spectrometry. There were significant differences between the A/J and C57BL/6J ∆9-THC plasma levels and some of the metabolites, with few notable sex differences. The overall pattern of these differences suggest that C57BL/6J mice metabolize ∆9-THC more rapidly than A/J mice. CAST/EiJ and NZO/HILtJ mice exhibit significant differences in ∆9-THC plasma concentrations, but not other metabolites. To our knowledge, this is the first study to include A/J, CAST/EiJ, and NZO/HILtJ mice in a ∆9-THC oral administration mouse model. These findings underscore the need for further research to explore genetic differences in the pharmacokinetics of ∆9-THC in preclinical models of oral Cannabis consumption.

¹Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045

²Institute for Behavioral Genetics, University of Colorado, Boulder, CO

Funding support: Skaggs School of Pharmacy and Pharmaceutical Science ADR Seed Grant Program, Institute of Cannabis Research, and NIH-NCRR grant 1S10OD010366-01A1