New psilocybin data highlights challenges for anorexia drug development

Researchers at Monash University have found that psilocybin, the psychoactive compound in magic mushrooms, produces subtle but distinct effects on social behaviour and inflammation in female mice, depending on metabolic state and physical activity. Led by Dr Claire Foldi, the study is the first systematic investigation of how psilocybin affects sociability in female mice exposed to activity-based anorexia (ABA), a preclinical model of anorexia nervosa.

The findings arrive as clinical trials explore psilocybin for anorexia nervosa, yet the mechanics of which are poorly understood. Early trials suggest only around 40 percent of participants experience symptom reduction.

The scientific challenge

Anorexia nervosa is among the psychiatric conditions with the highest mortality rates. Hospitalisations in young women aged 15-29 have risen steadily in Australia, accounting for 95 percent of related admissions. Beyond physical effects, individuals with anorexia experience social difficulties, including smaller social networks, reduced pleasure from interactions and impaired emotional empathy, which worsens during acute illness phases.

These social deficits share neurobiological roots with depression, anxiety and obsessive-compulsive disorder, involving serotonin dysfunction and elevated proinflammatory cytokines such as interleukin-6 and tumour necrosis factor-alpha. Psychedelics act through serotonin receptors and show anti-inflammatory properties, raising the question: could they address multiple symptoms simultaneously?

Previous studies suggest psilocybin enhances emotional empathy in depressed patients, but nearly all preclinical research has used male subjects.

Female-focused methodology

Dr Foldi’s team used the ABA model, which combines time-limited food access with voluntary running wheel availability, producing starvation-evoked hyperactivity, severe weight loss and elevated anxiety. Eight-week-old female mice were assigned to four conditions: ABA, food restriction alone, running wheel access with unlimited food or standard single housing.

Mice received psilocybin at 1.5 mg/kg after reaching 75-85 percent of baseline body weight. Four to five hours later, social preference and novelty tests were conducted, with blood samples collected seven hours post-injection to measure interleukin-6.

Both ABA and RW groups demonstrate elevated preference for novel social over other novel stimuli. Empty symbols represent SAL-treated mice; filled symbols represent psilocybin-treated mice. Data are presented as mean ± SEM and were analysed by one-way ANOVA with Šidák post hoc tests. Significance thresholds: ∗P < 0.05; ∗∗P <0.01; ∗∗∗ P < 0.001. For futher details see Figure 3 legend in the paper. Credit: Claire J Foldi.

Unexpected social patterns

ABA mice did not show anticipated social deficits. Instead, they displayed heightened novelty-seeking, preferring unfamiliar mice consistently. Exercising mice also preferred novel partners, but this emerged primarily during the choice phase. Food-restricted mice showed no such effects.

Psilocybin reduced novelty-seeking in control mice, equalising time spent with familiar and novel partners. In food-restricted mice, body weight correlated with attention to a novel object rather than a mouse, suggesting increased food-seeking motivation.

Inflammation and context

Baseline interleukin-6 levels were similar across groups. However, psilocybin significantly elevated interleukin-6 in exercising mice, correlating with greater social novelty preference. “Prior food restriction seemed to disrupt whatever mechanism linked psilocybin, inflammation and sociability in exercising mice,” the researchers noted.

The team suggests that exercise, as a rewarding activity activating dopamine pathways, may create a metabolic and immune context where psilocybin produces unique effects.

Implications and future research

Dr Foldi highlights the complexity of translating psychedelics to eating disorder treatment. Context-dependent effects suggest patients’ metabolic states, exercise histories or illness durations may influence outcomes. Exercise status or inflammatory profiles might serve as biomarkers for response.

This study advances psychedelic science, demonstrating that metabolic state shapes behavioural and immune responses to psilocybin. By focusing on female subjects and systematically comparing experimental conditions, the research provides a framework for personalised approaches in treating eating disorders.