Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Psilocybin: from ancient magic to modern medicine

Abstract

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is an indole-based secondary metabolite produced by numerous species of mushrooms. South American Aztec Indians referred to them as teonanacatl, meaning “god’s flesh,” and they were used in religious and healing rituals. Spanish missionaries in the 1500s attempted to destroy all records and evidence of the use of these mushrooms. Nevertheless, a 16th century Spanish Franciscan friar and historian mentioned teonanacatl in his extensive writings, intriguing 20th century ethnopharmacologists and leading to a decades-long search for the identity of teonanacatl. Their search ultimately led to a 1957 photo-essay in a popular magazine, describing for the Western world the use of these mushrooms. Specimens were ultimately obtained, and their active principle identified and chemically synthesized. In the past 10–15 years several FDA-approved clinical studies have indicated potential medical value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions. At present, assuming that the early clinical studies can be validated by larger studies, psilocybin is poised to make a significant impact on treatments available to psychiatric medicine.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Scheme 1
Scheme 2
Scheme 3

References

  1. 1.

    Nichols DE, Johnson MW, Nichols CD. Psychedelics as medicines: an emerging new paradigm. Clin Pharm Ther. 2017;101:209–19.

    CAS  Article  Google Scholar 

  2. 2.

    Wasson RG. Notes on the present status of ololiuhqui and the other hallucinogens of Mexico. Botanical Mus Leafl Harv Univ. 1963;20:161–93.

    CAS  Google Scholar 

  3. 3.

    Corne SJ, Pickering RW. A possible correlation between drug-induced hallucinations in man and a behavioural response in mice. Psychopharmacologia. 1967;11:65–78.

    CAS  Article  Google Scholar 

  4. 4.

    Hofmann A, Heim R, Brack A, Kobel H. [Psilocybin, a psychotropic substance from the Mexican mushroom Psilicybe mexicana Heim]. Experientia. 1958;14:107–9.

    CAS  Article  Google Scholar 

  5. 5.

    Hofmann A, Frey A, Ott H, Petrzilka T, Troxler F. [Elucidation of the structure and the synthesis of psilocybin]. Experientia. 1958;14:397–9.

    CAS  Article  Google Scholar 

  6. 6.

    Psilocybin. In: O’Neil MJ, editor. The Merck Index—An encyclopedia of chemicals, drugs, and biologicals,. 13th ed. Whitehouse Station, NJ: Merck and Co., Inc.; 2001. p. 1419.

  7. 7.

    Baker RW, Chothia C, Pauling P, Weber HP. Molecular structure of LSD. Science. 1972;178:614–5.

    CAS  Article  Google Scholar 

  8. 8.

    Beug MW, Bigwood J. Psilocybin and psilocin levels in twenty species from seven genera of wild mushrooms in the Pacific Northwest, USA. J Ethnopharmacol. 1982;5:271–85.

    CAS  Article  Google Scholar 

  9. 9.

    Hofmann A. Teonanacatl and Ololuiqui and Ololuiqui, two ancient magic drugs of Mexico. Bull Narc. 1971;XXIII:3–14.

    Google Scholar 

  10. 10.

    Horita A, Weber LJ. The enzymic dephosphorylation and oxidation of psilocybin and psilocin by mammalian tissue homogenates. Biochem Pharmacol. 1961;7:47–54.

    CAS  Article  Google Scholar 

  11. 11.

    Horita A. Some biochemical studies on psilocybin and psilocin. J Neuropsychiatry. 1963;4:270.

    CAS  Google Scholar 

  12. 12.

    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.

    CAS  Article  Google Scholar 

  13. 13.

    Nichols DE. Psychedelics. Pharm Rev.2016;68:264–355.

    CAS  Article  Google Scholar 

  14. 14.

    Nichols DE, Frescas S. Improvements to the synthesis of psilocybin and a facile method for preparing the O-acetyl prodrug of psilocin. Synthesis. 1999;6:935–8.

    Article  Google Scholar 

  15. 15.

    Shirota O, Hakamata W, Goda Y. Concise large-scale synthesis of psilocin and psilocybin, principal hallucinogenic constituents of “magic mushroom”. J Nat Prod. 2003;66:885–7.

    CAS  Article  Google Scholar 

  16. 16.

    Sherwood A, Meisenheimer P, Tarpley G, Kargbo R. An improved, practical, and scalable five-step synthesis of psilocybin. Synthesis. 2020;52:688–94.

    CAS  Article  Google Scholar 

  17. 17.

