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Investigating Steroid Hormone Changes After Short-term High-Dose Exposure to Cannabidiol in Healthy Subjects

Qingchen Zhang
University of Florida

Co-Authors: Christopher A Singleton1, Josephine Raeuscher2, Philip W Melchert2, David J Greenblatt3, John S Markowitz2
1Callen Analytical Service, 2University of Florida, 3Tufts University

Background: Cannabis-derived CBD (Epidiolex®) is FDA-approved for the treatment of seizures caused by Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. However, the pharmacology and bioactivities of CBD in humans are not fully understood.

Objective: This study evaluates potential changes in plasma steroid hormone concentrations following short-term high-dose oral CBD administration in healthy subjects.

Methods: Twelve subjects (6 males, and 6 females) participated in a randomized, placebo-controlled crossover study and received either oral Epidiolex® (750 mg twice daily for three and one-half days) or a placebo solution on separate occasions with an intervening washout. Plasma samples collected at nine-time points after the final dose were analyzed for steroid hormone concentrations using LC-MS/MS. Statistical analysis was used to evaluate CBD’s influence on steroid hormone concentrations and correlations of CBD/metabolites and any observed hormonal changes. This study was made possible in part by a grant from the State of Florida Consortium for Medical Marijuana Clinical Outcomes Research.

Results: In the CBD-exposed group compared to the placebo group, cortisol, and cortisone significantly decreased only in males, progesterone concentrations significantly increased only in males, while pregnenolone, dehydroepiandrosterone (DHEA), 7-alpha-hydroxy-DHEA, corticosterone, and deoxycorticosterone increased significantly in both sexes. No significant changes were noted in 11-deoxycortisol, testosterone, androstenedione, and aldosterone. Significant linear correlations were identified between corticosterone, pregnenolone, and progesterone with the area under the curve (AUC) of 7-COOH-CBD, the major metabolite of CBD.

Conclusions: The increase of progesterone, pregnenolone, DHEA, 7-alpha-hydroxy-DHEA, corticosterone, and deoxycorticosterone appeared to be a novel finding in clinical subjects. Further studies with a larger sample size are needed to validate the findings.