Chemistry:4-HO-MET

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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]

The drug acts as a non-selective serotonin receptor agonist, including of the serotonin 5-HT2A receptor.[2][3][4][5] 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.[6][7][1] It was first described in the literature by David Repke and colleagues in 1981.[8] The drug was encountered as a novel recreational and designer drug by 2008.[9]

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][10][11] However, a wider recreational dosage range of 2 to 45 mg or more, with a dose estimate of 15 mg, has also been reported.[12] 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.[11][6][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][6][11] 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.[6] On the other hand, it is said to still produce strong psychedelic visuals.[6] This has been described as being analogous to the case of 2C-B.[6]

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.[13][14][15]

Interactions

Pharmacology

Pharmacodynamics

4-HO-MET activities
Target Affinity (Ki, nM)
5-HT1A 135–950 (Ki)
1,390 (EC50)
90% (Emax)
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 12,000 (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 200–2,310 (Ki)
830–9,000 (IC50)
IA (EC50)
NET 13,000 (Ki)
11,000 (IC50)
IA (EC50)
DAT >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: [2][3][4][5][16]

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.[2][3][4][5] It is thought that the hallucinogenic effects of serotonergic psychedelics like 4-HO-MET are mediated by serotonin 5-HT2A receptor activation.[17]

Pharmacokinetics

The metabolism of 4-HO-MET has been studied.[18]

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][8]

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.[5]

History

4-HO-MET was first synthesized and discovered by Alexander Shulgin in the 1970s.[6][7][1] It was first described in the scientific literature by David Repke and colleagues by 1981.[8] 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.[9]

Society and culture

Finland

Scheduled in the "government decree on psychoactive substances banned from the consumer market".[19]

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]


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.[20]

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.[21]

It is a schedule I substance in some states, such as South Dakota[22] and West Virginia.[23]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 "#21. 4-HO-MET". Transform Press. September 1997. https://erowid.org/chemicals/4_ho_met/4_ho_met.shtml. 
  2. ↑ 2.0 2.1 2.2 "Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens". European Neuropsychopharmacology 26 (8): 1327–1337. August 2016. doi:10.1016/j.euroneuro.2016.05.001. PMID 27216487. https://psilosybiini.info/paperit/Receptor%20interaction%20profiles%20of%20novel%20psychoactive%20tryptamines%20compared%20with%20classic%20hallucinogens%20(Rickli%20et%20al.,%202016).pdf. 
  3. ↑ 3.0 3.1 3.2 "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. 
  4. ↑ 4.0 4.1 4.2 "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. 
  5. ↑ 5.0 5.1 5.2 5.3 "Investigation of the Structure-Activity Relationships of Psilocybin Analogues". ACS Pharmacol Transl Sci 4 (2): 533–542. April 2021. doi:10.1021/acsptsci.0c00176. PMID 33860183. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 "A qualitative descriptive analysis of effects of psychedelic phenethylamines and tryptamines". Human Psychopharmacology 35 (1). January 2020. doi:10.1002/hup.2719. PMID 31909513. 
  7. ↑ 7.0 7.1 "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. 2018. doi:10.3389/fnint.2018.00054. 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).". 
  8. ↑ 8.0 8.1 8.2 "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. 1981. doi:10.1002/jhet.5570180131. ISSN 0022-152X. 
  9. ↑ 9.0 9.1 "2015 Annual Reports on the implementation of Council Decision 2005/387/JHA". 2008. https://www.europol.europa.eu/publications-events/publications/emcdda%E2%80%93europol-2005-2015-annual-reports-implementation-of-council-decision-2005/387/jha. 
  10. ↑ "Basic Pharmacology and Effects". Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. 2003. pp. 67–137. ISBN 978-0-12-433951-4. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6. 
  11. ↑ 11.0 11.1 11.2 "Heaven and hell--a phenomenological study of recreational use of 4-HO-MET in Sweden". J Psychoactive Drugs 43 (3): 211–219. 2011. doi:10.1080/02791072.2011.605699. PMID 22111404. 
  12. ↑ "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. October 2018. doi:10.1093/ijnp/pyy047. PMID 29850881. 
  13. ↑ "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. 23 June 2023. https://2023.psychedelicscience.org/sessions/beyond-ecstasy-progress-in-developing-and-understanding-a-novel-class-of-therapeutic-medicine/. 
  14. ↑ 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.
  15. ↑ "Borax Combo (Synonyms: Blue Bliss)". National Association of Drug Diversion Investigators (NADDI). 14 December 2022. https://www.naddi.org/glossary/borax-combo/. 
  16. ↑ "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther 357 (1): 134–144. April 2016. doi:10.1124/jpet.115.229765. PMID 26791601. https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA. 
  17. ↑ "Psychedelics". Pharmacol Rev 68 (2): 264–355. April 2016. doi:10.1124/pr.115.011478. PMID 26841800. PMC 4813425. https://psilosybiini.info/paperit/Psychedelics%20(Nichols,%202016).pdf. 
  18. ↑ "Study of the in vitro and in vivo metabolism of 4-HO-MET". Forensic Sci Int 290: 103–110. September 2018. doi:10.1016/j.forsciint.2018.06.037. PMID 30015274. 
  19. ↑ "Valtioneuvoston asetus kuluttajamarkkinoilta kielletyistä psykoaktiivisista aineista" (in Finnish). Finlex. Finish Ministry of Justice. https://finlex.fi/fi/lainsaadanto/2014/1130. 
  20. ↑ "Föreskrifter om ändring i Läkemedelsverkets föreskrifter (LVFS 2011:10) om förteckningar över narkotika" (in sv). Elanders Sverige AB. 2012-04-20. http://www.lakemedelsverket.se/upload/lvfs/LVFS_2012_6.pdf. 
  21. ↑ "21 U.S. Code § 841 - Prohibited acts A". https://www.law.cornell.edu/uscode/text/21/841. 
  22. ↑ "Chapter 34-20B Drugs and Substances Control" (in en). https://sdlegislature.gov/Statutes/34-20B. 
  23. ↑ "Chapter 60A. Uniform Controlled Substances Act". https://code.wvlegislature.gov/60A-2-204/. 

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