DOx

For other uses, see Dox.

2,5-Dimethoxyamphetamine (2,5-DMA), the base chemical structure of the DOx family.

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. ^{[1] [2]} They are 4-substituted derivatives of 2,5-dimethoxyamphetamine (2,5-DMA, DOH) and are structurally related to the naturally occurring phenethylamine psychedelic mescaline.

The most well-known DOx drugs are DOM, DOI, DOB, DOET, and DOC. ^[3] DOI is widely used in scientific research. ^{[2] [4]} DOM has been used as a recreational drug, while DOET was an experimental pharmaceutical drug. ^[5]

Most compounds of this class are potent and long-lasting psychedelic drugs, and act as selective 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor agonists. ^{[6] [7]} A few bulkier derivatives such as DOAM have similarly high affinity for 5-HT₂ receptors but have reduced activational efficacy and do not produce psychedelic effects. ^{[2] [6]}

DOI has been found to have extraordinarily potent anti-inflammatory effects. ^{[8] [9] [10]} These properties are not shared by all other related drugs and appear to be mediated by functionally selective serotonin 5-HT_2A receptor activation. ^{[9] [11]} The anti-inflammatory effects of DOI and related drugs may have medical applications. ^{[8] [9]}

Side effects

DOx drugs like DOM have been associated with certain side effects that have not occurred to the same extent with other psychedelics like LSD. ^[5] Examples of such side effects include physical symptoms like sweating, tremors, and large increases in heart rate. ^[5]

Pharmacology

Pharmacodynamics

Actions

DOx drugs at the human 5-HT₂ receptors

Compound	Affinity (Ki, nM)
	5-HT2A	5-HT2B	5-HT2C
2,5-DMA Tooltip 2,5-Dimethoxyamphetamine	211–2,502	1,039	104–>5,070
DOM Tooltip 2,5-Dimethoxy-4-methylamphetamine	88–507.4	11.7	404–3,980
DOET Tooltip 2,5-Dimethoxy-4-ethylamphetamine	12–100	28.8	107.2–108
DOPR Tooltip 2,5-Dimethoxy-4-n-propylamphetamine	0.9	54.4	1.1
DOBU Tooltip 2,5-Dimethoxy-4-n-butylamphetamine	5.4	ND	60
DOTB Tooltip 2,5-Dimethoxy-4-t-butylamphetamine	3.7	24.6	2.2
DOAM Tooltip 2,5-Dimethoxy-4-amylamphetamine	3.5	ND	75
DOHx Tooltip 2,5-Dimethoxy-4-n-hexylamphetamine	0.1	30.3	0.7
DOF Tooltip 2,5-Dimethoxy-4-fluoroamphetamine	41.7	227	28.7
DOC Tooltip 2,5-Dimethoxy-4-chloroamphetamine	1.4	31.8	2.0
DOB Tooltip 2,5-Dimethoxy-4-bromoamphetamine	0.6–41	26.9	1.3–60
DOI Tooltip 2,5-Dimethoxy-4-iodoamphetamine	0.7–165.4	20.0–335.9	2.4–45.8
TMA-2 Tooltip 2,4,5-Trimethoxyamphetamine	57.9–584.2	154.4–307	87.7–4,062
MEM Tooltip 2,5-Dimethoxy-4-ethoxyamphetamine	73.0–3,948	64.5–763	124–>10,000
Aleph-2 Tooltip 2,5-Dimethoxy-4-ethylthioamphetamine	60.4	1.6	50.3
DOAc Tooltip 2,5-Dimethoxy-4-acetylamphetamine	80.5	313	91.3
DON Tooltip 2,5-Dimethoxy-4-nitroamphetamine	5.5	166	22.4
DOCN Tooltip 2,5-Dimethoxy-4-cyanoamphetamine	45.7	774	1,011
DOBZ Tooltip 2,5-Dimethoxy-4-benzylamphetamine	0.4	35.0	1.0
M-154 Tooltip N,N-Dimethyl-2,5-dimethoxy-4-bromoamphetamine	94.2	341	68.1
D-367 Tooltip N-n-Propyl-2,5-dimethoxy-4-bromoamphetamine	88.5	521	514
QDOB Tooltip N,N,N-Trimethyl-2,5-dimethoxy-4-bromoamphetamine	2,155	>10,000	6,298
Notes: The smaller the value, the more avidly the drug binds to the site. Refs: [12] [13] [7] [6] [14] [15]

