4-HO-MET

Last updated

4-HO-MET
4-HO-MET.svg
4-HO-MET 3D.png
Clinical data
Other names4-OH-MET; 4-Hydroxy-N-methyl-N-ethyltryptamine; Metocin; Methylcybin
Routes of
administration 		Oral [1]
Drug class Non-selective serotonin receptor agonist; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Legal status
Legal status
  • US:Unscheduled
Schedule I controlled substance in Virginia [2]
Pharmacokinetic data
Onset of action ≤30 minutes [1]
Duration of action 4–6 hours [1] [3]
Identifiers
  • 3-{2-[Ethyl(methyl)amino]ethyl}-1H-indol-4-ol
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C13H18N2O
Molar mass 218.300 g·mol−1
3D model (JSmol)
  • CCN(C)CCc2c[nH]c1cccc(O)c12
  • InChI=1S/C13H18N2O/c1-3-15(2)8-7-10-9-14-11-5-4-6-12(16)13(10)11/h4-6,9,14,16H,3,7-8H2,1-2H3
  • Key:ORWQBKPSGDRPPA-UHFFFAOYSA-N

4-HO-MET, also known as 4-hydroxy-N-methyl-N-ethyltryptamine, as well as metocin or methylcybin, is a psychedelic drug of the tryptamine and 4-hydroxytryptamine families related to psilocin (4-HO-DMT). [1] It is taken orally. [1]

Contents

The drug acts as a non-selective serotonin receptor agonist, including of the serotonin 5-HT2A receptor. [4] [5] [6] [7] It is a close structural analogue of psilocin (4-HO-DMT) and is the 4-hydroxyl analogue of methylethyltryptamine (MET). [1]

4-HO-MET was discovered by Alexander Shulgin in the 1970s. [8] [9] [1] It was first described in the literature by David Repke and colleagues in 1981. [10] The drug was encountered as a novel recreational and designer drug by 2008. [11]

Use and effects

In his book TiHKAL (Tryptamines I Have Known and Loved), Alexander Shulgin lists the dose range as 10 to 20 mg orally and its duration as 4 to 6 hours. [1] [12] [3] However, a wider recreational dosage range of 2 to 45 mg or more, with a dose estimate of 15 mg, has also been reported. [13] Its onset is within 30 minutes. [1]

The effects of 4-HO-MET have been reported to include pupil dilation, euphoria, tingling sensations, perceptual changes, closed- and open-eye visuals, synesthesia, time dilation, intensified perceptions, thoughts, and feelings, and a general change in thought processes. [3] [8] [1] Other specific effects include alteration of color and form, feeling sounds, and a wave-like experience with alternation between near-normal perception one moment and a "swirl of altered concept" the next moment. [1]

4-HO-MET is said to produce qualitative effects very similar to those of psilocin. [1] [8] [3] Shulgin has stated that he doubts it could be distinguished from psilocin in any blinded clinical study. [1] However, the drug has also been described as being relatively or very light, more clear-headed and functional, and having less head space. [8] On the other hand, it is said to still produce strong psychedelic visuals. [8] This has been described as being analogous to the case of 2C-B. [8]

In addition to its use on its own, 4-HO-MET, along with the related tryptamine psychedelic 5-MeO-MiPT, is employed as a component of the MDMA-mimicking Borax combo. [14] [15] [16]

Interactions

Pharmacology

Pharmacodynamics

4-HO-MET activities
Target Affinity (Ki, nM)
5-HT1A 135–950 (Ki)
1,390 (EC50 Tooltip half-maximal effective concentration)
90% (Emax Tooltip maximal efficacy)
5-HT1B 331
5-HT1D 197
5-HT1E 161
5-HT1F ND
5-HT2A 4.0–177 (Ki)
18–97 (EC50)
54–95% (Emax)
5-HT2B 12 (Ki)
2.64–>20,000 (EC50)
44–71% (Emax)
5-HT2C 141–164 (Ki)
30–113 (EC50)
87–101% (Emax)
5-HT3 ND
5-HT4 ND
5-HT5A 304
5-HT6 70
5-HT7 60
α1A 9,700
α1B, α1D ND
α2A 1,666–2,400
α2B, α2C IA
β1–β3 ND
β2 ND
D1 25,000
D2 4,000
D3 6,700
D4, D5 IA
H1 483–820
H2 IA
H3, H4 ND
M1–M3, M5 ND
M2 IA
I1 ND
σ1, σ2 IA
TAAR1 Tooltip Trace amine-associated receptor 112,000 (Ki) (mouse)
3,100 (Ki) (rat)
2,500 (EC50) (mouse)
2,100 (EC50) (rat)
>10,000 (EC50) (human)
78% (Emax) (mouse)
71% (Emax) (rat)
SERT Tooltip Serotonin transporter200–2,310 (Ki)
830–9,000 (IC50 Tooltip half-maximal inhibitory concentration)
IA (EC50)
NET Tooltip Norepinephrine transporter13,000 (Ki)
11,000 (IC50)
IA (EC50)
DAT Tooltip Dopamine transporter>26,000 (Ki)
>100,000 (IC50)
IA (EC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [4] [5] [6] [7] [17]

