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

(Press-News.org) CLAYTON, Victoria, AUSTRALIA, 3 February 2026 -- Researchers led by Dr. Claire Foldi at Monash University have discovered that psilocybin, the psychoactive compound found in magic mushrooms, produces subtle but distinct effects on social behavior and inflammation that depend critically on metabolic and exercise context in female mice. The peer-reviewed study, published in Psychedelics, represents the first systematic investigation of how this compound influences sociability in female mice exposed to activity-based anorexia (ABA), a widely recognized preclinical model that captures core features of anorexia nervosa.

The findings arrive at a pivotal moment. Clinical trials investigating psilocybin for anorexia nervosa are underway, yet mechanistic understanding remains sparse. Why do only 40% of participants in early trials show symptom reduction? What drives such variability? This research begins to untangle those questions by examining the compound through the lens of metabolic stress, exercise, and immune function.

The Scientific Challenge

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

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

Previous research suggested yes. Studies have shown psilocybin enhances emotional empathy in depressed patients. But nearly all preclinical work has used male subjects. This matters enormously when studying a condition that affects females at dramatically higher rates. The mechanisms relevant to anorexia nervosa require investigation in female subjects.

Methodological Innovation in a Female-Focused Model

Dr. Foldi's team employed the activity-based anorexia model, which combines time-limited food access with voluntary running wheel availability. This paradigm reliably produces starvation-evoked hyperactivity, severe weight loss, and elevated anxiety. Eight-week-old female mice were assigned to four conditions: activity-based anorexia (combining food restriction with wheel access), food restriction alone, running wheel access with unlimited food, or standard single housing.

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

What made this approach distinctive was its systematic comparison across conditions. Rather than examining psilocybin effects in isolation, the team could disentangle contributions from food restriction, exercise, and their combination. Could exercise alone explain observed social changes? Would metabolic stress mask or enhance drug effects?

Unexpected Patterns in Social Behavior

The activity-based anorexia mice did not show the social deficits researchers anticipated. Instead, they exhibited heightened novelty-seeking behavior, preferring unfamiliar mice over familiar ones with striking consistency. This pattern emerged during the initial exploratory phase of testing and persisted throughout.

Mice that were exercising only showed something different. They too preferred novel social partners, but this preference emerged primarily during the choice phase of testing rather than during initial exploration. Food-restricted mice showed no such enhancements.

Psilocybin did not broadly alter sociability across groups. However, it reduced novelty-seeking in control mice, causing them to spend equivalent time with familiar and novel partners. In food-restricted mice administered psilocybin, body weight correlated strongly with interest in a novel object rather than a novel mouse. Animals with lower body weight directed more attention toward the object, suggesting enhanced food-seeking motivation.

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

Inflammation Tells a Different Story

The immune findings proved equally nuanced. Baseline interleukin-6 levels did not differ between groups, contrary to expectations based on human studies showing elevated inflammatory markers in anorexia patients. But psilocybin administration changed this picture dramatically in one specific context.

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

No such relationship appeared in activity-based anorexia or food-restricted groups. Prior food restriction seemed to disrupt whatever mechanism linked psilocybin, inflammation, and sociability in exercising mice.

What explains this pattern? The researchers suggest that exercise alone, as an inherently rewarding activity that activates dopamine reward pathways, may create a metabolic and immune context where psilocybin produces distinct effects. The acute sampling timeframe 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 translating psychedelic treatments to eating disorders. The absence of social deficits in the acute anorexia model suggests that such impairments may require longer exposure periods or result from psychosocial factors not captured in preclinical paradigms.

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

The study also underscores gaps in understanding temporal dynamics. Human research shows psilocybin reduces interleukin-6 seven days after administration, correlating with sustained mood improvements. The acute timeframe employed here may have missed downstream anti-inflammatory effects.

The Team Behind the Discovery

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

The Road Ahead

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 emerging with sustained malnutrition. Time-course studies measuring interleukin-6 at one, four, twenty-four, and one hundred sixty-eight hours post-administration would clarify temporal dynamics. Additional inflammatory markers examined alongside brain-region-specific neuroplasticity markers would comprehensively link immune modulation to behavioral effects.

The researchers emphasize that male and female subjects likely differ not only in psychedelic metabolism but in how neural circuits respond to serotonergic modulation. Future research must systematically examine effects across both sexes and at multiple timepoints to identify sex-specific trajectories of change.

This peer-reviewed 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 therapeutic response. By employing a carefully controlled comparative approach, the research team has generated data that advances fundamental knowledge while suggesting that personalized approaches may prove essential for eating disorder treatment. The comprehensive nature of this investigation, spanning 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 subjects demonstrates the power of sex-appropriate model selection to tackle clinically relevant questions.

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

About Psychedelics: Psychedelics: The Journal of Psychedelic and Psychoactive Drug Research (ISSN: 2997-2671, online and 2997-268X, print) is a peer reviewed medical research journal published by Genomic Press, New York. Psychedelics is dedicated to advancing knowledge across the full spectrum of consciousness altering substances, from classical psychedelics to stimulants, cannabinoids, entactogens, dissociatives, plant derived compounds, and novel compounds including drug discovery approaches. Our multidisciplinary approach encompasses molecular mechanisms, therapeutic applications, neuroscientific discoveries, and sociocultural analyses. We welcome diverse methodologies and perspectives from fundamental pharmacology and clinical studies to psychological investigations and societal-historical contexts that enhance our understanding of how these substances interact with human biology, psychology, and society.

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