The DOx drugs act as agonists of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. ^{[6] [16] [7] [2] [3]} Their psychedelic effects are thought to be mediated specifically by activation of the serotonin 5-HT_2A receptor. ^{[16] [2]}

In contrast to other amphetamines, DOx drugs like DOC, DOET, and DOM are inactive as monoamine releasing agents and reuptake inhibitors. ^{[17] [18] [6]} Some of the DOx drugs, including DOB, DOET, DOI, and DOM, are agonists of the rat, rhesus monkey, and/or human TAAR1. ^{[19] [20]}

Effects

In contrast to amphetamines like (–)-cathinone, but similarly to mescaline, DOM has shown no stimulant-like or reinforcing effects in rhesus monkeys. ^{[21] [22] [23] [24]} Conversely however, DOC has shown reinforcing effects, including conditioned place preference (CPP) and self-administration, in rodents similarly to methamphetamine. ^[25] This is analogous to other findings in which various 2C and NBOMe drugs have been found to produce brain dopaminergic elevations and reinforcing effects in rodents. ^{[26] [27] [28] [29] [30] [31] [32]}

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. ^{[33] [3] [2] [34] [5]} Some DOx drugs, such as DOM and DOB, appear to have durations that increase non-linearly with dosage, for instance 8 hours at lower doses and as long as 30 hours or even up to 3 or 4 days at higher doses. ^{[5] [35]} This suggests that the pathways mediating the metabolism of these drugs can saturate. ^[5] The DOx drugs are metabolized primarily by O-demethylation. ^[3] However, DOM is primarily metabolized by hydroxylation at its methyl group. ^[3]

History

DOM was the first psychedelic of the DOx series to be discovered. ^[4] 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. ^{[4] [5] [36]} Shulgin personally tried DOM on January 4, 1964 and discovered its psychedelic effects. ^{[37] [4] [5] [36]} 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. ^{[38] [39] [40]} 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. ^{[38] [41] [42] [43]}

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. ^[5] Dow Chemical Company decided to move forward with clinical trials of DOET as a potential pharmaceutical drug for such purposes. ^[5] Shulgin and Dow Chemical Company filed a patent for DOET in 1966, although it was not published until 1970. ^{[5] [4] [44]} Dow Chemical Company tasked Solomon H. Snyder at Johns Hopkins University with clinically studying DOET. ^[5]

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. ^{[5] [45]} 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. ^{[5] [45]} 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. ^{[5] [45]} 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. ^[5] 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. ^[5] DOM was first reported on in the media and scientific literature in 1967 as a result of the crisis. ^{[5] [46] [47]} DOM became illegal in the United States in 1968. ^[5]

Dow Chemical Company terminated its clinical research program on DOET due to the DOM public health crisis. ^[5] DOET was subsequently first described in the literature by Snyder and colleagues in 1968. ^[47] Snyder continued to be interested in DOET as a potential medicine, but it was never further developed. ^[47] Snyder also described 2,5-dimethoxyamphetamine (2,5-DMA), which had been synthesized and tested by Shulgin, in the literature in 1968. ^[48] DOM and DOET were further described in the scientific literature by Shulgin in 1969. ^{[49] [4] [5]} In addition, Shulgin discussed DOM, DOET, TMA-2, and 2,5-DMA in a book chapter on hallucinogens published in 1970. ^[50]

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, ^{[4] [51]} and by DOI, DOC, and a few other analogues, which were developed by another research group, in 1973. ^{[4] [52]} After this, numerous other DOx drugs were synthesized and characterized, both by Shulgin and other scientists. ^{[38] [53] [35] [34] [36] [54] [2]}

Following its discovery, DOI has become widely used in scientific research in the study of the serotonin 5-HT₂ receptors. ^{[4] [2]}

List of DOx drugs

The DOx family includes the following members:

