Psilocybin shows context-dependent effects on social behavior and inflammation in female mice in an anorexia model

  • Associate Professor Claire Foldi and her team at Monash University’s Biomedicine Discovery Institute reveal that exercise history and food restriction alter how the psychedelic compound affects sociability and immune signaling in a preclinical model relevant to eating disorders
  • News release prepared by Genomic Press and first published on EurekAlert!
  • Study published in peer-reviewed Psychedelics

A/Prof Claire Foldi

Researchers led by Associate Professor Claire Foldi at Monash University have discovered that psilocybin, the psychoactive substance in hallucinogenic mushrooms, produces subtle but significant effects on social behavior and inflammation that are critically dependent on the metabolic and movement context in female mice. The study, published in Psychedelics (Genomic Press, NY), represents the first systematic investigation of how this substance affects sociability in female mice exposed to activity-based anorexia (ABA), a widely accepted preclinical model that captures core features of anorexia nervosa.

These findings come at a crucial time. Clinical trials investigating psilocybin for anorexia nervosa are already underway, but our mechanistic understanding remains limited. Why do only 40% of participants in early studies show a reduction in symptoms? What drives this variability? This peer-reviewed research begins to unravel these questions by examining the substance through the lens of metabolic stress, exercise, and immune function.

The scientific challenge

Anorexia nervosa takes lives. It carries one of the highest mortality rates among psychiatric disorders, and hospitalization rates among young women aged 15 to 29 have been steadily rising in Australia, where this demographic accounts for 95% of all related hospital admissions. Beyond the physical devastation, people with anorexia nervosa experience profound social difficulties. They report having fewer social networks, derive less pleasure from social interactions, and exhibit impaired emotional empathy, which worsens during acute episodes of illness.

These social deficits share neurobiological roots with depression, anxiety, and obsessive-compulsive disorder. All involve dysfunction of the serotonergic system. All show elevated pro-inflammatory cytokines, particularly interleukin-6 and tumor necrosis factor-alpha. Psychedelics act primarily via serotonin receptors and possess documented anti-inflammatory properties. Could they address multiple symptoms simultaneously?

Previous research suggested this. Studies have shown that psilocybin improves emotional empathy in depressed patients. But almost all preclinical work has used male animals. This is extremely important when investigating a disorder that affects women at dramatically higher rates. The mechanisms relevant to anorexia nervosa require studies in female animals.

Methodological innovation in a female-focused model

Associate Professor Foldi's team used the activity-based anorexia model, which combines time-restricted food access with the availability of a voluntary running wheel. This paradigm reliably produces hunger-induced hyperactivity, severe weight loss, and increased anxiety. Eight-week-old female mice were assigned to four conditions: activity-based anorexia (a combination of food restriction with running wheel access), food restriction only, running wheel access with unlimited food, or standard solitary confinement.

The researchers administered psilocybin at a dose of 1.5 mg/kg to mice in an anorexia model after they had reached 75 to 85 percent of their initial body weight. Four to five hours later, the animals completed a three-chamber test for social preference and novelty. Blood samples taken seven hours after injection allowed for the measurement of interleukin-6 levels.

What distinguished this approach was the systematic comparison between the conditions. Instead of examining the effects of psilocybin in isolation, the team was able to disentangle the contributions of dietary restriction, exercise, and their combination. Could exercise alone explain the observed social changes? Would metabolic stress mask or amplify the drug's effects?

Unexpected patterns in social behavior

The mice with activity-based anorexia did not exhibit the social deficits the researchers had expected. Instead, they displayed heightened curiosity and a strikingly consistent preference for unfamiliar mice over familiar ones. This pattern emerged during the initial exploratory phase of the tests and persisted throughout.

Mice that were only trained showed something different. They also preferred new social partners, but this preference emerged mainly during the choice phase of the tests, not during the initial exploration. Mice with food restriction did not show such improvements.

Psilocybin did not fundamentally alter sociability across groups. However, it reduced exploratory behavior in control mice and caused them to spend equal amounts of time with familiar and new partners. In mice with restricted feeding who were administered psilocybin, body weight correlated strongly with interest in a novel object rather than a new mouse. Lower-weight animals paid more attention to the object, suggesting increased foraging motivation.

