Psilocybin modulates social behaviour in male and female mice in a time-dependent manner

Published May 25, 2026Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

Psilocybin changes social behavior differently over time in male and female mice

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Page updated May 26, 2026

Abstract

A single dose of psilocybin (1.5 mg/kg) produced distinct effects on social behavior in male and female C57BL/6 J mice.

Psilocybin enhanced huddling and induced hypothermia only in female mice shortly after administration.
Female mice showed increased novelty-seeking and grooming 4 hours after psilocybin treatment, which was not observed in males.
At 24 hours, treated males exhibited reduced grooming and rearing but increased sociability toward a cage-mate.
Dopamine responses in the nucleus accumbens were blunted in males and persisted for up to 7 days after psilocybin administration.
By 7 days, females shifted their social preference toward familiar interactions, while males displayed increased grooming, reversing earlier trends.
Both 5-HT1A and 5-HT2A receptors played roles in the sex-specific behavioral effects of psilocybin.

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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.

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Psilocybin modulates social behaviour in male and female mice in a time-dependent manner

Abstract

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