Sex Differences in Acute Responses to Psychedelics: Evidence for Greater Subjective Intensity and Impairment in Female Participants

Abstract

Serotonergic psychedelics are advancing as psychiatric treatments, yet acute responses vary between individuals and the contribution of sex, a fundamental biological variable, remains largely unexamined. We pooled two double-blind, placebo-controlled randomized studies in healthy volunteers (N = 94 drug observations; 43 male, 51 female) comparing psilocybin 15 mg, 2C-B 20 mg, and LSD 50 ug. Linear mixed models tested sex differences in acute subjective effects (visual analogue scales), retrospective altered-states ratings (5D- and 11-ASC), empathy (Multifaceted Empathy Test), and peak (Cmax) and total (AUC) drug exposure, with treatment and sex as fixed factors and age as a covariate. Female participants reported numerically higher subjective ratings than male participants on most measures. After adjustment for age, sex differences were significant on five measures, most robustly for feeling under the drugs influence, reduced vigilance, and impaired control and cognition, with medium-to-large effects. These effects were largely consistent across the three drugs. No sex differences emerged on any empathy measure or in peak drug concentrations, indicating that female's stronger responses occurred at equivalent drug exposure. Female participants may experience more intense acute subjective effects and greater perceived impairment under psychedelics, independent of age and not explained by drug exposure. These preliminary findings, implicating pharmacodynamic rather than pharmacokinetic mechanisms, have implications for dosing, informed consent, and safety monitoring, and underscore the need to treat sex as a biological variable in adequately powered psychedelic trials.