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.
Esmethadone (REL-1017) and other uncompetitive NMDAR antagonists may rapidly relieve depression by preferentially blocking hyperactive GluN2D subtypes, restoring physiological neural plasticity. In major depressive disorder, upregulated tonic calcium currents through GluN2D subtypes reduce homeostatic availability of synaptic proteins, contributing to depressive behaviors. Low-potency NMDAR antagonists' selectivity for GluN2D may explain their rapid antidepressant effects without dissociative side effects.