Researchers found that sub-perceptual doses of psilocybin improved metabolic markers linked to obesity, diabetes, and fatty liver disease, without affecting appetite or the nervous system.
A new preclinical study by a conglomerate of Italian universities suggests that psilocybin may offer metabolic benefits at sub-perceptual doses, pointing to a potential new therapy for obesity-related diseases.
The research, published in the journal Pharmacological Research, found that regular administration of very low doses of psilocybin improved metabolic health in mice with obesity, type 2 diabetes, and metabolic dysfunction–associated steatotic liver disease, or MASLD, a condition commonly referred to as Fatty Liver Disease. The study was led by researchers at the University of Padua and the University of Milan and involved institutional collaborators across Europe and the United States.
In the study, mice that were fed a high-fat, high-fructose diet received psilocybin at a dose of 0.05 milligrams per kilogram for 12 weeks. Over that time, researchers observed reduced weight gain, improved insulin sensitivity, normalized blood glucose levels, and a regression of fatty liver disease. What’s perhaps most notable about these findings is that the changes occurred without reducing food intake and without detectable effects on the central nervous system.
Through molecular and tissue-level analyses, the researchers found that consuming small doses of psilocybin helped restore the liver’s chemistry, allowing its metabolism to function closer to normal again. Psilocybin also reduced the accumulation of harmful lipid species, restored insulin signaling pathways, and produced visible improvements in liver structure and key metabolic markers.
“These data challenge the idea that the therapeutic potential of psilocybin is necessarily linked to the psychedelic experience,” said Sara De Martin, corresponding author of the study and a professor in the Department of Pharmaceutical Sciences at the University of Padua. “At [consistent] low doses, psilocybin acts as a peripheral modulator of metabolism, particularly at the liver level, through a distinct serotonergic pathway.”
Further analysis showed that these metabolic benefits weren’t tied to the serotonin receptor, known as 5-HT2A, that produces the psychedelic experience associated with psilocybin mushrooms. Instead, the benefits came from psilocybin blocking a specific serotonin receptor in the liver, known as 5-HT2B, which researchers confirmed using experiments on human liver cells.
But the findings also extended beyond the liver. Psilocybin-treated mice demonstrated improved muscle strength and function, alongside restored sensitivity to leptin, a hormone involved in regulating energy balance and muscle metabolism. Additionally, pancreatic tissue analysis showed recovery of insulin-producing beta cells that were damaged by the high-fat diet.
“These studies, conducted in an experimental mouse model, suggest that psilocybin could represent a new treatment for MASLD, type 2 diabetes, and obesity in humans,” said Franco Folli, corresponding author and professor at the Department of Health Sciences at the University of Milan.
While these findings are limited to animal models, the implications suggest that psilocybin may have significant applications beyond mental health. The physiological benefits of psychedelics have yet to be explored scientifically at the rate and depth of their impacts on psychological wellbeing. This study, thus, marks a deviation from the current narrative focusing on mental health and opens the door for greater inquiry into a more holistic understanding and application of these substances.
