Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

This open-label study (n=12) gave healthy participants increasing doses of psilocybin (21-42mg/70kg). The study found the half-life to be about 3 hours, this was not predicted by body weight, and no adverse effects were observed.

Abstract

“Introduction: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.

Methods: Eligible healthy adults received 6–8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods.

Results: No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied.

Conclusions: The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild–moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose.”

Authors: Randall T. Brown, Christopher R. Nicholas, Nicholas V. Cozzi, Michele C. Gassman, Karen M. Cooper, Daniel Muller, Chantelle D. Thomas, Scott J. Hetzel, Kelsey M. Henriquez, Alexandra S. Ribaudo & Paul R. Hutson

Notes

Highlights from the authors:

• “Psilocybin, as its active metabolite psilocin, demonstrates linear pharmacokinetics over the 0.3–0.6 mg/kg oral dose range tested.
• Less than 2% of the psilocin in plasma is excreted in urine in that form, suggesting minimal effect of renal dysfunction in elimination of the active metabolite.
• A fixed oral dose of 25 mg is expected to approximate the area under the concentration–time curve and concentration profile of the 0.3 mg/kg oral dose used in this study.”

Summary of Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults