Steroid Hormone Changes after Short-Term High-Dose Exposure to Cannabidiol in Healthy Subjects: An Exploratory Study

Introduction: Cannabis-derived cannabidiol (CBD; Epidiolex®) is FDA-approved for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex, yet its effects on human steroid hormone regulation remain unclear. This study evaluated changes in five plasma steroid hormones and one precursor bile acid after short-term high-dose oral CBD administration in healthy subjects. Methods: Twelve participants (6 males, 6 females) completed a randomized, placebo-controlled crossover study and received oral CBD 750 mg twice daily for 3.5 days or placebo, separated by a washout period. All subjects received methylphenidate on the final clinical day for an additional independent study objective. Plasma samples collected after the final dose were analyzed by LC-MS/MS. Statistical analyses assessed CBD-associated hormonal changes and correlations with CBD and metabolite concentrations. This study was supported in part by the State of Florida Consortium for Medical Marijuana Clinical Outcomes Research. Results: A significant decrease in the precursor steroid 21-OH-progesterone was observed in the CBD group compared with the placebo group. Cortisol and corticosterone levels increased consistently across all CBD-administered participants, and testosterone levels rose significantly in male subjects. No significant differences were identified between the CBD and placebo groups in cholic acid concentrations. All measured hormone levels remained within physiological ranges. Conclusions: This study provides novel evidence that CBD modulates key components of the steroidogenic and endocrine systems, revealing previously unappreciated endocrine effects in humans.