4-Hydroxytryptamine

4-Hydroxytryptamine
Clinical data
Other names	4-HT; 4-HTA; N,N-Didesmethylpsilocin; Dinorpsilocin
Drug class	Serotonin receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist
Identifiers
	IUPAC name 3-(2-aminoethyl)-1H-indol-4-ol;
CAS Number	570-14-9;
PubChem CID	11297;
ChemSpider	10823;
UNII	DP0D1701D1;
KEGG	C21762;
ChEBI	CHEBI:139217;
ChEMBL	ChEMBL18855;
CompTox Dashboard (EPA)	DTXSID30205607 ;
Chemical and physical data
Formula	C10H12N2O
Molar mass	176.219 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1=CC2=C(C(=C1)O)C(=CN2)CCN;
	InChI InChI=1S/C10H12N2O/c11-5-4-7-6-12-8-2-1-3-9(13)10(7)8/h1-3,6,12-13H,4-5,11H2; Key:FKIRTWDHOWAQGX-UHFFFAOYSA-N;

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-HT_2A 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-HT_2A receptor similarly to psilocin (EC₅₀Tooltip half-maximal effective concentration = 38 nM and 21 nM, respectively).^[4]^[10]^[11] It also shows affinity for the serotonin 5-HT_2C receptor (K_i = 40 nM), the serotonin 5-HT_1A receptor (K_i = 95 nM), and the serotonin 5-HT_1B receptor (K_i = 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-HT_2A 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]

References

^ ^a ^b ^c ^d Keeper of the Trout and Friends (2007). "4-Hydroxytryptamine". Some Simple Tryptamines (2 ed.). Austin, Texas: Mydriatric Productions. p. 54. ISBN 978-0977087655. OCLC 948674100.
^ ^a ^b Wieczorek PP, Witkowska D, Jasicka-Misiak I, Poliwoda A, Oterman M, Zielińska K (2015). "Bioactive Alkaloids of Hallucinogenic Mushrooms". Studies in Natural Products Chemistry. Vol. 46. Elsevier. pp. 133–168. doi:10.1016/b978-0-444-63462-7.00005-1. ISBN 978-0-444-63462-7. ISSN 1572-5995.
^ ^a ^b ^c Wurst M, Kysilka R, Flieger M (2002). "Psychoactive tryptamines from basidiomycetes". Folia Microbiologica. 47 (1): 3–27. doi:10.1007/BF02818560. PMID 11980266.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Rakoczy RJ, Runge GN, Sen AK, Sandoval O, Wells HG, Nguyen Q, et al. (October 2024). "Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms". British Journal of Pharmacology. 181 (19): 3627–3641. 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).
^ ^a ^b ^c ^d "4-Hydroxytryptamine". PubChem. Retrieved 5 December 2024.
^ ^a ^b Lowe H, Toyang N, Steele B, Valentine H, Grant J, Ali A, et al. (May 2021). "The Therapeutic Potential of Psilocybin". Molecules. 26 (10): 2948. doi:10.3390/molecules26102948. PMC 8156539. PMID 34063505.
^ ^a ^b Sherwood AM, Halberstadt AL, Klein AK, McCorvy JD, Kaylo KW, Kargbo RB, et al. (February 2020). "Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin". Journal of Natural Products. 83 (2): 461–467. Bibcode:2020JNAtP..83..461S. doi:10.1021/acs.jnatprod.9b01061. PMID 32077284.
^ Repke DB, Leslie DT, Guzmán G (1977). "Baeocystin in psilocybe, conocybe and panaeolus". Lloydia. 40 (6): 566–578. PMID 600026.
^ Irvine W, Tyler M, Delgoda R (June 2023). "In silico characterization of the psilocybin biosynthesis pathway". Computational Biology and Chemistry. 104: 107854. doi:10.1016/j.compbiolchem.2023.107854. PMID 36990027.{{cite journal}}: CS1 maint: article number as page number (link)
^ ^a ^b Chen X, Li J, Yu L, Maule F, Chang L, Gallant JA, et al. (October 2023). "A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines". J Biol Chem. 299 (10): 105231. doi:10.1016/j.jbc.2023.105231. PMC 10570959. PMID 37690691.{{cite journal}}: CS1 maint: article number as page number (link)
^ ^a ^b Chen X, Li J, Yu L, Dhananjaya D, Maule F, Cook S, et al. (10 March 2023), Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery (PDF), doi:10.21203/rs.3.rs-2667175/v1, retrieved 18 March 2025
^ Glennon RA (January 1987). "Central serotonin receptors as targets for drug research". J Med Chem. 30 (1): 1–12. doi:10.1021/jm00384a001. PMID 3543362. Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
^ Cerletti A, Taeschler M, Weidmann H (1968). Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines. Advances in Pharmacology. Vol. 6. pp. 233–246. doi:10.1016/s1054-3589(08)60322-1. ISBN 978-0-12-032906-9. PMID 5658327.
^ "4-HYDROXYTRYPTAMINE". ChemSpider. 10 June 2024. Retrieved 5 December 2024.
^ ^a ^b ^c ^d Araújo AM, Carvalho F, Bastos Mde L, Guedes de Pinho P, Carvalho M (August 2015). "The hallucinogenic world of tryptamines: an updated review". Arch Toxicol. 89 (8): 1151–1173. Bibcode:2015ArTox..89.1151A. doi:10.1007/s00204-015-1513-x. PMID 25877327.
^ ^a ^b ^c ^d Catalani V, Corkery JM, Guirguis A, Napoletano F, Arillotta D, Zangani C, et al. (August 2021). "Psychonauts' psychedelics: A systematic, multilingual, web-crawling exercise". Eur Neuropsychopharmacol. 49: 69–92. doi:10.1016/j.euroneuro.2021.03.006. PMID 33857740.
^ ^a ^b ^c ^d Malaca S, Lo Faro AF, Tamborra A, Pichini S, Busardò FP, Huestis MA (December 2020). "Toxicology and Analysis of Psychoactive Tryptamines". Int J Mol Sci. 21 (23): 9279. doi:10.3390/ijms21239279. PMC 7730282. PMID 33291798. S2CID 228080489.
^ ^a ^b ^c ^d Shulgin A, Shulgin A (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252.
^ ^a ^b Glatfelter GC, Naeem M, Pham DN, Golen JA, Chadeayne AR, Manke DR, et al. (April 2023). "Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice". ACS Pharmacol Transl Sci. 6 (4): 567–577. doi:10.1021/acsptsci.2c00222. PMC 10111620. PMID 37082754.
^ ^a ^b Kozell LB, Eshleman AJ, Swanson TL, Bloom SH, Wolfrum KM, Schmachtenberg JL, et al. (April 2023). "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. doi:10.1124/jpet.122.001454. PMC 10029822. PMID 36669875.
^ Vane JR (March 1959). "The relative activities of some tryptamine analogues on the isolated rat stomach strip preparation". British Journal of Pharmacology and Chemotherapy. 14 (1): 87–98. doi:10.1111/j.1476-5381.1959.tb00933.x. PMC 1481817. PMID 13651584.
^ Erspamer V, Glasser A, Mantegazzini P (November 1960). "Pharmacological actions of 4-hydroxytryptamine and 4-hydroxytryptophan". Experientia. 16 (11): 505–506. doi:10.1007/BF02158367. PMID 13697285.

