A preclinical study, published in the journal Pharmacological Research, has 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 (MASLD).
Researchers from two Italian universities, alongside institutions from across Europe and the United States, fed mice a high-sugar and high-fat diet. The mice were given a low dose (0.05 milligrams per kg of body weight) of psilocybin for 12 weeks, during which researchers observed reduced weight gain, improved insulin sensitivity, normalised blood glucose levels and a regression of fatty liver disease. The changes occurred without reducing food intake and without detectable effects on the central nervous system.
Using molecular and tissue-level analyses, researchers found that psilocybin reduced the accumulation of harmful “toxic” fats, restored insulin signalling 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 chronic low doses, psilocybin acts as a peripheral modulator of metabolism, particularly at the liver level, through a distinct serotonergic pathway.”
Using human tissue cells to validate findings, the role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) was examined. The data showed that these metabolic benefits weren’t tied to the 5-HT2A receptor, commonly found in the brain, gut, and cardiovascular system, and which produces the psychedelic experience associated with psilocybin, but resulted from the molecule blocking the 5-HT2B receptor, which is situated in the liver and is involved with regulating cardiac development, growth, and function, amongst other roles.
The study also showed benefits from psilocybin treatment in improved muscle strength and function, and an increased sensitivity to a hormone involved in regulating energy balance and muscle metabolism called leptin. Additionally, analysis of pancreatic tissue showed evidence of psilocybin helping to repair insulin-producing beta cells that were damaged by the high-fat and high-sugar diet.
“In summary, we demonstrated that the 5-HT2BR-mediated beneficial metabolic effects induced by non-psychedelic psilocybin are correlated to a remodelling of the hepatic lipidome and accompanied by preservation of muscular strength and function in mice,” the authors said.
“These effects taken all-together, point to psilocybin as a potential muscle-sparing, CNS- and cardio-safe drug candidate for the treatment of MASLD, obesity and type 2 diabetes mellitus.”
While these findings are limited to animal models, the study suggests that psilocybin may have applications beyond mental health.
