Inhibitory effects of Δ8-tetrahydrocannabinol on major hepatic cytochrome P450 enzymes and implications for drug disposition

The increased use of cannabis in many parts of the United States and other countries has led to a need for a more comprehensive understanding of cannabis constituents and their potential for drug-drug interactions. Δ8-Tetrahydrocannabinol (Δ8-THC) is a psychoactive cannabinoid that is found at low concentrations in cannabis but is growing in popularity, especially where the use of Δ9-THC is restricted. Although certain cannabinoids including cannabidiol (CBD) are known to inhibit several metabolizing enzymes including many in the cytochrome P450 family, the effects of Δ8-THC remain poorly characterized. This study evaluated the inhibitory potential of Δ8-THC and its metabolites, 11-hydroxy-Δ8-THC and 11-nor-Δ8-THC-9-carboxylic acid, on major hepatic cytochrome P450 enzymes using in vitro assays with recombinant P450-overexpressing microsomes and pooled human liver microsomes. Δ8-THC and 11-hydroxy-Δ8-THC significantly inhibited CYP2C9- and CYP3A4-mediated metabolism in a dose-dependent, reversible manner. Lineweaver-Burk analysis indicated competitive inhibition for CYP2C9-mediated warfarin hydroxylation and noncompetitive inhibition for CYP2C9- and CYP3A4-mediated metabolism of diclofenac and midazolam, respectively. In contrast, 11-nor-Δ8-THC-9-carboxylic acid showed no significant inhibition of P450 enzymes. Static modeling predicted clinically relevant drug interactions, particularly with oral Δ8-THC. These findings underscore the potential for Δ8-THC to impact the pharmacokinetics of coadministered drugs and highlight the need for further clinical studies. SIGNIFICANCE STATEMENT: This study is the first to assess how Δ8-tetrahydrocannabinol and its active metabolites inhibit key hepatic P450 enzymes. Results suggest a high risk of Δ8-tetrahydrocannabinol-related drug interactions, especially with oral use, underscoring the need for clinical caution and further research.