4-HO-MET binds to various serotonin receptors and is known to act as an agonist of the serotonin 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors. [4] [5] [6] [7] It is thought that the hallucinogenic effects of serotonergic psychedelics like 4-HO-MET are mediated by serotonin 5-HT2A receptor activation. [18]

Pharmacokinetics

The metabolism of 4-HO-MET has been studied. [19]

Chemistry

4-HO-MET, also known as 4-hydroxy-N-methyl-N-ethyltryptamine, is a substituted tryptamine and 4-hydroxytryptamine. [1] It is the 4-hydroxy derivative of N-methyl-N-ethyltryptamine (MET) and is a close analogue of psilocin (4-hydroxy-N,N-dimethyltryptamine; 4-HO-DMT). [1]

Synthesis

The chemical synthesis of 4-HO-MET has been described. [1] [10]

Analogues

Analogues of 4-HO-MET include psilocin (4-HO-DMT), 4-HO-DET (ethocin), 4-HO-MiPT (miprocin), 4-HO-DPT (deprocin), 4-HO-MPT (meprocin), 4-HO-DALT (dalocin), and 4-HO-MALT (malocin), among others. [1] 4-AcO-MET (metacetin) is an ester prodrug of 4-HO-MET. [7]

History

4-HO-MET was first synthesized and discovered by Alexander Shulgin in the 1970s. [8] [9] [1] It was first described in the scientific literature by David Repke and colleagues by 1981. [10] Subsequently, 4-HO-MET was described by Shulgin in his book TiHKAL (Tryptamines I Have Known and Loved) in 1997. [1] It was encountered as a novel recreational and designer drug in Europe by 2008. [11]

Society and culture

Finland

Scheduled in the "government decree on psychoactive substances banned from the consumer market". [20]

Germany

4-HO-MET is ruled under the Neue-psychoaktive-Stoffe-Gesetz (NpSG) since July 18, 2019. Production and Import with intent to distribute is punishable. Possession is forbidden but not punishable, although ordering it in small quantities can still be seen as an intent to distribute it and be punished.[ citation needed ]

4-Propionoxy-N-methyl-N-ethyltryptamine (also referred to as 4-PrO-MET) is the ester prodrug of 4-HO-MET. Unlike many other tryptamine derivatives, it is currently not explicitly listed under the German Neue-psychoaktive-Stoffe-Gesetz (NpSG). This means that, while its use as a recreational substance is not legally permitted, the compound may be obtained and handled for legitimate research purposes, provided all other relevant legal requirements and safety regulations are observed.[ citation needed ]

Sweden

The Swedish Riksdag added 4-HO-MET to Schedule I ("substances, plant materials and fungi which normally do not have medical use") as narcotics in Sweden as of May 1, 2012, published by Medical Products Agency in their regulation LVFS 2012:6. [21]

United Kingdom

4-HO-MET is a class A drug in the United Kingdom, as a result of the tryptamine catch-all clause.[ citation needed ]

United States

4-HO-MET is not scheduled at the federal level in the United States, but it is possible that it could be considered an analogue of psilocin, in which case purchase, sale, or possession could be prosecuted under the Federal Analogue Act. [22]