Structure	Name	Abbreviation	CAS number
	2,5-Dimethoxyamphetamine	2,5-DMA	2801-68-5
	2,5-Dimethoxy-4-amylamphetamine	DOAM	63779-90-8
	2,5-Dimethoxy-4-bromoamphetamine	DOB	64638-07-9
	2,5-Dimethoxy-4-butylamphetamine	DOBU	63779-89-5
	2,5-Dimethoxy-4-chloroamphetamine	DOC	123431-31-2
	2,5-Dimethoxy-4-ethoxyamphetamine	MEM	16128-88-4
	2,5-Dimethoxy-4-(methoxymethyl)amphetamine	DOMOM [55]	260810-10-4
	2,5-Dimethoxy-4-(ethoxymethyl)amphetamine	DOMOE	930836-81-0
	2,5-Dimethoxy-4-ethylamphetamine	DOET	22004-32-6
	2,5-Dimethoxy-4-ethylthioamphetamine	Aleph-2	185562-00-9
	2,5-Dimethoxy-4-fluoroamphetamine	DOF	125903-69-7
	2,5-Dimethoxy-4-(2-fluoroethyl)amphetamine	DOEF	121649-01-2
	2,5-Dimethoxy-4-(3-fluoropropyl)amphetamine	DOPF	?
	2,5-Dimethoxy-4-iodoamphetamine	DOI	42203-78-1
	2,5-Dimethoxy-4-isopropylthioamphetamine	Aleph-4	123643-26-5
	2,4,5-Trimethoxyamphetamine	TMA-2 (DOMeO)	1083-09-6
	2,5-Dimethoxy-4-methylamphetamine	DOM	15588-95-1
	2,5-Dimethoxy-4-methylthioamphetamine	Aleph-1	61638-07-1
	2,5-Dimethoxy-4-nitroamphetamine	DON	67460-68-8
	2,5-Dimethoxy-4-phenylthioamphetamine	Aleph-6	952006-44-9
	2,5-Dimethoxy-4-benzylamphetamine	DOBZ [56]	125903-73-3
	2,5-Dimethoxy-4-(3-methoxybenzyl)amphetamine	DO3MeOBZ [57]	930836-90-1
	2,5-Dimethoxy-4-[(tetrahydrofuran-2-yl)methyl]amphetamine	DOTHFM	930776-12-8
	2,5-Dimethoxy-4-propylamphetamine	DOPR	63779-88-4
	2,5-Dimethoxy-4-isopropylamphetamine	DOiP	42306-96-7
	2,5-Dimethoxy-4-propylthioamphetamine	Aleph-7	207740-16-7
	2,5-Dimethoxy-4-(difluoromethyl)amphetamine	DODFM	?
	2,5-Dimethoxy-4-trifluoromethylamphetamine	DOTFM	159277-07-3
	2,5-Dimethoxy-4-(2,2,2-trifluoroethyl)amphetamine	DOTFE [58]	?
	2,5-Dimethoxy-4-cyanoamphetamine	DOCN [59]	125903-74-4
	2,5-Dimethoxy-4-ethynylamphetamine	DOYN [60]	633290-70-7
	2,5-Dimethoxy-4-acetylamphetamine	DOAc	?
	2,5-Dimethoxy-4-isobutylamphetamine	DOIB	89556-64-9
	2,5-Dimethoxy-4-sec-butylamphetamine	DOSB	89556-71-8
	2,5-Dimethoxy-4-tert-butylamphetamine	DOTB	41538-42-5
	2,5-Dimethoxy-4-hexylamphetamine	DOHx	?
	2,5-Dimethoxy-4-octylamphetamine	DOCT	?

Related compounds

A number of additional compounds are known with alternative substitutions:

Structure	Name	Abbreviation	CAS number
	Dimoxamine ("Ariadne")	4C-D	52842-59-8
	1-(2,5-Dimethoxy-4-ethylphenyl)butan-2-amine [61]	4C-E	?
	1-(2,5-Dimethoxy-4-(n-propyl)phenyl)butan-2-amine	4C-P	?
	1-(2,5-Dimethoxy-4-bromophenyl)butan-2-amine	4C-B	69294-23-1
	1-(2,5-Dimethoxy-4-chlorophenyl)butan-2-amine	4C-C	791010-74-7
	1-(2,5-Dimethoxy-4-iodophenyl)butan-2-amine	4C-I	758631-75-3
	1-(2,5-Dimethoxy-4-nitrophenyl)butan-2-amine	4C-N	775234-58-7
	1-[2,5-Dimethoxy-4-(ethylthio)phenyl]butan-2-amine	4C-T-2	850007-13-5
	Dimethoxymethamphetamine ("Beatrice")	N-Methyl-DOM	92206-37-6
	2,5-Dimethoxy-3,4-methylenedioxyamphetamine	DMMDA	15183-13-8
	2,5-Dimethoxy-3,4-dimethylamphetamine ("Ganesha")	3-Methyl-DOM	207740-37-2
	2,5-Dimethoxy-3,4-trimethylenylamphetamine	G-3	?
	2,5-Dimethoxy-3,4-tetramethylenylamphetamine	G-4	?
	2,5-Dimethoxy-3,4-norbornylamphetamine	G-5	?
	1-(5,8-Dimethoxy-3,4-dihydro-1H-isochromen-7-yl)propan-2-amine [62]	G-O	774538-38-4
	2,5-Dimethoxy-3,4-dichloroamphetamine	DODC	1373918-65-0
	2,5-Dimethoxy-4-iodo-N,N-dimethylamphetamine	IDNNA	67707-78-2
	Methyl-DOB	N-Methyl-DOB	155638-80-5
	2,3,4,5-Tetramethoxyamphetamine	TeMA	23693-26-7
	1-(4-Bromo-2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-8-yl)propan-2-amine	DOB-FLY	219986-75-1
	Bromo-DragonFLY	DOB-DFLY	502759-67-3
	3-(4-Bromo-2,5-dimethoxyphenyl)azetidine	ZC-B [63]	2641630-65-9