[Trout2007-1] Keeper of the Trout and Friends (2007). "4-Hydroxytryptamine". Some Simple Tryptamines (2 ed.). Austin, Texas: Mydriatric Productions. p. 54. ISBN 978-0977087655. OCLC 948674100.

[WieczorekWitkowskaJasicka-Misiak2015-2] Wieczorek PP, Witkowska D, Jasicka-Misiak I, Poliwoda A, Oterman M, Zielińska K (2015). "Bioactive Alkaloids of Hallucinogenic Mushrooms". Studies in Natural Products Chemistry. Vol. 46. Elsevier. pp. 133–168. doi:10.1016/b978-0-444-63462-7.00005-1. ISBN 978-0-444-63462-7. ISSN 1572-5995.

[WurstKysilkaFlieger2002-3] Wurst M, Kysilka R, Flieger M (2002). "Psychoactive tryptamines from basidiomycetes". Folia Microbiologica. 47 (1): 3–27. doi:10.1007/BF02818560. PMID 11980266.

[RakoczyRungeSen2024-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Rakoczy RJ, Runge GN, Sen AK, Sandoval O, Wells HG, Nguyen Q, et al. (October 2024). "Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms". British Journal of Pharmacology. 181 (19): 3627–3641. 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).

[PubChem-5] "4-Hydroxytryptamine". PubChem. Retrieved 5 December 2024.

[LoweToyangSteele2021-6] Lowe H, Toyang N, Steele B, Valentine H, Grant J, Ali A, et al. (May 2021). "The Therapeutic Potential of Psilocybin". Molecules. 26 (10): 2948. doi:10.3390/molecules26102948. PMC 8156539. PMID 34063505.

