Chemistry:4-Hydroxytryptamine

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4-Hydroxytryptamine (4-HT, 4-HTA), also known as N,N-didesmethylpsilocin, is a naturally occurring tryptamine alkaloid.[1][2][3][4] It is closely related chemically to the neurotransmitter serotonin, the psychedelic psilocin, and is the active form of the tryptamine alkaloid norbaeocystin.[5][6][4]

The compound is a serotonin receptor agonist, including of the serotonin 5-HT2A receptor, but in contrast to certain closely related compounds like psilocin, appears to be non-hallucinogenic.[4][7]

4-HT may occur naturally in Psilocybe baeocystis and Psilocybe cyanescens.[1][8] It may serve as an alternative precursor in the biosynthesis of psilocybin (4-PO-DMT) in psilocybin mushrooms.[2][9][3]

Pharmacology

4-HT is a potent agonist of the serotonin 5-HT2A receptor similarly to psilocin (EC50 = 38 nM and 21 nM, respectively).[4][10][11] It also shows affinity for the serotonin 5-HT2C receptor (Ki = 40 nM), the serotonin 5-HT1A receptor (Ki = 95 nM), and the serotonin 5-HT1B receptor (Ki = 1,050 nM).[10][11][12] The drug produces serotonergic peripheral effects in animals,[1][13] shows similar metabolism and metabolic stability to psilocin,[4] and appears to cross the blood–brain barrier and hence is centrally penetrant.[4]

Surprisingly however, the compound, similarly to baeocystin, norbaeocystin, and norpsilocin, does not produce the head-twitch response, a behavioral proxy of psychedelic effects, in animals, and hence is putatively non-hallucinogenic.[4][7] In older literature, the psychoactive effects of 4-hydroxylated tryptamines have been said to increase in the series of 4-hydroxytryptamine, 4-hydroxy-N-methyltryptamine (norpsilocin], and 4-hydroxy-N,N-dimethyltryptamine (psilocin).[3]

The reason for the lack of hallucinogenic effects with 4-HT and related compounds is unknown, but may be due to biased agonism of the serotonin 5-HT2A receptor; or, more specifically, biased agonism for the β-arrestin2 signaling pathway.[4]

Norbaeocystin is thought to be a prodrug of 4-HT, analogously to how psilocybin is a prodrug of psilocin and how baeocystin is thought to be a prodrug of norpsilocin.[6][4]

Chemistry

4-HT, also known as 4-hydroxytryptamine, is a substituted tryptamine derivative.[5] It is a positional isomer of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT), an analogue of the serotonergic psychedelic psilocin (4-HO-DMT), and the dephosphorylated form of the tryptamine alkaloid norbaeocystin (4-phosphoryloxytryptamine; 4-PO-T).[5]

The predicted log P of 4-HT is 0.65 to 1.1.[5][14]

Derivatives

A large number of 4-hydroxytryptamine derivatives are known.[15][16][17][18][19][20] These include psilocin (4-HO-DMT), norpsilocin (4-HO-NMT), 4-HO-DALT, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-DPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPT, 4-HO-NiPT, 4-HO-pyr-T, and 4-HO-TMT, among others.[15][16][17][18] In addition, 4-methoxy derivatives such as 4-MeO-DiPT, 4-MeO-DMT, and 4-MeO-MiPT; 4-acetoxy derivative such as 4-AcO-DMT (psilacetin), 4-AcO-DET, 4-AcO-DALT, 4-AcO-DiPT, 4-PrO-DiPT, and 4-PrO-DMT; and 4-phosphoryloxy derivatives such as psilocybin (4-PO-DMT), baeocystin (4-PO-NMT), norbaeocystin (4-PO-T), and aeruginascin (4-PO-TMT) are known.[15][16][17][18][19][20] Many or all of these compounds are serotonin receptor agonists and/or serotonergic psychedelics.[15][16][17][18]

