Psilocybin, the psychoactive ingredient in magic mushrooms, has recently attracted attention as a possible treatment for anorexia nervosa. While some patients in early clinical trials have shown improvement, results have been inconsistent. However, recent preclinical research suggests that these differences may be linked to metabolic state and exercise history, rather than occurring randomly.
A new study from Monash University, published in Genomic Press Psychedelics, found that psilocybin changes social behavior and immune signaling in female mice. These effects vary depending on food restriction and physical activity. The results show the importance of considering physiological context when evaluating the effects of psychedelic compounds.
Anorexia Research
Anorexia nervosa is among the most serious psychiatric disorders, with high rates of relapse and few effective treatments. In addition to severe weight loss, patients often show social withdrawal, difficulty processing emotions, and increased inflammation. Many of these symptoms are also seen in depression and anxiety, which are linked to changes in serotonin signaling.
Psilocybin primarily targets serotonin receptors and has demonstrated potential in the treatment of mood disorders. Human studies have further associated psychedelic therapy with reduced inflammation several days after administration. These observations have contributed to growing interest in psilocybin as a possible treatment for eating disorders.
Most preclinical studies on psychedelics have focused on male animals, even though anorexia is much more common in females. This new research helps address that imbalance.
Modeling Starvation and Exercise
The researchers used a model called activity-based anorexia, where the mice had limited access to food and could use a running wheel. This setup is typically known to lead to rapid weight loss, increased activity, and anxiety-like behaviors, similar to what happens in anorexia nervosa.
The female mice were divided into four groups: activity-based anorexia, food restriction only, exercise only with unlimited food, and standard controls. Once the anorexia group reached 75 to 85 percent of their starting body weight, the researchers administered a moderate dose of psilocybin.
A few hours after treatment, the mice underwent a three-chamber test to assess social preference and novelty-seeking. The researchers also collected blood samples to measure interleukin-6, an inflammatory marker associated with psychiatric and metabolic disorders. This approach allowed the team to see how food restriction, exercise, and their combination shaped the effects of psilocybin.
Unexpected Social Behavior
Mice in the activity-based anorexia group did not become less social as expected. Instead, they preferred spending time with unfamiliar mice, showing increased interest in social novelty. Mice in the exercise-only group also showed greater interest in social novelty, but this effect emerged later in the test. Mice with food restriction alone did not show this pattern.
Psilocybin did not make mice more social overall. In the control group, their interest in social novelty decreased, so they spent about the same amount of time with familiar and unfamiliar mice. In food-restricted mice, those with lower body weight focused more on a new object than on another mouse, which suggests they were more interested in food.
These results suggest that starvation and activity can influence social motivation. Increased novelty-seeking behavior might help animals find food during scarcity, but it could also reflect compulsive behaviors similar to those seen in anorexia and addiction.
Exercise Dependent Inflammation
Baseline interleukin-6 levels were similar across all groups of mice, which differs from human studies that often find higher inflammation in anorexia patients. Psilocybin only altered this pattern in the exercise-only group. These mice had higher interleukin-6 levels after treatment compared to controls and other groups. In these animals, greater inflammation was associated with greater interest in social novelty.
This relationship did not appear in food-restricted mice. Previous starvation seemed to disrupt the connection between psilocybin, inflammation, and social behavior. These results suggest that exercise may alter how psilocybin affects immune signaling, possibly by modulating metabolic pathways involved in reward. The timing of measurements is also important, since human studies usually find anti-inflammatory effects days after treatment, not hours.
Implications for Psychedelic Therapies
Overall, these findings show that physiological context can strongly influence how psychedelics work. A drug that reduces social novelty in one situation may have no effect or even the opposite effect in another.
This variability has important implications for clinical research. Patients with different exercise habits, metabolic states, or illness histories may respond differently to the same treatment. Biomarkers related to inflammation or activity could eventually be used to help identify which patients are most likely to benefit from psychedelic therapies.
Future studies will need to track immune and behavioral changes over longer periods and compare responses between males and females. Until then, these results show that psilocybin’s effects depend on interactions among the brain, body, and environment, rather than being fixed properties of the drug alone.
Austin Burgess is a writer and researcher with a background in sales, marketing, and data analytics. He holds a Master of Business Administration, a Bachelor of Science in Business Administration, and a Data Analytics certification. His work combines analytical training with a focus on emerging science, aerospace, and astronomical research.