A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects

OBJECTIVE: The pharmacokinetics (PK) and safety of single oral 750‐mg doses of a plant‐derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the USA and Epidyolex in Europe; 100‐mg/mL oral solution) were assessed in healthy adults following a high‐fat/calorie meal (n = 15), a low‐fat/calorie meal (n = 14), whole milk (n = 15), or alcohol (n = 14), relative to the fasted state (n = 29). METHODS: Blood samples were collected until 96 hours postdose in each period and evaluated by liquid chromatography and tandem mass spectrometry. PK parameters (maximum observed plasma concentration [C(max)], area under the plasma concentration‐time curve from time zero to the last observed quantifiable concentration, area under the concentration‐time curve from time zero to infinity [AUC(0‐∞)], and time to maximum plasma concentration [t(max)]) of CBD and its major metabolites were derived using noncompartmental analysis. RESULTS: CBD exposure increased by 3.8‐fold for AUC(0‐∞) and 5.2‐fold for C(max) when CBD was administered with a high‐fat/calorie meal versus fasted. To a lesser extent, a low‐fat/calorie meal enhanced CBD exposure versus fasted with a 2.7‐fold increase in AUC(0‐∞) and a 3.8‐fold increase in C(max). Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4‐fold for AUC(0‐∞) and 3.1‐fold for C(max). Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6‐fold for AUC(0‐∞) and 1.9‐fold for C(max). No clinically relevant effect of any test condition on CBD t(max) or t(½) versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7‐carboxy‐cannabidiol t(max) was considerably longer when CBD was administered with alcohol (14 vs 4 hours fasted). Inter‐ and intrasubject variability in PK parameters was moderate to high during the trial. SIGNIFICANCE: CBD and metabolite exposures were most affected by a high‐fat/calorie meal. CBD exposures also increased with a low‐fat/calorie meal, whole milk, or alcohol, but to a lesser extent. CBD was tolerated, and there were no severe or serious adverse events during the trial.