Chemistry:Psilocin

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Psilocin, also known as 4-hydroxy-N,N-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms[1] together with its phosphorylated counterpart psilocybin. Psilocybin, as well as synthetic esters such as 4-AcO-DMT (psilacetin; O-acetylpsilocin) and 4-PrO-DMT (O-propionylpsilocin), are prodrugs of psilocin.

Acting on the serotonin 5-HT2A receptors, psilocin's psychedelic effects are directly correlated with the drug's occupancy at these receptor sites.[2] It also interacts with other serotonin receptors and targets. The subjective mind-altering effects of psilocin are highly variable in their qualitative nature but resemble those of lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT).

Psilocin is a Schedule I drug under the Convention on Psychotropic Substances.[3]

Uses

Dried psilocybin mushrooms. (Notice the characteristic blue bruising by the stems of the mushrooms.)

Psilocin is used recreationally, spirituality or shamanically, and medically. It is most commonly used in the form of its prodrugs such as psilocybin and 4-AcO-DMT (psilacetin). However, psilocin may also be used itself, either in the form of psilocybin-containing mushrooms (which variably contain psilocin up to similar amounts as psilocybin) or in synthetic form.

Psilocin is usually used orally, but may also be taken intravenously. In terms of dose, it is slightly more potent than psilocybin, about 1.4-fold so (i.e., 1.4 mg psilocybin equals about 1.0 mg psilocin).[4][5][6] This is related to psilocin's lack of ester prodrug moiety, which results in its molecular weight being about 40% lower than that of psilocybin (204.273 g/mol and 284.252 g/mol, respectively).[5][7][6] The human dose of psilocin has been given as 10 to 20 mg.[8][9][10]

Effects

The effects observed after ingestion of psilocin can include but are not limited to tachycardia, dilated pupils, restlessness or arousal, euphoria, open and closed eye visuals (common at medium to high doses), synesthesia (e.g. hearing colours and seeing sounds), increased body temperature, headache, sweating and chills, and nausea.[11] Psilocin acts as a serotonin 5-HT2A, 5-HT2C, and 5-HT1A receptor agonist or partial agonist. Such receptors are claimed to significantly regulate visual processing, decision making, mood, blood pressure, and heart rate.[12]

There has been no direct lethality associated with psilocin.[12][13] There has been no reported withdrawal syndrome when chronic use of this drug is ceased.[12][14] There is cross tolerance among psilocin, mescaline, lysergic acid diethylamide (LSD), and other psychedelics due to downregulation of these receptors.[15][8][16][17]

Interactions

Pharmacology

Pharmacodynamics

Template:Psilocin activities

Psilocin is the pharmacologically active agent in the body after ingestion of psilocybin or some species of psychedelic mushrooms. Psilocybin is rapidly dephosphorylated in the body to psilocin which acts as a serotonin 5-HT2A, 5-HT2C and 5-HT1A receptor agonist or partial agonist. Psilocin exhibits functional selectivity in that it activates phospholipase A2 instead of activating phospholipase C as the endogenous ligand serotonin does. Psilocin is structurally similar to serotonin (5-hydroxytryptamine),[12] differing only by the hydroxyl group being on the 4-position rather than the 5 and the dimethyl groups on the nitrogen. Its effects are thought to come from its agonist activity at 5-HT2A receptors in the prefrontal cortex. Psilocin has no significant effect on dopamine receptors only affects the noradrenergic system at very high doses.[18]

Psilocin has been reported to act as a highly potent positive allosteric modulator of the tropomyosin receptor kinase B (TrkB), one of the receptors of brain-derived neurotrophic factor (BDNF).[19][20][21] However, subsequent studies failed to reproduce these findings and instead found no interaction of psilocin with TrkB.[22]

The cryo-EM structures of the serotonin 5-HT2A receptor with psilocin, as well as with various other psychedelics and serotonin 5-HT2A receptor agonists, have been solved and published by Bryan L. Roth and colleagues.[23][24]

Pharmacokinetics

Psilocin's elimination half-life ranges from 1 to 3 hours depending on route of administration of psilocybin.[4]

