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Psilocin

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Psilocin
Skeletal formula
Ball-and-stick model
Clinical data
Other namesPsilocine; Psilocyn; Psilotsin; 4-Hydroxy-N,N-dimethyltryptamine; 4-Hydroxy-DMT; 4-Hydroxy-N,N-DMT; 4-HO-DMT; 4-OH-DMT; PSOH; PAL-153; PAL153; CX-59; CX59
Routes of
administration		By mouth, intravenous[1]
Drug classSerotonergic psychedelic; Hallucinogen; Serotonin receptor agonist[2]
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral psilocybin: 52.7 ± 20.4% (as psilocin)[2][1]
MetabolismLiver, other tissues:[5][2][1][6]
• Demethylation and deamination (MAOTooltip monoamine oxidase)
• Oxidation (ALDHTooltip aldehyde dehydrogenase)
• Glucuronidation (UGTs)
Metabolites• Psilocin-O-glucuronide[2][1]
• 4-Hydroxy-indole-3-acetaldehyde[2][1]
• 4-Hydroxyindole-3-acetic acid (4-HIAA)[2][1]
• 4-Hydroxytryptophol[2][1]
Elimination half-lifeOral psilocybin: 2.3–3 hours (as psilocin)[2][1][4]
IVTooltip Intravenous injection psilocybin: 1.2 hours (as psilocin)[1][4]
ExcretionUrine (mainly as psilocin-O-glucuronide, 2–4% unchanged)[2][1][4]
Identifiers
  • 3-[2-(Dimethylamino)ethyl]-1H-indol-4-ol
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.007.543 Edit this at Wikidata
Chemical and physical data
FormulaC12H16N2O
Molar mass204.273 g·mol−1
3D model (JSmol)
Melting point173 to 176 °C (343 to 349 °F)
  • CN(C)CCc1c[nH]c2cccc(O)c12
  • InChI=1S/C12H16N2O/c1-14(2)7-6-9-8-13-10-4-3-5-11(15)12(9)10/h3-5,8,13,15H,6-7H2,1-2H3 checkY
  • Key:SPCIYGNTAMCTRO-UHFFFAOYSA-N checkY
  (verify)

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[7] 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.[8] 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.[9]

Uses

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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 dosage, it is slightly more potent than psilocin, about 1.4-fold so (i.e., 1.4 mg psilocybin equals about 1.0 mg psilocin).[4][10] 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).

Effects

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See also: Psilocybin § Effects, and 4-AcO-DMT § 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.[1] 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.[11]

There has been no direct lethality associated with psilocin.[11][12] There has been no reported withdrawal syndrome when chronic use of this drug is ceased.[11][13] There is cross tolerance among psilocin, mescaline, lysergic acid diethylamide (LSD), and other psychedelics due to downregulation of these receptors.[14][15][16][17]

Interactions

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See also: Psilocybin § Interactions, Psychedelic drug § Interactions, and Trip killer § Serotonergic psychedelic antidotes

Pharmacology

[edit]
See also: Psilocybin § Pharmacology, and Psychedelic drug § Mechanism of action

Pharmacodynamics

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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),[11] 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 (unlike lysergic acid diethylamide (LSD)) and only affects the noradrenergic system at very high doses.[18]

Pharmacokinetics

[edit]

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

Chemistry

[edit]

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

[edit]

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.[19]

Stability

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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.[20] Similar products are also formed in the presence of oxygen and Fe3+ ions.

Analogues

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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.

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.[21] 4-Fluoro-DMT is known.[21] Another analogue of psilocin is 1-isopropyl-6-fluoropsilocin (O-4310).

Sulfur analogues of psilocin are known with a benzothienyl replacement[22] as well as 4-SH-DMT.[23]

History

[edit]

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.[24]

Society and culture

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[edit]
See also: Psilocybin § Legal status, and Psilocybin mushroom § Legal status

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

[edit]

Psilocin is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[25] 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.[25]

Russia

[edit]

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.[26]

Research

[edit]
See also: Psilocybin § Research

Psilocin is being evaluated under the developmental code name PLZ-1015 for the treatment of pervasive developmental disorders like autism in children.[27] Its prodrug psilocybin is also being studied for treatment of depression and a variety of other conditions.[28][29]

