Chronic low-dose psilocybin (0.05 mg/kg) reduced body-weight gain, liver steatosis, hyperglycemia, and insulin resistance in mice fed a high-fat/high-fructose diet, without causing central nervous system effects. Multi-omics analyses showed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. The metabolic benefits were independent of the psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver, supporting psilocybin as a potential novel therapeutic for metabolic disorders.
A library of fluorinated reversible N-alkyl carbamate derivatives of psilocin was designed and synthesized to reduce acute psilocin exposure and limit hallucinogenic-like effects. By varying the number and positioning of fluorine atoms on the alkyl promoiety, carbamate bond stability was systematically modulated, yielding compounds with finely tuned hydrolysis under physiological conditions. A lead compound (4e) demonstrated favorable oral bioavailability and efficient brain penetration while undergoing partial bioconversion to psilocin. It exhibited intrinsic serotonergic activity at 5-HT2A and 5-HT2C receptors but induced attenuated psychotropic effects compared to psilocybin. Fluorinated carbamate chemistry provides a versatile platform to control psilocin exposure and serotonergic signaling.