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

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