Markowitz_2022_Med.Cannabis.Cannabinoids_5_199

INTRODUCTION: Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as an over-the-counter supplement, a component of medical cannabis, and a prescriptive treatment of childhood epilepsies. In vitro studies suggest CBD may inhibit a number of drug-metabolizing enzymes, including carboxylesterase 1 (CES1). The aim of this study was to evaluate effect of CBD on the disposition of the CES1 substrate methylphenidate (MPH). METHODS: In a randomized, placebo-controlled, crossover study, 12 subjects ingested 750 mg of CBD solution, or alternatively, a placebo solution twice daily for a 3-day run-in period followed by an additional CBD dose (or placebo) and a single 10 mg dose of MPH and completed serial blood sampling for pharmacokinetic analysis. MPH and CBD concentrations were measured by liquid chromatography with tandem mass spectrometry. RESULTS: The C(max) (mean +/- CV) for the CBD group and placebo group was 13.5 +/- 43.7% ng/mL and 12.2 +/- 36.4% ng/mL, respectively. AUC(inf) (ng/mL*h) for the CBD group and placebo group was 70.7 +/- 32.5% and 63.6 +/- 25.4%, respectively. The CBD AUC(0-8h) (mean +/- CV) was 1,542.2 +/- 32% ng/mL*h, and C(max) was 389.2 +/- 39% ng/mL. When compared to MPH only, the geometric mean ratio (CBD/control, 90% CI) for AUC(inf) and C(max) with CBD co-administration was 1.09 (0.89, 1.32) and 1.08 (0.85, 1.37), respectively. DISCUSSION/CONCLUSION: Although the upper bound of bioequivalence was not met, the mean estimates of AUC and C(max) ratios were generally small and unlikely to be of clinical significance.