See also

• 2,5-Dimethoxyamphetamine
• 2Cs, 25-NB
• Substituted amphetamines
• Substituted benzofurans
• Substituted cathinones
• Substituted methylenedioxyphenethylamines
• Substituted phenethylamines
• Substituted tryptamines
• PiHKAL
• The Shulgin Index

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33. Ballentine G, Friedman SF, Bzdok D (March 2022). "Trips and neurotransmitters: Discovering principled patterns across 6850 hallucinogenic experiences". Sci Adv. 8 (11): eabl6989. Bibcode:2022SciA....8L6989B. doi:10.1126/sciadv.abl6989. PMC   8926331 . PMID   35294242.
34. Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Res Monogr. 146: 74–91. PMID   8742795.
35. Shulgin, A.T.; Shulgin, A. (1991). PiHKAL: A Chemical Love Story. Transform Press. ISBN   978-0-9630096-0-9 . Retrieved 2 November 2024.
36. Shulgin, A.; Manning, T.; Daley, P.F. (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. ISBN   978-0-9630096-3-0 . Retrieved 2 November 2024. A short history of DOM (STP) notes that the original synthesis took place in 1963, psychological effects were discovered the following year, and that the compound had appeared in the Haight-Ashbury scene of mid-1967 (Shulgin, 1977b). The known congeners of DOM were reviewed for structure-activity relationships (Barfknecht et al., 1978). [...] Shulgin, AT. (1977b) Profiles of psychedelic drugs. 5. STP. J. Psych. Drugs 9(2): 171-172.
37. "Alexander Theodore Shulgin (1925-2014)". openDemocracy. 9 June 2014. Retrieved 26 January 2025. [Shulgin's] attention was drawn to the 4-position after he conceived of and synthesized the compound DOM, which he bioassayed on January 4, 1964 and discovered to be surprisingly potent: it was psychoactive at the 1 mg dose.
38. Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN   978-1-4757-0512-6. 3,4,5-Trimethoxyphenylisopropylamine (33, TMA, trimethoxyamphetamine) is the first psychotomimetic drug that evolved from the systematic application of the principles discovered in studying the relationships between chemical structure and biological activity. Armed with the known structure of mescaline, the proclivity of most phenethylamines to be of only fleeting activity centrally (due to facile deamination), and the effectiveness of a methyl group alpha- to the nitrogen as a stabilizing factor in central activity, Her (1947) synthesized TMA. His favorable impressions on the euphoric properties of the compound encouraged the Canadian group of Peretz and co-workers (1955) to explore its psychopharmacological nature and to evaluate its potential as a psychotomimetic. [...] 3.1.6. 2,4,5-Trimethoxyphenylisopropylamine This geometric isomer of TMA was first synthesized by Bruckner (1933) and its psychotomimetic properties were first observed some 30 years later (Shulgin, 1964a), 2,4,5-Trimethoxyphenylisopropylamine (34, TMA-2, 2,4,5-trimethoxyamphetamine) was the second of the six possible positional isomers found to be psychotomimetic, and was thus called TMA-2.
39. Bruckner, Viktor (24 October 1933). "Über das Pseudonitrosit des Asarons". Journal für Praktische Chemie. 138 (9–10): 268–274. doi:10.1002/prac.19331380907. ISSN   0021-8383.
40. Shulgin AT (July 1964). "Psychotomimetic amphetamines: methoxy 3,4-dialkoxyamphetamines". Experientia. 20 (7): 366–367. doi:10.1007/BF02147960. PMID   5855670.
