DOx

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.

For other uses, see Dox.

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

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]

Use

Doses and durations of DOx drugs

Compound	Chemical name	Dosage	Duration
DOAM	4-Amyl-2,5-dimethoxyamphetamine	≥5–40 mg	Unknown
DOB	4-Bromo-2,5-dimethoxyamphetamine	1–3 mg	18–30 hours
DOBU	4-Butyl-2,5-dimethoxyamphetamine	≥1–10 mg	Very long
DOBz (DOBN)	4-Benzyl-2,5-dimethoxyamphetamine	Unknown	Unknown
DOC	4-Chloro-2,5-dimethoxyamphetamine	1.5–5 mg	12–24 hours
DOEF	4-(2-Fluoroethyl)-2,5-dimethoxyamphetamine	2–3.5 mg	12–16 hours
DOET	4-Ethyl-2,5-dimethoxyamphetamine	2–6 mg	5–20 hours
DOF	4-Fluoro-2,5-dimethoxyamphetamine	>18 mg	Unknown
DOH (2,5-DMA)	2,5-Dimethoxyamphetamine	80–160 mg	6–8 hours
DOHx	4-Hexyl-2,5-dimethoxyamphetamine	Unknown	Unknown
DOI	4-Iodo-2,5-dimethoxyamphetamine	1.5–3 mg	16–30 hours
DOIB	4-Isobutyl-2,5-dimethoxyamphetamine	10–15 mg	Unknown
DOIP	4-Isopropyl-2,5-dimethoxyamphetamine	20–30 mg	Unknown
DOM	4-Methyl-2,5-dimethoxyamphetamine	3–10 mg	14–20 hours
DON	4-Nitro-2,5-dimethoxyamphetamine	3–4.5 mg	8–15 hours
DOPP	4-(3-Phenylpropyl)-2,5-dimethoxyamphetamine	Unknown	Unknown
DOPR	4-Propyl-2,5-dimethoxyamphetamine	2.5–5 mg	20–30 hours
DOSB	4-sec-Butyl-2,5-dimethoxyamphetamine	25–30 mg	Very long
DOTB	4-tert-Butyl-2,5-dimethoxyamphetamine	>25 mg	Unknown
DOTFE	4-(2,2,2-Trifluoroethyl)-2,5-dimethoxyamphetamine	>3 mg	Unknown
DOTFM	4-(Trifluoromethyl)-2,5-dimethoxyamphetamine	0.3–1 mg	Unknown
DOYN	4-Ethynyl-2,5-dimethoxyamphetamine	2–6 mg	10–15 hours
MEM	4-Ethoxy-2,5-dimethoxyamphetamine	20–50 mg	10–14 hours
Aleph (DOT)	4-Methylthio-2,5-dimethoxyamphetamine	5–10 mg	6–8 hours
Aleph-2	4-Ethylthio-2,5-dimethoxyamphetamine	4–8 mg	8–16 hours
Aleph-4	4-Isopropylthio-2,5-dimethoxyamphetamine	7–12 mg	12–20 hours
Aleph-6	4-Phenylthio-2,5-dimethoxyamphetamine	≥40 mg	Very long
Aleph-7	4-Propylthio-2,5-dimethoxyamphetamine	4–7 mg	15–30 hours
G-1	3,4-Dimethyl-2,5-dimethoxyamphetamine	20–32 mg	18–24 hours
G-3	3,4-(Trimethylene)-2,5-dimethoxyamphetamine	12–18 mg	8–12 hours
G-5	3,4-Norbornyl-2,5-dimethoxyamphetamine	14–20 mg	16–30 hours
TMA-2 (2,4,5-TMA)	4-Methoxy-2,5-dimethoxyamphetamine	20–40 mg	8–12 hours
Refs: [2][12][13][3][14][15][16][17][18][19][20][21][22][23]

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]

Interactions

See also: Psychedelic drug § Interactions, and Trip killer § Serotonergic psychedelic antidotes

