Psilocybin, the main psychoactive compound in magic mushrooms, acts as a prodrug that is rapidly converted in the body to its active form, psilocin. After ingestion, psilocin levels in blood and brain peak quickly and depend on the dose given. Psilocin is broken down through multiple metabolic pathways and has a short half-life of 2–3 hours. This review of 20 studies highlights that while basic pharmacokinetics are understood, important gaps remain—such as incomplete information on metabolism and limitations in study design—that future research should address to improve dosing and treatment optimization for conditions like major depressive disorder.
A physiologically based pharmacokinetic (PBPK) model was developed to describe how psilocybin and its active metabolite psilocin distribute through the body in mice, rats, and humans. Psilocybin is assumed to convert completely to psilocin before entering systemic circulation. The model accurately characterizes concentration-time profiles across different doses and routes of administration. It can help guide therapeutic strategies and improve clinical trial designs for using psilocybin to treat major depressive disorder.