Psilocybin modulates social behaviour in male and female mice in a time-dependent manner
Sheida Shadani, Kaspar McCoy, Lina Ong, Erika Greaves, Kyna Conn, Zane B. Andrews, Claire J. Foldi
bioRxiv (Cold Spring Harbor Laboratory) December 22, 2025 preprint DOI: 10.64898/2025.12.18.695064 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | C57BL/6J mice |
| Intervention | Psilocybin |
| Dose | 1.5 mg/kg |
| Duration | Single dose, assessed at 4 hours, ~24 hours, and 7 days post-administration |
| Topics | Psilocybin |
| Keywords | Prosocial behavior Empathy Novelty Nucleus accumbens Anhedonia Hallucinogen Dopamine Social inhibition Anorexia Social relation Developmental psychology Social behaviour Preference Social identity approach |
| Key findings | Psilocybin produces sex-specific, temporally distinct changes in social behaviors in mice, involving differential dopamine signaling and receptor involvement. |
Abstract
Abstract With the resurgence of psychedelic research and the growing interest in their therapeutic potential, there is an urgent need to understand how these compounds act across biological sexes. Despite widespread interest in their use for conditions marked by social impairments, including depression, anxiety, and anorexia nervosa, the influence of sex as a biological variable (SABV) on the prosocial effects of psychedelics remains poorly understood. Indeed, enhanced connectedness, sociability and empathy are common outcomes of psychedelic use and these have shaped human social structures for millennia. Here, we investigated the sex-specific effects of a single dose of psilocybin (1.5 mg/kg) in C57BL/6J mice on various aspects of social behaviours. We show an intriguing connection between huddling behaviour and body temperature acutely elicited by psilocybin that was restricted to females. We also observe temporally distinct patterns of social behaviour alterations in female mice, whereby enhanced preference for social novelty was observed after acute effects subsided (4 h post-administration), which was maintained for ∼24 h. Longer-term, the impact of psilocybin was reversed and promoted preference for familiar over novel conspecifics when assessed 7d post-administration, which was associated with prolonged nucleus accumbens dopamine signalling during familiar sniffing. In males, psilocybin reduced stress-related behaviours at 24 h and increased preference for familiar conspecifics, along with blunted novelty-evoked dopamine responses at both 24 h and 7 days post-treatment. Both 5-HT1A and 5-HT2A receptors were involved in modulating these behaviours, though in sex-specific ways. These findings highlight that the prosocial effects of psychedelics are not universal and emphasize the importance of sex-informed approaches in both preclinical research and clinical application. Graphical Abstract
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
Cites 29
- 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
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder The Journal of Clinical Psychiatry November 15, 2006
- The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology April 26, 2017
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 24 more in the library