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

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.

In this new study, researchers investigated how a single dose of psilocybin affected social behaviour in male and female mice across different time points (acute, 4 hours, 24 hours, and 7 days after administration). The central finding was that psilocybin did not produce a simple, universal increase in sociability; instead, its effects were highly dependent on sex and timing

Females showed early prosocial effects. Shortly after psilocybin administration, female mice displayed:

• Increased huddling (social thermoregulation and affiliative behaviour).

• Increased social novelty-seeking.

• Increased grooming behaviour.

These effects were not observed in males at the same time points.

Males showed delayed social effects

At 24 hours after treatment, male mice:

• Showed greater sociability toward familiar cage-mates.

• Displayed reduced grooming and exploratory rearing behaviour.

This suggests that social effects emerged later in males than in females

Social preferences changed differently over time and psilocybin altered dopamine signalling in sex-specific ways

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. T

his 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.”

Shadani, S., McCoy, K., Ong, L. et al. Psilocybin modulates social behaviour in male and female mice in a time-dependent manner. Neuropsychopharmacol. (2026). Read Paper

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