Psilocybin, a serotonergic psychedelic, shows rapid and lasting therapeutic effects for depression and other hard-to-treat neuropsychiatric conditions, likely due to its ability to enhance neuronal plasticity. While these effects are often attributed to activation of the serotonin 2A (5-HT2A) receptor, emerging evidence indicates a more complex pharmacological profile involving multiple serotonin receptor subtypes and non-serotonergic targets like TrkB. This review integrates current findings on the molecular interactome of psilocin, the active metabolite of psilocybin, focusing on receptor selectivity, biased agonism, and intracellular receptor localization. These insights provide a refined framework for understanding psilocybin's enduring effects and guiding the development of next-generation neuroplastogens with improved specificity and safety.
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.