    Kargbo R, Sherwood A, Kaylo K, Meisenheimer P, O’Hern K, Patterson T, et al. The First Direct Phosphorylation of Psilocin to Psilocybin under cGMP Conditions. International Society for Research on Psychedelics. New Orleans 2019.

  18. 18.

    Agurell S, Nilsson JL. A biosynthetic sequence from tryptophan to psilocybin. Tetrahedron Lett. 1968;9:1063–4.

    CAS  Article  Google Scholar 

  19. 19.

    Agurell S, Nilsson JL. Biosynthesis of psilocybin. II. Incorporation of labelled tryptamine derivatives. Acta Chem Scand. 1968;22:1210–8.

    CAS  Article  Google Scholar 

  20. 20.

    Fricke J, Blei F, Hoffmeister D. Enzymatic synthesis of psilocybin. Angew Chem Int Ed Engl. 2017;56:12352–5.

    CAS  Article  Google Scholar 

  21. 21.

    Adams AA, Kaplan NA, Wei Z, Brinton JD, Monnier CS, Enacopol AL, et al. In vivo production of psilocybin in E. coli. Metab Eng. 2019;56:111–9.

    CAS  Article  Google Scholar 

  22. 22.

    Fricke J, Kargbo R, Regestein L, Lenz C, Peschel G, Rosenbaum M, et al. Scalable hybrid synthetic/biocatalytic route to psilocybin. Chemistry. 2020. https://doi.org/10.1002/chem.202000134.

  23. 23.

    Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry. 2006;67:1735–40.

    CAS  Article  Google Scholar 

  24. 24.

    Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacol. 2006;187:268–83.

    CAS  Article  Google Scholar 

  25. 25.

    Maclean KA, Johnson MW, Griffiths RR. Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol. 2011;25:1453–61.

    CAS  Article  Google Scholar 

  26. 26.

    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.

    CAS  Article  Google Scholar 

  27. 27.

    Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 2014;28:983–92.

    Article  Google Scholar 

  28. 28.

    Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29:289–99.

    CAS  Article  Google Scholar 

  29. 29.

    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.

    CAS  Article  Google Scholar 

  30. 30.

    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.

    CAS  Article  Google Scholar 

  31. 31.

    Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology. 1997;16:357–72.

    CAS  Article  Google Scholar 

  32. 32.

    Gouzoulis-Mayfrank E, Schreckenberger M, Sabri O, Arning C, Thelen B, Spitzer M, et al. Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology. 1999;20:565–81.

    CAS  Article  Google Scholar 

  33. 33.

    Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci USA. 2012;109:2138–43.

    CAS  Article  Google Scholar 

  34. 34.

    Lewis CR, Preller KH, Kraehenmann R, Michels L, Staempfli P, Vollenweider FX. Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow. Neuroimage. 2017;159:70–8.

    CAS  Article  Google Scholar 

  35. 35.

    Muthukumaraswamy SD, Carhart-Harris RL, Moran RJ, Brookes MJ, Williams TM, Errtizoe D, et al. Broadband cortical desynchronization underlies the human psychedelic state. J Neurosci. 2013;33:15171–83.

    CAS  Article  Google Scholar 

  36. 36.

    Beique JC, Imad M, Mladenovic L, Gingrich JA, Andrade R. Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci USA. 2007;104:9870–5.

    Article  Google Scholar 

  37. 37.

    Martin DA, Nichols CD. Psychedelics recruit multiple cellular types and produce complex transcriptional responses within the brain. EBioMedicine. 2016;11:262–77.

    Article  Google Scholar 

  38. 38.

    Carhart-Harris RL, Leech R, Williams TM, Erritzoe D, Abbasi N, Bargiotas T, et al. Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. Br J Psychiatry. 2012;200:238–44.

    CAS  Article  Google Scholar 

  39. 39.

    Petri G, Expert P, Turkheimer F, Carhart-Harris R, Nutt D, Hellyer PJ, et al. Homological scaffolds of brain functional networks. J R Soc Interface. 2014;11:20140873.

    CAS  Article  Google Scholar 

  40. 40.

    Barrett FS, Doss MK, Sepeda ND, Pekar JJ, Griffiths RR. Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci Rep. 2020;10:2214.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to David E. Nichols.

Ethics declarations

Conflict of interest

The author declares that he has no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nichols, D.E. Psilocybin: from ancient magic to modern medicine. J Antibiot 73, 679–686 (2020). https://doi.org/10.1038/s41429-020-0311-8

Download citation

Search

Quick links