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Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

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.

Clinical Trials Identifier

NCT02163707.

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Acknowledgements

The project described was supported by gifts from the University of Wisconsin-Madison Foundation and the Usona Research Institute, and by the Clinical and Translational Science Award (CTSA) program through the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors would like to thank Dr. Diane Mould for advice on the population pharmacokinetic modeling, and Dr. Edmund Elder and the staff of the University of Wisconsin Zeeh Pharmaceutical Experiment Station for their assistance in the quality affirmation of the psilocybin API, and the preparation of the capsules for dosing.

Author information

Correspondence to Paul R. Hutson.

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Funding

This study was funded by gifts from the Psilocybin Research Fund at the University of Wisconsin-Madison Foundation, and by the Usona Research Institute.

Conflicts of interest

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, and Paul R. Hutson declare that they have no conflicts of interest that might be relevant to the contents of this article.

Ethical approval

All procedures performed in these studies involving human subjects were in accordance with the ethical standards of the institutional research committee, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in this study. Consent was re-established after any change in protocol while the subject was still on study.

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Brown, R.T., Nicholas, C.R., Cozzi, N.V. et al. Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Clin Pharmacokinet 56, 1543–1554 (2017). https://doi.org/10.1007/s40262-017-0540-6

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