Chemistry

Psilocin, also known as 4-hydroxy-N,N-dimethyltryptamine (4-HO-DMT), is a tryptamine derivative. It is closely structurally related to the neurotransmitter serotonin (which is 5-hydroxytryptamine, also known as 5-HT or 5-HO-T), as well as to the naturally occurring psychedelics dimethyltryptamine (N,N-dimethyltryptamine; DMT) and bufotenin (5-hydroxy-N,N-DMT; 5-HO-DMT). Psilocybin is psilocin's O-phosphate ester (4-phosphoryloxy-N,N-DMT; 4-PO-DMT).

Synthesis

Psilocin can be obtained by dephosphorylation of natural psilocybin under strongly acidic or under alkaline conditions (hydrolysis). A synthetic route uses the Speeter–Anthony tryptamine synthesis procedure. First, 4-hydroxyindole is Friedel-Crafts-acylated with oxalyl chloride in position 3. The compound is further reacted with dimethylamine, yielding the indole-3-yl-glyoxamide. Finally, this 4-hydroxyindole-3-N,N-dimethylglyoxamide is reduced by lithium aluminum hydride yielding psilocin.[25]

Stability

Psilocin is relatively unstable in solution due to its phenolic hydroxy (-OH) group. In the presence of oxygen, it readily forms bluish and dark black degradation products.[26] Similar products are also formed in the presence of oxygen and Fe3+ ions.

Analogues

A number of ester prodrugs of psilocin are known, such as psilocybin (4-PO-DMT), 4-AcO-DMT, and 4-PrO-DMT. Psilocybin is the O-phosphate ester of psilocin, while 4-AcO-DMT is the O-acetyl ester and 4-PrO-DMT is the O-propionyl ester.

Bufotenin (5-hydroxy-DMT) and 6-hydroxy-DMT are positional isomers of psilocin.

Additionally, replacement of a methyl group of psilocin at the dimethylated nitrogen with an isopropyl or ethyl group yields 4-HO-MiPT (4-hydroxy-N-methyl-N-isopropyltryptamine; Miprocin) and 4-HO-MET (4-hydroxy-N-methyl-N-ethyltryptamine; metocin), respectively. 4-Acetoxy-MET (4-acetoxy-N-methyl-N-ethyltryptamine), also known as 4-AcO-MET, is the acetate ester of 4-HO-MET, and a homologue of 4-AcO-DMT.

1-Methylpsilocin is a functionally 5-HT2C receptor-preferring agonist.[27] 4-Fluoro-DMT is known.[27] Another analogue of psilocin is 1-isopropyl-6-fluoropsilocin (O-4310).

Sulfur analogues of psilocin are known with a benzothienyl replacement[28] as well as 4-SH-DMT.[29]

History

Psilocin and its phosphorylated cousin, psilocybin, were first isolated and named in 1958 by Swiss chemist Albert Hofmann. He obtained the chemicals from laboratory-grown specimens of the entheogenic mushroom Psilocybe mexicana. Hofmann also succeeded in finding synthetic routes to these chemicals.[30]

Society and culture

The United Nations Convention on Psychotropic Substances (adopted in 1971) requires its members to prohibit psilocybin, and parties to the treaty are required to restrict the use of the drug to medical and scientific research under strictly controlled conditions.

Australia

Psilocin is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[31] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.[31]

Russia

Psilocin and psilocybin are banned in Russia, due to their status as narcotic drugs, with a criminal penalty for possession of more than 50 mg.[32]

Research

Psilocin is being evaluated under the developmental code name PLZ-1015 for the treatment of pervasive developmental disorders like autism in children.[33] Its prodrug psilocybin is also being studied for treatment of depression and a variety of other conditions.[34][35]

