Sex-sensitive serotonergic signaling in psychedelic pharmacology.
Sofia Nasini, Benedetta Barzon, A. Casile, B. Richardson, Gabriella Gobbi, Stefano Comai
TIPS - Trends in Pharmacological Sciences August 1, 2026 DOI: 10.1016/j.tips.2026.07.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Serotonin |
| Key findings | Argues that sex and endocrine state can modulate serotonergic mechanisms relevant to psychedelic action, and that many clinical and preclinical studies lack design to test sex-by-treatment effects, limiting understanding of variability in responses. |
Abstract
Classic serotonergic psychedelics act primarily via 5-HT2A receptor agonism, yet their therapeutic effects and biological responses are heterogeneous. Biological sex remains an underexamined source of this variability because many clinical and preclinical studies have not been designed to test sex-by-treatment effects. Recent preclinical findings, together with more limited human evidence, suggest that sex and endocrine state can modulate serotonergic mechanisms relevant to psychedelic action, including 5-HT1A autoregulatory feedback, 5-HT2A signaling, serotonin clearance, neuroendocrine coupling, and neuroplastic cascades. This review synthesizes how sex- and state-sensitive serotonergic regulation may influence psychedelic signaling and outlines priorities for sex-informed translational research in preclinical and clinical settings.