Psilocybin effects in anorexic mice depend on exercise, metabolic state

A preclinical study in female mice has reported that psilocybin alters social behaviour and inflammatory signalling in ways that depend on exercise and metabolic context, offering mechanistic clues for ongoing clinical trials in anorexia nervosa

Researchers led by Dr Claire Foldi at Monash University, Melbourne, Australia, have reported that psilocybin – the psychoactive compound present in so-called ‘magic mushrooms’ – produced subtle but distinct effects on social behaviour and inflammation that depended on metabolic state and exercise exposure in female mice.

The peer-reviewed study represented the first systematic examination of how psilocybin influenced sociability in female mice exposed to activity-based anorexia, a widely used preclinical model that captured core behavioural and physiological features of anorexia nervosa.

The findings have emerged at a pivotal point for the field where clinical trials that have investigated psilocybin as a potential treatment for anorexia nervosa have been underway, despite mechanistic understanding remaining limited. Early studies have indicated that only around 40 per cent of participants have shown symptom reduction, raising questions about variability in response. By examining psilocybin effects within defined contexts of metabolic stress, voluntary exercise and immune signalling, the present work has begun to clarify biological factors that may shape therapeutic outcomes.

Anorexia nervosa carries one of the highest mortality rates among psychiatric conditions. Beyond severe physical consequences, patients commonly experience marked social impairment, including reduced social networks, diminished enjoyment of social interaction and deficits in emotional empathy that intensify during acute illness.

These social difficulties share neurobiological features with depression, anxiety and obsessive-compulsive disorder. Each involves disruption of serotonergic signalling alongside elevations in pro-inflammatory cytokines, particularly interleukin-6 and tumour necrosis factor alpha. Psychedelic compounds act primarily through serotonin receptors and have demonstrated anti-inflammatory effects in several contexts, raising the possibility that they may influence mood, social behaviour and immune function in parallel.

Previous clinical and preclinical studies have suggested that psilocybin enhanced emotional empathy in depression. However, most animal research has relied almost exclusively on male subjects, despite anorexia nervosa affecting females at far higher rates. The Monash team therefore focused explicitly on female mice to address this gap.

The researchers employed the activity-based anorexia model, which combined time-limited food access with voluntary access to a running wheel. This paradigm reliably induced starvation-associated hyperactivity, rapid weight loss and heightened anxiety-like behaviour. Eight-week-old female mice were allocated to one of four conditions:

• combined food restriction and wheel access

• food restriction alone

• wheel access with unrestricted food

• standard single housing with ad libitum food.

Psilocybin was administered at a dose of 1.5 mg per kg once mice in the anorexia model reached between 75 and 85 per cent of baseline body weight. Four to five hours after administration, animals completed a three-chamber social preference and social novelty test. Blood samples collected seven hours after dosing enabled measurement of circulating interleukin-6.

This design allowed direct comparison across metabolic and behavioural contexts, enabling separation of effects attributable to food restriction, exercise, or their interaction. Rather than assessing psilocybin in isolation, the study tested whether metabolic stress or voluntary activity modified behavioural and immune responses to the compound.

Contrary to expectations, mice in the activity-based anorexia condition did not exhibit reduced sociability. Instead, they showed pronounced novelty-seeking behaviour, consistently preferring unfamiliar mice to familiar social partners from the initial exploratory phase onwards. Mice with access to a running wheel but unrestricted food intake also displayed a preference for social novelty, although this emerged primarily during the choice phase. By contrast, mice exposed to food restriction alone showed no enhancement in novelty preference.

Psilocybin did not, however, exert uniform effects on sociability. In control mice, the compound reduced novelty preference, leading animals to divide their time between familiar and unfamiliar partners. In food-restricted mice that received psilocybin, body weight correlated strongly with interest in a novel object rather than a novel mouse, with lower body weight associated with greater object exploration. The authors interpreted this pattern as a shift towards food-seeking motivation.

These behavioural findings raised questions about the functional meaning of increased novelty seeking in the anorexia model. The authors suggested that it could reflect adaptive foraging behaviour under conditions of food scarcity. Alternatively, it may indicate a phenotype linked to compulsivity or reward seeking, consistent with elevated rates of substance use disorders reported in patients with anorexia nervosa.

Immune analyses revealed an equally context-specific pattern with baseline interleukin-6 concentrations not differing significantly between groups, contrasting with reports of elevated inflammatory markers in human anorexia nervosa.

However, psilocybin administration altered inflammatory signalling in one condition. Mice with running wheel access that received psilocybin exhibited significantly higher interleukin-6 levels than saline-treated runners, psilocybin-treated controls and psilocybin-treated activity-based anorexia mice. In this group, interleukin-6 concentrations correlated positively with social novelty preference.

No comparable relationship appeared in food-restricted mice or in those exposed to activity-based anorexia, suggesting that prior food restriction disrupted the link between psilocybin, inflammatory signalling and sociability observed in exercising animals. The researchers proposed that voluntary exercise, as a rewarding activity engaging dopaminergic pathways, created a metabolic and immune context in which psilocybin elicited distinct effects. They also noted that the acute sampling window may have captured transient immune responses, whereas anti-inflammatory effects reported in human studies typically emerged only days later.

“The findings emphasise the complexity of translating psychedelic treatments to eating disorders,” Foldi said.

“The absence of social deficits in the acute anorexia model suggests that these impairments may require longer exposure to malnutrition or arise from psychosocial factors that preclinical models cannot fully capture,” she added.

The authors noted that patients with differing metabolic states, exercise histories or illness durations may respond differently to psilocybin treatment. They also highlighted gaps in knowledge about temporal dynamics, as human studies have shown reductions in interleukin-6 around seven days after administration, coinciding with sustained mood improvement.

The work was led by doctoral candidate Sheida Shadani at the Monash Biomedicine Discovery Institute, with contributions from lab manager Erika Greaves, Professor Zane B Andrews and Associate Professor Foldi. Funding was provided through an Ideas Grant from Australia’s National Health and Medical Research Council.

Overall, the study has provided evidence that psilocybin effects were not uniform but depended on metabolic and behavioural context. By combining controlled comparisons across multiple conditions with parallel behavioural and immune analyses, the research has advanced understanding of psychedelic mechanisms in metabolically compromised states and reinforced the case for more personalised approaches in future eating disorder research.

For further reading please visit: 10.61373/pp026a.0003