DOx

Effects

Overview

Substituted dimethoxyamphetamines (also known as DOx) refers to a class of psychedelic amphetamines originally synthesized and documented by Alexander Shulgin in his investigation of psychoactive phenethylamines in the 1970s. Shulgin later published his findings along with other mescaline-derived compounds in his semi-autobiographical book/organic synthesis reference PiHKAL ("Phenethylamines I Have Known and Loved").[1] PW

4-Substituted-2,5-dimethoxyamphetamines (DOx) is a chemical class of substituted amphetamine derivatives featuring methoxy groups at the 2- and 5- positions of the phenyl ring, and a substituent such as alkyl or halogen at the 4- position of the phenyl ring. They are 4-substituted derivatives of 2,5-dimethoxyamphetamine (2,5-DMA, DOH) and are structurally related to the naturally occurring phenethylamine psychedelic mescaline.[2][3] WP

The most well-known DOx drugs are DOM, DOI, DOB, DOET, and DOC. DOI is widely used in scientific research. DOM has been used as a recreational drug, while DOET was an experimental pharmaceutical drug.[3–6] WP

Most compounds of this class are potent and long-lasting psychedelic drugs, and act as selective 5-HT2A, 5-HT2B, and 5-HT2C receptor agonists. A few bulkier derivatives such as DOAM have similarly high affinity for 5-HT₂ receptors but have reduced efficacy and potency as psychedelics.[3][7][8] WP

DOI has been found to have extraordinarily potent anti-inflammatory effects. These properties are not shared by all other related drugs and appear to be mediated by functionally selective serotonin 5-HT2A receptor activation. The anti-inflammatory effects of DOI and related drugs may have medical applications.[9–12] WP

History

History

DOM was the first psychedelic of the DOx series to be discovered. It was first synthesized by Alexander Shulgin at Dow Chemical Company in 1963, who had had his first psychedelic experience, with mescaline (3,4,5-trimethoxyphenethylamine), in 1960. Shulgin personally tried DOM on January 4, 1964 and discovered its psychedelic effects. 2,4,5-Trimethoxyamphetamine (TMA-2; "DOMeO") had been synthesized by Bruckner in 1933, but its psychedelic effects were not described until Shulgin tried the compound and reported its effects in the scientific literature in 1964. Prior to this, 3,4,5-trimethoxyamphetamine (TMA; α-methylmescaline) had been synthesized by Hey in 1947, being found by him to produce euphoria, and was described by Peretz and colleagues in 1955 as clearly producing psychedelic effects.[5][6][14–21] WP

Following his discovery of DOM, Shulgin developed DOET and found that at low doses it was a remarkable "psychic energizer" without producing psychedelic effects at these doses. Dow Chemical Company decided to move forward with clinical trials of DOET as a potential pharmaceutical drug for such purposes. Shulgin and Dow Chemical Company filed a patent for DOET in 1966, although it was not published until 1970. Dow Chemical Company tasked Solomon H. Snyder at Johns Hopkins University with clinically studying DOET.[5][6][22] WP

In April 1967, following the banning of LSD in California in 1966, DOM emerged as a street drug and legal LSD alternative with the name "STP" (allegedly short for "Serenity, Tranquility, and Peace") in the Haight-Ashbury district in San Francisco. This occurred due to DOM being publicly distributed for free in the form of high-dose tablets by LSD distributor Owsley Stanley, who had personally learned of DOM from Shulgin. It is unclear why Shulgin provided information about DOM to Stanley, since doing so had the potential to risk Shulgin's professional career and the DOET clinical studies. One possibility is that Dow Chemical Company was not further looking into DOM and Shulgin thought that it was a promising drug that would otherwise be forgotten. In any case, street use of DOM was short-lived because the tablets caused a public health crisis due to them often producing very long durations (up to 3–4 days), intense experiences, worrying physical side effects, and hospitalizations. DOM was first reported on in the media and scientific literature in 1967 as a result of the crisis. DOM became illegal in the United States in 1968.[6][23][24][25] WP

Dow Chemical Company terminated its clinical research program on DOET due to the DOM public health crisis. DOET was subsequently first described in the literature by Snyder and colleagues in 1968. Snyder continued to be interested in DOET as a potential medicine, but it was never further developed. Snyder also described 2,5-dimethoxyamphetamine (2,5-DMA), which had been synthesized and tested by Shulgin, in the literature in 1968. DOM and DOET were further described in the scientific literature by Shulgin in 1969. In addition, Shulgin discussed DOM, DOET, TMA-2, and 2,5-DMA in a book chapter on hallucinogens published in 1970.[5][6][25–28] WP

The earlier DOx drugs like DOM and DOET were subsequently followed by DOB, which was developed by Shulgin and colleagues like Claudio Naranjo, in 1971, and by DOI, DOC, and a few other analogues, which were developed by another research group, in 1973. After this, numerous other DOx drugs were synthesized and characterized, both by Shulgin and other scientists.[3][5][14][16][29–34] WP

Following its discovery, DOI has become widely used in scientific research in the study of the serotonin 5-HT₂ receptors.[3][5] WP

