Psilocybin exerts differential effects on social behavior and inflammation in mice in contexts of activity-based anorexia

Psilocybin did not alter sociability in female mice under metabolic stressors—activity-based anorexia, food restriction, or running wheels—but increased preference for social familiarity (reduced novelty-seeking) in control mice. Both activity-based anorexia and running wheel groups showed elevated novelty-seeking behavior, though with distinct social patterns. Psilocybin raised levels of the proinflammatory cytokine interleukin-6 (IL-6) in running wheel mice, and that increase correlated with preference for novelty; no such relationship appeared in the other groups. These context-dependent effects on social behavior and inflammation highlight the need for further research on psilocybin's mechanisms across sexes and disease models.

Study at a glance

Abstract

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 behavior 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 characterize their social behavior compared to mice exposed to food restriction (FR), running wheels (RW) or standard housing (Controls) in female mice. 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 social familiarity (reduced novelty-seeking) in Controls. Novelty-seeking behavior 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 behavior and inflammation in female mice, advancing our understanding of how ABA and exercise influence social behavior and inflammatory signaling. They underscore the need to clarify the temporal, neuroplastic, and immune-related mechanisms of psilocybin across sexes and disease models.