Sex Differences in the Acute Effects of Oral THC: A Randomized, Placebo-Controlled, Crossover Human Laboratory Study

Abstract

AbstractRationaleCannabis is one of the most commonly used psychoactive substances, and recent reports have shown increased use among women, leading to growing concerns about cannabis use disorder. Some evidence suggests a faster progression to addiction in women, known as the “telescoping effect.” While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the response to oral tetrahydrocannabinol (THC) in humans.Methods55 healthy men and women with prior exposure to cannabis but no history of cannabis use disorder participated in a randomized, placebo-controlled, double-blind, counter-balanced study, receiving a single 10 mg dose of oral THC (dronabinol). Subjective intoxicating effects were assessed by the Visual Analog Scale (VAS) of “high”, psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale (CADSS) and Psychotomimetic States Inventory (PSI), cognitive effects by Rey Auditory Verbal Learning Test (RAVLT), and physiologic effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures.ResultsOral THC demonstrated significant dose-related effects in psychotomimetic and physiologic domains, but not in cognition. A notable interaction between THC dose and sex emerged concerning the subjective “high” scores, with women reporting heightened sensations (ATS=3.81, num df=1, p=0.05). No other significant effects of sex and THC dose interaction were observed.ConclusionOral THC yields similar psychotomimetic and physiologic effects across sexes, but women may experience a pronounced subjective intoxicating effect. Given the escalating accessibility of cannabinoids, further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing cannabis use disorder.