Legal status

Canada

The DOx drugs are controlled substances as amphetamines in Canada.[35] WP

Pharmacology

Actions

The DOx drugs act as agonists of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. Their psychedelic effects are thought to be mediated specifically by activation of the serotonin 5-HT2A receptor.[3][4][7][8][40][41] WP

In contrast to other amphetamines, DOx drugs like DOC, DOET, and DOM are inactive as monoamine releasing agents and reuptake inhibitors. Some of the DOx drugs, including DOB, DOET, DOI, and DOM, are agonists of the rat, rhesus monkey, and/or human trace amine-associated receptor 1 (TAAR1) with varying potencies.[7][42–45] WP

Pharmacokinetics

The DOx drugs are orally active and many have doses in the range of 1 to 10 mg and durations in the range of 8 to 30 hours. Some DOx drugs, such as DOM and DOB, appear to have durations that increase non-linearly with dose, for instance 8 hours at lower doses and as long as 30 hours or even up to 3 or 4 days at higher doses. This suggests that the pathways mediating the metabolism of these drugs can saturate. The DOx drugs are metabolized primarily by O-demethylation. However, DOM is primarily metabolized by hydroxylation at its methyl group.[3][4][6][32][33][46] WP

Receptor binding · Wikipedia

DOx drugs at the human 5-HT₂ receptors

Every row cites [7][8][36–39]

Chemistry

Pop culture

No references added yet.