Pharmacology

Pharmacodynamics

Actions

DOx drugs at the human 5-HT₂ receptors

Compound	Affinity (Ki, nM)
	5-HT2A	5-HT2B	5-HT2C
2,5-DMATooltip 2,5-Dimethoxyamphetamine	211–2,502	1,039	104–>5,070
DOMTooltip 2,5-Dimethoxy-4-methylamphetamine	88–507.4	11.7	404–3,980
DOETTooltip 2,5-Dimethoxy-4-ethylamphetamine	12–100	28.8	107.2–108
DOPRTooltip 2,5-Dimethoxy-4-n-propylamphetamine	0.9	54.4	1.1
DOBUTooltip 2,5-Dimethoxy-4-n-butylamphetamine	5.4	ND	60
DOTBTooltip 2,5-Dimethoxy-4-t-butylamphetamine	3.7	24.6	2.2
DOAMTooltip 2,5-Dimethoxy-4-amylamphetamine	3.5	ND	75
DOHxTooltip 2,5-Dimethoxy-4-n-hexylamphetamine	0.1	30.3	0.7
DOFTooltip 2,5-Dimethoxy-4-fluoroamphetamine	41.7	227	28.7
DOCTooltip 2,5-Dimethoxy-4-chloroamphetamine	1.4	31.8	2.0
DOBTooltip 2,5-Dimethoxy-4-bromoamphetamine	0.6–41	26.9	1.3–60
DOITooltip 2,5-Dimethoxy-4-iodoamphetamine	0.7–165.4	20.0–335.9	2.4–45.8
TMA-2Tooltip 2,4,5-Trimethoxyamphetamine	57.9–584.2	154.4–307	87.7–4,062
MEMTooltip 2,5-Dimethoxy-4-ethoxyamphetamine	73.0–3,948	64.5–763	124–>10,000
Aleph-2Tooltip 2,5-Dimethoxy-4-ethylthioamphetamine	60.4	1.6	50.3
DOAcTooltip 2,5-Dimethoxy-4-acetylamphetamine	80.5	313	91.3
DONTooltip 2,5-Dimethoxy-4-nitroamphetamine	5.5	166	22.4
DOCNTooltip 2,5-Dimethoxy-4-cyanoamphetamine	45.7	774	1,011
DOBZTooltip 2,5-Dimethoxy-4-benzylamphetamine	0.4	35.0	1.0
M-154Tooltip N,N-Dimethyl-2,5-dimethoxy-4-bromoamphetamine	94.2	341	68.1
D-367Tooltip N-n-Propyl-2,5-dimethoxy-4-bromoamphetamine	88.5	521	514
QDOBTooltip 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: [24][25][7][6][26][27]

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][28][7][2][3][29]} Their psychedelic effects are thought to be mediated specifically by activation of the serotonin 5-HT_2A receptor.^[28][2]

In contrast to other amphetamines, DOx drugs like DOC, DOET, and DOM are inactive as monoamine releasing agents and reuptake inhibitors.^[30][31][6] 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.^[32][33]

Effects

In contrast to amphetamines like (–)-cathinone, but similarly to mescaline, DOM has shown no stimulant-like or reinforcing effects in rhesus monkeys.^{[34][35][36][37]} Conversely however, DOC has shown reinforcing effects, including conditioned place preference (CPP) and self-administration, in rodents similarly to methamphetamine.^[38] 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.^{[39][40][41][42][43][44][45]}

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.^{[14][3][2][12][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][15] 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][16] Shulgin personally tried DOM on January 4, 1964 and discovered its psychedelic effects.^{[46][4][5][16]} 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.^[22][47][48] 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.^{[22][49][50][51]}

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][52] 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][53] 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][53] 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][53] 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][54][55] 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.^[55] Snyder continued to be interested in DOET as a potential medicine, but it was never further developed.^[55] Snyder also described 2,5-dimethoxyamphetamine (2,5-DMA), which had been synthesized and tested by Shulgin, in the literature in 1968.^[56] DOM and DOET were further described in the scientific literature by Shulgin in 1969.^[57][4][5] In addition, Shulgin discussed DOM, DOET, TMA-2, and 2,5-DMA in a book chapter on hallucinogens published in 1970.^[58]

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][59] and by DOI, DOC, and a few other analogues, which were developed by another research group, in 1973.^[4][60] After this, numerous other DOx drugs were synthesized and characterized, both by Shulgin and other scientists.^{[22][13][15][12][16][61][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 #	Ref
	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	260810-10-4	[62]
	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 (DOT)	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	125903-73-3
	2,5-Dimethoxy-4-(3-methoxybenzyl)amphetamine	DO3MeOBZ	930836-90-1	[63]
	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	?	[64]
	2,5-Dimethoxy-4-cyanoamphetamine	DOCN	125903-74-4	[65]
	2,5-Dimethoxy-4-ethynylamphetamine	DOYN	633290-70-7	[66]
	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	?
	4-(3-Phenylpropyl)-2,5-dimethoxyamphetamine	DOPP	?
	4-Methallyloxy-2,5-dimethoxyamphetamine	MMALM	?	[67]
	4-Allyloxy-2,5-dimethoxyamphetamine	MALM	?	[67]
	4-(2-Fluoroethoxy)-2,5-dimethoxyamphetamine	MFEM	?	[67]
	4-(2,2-Difluoroethoxy)-2,5-dimethoxyamphetamine	MDFEM	?	[67]
	4-(2,2,2-Trifluoroethoxy)-2,5-dimethoxyamphetamine	MTFEM	?	[67]
	4-Isopropoxy-2,5-dimethoxyamphetamine	MIPM	?	[67]

Related compounds

See also: 4C (psychedelics)

A number of additional compounds are known with alternative substitutions:

Structure	Name	Abbreviation	CAS #
	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	?
	1,4-Dimethoxynaphthyl-2-isopropylamine	G-N	?
	1-(5,8-Dimethoxy-3,4-dihydro-1H-isochromen-7-yl)propan-2-amine[68]	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
	2,5-Dimethoxy-4-methylphenylcyclopropylamine	DMCPA	15183-13-8
	3-(4-Bromo-2,5-dimethoxyphenyl)azetidine	ZC-B[69]	2641630-65-9

See also

• 2,5-Dimethoxyamphetamine
• Substituted mescaline analogue
• 2Cs, 4Cs, 25-NB, FLY
• Substituted amphetamines
• Substituted benzofurans
• Substituted cathinones
• Substituted methoxyphenethylamine
• Substituted methylenedioxyphenethylamines
• Substituted phenethylamines
• Substituted tryptamines
• PiHKAL
• The Shulgin Index