Chemistry:6-MeO-DMT

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6-MeO-DMT, or 6-methoxy-N,N-dimethyltryptamine, also known as 6-OMe-DMT, is a serotonergic drug of the tryptamine family.[1][2][3] It is the 6-methoxy derivative of the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and is a positional isomer of the psychedelic 5-MeO-DMT.[3][4]

Use and effects

6-MeO-DMT was only briefly mentioned in Alexander Shulgin's book TiHKAL (Tryptamines I Have Known and Loved) and its properties and effects were not described.[5]

Pharmacology

Pharmacodynamics

Similarly to analogues like DMT and 5-MeO-DMT, 6-MeO-DMT acts as a serotonin 5-HT2A receptor agonist as well as a non-selective agonist of many other serotonin receptors.[1][2][6][3] However, in contrast to these agents, but similarly to certain other serotonin 5-HT2A receptor agonists like 6-fluoro-DET, 2-bromo-LSD, lisuride, 25N-N1-Nap, and tabernanthalog, 6-MeO-DMT does not produce the head-twitch response (HTR) or other psychedelic-like effects in animals and hence appears to be non-hallucinogenic.[1][2][7][6] Similarly, 6-MeO-DMT failed to substitute for DOM in rodent drug discrimination tests.[8] On the other hand, it did substitute for the atypical psychedelic 5-MeO-DMT in rodent drug discrimination tests, with about 4-fold lower potency than 5-MeO-DMT.[9] 6-MeO-DMT has yet to be tested in humans.[10][2]

In addition to its apparent lack of hallucinogenicity, 6-MeO-DMT shows dramatically reduced potency as an agonist of all of the serotonin receptors compared to 5-MeO-DMT.[6] Its affinity for the serotonin 5-HT2A receptor was 12- to 43-fold lower than that of 5-MeO-DMT and was 6-fold lower than that of DMT and its affinity for the serotonin 5-HT1A receptor was 110-fold lower relative to 5-MeO-DMT.[3][1][11]

Chemistry

Analogues

Analogues of 6-MeO-DMT include dimethyltryptamine (DMT), 6-methoxytryptamine (6-MT or 6-MeO-T), 6-hydroxy-DMT (6-HO-DMT), 6-methyl-DMT, 6-fluoro-DMT, 4-MeO-DMT, 5-MeO-DMT, and 7-MeO-DMT, among others. Some further analogues include the isotryptamines 5-MeO-isoDMT, 6-MeO-isoDMT, and zalsupindole ((R)-5-MeO-α-Me-isoDMT).

History

6-MeO-DMT was first described in the scientific literature by 1968.[12][13][14] It was specifically assessed in a structure–activity relationship (SAR) animal study of serotonergic tryptamines.[12][13] The drug's lack of hallucinogen-like effects in animals was first described by at least 1983.[8]

Society and culture

United States

6-MeO-DMT is not an explicitly controlled substance in the United States, but may be considered a Schedule I controlled substance in this country as it is a positional isomer of 5-MeO-DMT.[15][16]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chemical Reviews 124 (1): 124–163. January 2024. doi:10.1021/acs.chemrev.3c00375. PMID 38033123. "Nevertheless, substitutions at positions 6 or 7 were reported to reduce or even abolish the binding ability to 5-HT2 receptors. For example, 6-OMe-DMT (35, Ki = 7300 nM) and 7-OMe-DMT (36, Ki = 5400 nM) exhibited reduced affinity compared to that of DMT (Ki = 1200 nM) at [3H]-ketanserin-labeled 5-HT2Rs.124". 
  2. ↑ 2.0 2.1 2.2 2.3 "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nature Communications 14 (1): 8221. December 2023. doi:10.1038/s41467-023-44016-1. PMID 38102107. Bibcode: 2023NatCo..14.8221W. 
  3. ↑ 3.0 3.1 3.2 3.3 "Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors". Drug Alcohol Depend 60 (2): 121–132. August 2000. doi:10.1016/s0376-8716(99)00148-9. PMID 10940539. 
  4. ↑ "2-(6-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/12017579. 
  5. ↑ 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. 
  6. ↑ 6.0 6.1 6.2 "A non-hallucinogenic psychedelic analogue with therapeutic potential". Nature 589 (7842): 474–479. January 2021. doi:10.1038/s41586-020-3008-z. PMID 33299186. Bibcode: 2021Natur.589..474C. "Extended Data Fig. 5: Pharmacological profiles of ibogalogs and related compounds. [...]". 
  7. ↑ "Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies". Journal of Medicinal Chemistry 63 (3): 1142–1155. February 2020. doi:10.1021/acs.jmedchem.9b01404. PMID 31977208. 
  8. ↑ 8.0 8.1 "DOM-stimulus generalization to LSD and other hallucinogenic indolealkylamines". Eur J Pharmacol 86 (3-4): 453–459. January 1983. doi:10.1016/0014-2999(83)90196-6. PMID 6572591. 
  9. ↑ "Hallucinogenic agents as discriminative stimuli: a correlation with serotonin receptor affinities". Psychopharmacology (Berl) 68 (2): 155–158. 1980. doi:10.1007/BF00432133. PMID 6776558. 
  10. ↑ "1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review". ACS Pharmacology & Translational Science 7 (6): 1722–1745. June 2024. doi:10.1021/acsptsci.4c00157. PMID 38898956. 
  11. ↑ "Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens". Eur J Pharmacol 145 (3): 291–297. January 1988. doi:10.1016/0014-2999(88)90432-3. PMID 3350047. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=cabb8bfdccd28f358a469865fe8f08afe29d7086. 
  12. ↑ 12.0 12.1 "Hallucinogens". Psychopharmacology of Aversively Motivated Behavior. Boston, MA: Springer US. 1978. pp. 345–383. doi:10.1007/978-1-4684-2394-5_6. ISBN 978-1-4684-2396-9. 
  13. ↑ 13.0 13.1 "Structure-activity relationships among 5-methoxy-n:n-dimethyltryptamine, 4-hydroxy-n:n-dimethyltryptamine (psilocin) and other substituted tryptamines". Life Sciences 7 (5): 267–277. March 1968. doi:10.1016/0024-3205(68)90200-2. PMID 5641719. 
  14. ↑ "Fate and metabolism of some hallucinogenic indolealkylamines". Pharmacology, Behavior, and Clinical Aspects, Proceedings of a Symposium held at the College of Physicians and Surgeons, Columbia University, New York. Advances in Pharmacology. 6. 1968. pp. 213–229. doi:10.1016/s1054-3589(08)60320-8. ISBN 978-0-12-032906-9. 
  15. ↑ Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026), United States: U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division, January 2026, https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf 
  16. ↑ Drug Enforcement Administration (3 December 2007). "Definition of “Positional Isomer” as It Pertains to the Control of Schedule I Controlled Substances". https://www.federalregister.gov/documents/2007/12/03/E7-23413/definition-of-positional-isomer-as-it-pertains-to-the-control-of-schedule-i-controlled-substances. 



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