Pharmacokinetic Variability of Oral Cannabidiol and Its Major Metabolites after Short-Term High-Dose Exposure in Healthy Subjects.

INTRODUCTION

Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as a prescriptive drug treatment and over-the-counter supplement. In humans, CBD is metabolized and forms the major active metabolite 7-hydroxy-cannabidiol (7-OH-CBD), which is further metabolized to 7-carboxy-cannabidiol (7-COOH-CBD). In the current study, plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were measured, and the potential influences of sex, race, and body mass index (BMI) on the pharmacokinetic variability were assessed.

METHODS

Blood samples from a previously conducted CBD drug interaction study in healthy volunteers ( = 12) were utilized. The subjects received orally administered CBD (Epiodiolex), 750 mg twice daily for 3 days and a single dose on the 4th day. Nine plasma samples were collected, and plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were analyzed by LC-MS/MS. Peak plasma concentration (C), time to C (T), area under the curve (AUC), and metabolite-to-parent drug exposure ratios (MPR) were calculated. Statistical analysis was performed to determine the correlations of C, AUC, and MPR of CBD, 7-OH-CBD, and 7-COOH-CBD in different sex, race, BMI, and body weight.

RESULTS

For CBD, the mean C was 389.17 ± 153.23 ng/mL, and the mean AUC was 1,542.19 ± 488.04 ng/mLh. For 7-OH-CBD, the mean C was 81.35 ± 36.64 ng/mL, the mean AUC was 364.70 ± 105.59 ng/mLh, and the mean MPR was 0.25 ± 0.07. For 7-COOH-CBD, the mean C was 1,717.33 ± 769.22 ng/mL, the mean AUC was 9,888.42 ± 3,961.47 ng/mL*h, and the mean MPR was 7.11 ± 3.48. For 7-COOH-CBD, a 2.25-fold higher C was observed in female subjects ( = 0.0155) and a 1.97-fold higher AUC for female subjects ( = 0.0285) with the normalization of body weight. A significant linearity ( = 0.0135) of 7-OH-CBD AUC with body weight in females was observed. No significant differences were identified in C, AUC, and PMR with race and BMI.

CONCLUSION

Observed differences in sex were in agreement with previously reported findings. A larger population pharmacokinetics study is warranted to validate the observed higher C and AUC in females and significant linearity with body weight in females from the current study.