Chemistry:4-MeO-DMT

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4-MeO-DMT, or 4-methoxy-DMT, also known as 4-methoxy-N,N-dimethyltryptamine or as O-methylpsilocin (PSOM), is a serotonin receptor modulator and possible psychedelic drug of the tryptamine and 4-hydroxytryptamine families.[1][2][3][4][5] It is the O-methylated analogue of psilocin (4-HO-DMT) and a positional isomer of 5-MeO-DMT.[1][5]

Use and effects

According to Alexander Shulgin in his book TiHKAL (Tryptamines I Have Known and Loved), 4-MeO-DMT is not known to have been tested in humans.[6] However, the N,N-diethyl analogue 4-MeO-DET has been tested in humans and was found to be completely inactive at doses of up to 30 mg orally or smoked.[6]

Interactions

Pharmacology

Pharmacodynamics

4-MeO-DMT activities
Target Affinity (Ki, nM)
5-HT1A 235
5-HT2A 68–1,300
5-HT2C 340
Notes: The smaller the value, the more avidly the drug interacts with the site. Sources:[7][8]

4-MeO-DMT has shown high affinity for several serotonin receptors, including the serotonin 5-HT1A receptor (Ki = 235 nM), the serotonin 5-HT2A receptor (Ki = 68–1,300 nM), and the serotonin 5-HT2C receptor (Ki = 340 nM).[7][8] Compared to 5-MeO-DMT, 4-MeO-DMT had similar affinity for the serotonin 5-HT2A receptor, but showed much lower affinity (21-fold) for the serotonin 5-HT1A receptor.[7][8] The drug shows pronounced biased agonism at the serotonin 5-HT2C receptor.[9]

4-MeO-DMT produces serotonergic psychedelic-like effects in animals, including rodents and monkeys.[1][2][3][4][5] It has been found to disrupt object size discrimination performance in monkeys, suggesting that it may have psychedelic effects in humans.[1][10] However, whereas 5-MeO-DMT has greater potency than bufotenin (5-HO-DMT), 4-MeO-DMT has lower potency than psilocybin (4-PO-DMT).[1] This may be due to the fact that the lipophilicity of psilocin is not importantly enhanced by O-methylation, in contrast to the case of bufotenin, which has associated limitations in terms of blood–brain barrier permeability.[1] Besides psilocin/psilocybin, 4-MeO-DMT is also less potent than 5-MeO-DMT.[2]

4-MeO-DMT fully substituted for DOM in rodent drug discrimination tests, with an ED50 of about 3.53 mg/kg and about 3-fold lower potency than 5-MeO-DMT.[11] 4-MeO-DMT also substituted for 5-MeO-DMT in rodent drug discrimination tests, with an ED50 of 3.47 μmol/kg and about 2.7-fold lower potency than 5-MeO-DMT.[12]

Chemistry

Analogues

Analogues of 4-MeO-DMT include dimethyltryptamine (DMT), 4-methoxytryptamine (4-MT or 4-MeO-T), psilocin (4-HO-DMT), 4-AcO-DMT (psilacetin), 4-MeO-DET, 4-MeO-DiPT, 4-MeO-MiPT, 4-methyl-DMT, 5-MeO-DMT, 6-MeO-DMT, and 7-MeO-DMT, among others.[6]

History

4-MeO-DMT was first described in the scientific literature by at least 1968.[1][13]

Society and culture

Canada

4-MeO-DMT is not a controlled substance in Canada.[14]

