Sex-dependent effects of psychedelics: review of evidence from rodent models

Summary

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.

Study at a glance

Abstract

Classic psychedelics, including psilocybin, LSD, DMT, 5-MeO-DMT, mescaline, and phenethylamines such as DOI, exert their core effects through 5-HT2A receptor agonism, inducing widespread neurobiological and behavioral changes relevant to psychiatric research. Emerging evidence suggests that these effects are modulated by sex, yet this dimension remains underrepresented in studies. This review synthesizes findings from rodent research to examine sex-dependent variability across pharmacokinetics, physiology, neuroplasticity, behavior, and disease models. Notable sex differences appear in pharmacodynamics and neurobiological responses, such as divergent serotonergic and dopaminergic signaling patterns, sex specific central amygdala reactivity to psilocin, and differential patterns of dendritic spine formation following psilocybin administration. Behavioral outcomes - including head twitch responses, locomotor activity, prepulse inhibition, stress reactivity, and social behavior - frequently show stronger or qualitatively distinct effects in females than in males, with ovarian cycle phase further modulating several responses. Disease model studies similarly reveal divergent therapeutic or adverse outcomes, such as sex dependent effects of psilocybin on alcohol consumption and of DMT microdosing on affective behavior and neuroplasticity. Collectively, the evidence demonstrates that sex is a critical biological variable shaping the neural, physiological, and behavioral effects of psychedelics in rodents. Integrating sex specific analyses into experimental design is essential for improving translational validity and guiding clinical applications that account for biological differences in treatment response.