Sex Differences in the Pharmacokinetics of Cannabidiol and Metabolites Following Oral Administration of a Cannabidiol-Dominant Cannabis Oil in Healthy Adults.

Abstract

Introduction: Oral cannabidiol (CBD) product use is increasingly growing among women; however, there is a lack of data on sex differences in the pharmacokinetics (PKs) of CBD and its primary metabolites, 7-hydroxy-CBD (7-OH-CBD) and 7-carboxy-CBD (7-COOH-CBD), after repeated doses. Materials and Methods: The present study is a secondary analysis of data from a randomized, double-blind, placebo-controlled multiple-dose trial of a commercially available, CBD-dominant oral cannabis product. Healthy participants (n=17 males and 15 females) were randomized to receive 120 to 480 mg of CBD daily for 7 days. Dosing groups were pooled for all analyses due to sample size limitations. Analyses compared plasma PK parameters by sex, day, and sex×day. Results: For raw PK parameters for CBD and metabolites, there were no statistically significant effects of sex×day or sex (all p-values >0.05). For metabolite-to-parent ratios (MPRs) of AUC_0-t, there were significant effects of the sex×day interactions for 7-OH-CBD (F=6.89, p=0.016) and 7-COOH-CBD (F=5.96, p=0.021). For 7-OH-CBD, follow-up analyses showed significant simple effects of day within females (t=4.13, p<0.001), but not within males (t=0.34, p=0.73), such that 7-OH-CBD MPRs increased significantly from day 1 to 7 for females, but not for males. For 7-COOH-CBD, follow-up analyses revealed significant simple effects of day within females (t=8.24, p<0.001) and males (t=5.20, p<0.001), therefore 7-COOH-CBD MPRs increased significantly from day 1 to 7 in both sexes, but the increase was significantly greater among females than among males. Within dosing days, there were no statistically significant simple effects of sex on MPRs of 7-OH-CBD or 7-COOH-CBD. Conclusions: Females exhibited greater relative exposure to CBD metabolites in plasma over time, which may reflect sex differences in CBD metabolism or elimination. Further research assessing the safety implications of higher relative exposure to CBD metabolites over longer periods of time is warranted to mirror typical consumer use patterns.