References

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  1. ^ a b c d e f g h i j k Lowe H, Toyang N, Steele B, Valentine H, Grant J, Ali A, Ngwa W, Gordon L (May 2021). "The Therapeutic Potential of Psilocybin". Molecules. 26 (10): 2948. doi:10.3390/molecules26102948. PMC 8156539. PMID 34063505. S2CID 235227972.
  2. ^ a b c d e f g h i Dodd S, Norman TR, Eyre HA, Stahl SM, Phillips A, Carvalho AF, Berk M (July 2022). "Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy". CNS Spectr. 28 (4): 416–426. doi:10.1017/S1092852922000888. PMID 35811423.
  3. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  4. ^ a b c d e Tylš F, Páleníček T, Horáček J (March 2014). "Psilocybin--summary of knowledge and new perspectives". European Neuropsychopharmacology. 24 (3): 342–356. doi:10.1016/j.euroneuro.2013.12.006. PMID 24444771. S2CID 10758314.
  5. ^ MacCallum CA, Lo LA, Pistawka CA, Deol JK (2022). "Therapeutic use of psilocybin: Practical considerations for dosing and administration". Frontiers in Psychiatry. 13: 1040217. doi:10.3389/fpsyt.2022.1040217. PMC 9751063. PMID 36532184.
  6. ^ Coppola M, Bevione F, Mondola R (February 2022). "Psilocybin for Treating Psychiatric Disorders: A Psychonaut Legend or a Promising Therapeutic Perspective?". Journal of Xenobiotics. 12 (1): 41–52. doi:10.3390/jox12010004. PMC 8883979. PMID 35225956.
  7. ^ Gotvaldová K, Borovička J, Hájková K, Cihlářová P, Rockefeller A, Kuchař M (November 2022). "Extensive Collection of Psychotropic Mushrooms with Determination of Their Tryptamine Alkaloids". International Journal of Molecular Sciences. 23 (22): 14068. doi:10.3390/ijms232214068. PMC 9693126. PMID 36430546.
  8. ^ Madsen MK, Fisher PM, Burmester D, Dyssegaard A, Stenbæk DS, Kristiansen S, et al. (June 2019). "Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels". Neuropsychopharmacology. 44 (7): 1328–1334. doi:10.1038/s41386-019-0324-9. PMC 6785028. PMID 30685771.
  9. ^ "List of psychotropic substances under international control" (PDF) (23rd ed.). Vienna Austria: International Narcotics Control Board. August 2003. Archived from the original (PDF) on 4 February 2012. Retrieved 2012-10-11.
  10. ^ Wolbach AB, Miner EJ, Isbell H (1962). "Comparison of psilocin with psilocybin, mescaline and LSD-25". Psychopharmacologia. 3 (3): 219–223. 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.
  11. ^ a b c d Diaz J (1996). How Drugs Influence Behavior: A Neurobehavioral Approach. Englewood Cliffs: Prentice Hall. ISBN 978-0-02-328764-0.
  12. ^ Garcia-Romeu A, Kersgaard B, Addy PH (August 2016). "Clinical applications of hallucinogens: A review". Experimental and Clinical Psychopharmacology. 24 (4): 229–68. doi:10.1037/pha0000084. PMC 5001686. PMID 27454674.
  13. ^ Assessing Drug Risks: A Scientific Framework. European Monitoring Centre for Drugs and Drug Addiction. Luxembourg: EMCDDA. 2016.
  14. ^ Geiger HA, Wurst MG, Daniels RN (October 2018). "DARK Classics in Chemical Neuroscience: Psilocybin" (PDF). ACS Chem Neurosci. 9 (10): 2438–2447. doi:10.1021/acschemneuro.8b00186. PMID 29956917.
  15. ^ Nichols DE (February 2004). "Hallucinogens". Pharmacol Ther. 101 (2): 131–181. doi:10.1016/j.pharmthera.2003.11.002. PMID 14761703.
  16. ^ Halberstadt AL (January 2015). "Recent advances in the neuropsychopharmacology of serotonergic hallucinogens". Behav Brain Res. 277: 99–120. doi:10.1016/j.bbr.2014.07.016. PMC 4642895. PMID 25036425.
  17. ^ Halberstadt AL, Geyer MA (September 2011). "Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens". Neuropharmacology. 61 (3): 364–381. doi:10.1016/j.neuropharm.2011.01.017. PMC 3110631. PMID 21256140.
  18. ^ Jerome L (March–April 2007). "Psilocybin Investigator's Brochure" (PDF). Retrieved 2012-10-11.
  19. ^ Kargbo RB, Sherwood A, Walker A, Cozzi NV, Dagger RE, Sable J, et al. (July 2020). "Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin". ACS Omega. 5 (27): 16959–16966. doi:10.1021/acsomega.0c02387. PMC 7364850. PMID 32685866. S2CID 220599227.
  20. ^ Lenz C, Wick J, Braga D, García-Altares M, Lackner G, Hertweck C, et al. (January 2020). "Injury-Triggered Blueing Reactions of Psilocybe "Magic" Mushrooms". Angewandte Chemie. 59 (4): 1450–1454. doi:10.1002/anie.201910175. PMC 7004109. PMID 31725937.
  21. ^ a b Sard H, Kumaran G, Morency C, Roth BL, Toth BA, He P, Shuster L (October 2005). "SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist". Bioorganic & Medicinal Chemistry Letters. 15 (20): 4555–4559. doi:10.1016/j.bmcl.2005.06.104. PMID 16061378.
  22. ^ Chapman NB, Scrowston RM, Sutton TM (1972). "Synthesis of the sulphur analogue of psilocin and some related compounds". Journal of the Chemical Society, Perkin Transactions 1: 3011–15. doi:10.1039/P19720003011.
  23. ^ CH 421960, Hofmann A, Troxler F, issued 1967 ; CA 68:95680n
  24. ^ Hofmann A, Heim R, Brack A, Kobel H, Frey A, Ott H, Petrzilka T, Troxler F (1959). "Psilocybin und Psilocin, zwei psychotrope Wirkstoffe aus mexikanischen Rauschpilzen" [Psilocybin and psilocin, two psychotropic substances in Mexican magic mushrooms]. Helvetica Chimica Acta (in German). 42 (5): 1557–72. doi:10.1002/hlca.19590420518.
  25. ^ a b "Poisons Standard". Therapeutics Goods Administration, Department of Health. Australian Government. October 2015.
  26. ^ "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. 1002. Retrieved 1 April 2018.
  27. ^ "Psilocin - Pilz Bioscience". AdisInsight.
  28. ^ Madden K, Flood B, Young Shing D, Ade-Conde M, Kashir I, Mark M, MacKillop J, Bhandari M, Adili A (October 2024). "Psilocybin for clinical indications: A scoping review". J Psychopharmacol. 38 (10): 839–845. doi:10.1177/02698811241269751. PMC 11481402. PMID 39135496.
  29. ^ Najib J (October 2024). "The role of psilocybin in depressive disorders". Curr Med Res Opin. 40 (10): 1793–1808. doi:10.1080/03007995.2024.2396536. PMID 39177339.
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