It is a schedule I substance in some states, such as South Dakota [23] and West Virginia. [24]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Shulgin A, Shulgin A (September 1997). "#21. 4-HO-MET". Isomer Design. Transform Press. Retrieved 28 November 2023.
  2. ↑ "§ 54.1-3446. Schedule I." Virginia Law. Retrieved 29 October 2023.
  3. 1 2 3 4 Kjellgren A, Soussan C (2011). "Heaven and hell--a phenomenological study of recreational use of 4-HO-MET in Sweden". J Psychoactive Drugs. 43 (3): 211–219. doi:10.1080/02791072.2011.605699. PMID   22111404.
  4. 1 2 3 Rickli A, Moning OD, Hoener MC, Liechti ME (August 2016). "Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens" (PDF). European Neuropsychopharmacology. 26 (8): 1327–1337. doi:10.1016/j.euroneuro.2016.05.001. PMID   27216487. S2CID   6685927.
  5. 1 2 3 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.
  6. 1 2 3 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.
  7. 1 2 3 4 Klein AK, Chatha M, Laskowski LJ, Anderson EI, Brandt SD, Chapman SJ, et al. (April 2021). "Investigation of the Structure-Activity Relationships of Psilocybin Analogues". ACS Pharmacol Transl Sci. 4 (2): 533–542. doi:10.1021/acsptsci.0c00176. PMC   8033608 . PMID   33860183.
  8. 1 2 3 4 5 6 7 Palamar JJ, Acosta P (January 2020). "A qualitative descriptive analysis of effects of psychedelic phenethylamines and tryptamines". Human Psychopharmacology. 35 (1) e2719. doi:10.1002/hup.2719. PMC   6995261 . PMID   31909513.
  9. 1 2 Zamberlan F, Sanz C, Martínez Vivot R, Pallavicini C, Erowid F, Erowid E, et al. (2018). "The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines". Front Integr Neurosci. 12 54. doi: 10.3389/fnint.2018.00054 . PMC   6235949 . PMID   30467466. 4-OH-MET (4-Hydroxy-N-methyl-N-ethyltryptamine): substituted tryptamine and close analog of psilocin, first synthesized by A. Shulgin (Shulgin and Shulgin, 1997).
  10. 1 2 3 Repke DB, Ferguson WJ, Bates DK (1981). "Psilocin analogs II. Synthesis of 3-[2-(dialkylamino)ethyl]-, 3-[2-( N -methyl- N -alkylamino)ethyl]-, and 3-[2-(cycloalkylamino)ethyl]indol-4-ols". Journal of Heterocyclic Chemistry. 18 (1): 175–179. doi:10.1002/jhet.5570180131. ISSN   0022-152X.
  11. 1 2 "2015 Annual Reports on the implementation of Council Decision 2005/387/JHA". Europol. 2008. Retrieved 30 March 2025.
  12. ↑ Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN   978-0-12-433951-4.
  13. ↑ Luethi D, Liechti ME (October 2018). "Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics". Int J Neuropsychopharmacol. 21 (10): 926–931. doi:10.1093/ijnp/pyy047. PMC   6165951 . PMID   29850881.
  14. ↑ Baggott M (23 June 2023). Beyond Ecstasy: Progress in Developing and Understanding a Novel Class of Therapeutic Medicine. PS2023 [Psychedelic Science 2023, June 19–23, 2023, Denver, Colorado]. Denver, CO: Multidisciplinary Association for Psychedelic Studies.
  15. ↑ Hamilton Morris (28 November 2023). "POD 92: Understanding and Improving MDMA with Dr. Matthew Baggott". The Hamilton Morris Podcast (Podcast). Patreon. Retrieved 30 November 2024.
  16. ↑ "Borax Combo (Synonyms: Blue Bliss)". naddi.org. National Association of Drug Diversion Investigators (NADDI). 14 December 2022. Retrieved 21 November 2024.
  17. ↑ Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1" (PDF). J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID   26791601. Archived from the original (PDF) on 9 May 2025.
  18. ↑ Nichols DE (April 2016). "Psychedelics" (PDF). Pharmacol Rev. 68 (2): 264–355. doi:10.1124/pr.115.011478. PMC   4813425 . PMID   26841800.
  19. ↑ Bruni PS, Grafinger KE, Nussbaumer S, König S, Schürch S, Weinmann W (September 2018). "Study of the in vitro and in vivo metabolism of 4-HO-MET". Forensic Sci Int. 290: 103–110. doi:10.1016/j.forsciint.2018.06.037. PMID   30015274.
  20. ↑ "Valtioneuvoston asetus kuluttajamarkkinoilta kielletyistä psykoaktiivisista aineista" [Government Decree on psychoactive substances banned from the consumer market]. Finlex (in Finnish). Finish Ministry of Justice.
  21. ↑ "Föreskrifter om ändring i Läkemedelsverkets föreskrifter (LVFS 2011:10) om förteckningar över narkotika" [Regulations on changes in the Swedish Medicines Agency's regulations (LVFS 2011:10) on lists of narcotics](PDF) (in Swedish). Elanders Sverige AB. 2012-04-20. Archived from the original (PDF) on 2013-09-28. Retrieved 2014-02-25.
  22. ↑ "21 U.S. Code § 841 - Prohibited acts A", LII / Legal Information Institute, retrieved 2016-08-02
  23. ↑ "Chapter 34-20B Drugs and Substances Control". South Dakota Legislature. Retrieved 2023-10-09.
  24. ↑ "Chapter 60A. Uniform Controlled Substances Act". West Dakota Legislature. Retrieved 2023-10-09.
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