Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

Psilocybin is a psychedelic tryptamine being studied for depression and substance use disorders. In an open-label study of 12 healthy adults, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg were given at monthly intervals. No psilocybin was found in plasma or urine; its active metabolite psilocin had an elimination half-life of 3 hours (standard deviation 1.1). Renal clearance of intact psilocin accounted for less than 2% of total clearance, indicating no dose reduction is needed for mild-moderate renal impairment. Body weight did not predict variation in psilocin clearance. No serious adverse events occurred. A fixed 25 mg dose approximates the exposure of a 0.3 mg/kg dose.

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Abstract

IntroductionPsilocybin 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.MethodsEligible 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.ResultsNo 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.ConclusionsThe 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.Clinical trials identifierNCT02163707.