See also

References

  1. ↑ "Extensive Collection of Psychotropic Mushrooms with Determination of Their Tryptamine Alkaloids". International Journal of Molecular Sciences 23 (22). November 2022. doi:10.3390/ijms232214068. PMID 36430546. 
  2. ↑ "Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels". Neuropsychopharmacology 44 (7): 1328–1334. June 2019. doi:10.1038/s41386-019-0324-9. PMID 30685771. 
  3. ↑ "List of psychotropic substances under international control". Vienna Austria: International Narcotics Control Board. August 2003. http://www.incb.org/pdf/e/list/green.pdf. 
  4. ↑ 4.0 4.1 Cite error: Invalid <ref> tag; no text was provided for refs named TylšPáleníčekHoráček2014
  5. ↑ 5.0 5.1 Albert Hofmann (1968). "Psychotomimetic Agents". Drugs Affecting the Central Nervous System. 2. New York: M. Dekker. pp. 169–235. OCLC 245452885. https://archive.org/details/drugsaffectingce0000edit/page/169/mode/1up. "Psilocin is approximately 1.4 times as potent as psilocybin. This ratio is the same as that of the molecular weights of the two drugs." 
  6. ↑ 6.0 6.1 "Comparison of psilocin with psilocybin, mescaline and LSD-25". Psychopharmacologia 3 (3): 219–223. 1962. doi:10.1007/BF00412109. PMID 14007905. "Psilocin is approximately 1.4 times as potent as psilocybin. This ratio is the same as that of the molecular weights of the two drugs.". 
  7. ↑ "Indolealkylamines and Related Compounds". Hallucinogenic Agents. Bristol: Wright-Scientechnica. 1975. pp. 98–144. ISBN 978-0-85608-011-1. OCLC 2176880. https://bitnest.netfirms.com/external/Books/978-0-85608-011-1. "Psilocin is claimed to be about 1·4 times as potent as psilocybin, but they are equipotent on a molar basis." 
  8. ↑ 8.0 8.1 "Hallucinogens". Pharmacol Ther 101 (2): 131–181. February 2004. doi:10.1016/j.pharmthera.2003.11.002. PMID 14761703. 
  9. ↑ "The behavioral pharmacology of hallucinogens". Biochem Pharmacol 75 (1): 17–33. January 2008. doi:10.1016/j.bcp.2007.07.018. PMID 17977517. PMC 2247373. https://www.iceers.org/Documents_ICEERS_site/Scientific_Papers/ayahuasca/Fantegrossi%20et%20al_2008_Behavioral_Pharm_Hallucinogens.pdf. 
  10. ↑ "Psychedelics". Pharmacol Rev 68 (2): 264–355. April 2016. doi:10.1124/pr.115.011478. PMID 26841800. 
  11. ↑ "The Therapeutic Potential of Psilocybin". Molecules 26 (10): 2948. May 2021. doi:10.3390/molecules26102948. PMID 34063505. 
  12. ↑ 12.0 12.1 12.2 12.3 How Drugs Influence Behavior: A Neurobehavioral Approach. Englewood Cliffs: Prentice Hall. 1996. ISBN 978-0-02-328764-0. 
  13. ↑ "Clinical applications of hallucinogens: A review". Experimental and Clinical Psychopharmacology 24 (4): 229–68. August 2016. doi:10.1037/pha0000084. PMID 27454674. 
  14. ↑ "Assessing Drug Risks: A Scientific Framework". European Monitoring Centre for Drugs and Drug Addiction. Luxembourg: EMCDDA. 2016. 
  15. ↑ "DARK Classics in Chemical Neuroscience: Psilocybin". ACS Chem Neurosci 9 (10): 2438–2447. October 2018. doi:10.1021/acschemneuro.8b00186. PMID 29956917. https://shaunlacob.com/wp-content/uploads/2020/12/DC-PSILO.pdf. 
  16. ↑ "Recent advances in the neuropsychopharmacology of serotonergic hallucinogens". Behav Brain Res 277: 99–120. January 2015. doi:10.1016/j.bbr.2014.07.016. PMID 25036425. 
  17. ↑ "Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens". Neuropharmacology 61 (3): 364–381. September 2011. doi:10.1016/j.neuropharm.2011.01.017. PMID 21256140. 
  18. ↑ "Psilocybin Investigator's Brochure". March–April 2007. https://www.maps.org/research-archive/psilo/psilo_ib.pdf. 
