Psilocybin exerts differential effects on social behaviour and inflammation in mice in contexts of activity-based anorexia (ABA)

Psychedelics, particularly psilocybin, have shown therapeutic potential across several psychiatric conditions, including depression, anxiety, obsessive-compulsive disorder, and anorexia nervosa (AN). These disorders often share social deficits that may be effectively alleviated by psychedelics considering their use has been linked with emotional empathy and enhanced social cognition. However, the mechanisms through which psychedelics alter social behaviour are unclear, and mechanistic studies in animal models have largely focused on male subjects. This is problematic for understanding the therapeutic effects relevant for disorders that predominantly affect females, such as AN. Here, we used the activity-based anorexia (ABA) mouse model to examine the effects of a single psilocybin dose on social behaviour in female mice and compared outcomes to mice exposed to food restriction (FR), exercise (RW) or standard housing (Controls). Together with these metabolic stressors, we also investigated the effects of psilocybin on the circulating proinflammatory cytokine interleukin-6 (IL-6), which is implicated in AN and is suppressed by psychedelics. Psilocybin did not alter sociability in ABA, RW, or FR mice but increased preference for familiarity in Controls. Novelty-seeking behaviour was elevated in both ABA and RW groups, although with distinct social patterns. Psilocybin elevated IL-6 levels in RW mice, which was positively correlated with preference for novelty. No such relationships were found in ABA or FR groups. These findings reveal subtle, context-dependent effects of psilocybin on social behaviour and inflammation in female mice, highlighting the need to clarify its temporal, neuroplastic, and immune-related mechanisms across sexes and disease models.