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.
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.
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.
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
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Nichols DE. Psychedelics. Pharmacol Rev. 2016;68:264–355.
Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68:71–8.
Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30:1181–97.
Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30:1165–80.
Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3:619–27.
Horita A, Weber LJ. The enzymic dephosphorylation and oxidation of psilocybin and psilocin by mammalian tissue homogenates. Biochem Pharmacol. 1961;7:47–54.
Hasler F, Bourquin D, Brenneisen R, Bar T, Vollenweider FX. Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man. Pharm Acta Helv. 1997;72:175–84.
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998;9:3897–902.
Fantegrossi WE, Reissig CJ, Katz EB, Yarosh HL, Rice KC, Winter JC. Hallucinogen-like effects of N,N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents. Pharmacol Biochem Behav. 2008;88:358–65.
McKenna DJ, Repke DB, Lo L, Peroutka SJ. Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes. Neuropharmacology. 1990;29:193–8.
Nichols DE. Hallucinogens. Pharmacol Ther. 2004;101:131–81.
Smith RL, Canton H, Barrett RJ, Sanders-Bush E. Agonist properties of N, N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors. Pharmacol Biochem Behav. 1998;61:323–30.
Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzalez-Maes J. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett. 2011;493:76–9.
Ray TS. Psychedelics and the human receptorome. PLoS One. 2010;5:e9019.
Rickli A, Moning OD, Hoener MC, Liechti ME. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol. 2016;26:1327–37.
Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology (Berlin). 2011;218:649–65.
Hasler F, Bourquin D, Brenneisen R, Vollenweider FX. Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. J Pharm Biomed Anal. 2002;30:331–9.
Williams JBW, Gibbon M, First MB, Spitzer RL, Davis M, Borus J, et al. The Structured Clinical Interview for DSM-III-R (SCID) II. Multi-site test-retest reliability. Arch Gen Psychiatry. 1992;49:630–6.
Milanowski D, Leahy M, Freeman D. Validation of a method for the determination of psilocybin and psilocin in ascorbic acid treated human plasma by HPLC with MS/MS detection method validation report. Covance Study No. 8290845.
Milanowski D, Leahy M, Freeman D. Validation of a method for the determination of psilocybin and psilocin human urine by HPLC with MS/MS detection method validation report. Covance Study No. 8290843.
Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ, editors. NONMEM 7.3.0 users guides (1989–2013). Hanover: ICON Development Solutions. 2013.
Reporting the results of population pharmacokinetic analyses. CHMP/EWP/185990/06. European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001284.jsp&mid=WC0b01ac0580032ec5. Accessed 25 Mar 2017.
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2015. https://www.R-project.org/. Accessed 21 Apr 2016.
Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Progr Biomed. 1999;58:51–64.
Holford N. Wings for NONMEM. http://wfn.sourceforge.net. Accessed 28 June 2016.
Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28:481–504.
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317:1098.
Devine BJ. Gentamicin therapy. Drug Intell Clin Pharm. 1974;8:650–5.
Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44(10):1051–65.
Parke J, Holford NH, Charles BG. A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Progr Biomed. 1999;59:19–29.
Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007;82:17–20.
Keizer R. Creating visual predictive checks in R. https://github.com/ronkeizer/vpc. Accessed 25 Mar 2017.
Comets E, Brendel K, Mentré F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Progr Biomed. 2008;90:154–66.
Studerus E, Kometer M, Hasler F, Vollenweider FX. Acute, subacute, and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol. 2010;25:1434–52.
Johnson MW, Richards WA, Griffiths RR. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22:603–20.
Johnson MW, Sewell RA, Griffiths RR. Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers. Drug Alcohol Depend. 2012;123:132–40.
Woollen JW, Walker PG. The fluorimetric estimation of β-glucuronidase in blood plasma. Clin Chim Acta. 1965;12:659–70.
Manevski N, Kurkela M, Hoglund C, Mauriala T, Court MH, Yli-Kauhaluoma J, et al. Glucuronidation of psilocin and 4-hydroxyindole by the human UDP-glucuronosyltransferases. Drug Metab Disp. 2010;38:386–95.
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.
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.
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 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.
About this article
Cite this article
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