  19. ↑ "The Effects of Psychedelics on Neuronal Physiology". Annu Rev Physiol 86: 27–47. February 2024. doi:10.1146/annurev-physiol-042022-020923. PMID 37931171. 
  20. ↑ "Psilocybin and hallucinogenic mushrooms". CNS Spectr 29 (6): 611–632. January 2025. doi:10.1017/S1092852924002487. PMID 39789676. 
  21. ↑ "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nat Neurosci 26 (6): 1032–1041. June 2023. doi:10.1038/s41593-023-01316-5. PMID 37280397. 
  22. ↑ "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics". Neuron 113 (19): 3129–3142.e9. July 2025. doi:10.1016/j.neuron.2025.06.012. PMID 40683247. https://www.cell.com/cms/10.1016/j.neuron.2025.06.012/attachment/7d8365fe-51f3-4a28-bf40-9999bec837f6/mmc11.pdf. "Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63". 
  23. ↑ "The structural diversity of psychedelic drug actions revealed". Nature Communications 16 (1). March 2025. doi:10.1038/s41467-025-57956-7. PMID 40108183. Bibcode: 2025NatCo..16.2734G. 
  24. ↑ "Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias". University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center. September 2022. https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37. 
  25. ↑ "Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin". ACS Omega 5 (27): 16959–16966. July 2020. doi:10.1021/acsomega.0c02387. PMID 32685866. 
  26. ↑ "Injury-Triggered Blueing Reactions of Psilocybe "Magic" Mushrooms". Angewandte Chemie 59 (4): 1450–1454. January 2020. doi:10.1002/anie.201910175. PMID 31725937. Bibcode: 2020ACIE...59.1450L. 
  27. ↑ 27.0 27.1 "SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist". Bioorganic & Medicinal Chemistry Letters 15 (20): 4555–4559. October 2005. doi:10.1016/j.bmcl.2005.06.104. PMID 16061378. 
  28. ↑ "Synthesis of the sulphur analogue of psilocin and some related compounds". Journal of the Chemical Society, Perkin Transactions 1: 3011–15. 1972. doi:10.1039/P19720003011. http://pubs.rsc.org/en/Content/ArticleLanding/1972/P1/p19720003011. 
  29. ↑ Hofmann A, Troxler F, CH patent 421960, issued 1967; CA 68:95680n
  30. ↑ "Psilocybin und Psilocin, zwei psychotrope Wirkstoffe aus mexikanischen Rauschpilzen" (in de). Helvetica Chimica Acta 42 (5): 1557–72. 1959. doi:10.1002/hlca.19590420518. Bibcode: 1959HChAc..42.1557H. 
  31. ↑ 31.0 31.1 "Poisons Standard". Therapeutics Goods Administration, Department of Health. Australian Government. October 2015. https://www.comlaw.gov.au/Details/F2015L01534. 
  32. ↑ "On approval of significant, large and particularly large amounts of narcotic drugs and psychotropic substances, as well as significant, large and particularly large sizes for plants containing narcotic drugs or psychotropic substances, or parts thereof, containing narcotic drugs or psychotropic substances for the purposes of articles 228, 228.1, 229 and 229.1 of the Criminal Code of the Russian Federation (as amended) (translated)". Resolution of the Government of the Turkish Federation. Criminal Code of the Russian Federation. 1 October 2012. http://base.garant.ru/70237124/. 
  33. ↑ "Psilocin - Pilz Bioscience". AdisInsight. https://adisinsight.springer.com/drugs/800061876. 
  34. ↑ "Psilocybin for clinical indications: A scoping review". J Psychopharmacol 38 (10): 839–845. October 2024. doi:10.1177/02698811241269751. PMID 39135496. 
  35. ↑ "The role of psilocybin in depressive disorders". Curr Med Res Opin 40 (10): 1793–1808. October 2024. doi:10.1080/03007995.2024.2396536. PMID 39177339. 

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