The pharmacology of psilocybin

This study (2002) details the pharmacology of psilocybin.

Abstract

“Psilocybin (4‐phosphoryloxy‐N,N‐dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide.These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.”

Authors: Torsten Passie, Juergen Seifert, Udo Schneider & Hinderk M. Emrich

Summary

Psilocybin is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. It is a growing problem regarding hallucinogenic drug abuse.

Introduction

Psilocybin-containing mushrooms are one of the major hallucinogenic drugs of abuse today. Recent research has reported on the treatment of compulsive disorders in humans with psilocybin, therefore it is important to know the essential pharmacological data about psilocybin.

Pharmacology of psilocybin

Psilocybin is a substituted indolealkylamine that was isolated from Central American mushrooms in 1957 and produced synthetically in 1958.

Psychic effects

Psilocybin produces a well-controllable altered state of consciousness, marked by stimulation of affect, enhanced ability for introspection and altered psychological functioning.

Somatic effects

Cerletti reported an LD50 of 280mg/kg for mice, which may imply an LD50 of some grams of psilocybin in humans. Psilocybin caused autonomic excitatory effects in mice, rats, rabbits, cats and dogs, as well as changes in physiological parameters and a central excitatory syndrome.

In a non-blind study, psilocybin caused physiological changes in healthy volunteers, which were confirmed qualitatively by another early non-blind study. In a double-blind placebo-controlled study, psilocybin caused no significant aberrations of electrolyte levels, liver toxicity tests and blood sugar levels.

Experiments in mice showed no evidence of genetic aberrations through psilocybin, but further tests are required to confirm these negative results.

Pharmacokinetics

Pharmacokinetic studies showed that 50% of 14 C-labelled psilocybin was absorbed following oral administration, and that four metabolites of psilocybin were identified.

According to two pharmacokinetic studies in humans, psilocybin is detectable in significant amounts in the plasma within 20 – 40 minutes, and psychological effects occur with plasma levels of 4 – 6 mg/ml. Psilocin appears in the plasma after 30 minutes, and is the main, if not the solely pharmacologically active substance.

Psilocybin can be referred to as a prodrug, because equimolar amounts evoke qualitatively and quantitatively similar psychotropic effects in humans. However, it is not possible to prove this assumption by showing the absence of the parent drug in plasma after psilocybin administration.

The renal excretion of psilocybin is completed after 3 hours, with great interindividual differences.

Early single-blind randomized comparative studies showed that 100 mg psilocybin was equivalent to 1 mg LSD and 1000 mg mescaline.

Pharmacodynamics

Two recent double-blind placebo controlled PET studies using [F-18]-fluorodeoxyglucose showed brain metabolic activation under the influence of psilocybin. The highest activation was found in the right hemispheric frontotemporal cortical regions and decreased in the thalamus.

Psilocybin interacts mainly with serotonergic neurotransmission ( 5-HT1A, 5-HT1D, 5-HT2A and 5-HT2C receptor subtypes), and to a lesser extent with 5-HT1A receptors. It has no affinity for dopamine D2 receptors, and its psychotomimetic effects can be blocked completely using the preferential 5HT2A receptor antagonist ketanserin.

Psilocybin interacts mainly with serotonin receptors of the dorsal raphe nucleus and noradrenergic neurones of the nearby locus coeruleus. This may explain some forms of perceptual alterations such as synaesthesias.

The evidence reviewed suggests psilocybin to exhibit low toxicity and may be physiologically well tolerated, but proper safety pharmacology studies are lacking.