[SherwoodHalberstadtKlein2020-7] Sherwood AM, Halberstadt AL, Klein AK, McCorvy JD, Kaylo KW, Kargbo RB, et al. (February 2020). "Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin". Journal of Natural Products. 83 (2): 461–467. Bibcode:2020JNAtP..83..461S. doi:10.1021/acs.jnatprod.9b01061. PMID 32077284.

[RepkeLeslieGuzmán1977-8] Repke DB, Leslie DT, Guzmán G (1977). "Baeocystin in psilocybe, conocybe and panaeolus". Lloydia. 40 (6): 566–578. PMID 600026.

[IrvineTylerDelgoda2023-9] Irvine W, Tyler M, Delgoda R (June 2023). "In silico characterization of the psilocybin biosynthesis pathway". Computational Biology and Chemistry. 104: 107854. doi:10.1016/j.compbiolchem.2023.107854. PMID 36990027.{{cite journal}}: CS1 maint: article number as page number (link)

[ChenLiYu2023a-10] Chen X, Li J, Yu L, Maule F, Chang L, Gallant JA, et al. (October 2023). "A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines". J Biol Chem. 299 (10): 105231. doi:10.1016/j.jbc.2023.105231. PMC 10570959. PMID 37690691.{{cite journal}}: CS1 maint: article number as page number (link)

[ChenLiYu2023b-11] Chen X, Li J, Yu L, Dhananjaya D, Maule F, Cook S, et al. (10 March 2023), Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery (PDF), doi:10.21203/rs.3.rs-2667175/v1, retrieved 18 March 2025

[Glennon1987-12] Glennon RA (January 1987). "Central serotonin receptors as targets for drug research". J Med Chem. 30 (1): 1–12. doi:10.1021/jm00384a001. PMID 3543362. Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites

[CerlettiTaeschlerWeidmann1968-13] Cerletti A, Taeschler M, Weidmann H (1968). Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines. Advances in Pharmacology. Vol. 6. pp. 233–246. doi:10.1016/s1054-3589(08)60322-1. ISBN 978-0-12-032906-9. PMID 5658327.

[ChemSpider-14] "4-HYDROXYTRYPTAMINE". ChemSpider. 10 June 2024. Retrieved 5 December 2024.

[AraújoCarvalhoBastos2015-15] Araújo AM, Carvalho F, Bastos Mde L, Guedes de Pinho P, Carvalho M (August 2015). "The hallucinogenic world of tryptamines: an updated review". Arch Toxicol. 89 (8): 1151–1173. Bibcode:2015ArTox..89.1151A. doi:10.1007/s00204-015-1513-x. PMID 25877327.

[CatalaniCorkeryGuirguis2021-16] Catalani V, Corkery JM, Guirguis A, Napoletano F, Arillotta D, Zangani C, et al. (August 2021). "Psychonauts' psychedelics: A systematic, multilingual, web-crawling exercise". Eur Neuropsychopharmacol. 49: 69–92. doi:10.1016/j.euroneuro.2021.03.006. PMID 33857740.

[MalacaLoFaroTamborra2020-17] Malaca S, Lo Faro AF, Tamborra A, Pichini S, Busardò FP, Huestis MA (December 2020). "Toxicology and Analysis of Psychoactive Tryptamines". Int J Mol Sci. 21 (23): 9279. doi:10.3390/ijms21239279. PMC 7730282. PMID 33291798. S2CID 228080489.

[TiHKAL-18] Shulgin A, Shulgin A (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252.

[GlatfelterNaeemPham2023-19] Glatfelter GC, Naeem M, Pham DN, Golen JA, Chadeayne AR, Manke DR, et al. (April 2023). "Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice". ACS Pharmacol Transl Sci. 6 (4): 567–577. doi:10.1021/acsptsci.2c00222. PMC 10111620. PMID 37082754.

[KozellEshlemanSwanson2023-20] Kozell LB, Eshleman AJ, Swanson TL, Bloom SH, Wolfrum KM, Schmachtenberg JL, et al. (April 2023). "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. doi:10.1124/jpet.122.001454. PMC 10029822. PMID 36669875.

[Vane1959-21] Vane JR (March 1959). "The relative activities of some tryptamine analogues on the isolated rat stomach strip preparation". British Journal of Pharmacology and Chemotherapy. 14 (1): 87–98. doi:10.1111/j.1476-5381.1959.tb00933.x. PMC 1481817. PMID 13651584.

[ErspamerGlasserMantegazzini1960-22] Erspamer V, Glasser A, Mantegazzini P (November 1960). "Pharmacological actions of 4-hydroxytryptamine and 4-hydroxytryptophan". Experientia. 16 (11): 505–506. doi:10.1007/BF02158367. PMID 13697285.

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