Psilocybin, a naturally occurring compound found in certain mushroom species, must undergo a chemical transformation within the body to exert its effects. This process, known as metabolism, is how the body breaks down and converts substances, determining the onset, intensity, and duration of the compound’s psychoactive properties. Psilocybin is considered a prodrug, meaning it is biologically inactive until it is converted into a different molecule by the body’s enzymatic systems. The metabolic journey involves distinct phases, starting with activation and culminating in deactivation and elimination.
Initial Journey and Activation
The metabolic journey begins immediately after ingestion, as psilocybin is absorbed primarily in the gastrointestinal tract and enters the bloodstream. During this initial absorption, a portion of the compound is lost due to first-pass metabolism, which occurs as the substance passes through the gut wall and the liver. This processing reduces the amount of psilocybin that reaches systemic circulation.
The crucial step for activation is dephosphorylation, a chemical reaction that removes a phosphate group from the psilocybin molecule. This conversion is catalyzed by various enzymes, most notably alkaline phosphatase, found in high concentrations in the small intestine and the liver. This enzymatic action cleaves the phosphate group, transforming inactive psilocybin into its biologically active form, psilocin.
The conversion from psilocybin to psilocin is a prerequisite for the compound to become psychoactive. Psilocybin, with its phosphate group, possesses a low affinity for the brain’s serotonin receptors. Without this metabolic conversion, the compound cannot effectively bind to the receptors responsible for the effects. Once dephosphorylation is complete, the resulting psilocin molecule is ready to interact with the central nervous system.
The Active Metabolite Psilocin
Psilocin is the active metabolite, directly responsible for the compound’s psychoactive effects. The removal of the phosphate group during activation results in a molecule that is more lipid-soluble, which is necessary for crossing the blood-brain barrier. This characteristic allows psilocin to reach the brain tissue where it exerts its influence.
Once across the barrier, psilocin chemically resembles the neurotransmitter serotonin, allowing it to bind to serotonin receptors in the brain. It acts as a non-selective agonist, with its psychoactive properties linked specifically to its interaction with the serotonin 5-HT2A receptor. Psilocin reaches its peak concentration in the plasma approximately two hours after oral administration, corresponding to the peak of the subjective effects.
The duration and intensity of the effects are tied to the concentration of psilocin in the blood and brain. This active metabolite has a relatively short half-life, ranging from two to three hours in humans. The structure of psilocin, featuring a hydroxyl group where psilocybin had a phosphate group, defines its activity and marks it for the next phase of metabolism: deactivation.
Deactivation and Elimination
The body deactivates psilocin through conjugation, which makes the compound suitable for excretion. The primary deactivation pathway is glucuronidation, a Phase II metabolic reaction occurring mainly in the liver. During this process, enzymes known as UDP-glucuronosyltransferases (UGTs) attach a large, water-soluble molecule called glucuronic acid to the psilocin.
Specific UGT enzymes, such as UGT1A10 in the small intestine and UGT1A9 in the liver, are the major contributors to this deactivation. This attachment creates the inactive metabolite psilocin-O-glucuronide, which is significantly more polar and water-soluble than the original psilocin. The increased water solubility prepares the substance for rapid removal from the system.
In addition to glucuronidation, a small amount of psilocin undergoes oxidative deamination, catalyzed by enzymes like monoamine oxidase A (MAO-A) and Cytochrome P450 enzymes (CYP2D6, CYP3A4). This forms other inactive metabolites like 4-hydroxyindole-3-acetic acid (4-HIAA). Once deactivated, both psilocin-O-glucuronide and 4-HIAA are efficiently eliminated from the body, with the majority excreted through the urine within 24 hours.