References

1. Harm reduction site Erowid Online Books : “PIHKAL” - The Chemical Story
2. Other Daniel Trachsel. Phenethylamine: Von der Struktur zur Funktion. 2013
3. Journal / agency Glennon RA, Dukat M. 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 Pharmacol Transl Sci. June 2024. doi:10.1021/acsptsci.4c00157 · PMID 38898956 · PMC11184610
4. Journal / agency Wills B, Erickson T. Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. 9 March 2012. doi:10.1002/9781118105955.ch10
5. Journal / agency Canal CE, Morgan D. Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Anal. 2012. doi:10.1002/dta.1333 · PMID 22517680 · PMC3722587
6. Journal / agency Baggott, Matthew J. Learning about STP: A Forgotten Psychedelic from the Summer of Love. History of Pharmacy and Pharmaceuticals. 1 October 2023. doi:10.3368/hopp.65.1.93
7. Journal / agency Luethi, Dino; Rudin, Deborah; Hoener, Marius C.; Liechti, Matthias E. Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines. The FASEB Journal. 2022. doi:10.1096/fasebj.2022.36.S1.R2691
8. Journal / agency Ray TS. Psychedelics and the human receptorome. PLOS ONE. February 2010. doi:10.1371/journal.pone.0009019 · PMID 20126400 · PMC2814854
9. Journal / agency Nichols DE, Johnson MW, Nichols CD. Psychedelics as Medicines: An Emerging New Paradigm. Clin Pharmacol Ther. February 2017. doi:10.1002/cpt.557 · PMID 28019026
10. Journal / agency Flanagan TW, Nichols CD. Psychedelics as anti-inflammatory agents. Int Rev Psychiatry. August 2018. doi:10.1080/09540261.2018.1481827 · PMID 30102081
11. Journal / agency Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD. Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency. J Pharmacol Exp Ther. November 2008. doi:10.1124/jpet.108.143461 · PMID 18708586
12. Journal / agency Flanagan TW, Foster TP, Galbato TE, Lum PY, Louie B, Song G, Halberstadt AL, Billac GB, Nichols CD. Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression. ACS Pharmacol Transl Sci. February 2024. doi:10.1021/acsptsci.3c00297 · PMID 38357283 · PMC10863441
13. Harm reduction site Erowid Online Books : “PIHKAL” - #68 DOM
14. Other Shulgin, A.; Manning, T.; Daley, P.F. The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. 2011
15. Other Alexander Theodore Shulgin (1925-2014). 9 June 2014
16. Journal / agency Shulgin, Alexander T. Stimulants. 1978. doi:10.1007/978-1-4757-0510-2_6
17. Journal / agency Bruckner, Viktor. Über das Pseudonitrosit des Asarons. Journal für Praktische Chemie. 24 October 1933. doi:10.1002/prac.19331380907
18. Journal / agency Shulgin AT. Psychotomimetic amphetamines: methoxy 3,4-dialkoxyamphetamines. Experientia. July 1964. doi:10.1007/BF02147960 · PMID 5855670
19. Journal / agency Peretz DI, Smythies JR, Gibson WC. A new hallucinogen: 3,4,5-trimethoxyphenyl-beta-aminopropane with notes on the stroboscopic phenomenon. J Ment Sci. April 1955. doi:10.1192/bjp.101.423.317 · PMID 13243046
20. Journal / agency Shulgin, Alexander T.; Bunnell, Sterling; Sargent, Thornton. The Psychotomimetic Properties of 3,4,5-Trimethoxyamphetamine. Nature. 1961. doi:10.1038/1891011a0
21. Journal / agency Hey P. The synthesis of a new homologue of mescaline. Q J Pharm Pharmacol. 1947. PMID 20260568
22. Other phenethylamines and their pharmacologically-acceptable salts. 1970
23. Journal / agency Trout K, Daley PF. The origin of 2,5-dimethoxy-4-methylamphetamine (DOM, STP). Drug Test Anal. December 2024. doi:10.1002/dta.3667 · PMID 38419183
24. Journal / agency Snyder SH, Faillace L, Hollister L. 2,5-dimethoxy-4-methyl-amphetamine (STP): a new hallucinogenic drug. Science. November 1967. doi:10.1126/science.158.3801.669 · PMID 4860952
25. Journal / agency Snyder SH, Faillace LA, Weingartner H. DOM (STP), a new hallucinogenic drug, and DOET: effects in normal subjects. Am J Psychiatry. September 1968. doi:10.1176/ajp.125.3.357 · PMID 4385937
26. Journal / agency Snyder SH, Richelson E. Psychedelic drugs: steric factors that predict psychotropic activity. Proc Natl Acad Sci U S A. May 1968. doi:10.1073/pnas.60.1.206 · PMID 5241523 · PMC539103
27. Journal / agency Shulgin, Alexander T. Psychotomimetic Agents Related to the Catecholamines. Journal of Psychedelic Drugs. 1969. doi:10.1080/02791072.1969.10524409
28. Harm reduction site Alexander Shulgin. Psychotomimetic Drugs. 1970
29. Journal / agency Shulgin AT, Sargent T, Naranjo C. 4-Bromo-2,5-dimethoxyphenylisopropylamine, a new centrally active amphetamine analog. Pharmacology. 1971. doi:10.1159/000136181 · PMID 5570923
30. Journal / agency Coutts, Ronald T.; Malicky, Jerry L. The Synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM). Canadian Journal of Chemistry. 1 May 1973. doi:10.1139/v73-210
31. Other Nichols DE, Glennon RA. Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. 1984
32. Other Shulgin, A.T.; Shulgin, A. PiHKAL: A Chemical Love Story. 1991
33. Journal / agency Jacob P, Shulgin AT. Structure-activity relationships of the classic hallucinogens and their analogs. NIDA Res Monogr. 1994. PMID 8742795
34. Journal / agency Nichols DE. Chemistry and Structure-Activity Relationships of Psychedelics. 2018. doi:10.1007/7854_2017_475 · PMID 28401524
35. Other Controlled Drugs and Substances Act
36. Journal / agency Nelson DL, Lucaites VL, Wainscott DB, Glennon RA. Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors. Naunyn Schmiedebergs Arch Pharmacol. January 1999. doi:10.1007/pl00005315 · PMID 9933142
37. Journal / agency Hemanth P, Nistala P, Nguyen VT, Eltit JM, Glennon RA, Dukat M. Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors. Front Pharmacol. 2023. doi:10.3389/fphar.2023.1101290 · PMID 36762110 · PMC9902381
38. Journal / agency Rudin, Deborah; Luethi, Dino; Hoener, Marius C.; Liechti, Matthias E. Structure-activity Relation of Halogenated 2,5-Dimethoxyamphetamines Compared to their α-Desmethyl (2C) Analogues. The FASEB Journal. 2022. doi:10.1096/fasebj.2022.36.S1.R2121
39. Journal / agency van Wijngaarden, I.; Soudijn, W. Pharmacochemistry Library. 1997. doi:10.1016/s0165-7208(97)80013-x
40. Other Nichols, D.E.; Nichols, C. D. Handbook of Medical Hallucinogens. 2021
41. Journal / agency Pottie E, Cannaert A, Stove CP. In vitro structure-activity relationship determination of 30 psychedelic new psychoactive substances by means of β-arrestin 2 recruitment to the serotonin 2A receptor. Arch Toxicol. October 2020. doi:10.1007/s00204-020-02836-w · PMID 32627074
42. Journal / agency Eshleman AJ, Forster MJ, Wolfrum KM, Johnson RA, Janowsky A, Gatch MB. Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function. Psychopharmacology (Berl). March 2014. doi:10.1007/s00213-013-3303-6 · PMID 24142203 · PMC3945162
43. Journal / agency Eshleman AJ, Wolfrum KM, Reed JF, Kim SO, Johnson RA, Janowsky A. Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines: High potency agonists at 5-HT2A receptors. Biochem Pharmacol. December 2018. doi:10.1016/j.bcp.2018.09.024 · PMID 30261175 · PMC6298744
44. Journal / agency Lewin AH, Miller GM, Gilmour B. Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class. Bioorg Med Chem. December 2011. doi:10.1016/j.bmc.2011.10.007 · PMID 22037049 · PMC3236098
45. Journal / agency Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. December 2001. doi:10.1124/mol.60.6.1181 · PMID 11723224
46. Journal / agency Ballentine G, Friedman SF, Bzdok D. Trips and neurotransmitters: Discovering principled patterns across 6850 hallucinogenic experiences. Sci Adv. March 2022. doi:10.1126/sciadv.abl6989 · PMID 35294242 · PMC8926331

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