41. Peretz DI, Smythies JR, Gibson WC (April 1955). "A new hallucinogen: 3,4,5-trimethoxyphenyl-beta-aminopropane with notes on the stroboscopic phenomenon". J Ment Sci. 101 (423): 317–329. doi:10.1192/bjp.101.423.317. PMID   13243046. 3,4,5-Trimethoxyphenyl-β-aminopropane (Trimethoxyamphetamine, TMA) was first synthesized by Hey in 1947 (Hey, 1947) who was impressed with its euphoric properties (private communication). [...]
42. Shulgin, Alexander T.; Bunnell, Sterling; Sargent, Thornton (1961). "The Psychotomimetic Properties of 3,4,5-Trimethoxyamphetamine". Nature. 189 (4769): 1011–1012. Bibcode:1961Natur.189.1011S. doi:10.1038/1891011a0. ISSN   0028-0836.
43. Hey P (1947). "The synthesis of a new homologue of mescaline". Q J Pharm Pharmacol. 20 (2): 129–134. PMID   20260568. Archived from the original on 19 July 2019.
44. "phenethylamines and their pharmacologically-acceptable salts". Google Patents. 1970. Retrieved 26 January 2025.
45. Trout K, Daley PF (December 2024). "The origin of 2,5-dimethoxy-4-methylamphetamine (DOM, STP)". Drug Test Anal. 16 (12): 1496–1508. doi:10.1002/dta.3667. PMID   38419183.
46. Snyder SH, Faillace L, Hollister L (November 1967). "2,5-dimethoxy-4-methyl-amphetamine (STP): a new hallucinogenic drug". Science. 158 (3801): 669–670. Bibcode:1967Sci...158..669S. doi:10.1126/science.158.3801.669. PMID   4860952.
47. Snyder SH, Faillace LA, Weingartner H (September 1968). "DOM (STP), a new hallucinogenic drug, and DOET: effects in normal subjects". Am J Psychiatry. 125 (3): 113–120. doi:10.1176/ajp.125.3.357. PMID   4385937.
48. Snyder SH, Richelson E (May 1968). "Psychedelic drugs: steric factors that predict psychotropic activity". Proc Natl Acad Sci U S A. 60 (1): 206–213. Bibcode:1968PNAS...60..206S. doi: 10.1073/pnas.60.1.206 . PMC   539103 . PMID   5241523. Shulgin (personal communication) has synthesized 2,5-dimethoxyamphetamine (2,5-DMA) (Fig. 4) and observed its potency in man as between 8 and 10 MU. This compound corresponds to TMA-2 with the absence of the methoxy at C-4. 2,5-DMA is considerably more potent than TMA, TMA-3, or TMA-4, all of which have three methoxy groupings. [...]
49. Shulgin, Alexander T. (1969). "Psychotomimetic Agents Related to the Catecholamines". Journal of Psychedelic Drugs. 2 (2): 14–19. doi:10.1080/02791072.1969.10524409. ISSN   0022-393X.
50. Alexander Shulgin (1970). "Chemistry and Structure-Activity Relationships of the Psychotomimetics". In D. H. Efron (ed.). Psychotomimetic Drugs (PDF). New York: Raven Press. pp. 21–41.
51. Shulgin AT, Sargent T, Naranjo C (1971). "4-Bromo-2,5-dimethoxyphenylisopropylamine, a new centrally active amphetamine analog". Pharmacology. 5 (2): 103–107. doi:10.1159/000136181. PMID   5570923.
52. Coutts, Ronald T.; Malicky, Jerry L. (1 May 1973). "The Synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM)". Canadian Journal of Chemistry. 51 (9): 1402–1409. doi: 10.1139/v73-210 . ISSN   0008-4042.
53. Nichols DE, Glennon RA (1984). "Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". In Jacobs BL (ed.). Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. pp. 95–142. ISBN   978-0-89004-990-7. OCLC   10324237.
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External links

• PiHKAL ("Phenethylamines I Have Known And Loved") by Alexander "Sasha" Shulgin (1991)
• Psychotomimetic Drugs: Structure-Activity Relationships by Alexander "Sasha" Shulgin (1978)