A Phase 1 Open‐Label, Fixed‐Sequence Pharmacokinetic Drug Interaction Trial to Investigate the Effect of Cannabidiol on the CYP1A2 Probe Caffeine in Healthy Subjects

This pharmacokinetic (PK) drug‐interaction trial investigated the effects of repeated dosing of a plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the United States and Epidyolex in Europe; 100 mg/mL oral solution) on caffeine clearance via modulation of cytochrome P450 (CYP) 1A2 activity in healthy adults. In this phase 1 open‐label, fixed‐sequence trial, all subjects received a single 200 mg caffeine dose and placebo on day 1. Subjects then titrated CBD from 250 mg once daily to 750 mg twice daily between days 3 and 11 and took 750 mg CBD twice daily between days 12 and 27. On day 26, subjects received a single 200‐mg caffeine dose with their morning CBD dose. Plasma concentrations of caffeine and its CYP1A2‐mediated metabolite, paraxanthine, were determined on days 1 and 26 and PK parameters derived using noncompartmental analysis. Safety was monitored throughout. Sixteen subjects enrolled, and 9 completed treatment. When caffeine was administered with steady‐state CBD, caffeine exposure increased by 15% for C(max) and 95% for AUC(0‐∞), t(max) increased from 1.5 to 3.0 hours, and t(1/2) increased from 5.4 to 10.9 hours compared with caffeine administered with placebo. Under the same conditions, paraxanthine exposure decreased by 22% for C(max) and increased by 18% for AUC(0‐∞), t(max) increased from 8.0 to 14.0 hours, and t(1/2) increased from 7.2 to 13.7 hours. Overall, there were no unexpected adverse events; diarrhea was most common, and 6 subjects discontinued because of elevated liver transaminases. These data suggest that CBD is an inhibitor of CYP1A2.