Pharmacokinetics of Psilocybin, a Tryptamine Alkaloid in Magic Mushroom ( Psilocybe cubensis ): A Systematic Review

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.

Study at a glance

Abstract

Psilocybin, a major indole alkaloid found in magic mushrooms (Psilocybe cubensis), has recently drawn attention as a breakthrough therapy to treat major depressive disorder. This review aimed to summarize and identify knowledge gaps concerning their pharmacokinetic characteristics of psilocybin and its active metabolite, psilocin. Original studies related to pharmacokinetics of psilocybin conducted in vitro, animals, and humans were systematically collected from PubMed, Scopus, and ScienceDirect, from their inceptions to November 2023. Twenty articles were included in this work and assessed for study quality. A comprehensive review of the pharmacokinetics of psilocybin and psilocin in both animals and humans was performed. Psilocybin is considered a prodrug that is dephosphorylated to psilocin by alkaline phosphatase. Following ingestion, the peak psilocin plasma and brain levels were rapidly achieved in a dose-dependent manner. Psilocin is metabolized primarily through both Phase I and Phase II processes with the half-life of 2-3 hours. This review also identified lack of some pharmacokinetic related information and limitations of available research that may help direct future investigations to better understand the pharmacokinetics and improve study design including dose selection and dosage optimization.