History

4-HT was first described in the scientific literature by 1959.[1][21][22] Its pharmacology was first thoroughly characterized in 2024.[4]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Keeper of the Trout and Friends (2007). "4-Hydroxytryptamine". Some Simple Tryptamines (2 ed.). Austin, Texas: Mydriatric Productions. p. 54. ISBN 978-0-9770876-5-5. OCLC 948674100. https://bitnest.netfirms.com/external/SST/54. 
  2. ↑ 2.0 2.1 "Bioactive Alkaloids of Hallucinogenic Mushrooms". Studies in Natural Products Chemistry. 46. Elsevier. 2015. pp. 133–168. doi:10.1016/b978-0-444-63462-7.00005-1. ISBN 978-0-444-63462-7. 
  3. ↑ 3.0 3.1 3.2 "Psychoactive tryptamines from basidiomycetes". Folia Microbiologica 47 (1): 3–27. 2002. doi:10.1007/BF02818560. PMID 11980266. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 "Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms". British Journal of Pharmacology 181 (19): 3627–3641. October 2024. doi:10.1111/bph.16466. PMID 38825326. "Norpsilocin, 4-hydroxytryptamine and 4-hydroxy-N,N,N-trimethyltryptamine have similar stability, metabolism and blood brain barrier penetration to psilocin. [...] As norpsilocin and 4-HT (active forms of baeocystin and norbaeocystin, respectively) are evidenced to be capable of crossing the BBB and bind with 5-HT2A receptors, it was surprising that neither induced significant head twitch responses at any concentration tested. However, these results concur with previous studies demonstrating these compounds do not significantly induce head twitch responses in rodents (Glatfelter et al., 2022; Sherwood et al., 2020).". 
  5. ↑ 5.0 5.1 5.2 5.3 "4-Hydroxytryptamine". https://pubchem.ncbi.nlm.nih.gov/compound/11297. 
  6. ↑ 6.0 6.1 "The Therapeutic Potential of Psilocybin". Molecules 26 (10): 2948. May 2021. doi:10.3390/molecules26102948. PMID 34063505. 
  7. ↑ 7.0 7.1 "Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin". Journal of Natural Products 83 (2): 461–467. February 2020. doi:10.1021/acs.jnatprod.9b01061. PMID 32077284. Bibcode: 2020JNAtP..83..461S. 
  8. ↑ "Baeocystin in psilocybe, conocybe and panaeolus". Lloydia 40 (6): 566–578. 1977. PMID 600026. 
  9. ↑ "In silico characterization of the psilocybin biosynthesis pathway". Computational Biology and Chemistry 104. June 2023. doi:10.1016/j.compbiolchem.2023.107854. PMID 36990027. 
  10. ↑ 10.0 10.1 "A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines". J Biol Chem 299 (10). October 2023. doi:10.1016/j.jbc.2023.105231. PMID 37690691. 
  11. ↑ 11.0 11.1 Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery, 10 March 2023, doi:10.21203/rs.3.rs-2667175/v1, https://www.researchsquare.com/article/rs-2667175/latest.pdf, retrieved 18 March 2025 
  12. ↑ "Central serotonin receptors as targets for drug research". J Med Chem 30 (1): 1–12. January 1987. doi:10.1021/jm00384a001. PMID 3543362. "Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites". 
  13. ↑ Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines. Advances in Pharmacology. 6. 1968. pp. 233–246. doi:10.1016/s1054-3589(08)60322-1. ISBN 978-0-12-032906-9. 
  14. ↑ "4-HYDROXYTRYPTAMINE". 10 June 2024. https://www.chemspider.com/Chemical-Structure.10823.html. 
  15. ↑ 15.0 15.1 15.2 15.3 "The hallucinogenic world of tryptamines: an updated review". Arch Toxicol 89 (8): 1151–1173. August 2015. doi:10.1007/s00204-015-1513-x. PMID 25877327. Bibcode: 2015ArTox..89.1151A. 
  16. ↑ 16.0 16.1 16.2 16.3 "Psychonauts' psychedelics: A systematic, multilingual, web-crawling exercise". Eur Neuropsychopharmacol 49: 69–92. August 2021. doi:10.1016/j.euroneuro.2021.03.006. PMID 33857740. https://cronfa.swan.ac.uk/Record/cronfa55715. 
  17. ↑ 17.0 17.1 17.2 17.3 "Toxicology and Analysis of Psychoactive Tryptamines". Int J Mol Sci 21 (23): 9279. December 2020. doi:10.3390/ijms21239279. PMID 33291798. 
  18. ↑ 18.0 18.1 18.2 18.3 Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. http://www.erowid.org/library/books_online/tihkal/tihkal.shtml. 
  19. ↑ 19.0 19.1 "Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice". ACS Pharmacol Transl Sci 6 (4): 567–577. April 2023. doi:10.1021/acsptsci.2c00222. PMID 37082754. 
  20. ↑ 20.0 20.1 "Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2A Receptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter". J Pharmacol Exp Ther 385 (1): 62–75. April 2023. doi:10.1124/jpet.122.001454. PMID 36669875. 
  21. ↑ "The relative activities of some tryptamine analogues on the isolated rat stomach strip preparation". British Journal of Pharmacology and Chemotherapy 14 (1): 87–98. March 1959. doi:10.1111/j.1476-5381.1959.tb00933.x. PMID 13651584. 
  22. ↑ "Pharmacological actions of 4-hydroxytryptamine and 4-hydroxytryptophan". Experientia 16 (11): 505–506. November 1960. doi:10.1007/BF02158367. PMID 13697285. 

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