These findings raise fascinating questions. Does the increased curiosity in mice in the anorexia model reflect adaptive foraging behavior under food scarcity? Or could it represent an addiction-prone phenotype, consistent with the increased rates of substance use disorders in patients? Could this behavioral profile serve as a marker for obsessive-compulsive tendencies?

The inflammation tells a different story.

The immunological findings proved to be equally nuanced. Baseline interleukin-6 levels did not differ between the groups, contrary to expectations based on human studies showing elevated inflammatory markers in anorexia patients. However, psilocybin administration dramatically altered this picture in a specific context.

Running wheel mice treated with psilocybin showed significantly elevated levels of interleukin-6 compared to saline-treated running wheel mice, psilocybin-treated controls, and psilocybin-treated anorexia model animals. Even more intriguing was that these elevated levels correlated positively with social novelty preference. Higher interleukin-6 levels predicted greater interest in unfamiliar social partners.

No such relationship appeared in groups with activity-based anorexia or food restriction. Prior food restriction seemed to disrupt the mechanism linking psilocybin, inflammation, and sociability in exercise mice.

What explains this pattern? The researchers suggest that exercise alone, as an inherently rewarding activity that activates dopaminergic reward pathways, can create a metabolic and immunological context in which psilocybin produces different effects. The acute sampling period may also have captured transient immune changes that require longer observation periods to resolve into the anti-inflammatory effects reported in human studies.

Implications for treatment development

Dr. Foldi notes that these findings highlight the complexity of applying psychedelic treatments to eating disorders. The absence of social deficits in the acute anorexia model suggests that such impairments may require longer exposure times or result from psychosocial factors not captured in preclinical paradigms.

The context-dependent nature of psilocybin effects has clinical implications. Patients with different metabolic states, exercise histories, or disease durations may respond differently to treatment. Could exercise status serve as a biomarker for treatment response? Could inflammatory profiles help identify candidates likely to benefit?

The study also highlights gaps in our understanding of the temporal dynamics. Human research shows that psilocybin reduces interleukin-6 seven days after administration, correlating with sustained mood improvements. The acute timeframe used here may have missed subsequent anti-inflammatory effects.

The team behind the discovery

Sheida Shadani designed and conducted all experiments as part of her doctoral research at the Monash Biomedicine Discovery Institute. Erika Greaves assisted with the experimental procedures. Professor Zane B. Andrews contributed to the experimental design and analysis. Associate Professor Foldi conceived the study and supervised the entire investigation. The work was supported by an Ideas Grant from the National Health and Medical Research Council.

The way forward

Three concrete next steps emerge from this research. Extended exposure protocols with multiple restriction and refeeding cycles would better model chronic anorexia nervosa and potentially reveal social deficits that arise with persistent malnutrition. Time-course studies measuring interleukin-6 one, four, twenty-four, and one hundred and sixty-eight hours post-administration would clarify the temporal dynamics. Additional inflammatory markers, investigated alongside brain region-specific neuroplasticity markers, would comprehensively link immunomodulation with behavioral effects.

The researchers emphasize that male and female test animals likely differ not only in their psychedelic metabolism but also in how their neural circuits respond to serotonergic modulation. Future research must systematically investigate effects in both sexes and at multiple time points to identify sex-specific trajectories of change.

This original research represents a significant advance in psychedelic science, offering new insights into context-dependent mechanisms through rigorous experimental investigation. The findings challenge assumptions about consistent drug effects and open new avenues for understanding how metabolic state shapes the therapeutic response. By employing a carefully controlled comparative approach, the research team has generated data that advance fundamental knowledge while suggesting that personalized approaches may be essential for the treatment of eating disorders. The comprehensive nature of this study, encompassing multiple experimental conditions and examining both behavioral and immune outcomes, provides important insights that will reshape how researchers approach psychedelic mechanisms in metabolically compromised populations. Furthermore, the focus on female animals demonstrates the power of sex-appropriate model selection for addressing clinically relevant questions.

The research article in Psychedelics entitled “Psilocybin exerts differential effects on social behavior and inflammation in mice in contexts of activity-based anorexia” is freely available via Open Access on February 3, 2026 in Psychedelics at the following hyperlink: https://doi.org/10.61373/pp026a.0003.

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About the Monash Biomedicine Discovery Institute at Monash University

Committed to making discoveries that will relieve the future burden of disease, Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.