Chronic psilocybin administration increases sociability and alters the gut microbiome in male wild-type mice but not in a preclinical model of obsessive-compulsive disorder
James J Gattuso, Geraldine Kong, Bilgenur Bezcioglu, Da Lü, Millicent N. Ekwudo, Carey Wilson, Carolina Gubert, Anthony J. Hannan, Thibault Renoir
Neuropharmacology August 21, 2025 DOI: 10.1016/j.neuropharm.2025.110648 (opens in new tab)
The journal has published a correction to this paper. Read the correction (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Wild-type and SAPAP3 knockout mice |
| Intervention | Psilocybin |
| Dose | 0.1 and 1 mg/kg |
| Duration | Chronic administration |
| Topics | Psilocybin |
| Keywords | Gut microbiome Obsessive compulsive Clinical psychology |
| Citations | 7 |
| Key points | Chronic psilocybin increased sociability in male wild-type mice and altered specific gut bacteria in a sex-dependent manner without affecting overall microbiome diversity or improving OCD-like behaviors. |
Abstract
Psilocybin, a serotonergic compound that produces psychedelic effects primarily through activation of the 5-HT2A receptor, has shown promise in treating neuropsychiatric conditions, including obsessive-compulsive disorder (OCD). However, the effects of chronic psilocybin administration on gut function, microbiota, and behavioural phenotypes remain understudied. The present study investigated the effects of chronic psilocybin (0.1 and 1 mg/kg, oral gavage) on gut and behavioural measures in wild-type (WT) and SAPAP3 knockout (KO) mice, a model of OCD-like phenotypes. We present novel evidence that SAPAP3 KO mice exhibit social deficits, and that chronic psilocybin increases sociability in male WT mice. Although no therapeutic effects were observed at either dose on anxiety-, compulsive-, or depressive-like behaviour, chronic psilocybin also did not induce psychosis-like behaviours. A dose-dependent effect of psilocybin was observed on gut motility. Although chronic administration did not significantly alter overall gut microbiome diversity, reductions in Lactobacillus murinus, Lactobacillus animalis, and Alistipes dispar were observed in male WT mice, but not in KO mice or female mice. Integrative analysis revealed that a microbial cluster, comprising Lactobacillus and Alistipes species, correlated with locomotion, head-twitch response and gut motility, effectively differentiating psilocybin-treated mice from vehicle controls. This suggests a potential host-microbiome feedback mechanism regulating host serotonin signalling, linked to central and peripheral 5-HT2A receptor activation. Additionally, separate microbial clusters were associated with startle response and sociability, indicating that psilocybin may engage distinct neural pathways to mediate these behaviours. These findings highlight the importance of considering the microbiome and sex in future psychedelic research and open new avenues for exploring the microbiota-gut-brain axis as a target for future therapeutic strategies.
Comparable studies
Other preclinical and animal studies on psilocybin, 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 | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 9
- Psilocybin's effects on obsessive-compulsive behaviors: A systematic review of preclinical and clinical evidence Psychedelics October 28, 2025
- Psilocybin restores social novelty investigation in male SAPAP3 knockout mice and engages prefrontal–hippocampal circuitry Molecular Psychiatry September 17, 2026
- Psilocybin produces amplified acute responses and sex-specific long-term increases in sensorimotor gating in the mGlu5 knockout mouse model of schizophrenia Neuropsychopharmacology July 18, 2026
- Sex-dependent effects of psychedelics: review of evidence from rodent models Frontiers in Psychiatry July 15, 2026
- Psilocybin modulates social behaviour in male and female mice in a time-dependent manner. Neuropsychopharmacology May 25, 2026
and 4 more in the library
Cites 28
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder The Journal of Clinical Psychiatry November 15, 2006
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act Neuropharmacology June 5, 2018
- Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers Biological Psychiatry April 26, 2014
and 23 more in the library