Sex-dependent effects of psychedelics: review of evidence from rodent models
Rafał Marecki, Wiktoria Zaniewska, Adam Hamed, Napoleon Waszkiewicz, Jacob J. Baker, Kacper Łukasiewicz
Frontiers in Psychiatry July 15, 2026 DOI: 10.3389/fpsyt.2026.1824073 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Rodents |
| Topics | Serotonin |
| Keywords | Prepulse inhibition Anhedonia Schizophrenia object-oriented programming Disease Neuropsychopharmacology Research domain criteria Translational research Preclinical research Hallucinogen Psychosis Cognition Dopaminergic pathways Expectancy theory |
| Key findings | Sex is a critical biological variable that shapes the neural, physiological, and behavioral effects of classic psychedelics in rodents, with females often showing stronger or qualitatively distinct responses. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 63
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
and 58 more in the library