Sex-dependent effects of psychedelics: review of evidence from rodent models
Frontiers in Psychiatry July 15, 2026 Rafał Marecki, Wiktoria Zaniewska, Adam Hamed et al.
Classic psychedelics such as psilocybin, LSD, DMT, 5-MeO-DMT, mescaline, and DOI work primarily by activating 5-HT2A receptors, causing widespread brain and behavior changes relevant to psychiatric research. Evidence from rodent studies shows that these effects differ by sex across pharmacokinetics, physiology, neuroplasticity, behavior, and disease models. Females often show stronger or qualitatively distinct behavioral responses, including head twitch, locomotor activity, prepulse inhibition, stress reactivity, and social behavior, with ovarian cycle phase further modulating some effects. Disease model studies also find sex-dependent outcomes, such as psilocybin's effects on alcohol consumption and DMT microdosing on mood and neuroplasticity. The review concludes that sex is a critical biological variable shaping psychedelic effects in rodents, and integrating sex-specific analyses is essential for improving translational validity and guiding clinical applications.