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
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 25, 2026 Peer reviewed DOI: 10.1038/s41386-026-02450-x via PubMed
Summary
Psilocybin, at a dose of 1.5 mg/kg, produced distinct effects on social behavior in male and female C57BL/6 J mice. Female mice showed increased huddling and grooming, while males displayed reduced grooming but increased sociability after 24 hours. Notably, dopamine responses in the nucleus accumbens varied by sex over time, highlighting the need for sex-specific considerations in psychedelic research.
Study at a glance
| Population | C57BL/6 J mice |
|---|---|
| Key finding | Psilocybin induced different social behaviors and dopamine responses in male and female mice, with females showing enhanced huddling and grooming while males exhibited increased sociability after 24 hours. |
Abstract
With the resurgence of psychedelic research and growing evidence of 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 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/6 J mice across multiple aspects of social behaviour. Psilocybin acutely enhanced huddling and induced hypothermia selectively in female mice and post-acutely (4 h) enhanced novelty-seeking and grooming in females, with no comparable effects in males. By 24 h, psilocybin-treated males showed reduced grooming and rearing alongside increased sociability directed toward a cage-mate. This was accompanied by blunted novelty-evoked nucleus accumbens dopamine responses that persisted to 7 days post-administration. At 7 days, psilocybin shifted female social preference toward familiarity over novelty, associated with prolonged nucleus accumbens dopamine release during familiar conspecific interactions, while males exhibited increased grooming, opposing the effect observed at 24 h. Both 5-HT1AR and 5-HT2AR contributed to psilocybin's behavioural effects in sex-specific ways. These findings reveal temporally dynamic, sex-differentiated patterns of social behaviour and dopaminergic modulation following psilocybin, underscoring the importance of sex-informed approaches in preclinical research and clinical application of psychedelic compounds.