United States

In the United States, 4-MeO-DMT is a Schedule I controlled substance as it is a positional isomer of 5-MeO-DMT.[15][16]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Indolealkylamines and Related Compounds". Hallucinogenic Agents. Bristol: Wright-Scientechnica. 1975. pp. 98–144. ISBN 978-0-85608-011-1. OCLC 2176880. https://bitnest.netfirms.com/external/Books/978-0-85608-011-1. "In contrast to the pronounced enhancement of hallucinogenic activity associated with methylation of the 5-hydroxyl group of bufotenin, 4-methoxy-N,N-dimethyltryptamine (4.26) is less potent than psilocybin. The respective ED50 values (µmoles/kg., i.p.) for disrupting size-discrimination performance in monkeys and swimming ability in rodents are 18·9 and 2·9 (Uyeno, 1969) and 20·1 and 8·7 (Uyeno, 1971). Perhaps these results reflect the differing lipid solubilities of the compounds, because bufotenin, 5-MeO-DMT, psilocin, and compound 4.26 have respective chloroform-water partition coefficients of 0·06, 3·30, 5·52, and 2·28 (Gessner and others, 1968). Clearly, little advantage in physico-chemical characteristics is gained by methylation of the 4-hydroxy group of psilocin compared to the 5-hydroxy group of bufotenin." 
  2. ↑ 2.0 2.1 2.2 "Hallucinogens as discriminative stimuli: a comparison of 4-OMe DMT and 5-OMe DMT with their methythio counterparts". Life Sciences 30 (5): 465–7. February 1982. doi:10.1016/0024-3205(82)90463-5. PMID 6801410. 
  3. ↑ 3.0 3.1 "Structure-activity relationships in potentially hallucinogenic N,N-dialkyltryptamines substituted in the benzene moiety". Journal of Medicinal Chemistry 25 (8): 908–13. August 1982. doi:10.1021/jm00350a005. PMID 7120280. 
  4. ↑ 4.0 4.1 "Structure-activity relationships for hallucinogenic N,N-dialkyltryptamines: photoelectron spectra and serotonin receptor affinities of methylthio and methylenedioxy derivatives". Journal of Medicinal Chemistry 25 (11): 1381–3. November 1982. doi:10.1021/jm00353a021. PMID 6815326. 
  5. ↑ 5.0 5.1 5.2 "Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. 1984. pp. 95–142. ISBN 978-0-89004-990-7. OCLC 10324237. https://bitnest.netfirms.com/external/Books/HallucinogensNBCP95. 
  6. ↑ 6.0 6.1 6.2 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.  "The 4-methyl ether of psilocin, 4-MeO-DMT, is especially appealing, in that it is a simple homologue of psilocin and it is quite stable. But the methyl group as an ether link lacks the lability of the phosphate or acetate esters, and it cannot be easily hydrolyzed off to form psilocin. The immediate homologue is 4-MeO-DET which is completely without action either orally or by smoking at dosages up to 30 mgs. [...] The 5-MeO-DMT has already been mentioned, and the remaining two would be 4-MeO-DMT and 4-MeO-DIPT. The former is a known compound but has not been measured in man. The latter is not a known compound."
  7. ↑ 7.0 7.1 7.2 "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. 
  8. ↑ 8.0 8.1 8.2 "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. 
  9. ↑ "Serotonin 5-HT2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism". ACS Chem Neurosci 16 (19): 3899–3914. October 2025. doi:10.1021/acschemneuro.5c00647. PMID 40944639. 
  10. ↑ "Alteration of a learned response of the squirrel monkey by hallucinogens". Int J Neuropharmacol 8 (3): 245–253. May 1969. doi:10.1016/0028-3908(69)90045-8. PMID 4978723. 
  11. ↑ "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. 
  12. ↑ "Hallucinogenic agents as discriminative stimuli: a correlation with serotonin receptor affinities". Psychopharmacology (Berl) 68 (2): 155–158. 1980. doi:10.1007/BF00432133. PMID 6776558. 
  13. ↑ "Structure-activity relationships among 5-methoxy-n:n-dimethyltryptamine, 4-hydroxy-n:n-dimethyltryptamine (psilocin) and other substituted tryptamines". Life Sci 7 (5): 267–277. March 1968. doi:10.1016/0024-3205(68)90200-2. PMID 5641719. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=b45d79b71663e4451de894d16a1c868141dfeaaf. 
  14. ↑ "Controlled Drugs and Substances Act". 5 December 2025. https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html. 
  15. ↑ "Lists of Scheduling Actions Controlled Substances Regulated Chemical". 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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