2,5-Dimethoxy-4-ethylamphetamine

Clinical data
Other names	DOET; DOEt; DOE; HECATE; Hecate; DMEA; 2,5-Dimethoxy-4-ethylamphetamine; 4-Ethyl-2,5-dimethoxyamphetamine; Dimethoxyethylamphetamine; Ethyldimethoxyamphetamine
Drug class	Serotonergic psychedelic;Serotonin5-HT2 receptoragonist;Antidepressant;Psychic energizer;Cognitive enhancer
ATC code	None
Legal status
Legal status	AU: S9 (Prohibited substance) BR: Class F2 (Prohibited psychotropics)[1] CA: Schedule I DE: Anlage I (Authorized scientific use only) UK: Class A US: Schedule I UN: Psychotropic Schedule I
Pharmacokinetic data
Metabolism	Oxidation of the 4-positionethyl group[2][7]
Onset of action	1–3 hours[2][3][4][5]
Duration of action	5–20 hours[4][6]
Excretion	Urine (10–40% unchanged within 24 hours)[2][3][4]
Identifiers
IUPAC name 1-(4-Ethyl-2,5-dimethoxyphenyl)propan-2-amine
CAS Number	22004-32-6 Y
PubChemCID	27402
DrugBank	DB01467 Y
ChemSpider	25499 Y
UNII	9SK6K682UL
KEGG	C22714 Y
ChEMBL	ChEMBL8224 Y
CompTox Dashboard(EPA)	DTXSID00860585
Chemical and physical data
Formula	C13H21NO2
Molar mass	223.316 g·mol−1
3D model (JSmol)	Interactive image
SMILES O(c1cc(c(OC)cc1CC(N)C)CC)C
InChI InChI=1S/C13H21NO2/c1-5-10-7-13(16-4)11(6-9(2)14)8-12(10)15-3/h7-9H,5-6,14H2,1-4H3 Y Key:HXJKWPGVENNMCC-UHFFFAOYSA-N Y
(verify)

2,5-Dimethoxy-4-ethylamphetamine (DOET) is apsychedelicdrug of thephenethylamine,amphetamine, andDOx families.^[8][6][3][2] It is closely related toDOM and is asyntheticanalogue of thenaturally occurring phenethylamine psychedelicmescaline.^[2][9] The drug acts as aselectiveagonist of theserotonin5-HT₂ receptors, including of the serotonin5-HT_2A,5-HT_2B, and5-HT_2C receptors.^[10][11]

DOET was first discovered byAlexander Shulgin in the 1960s.^[12] It was clinically studied at low and sub-hallucinogenic doses for potential use as apharmaceutical drug acting as a "psychic energizer" byDow Chemical Company in the 1960s.^[12] However, its development was terminated after DOM emerged as astreet drug and caused apublic health crisis inSan Francisco in 1967.^[12][13] Nonetheless, DOET's effects at low doses were extensively characterized in smallclinical trials.^{[2][4][14][15][5]} The psychedelic effects of DOET at higher doses were subsequently described by Shulgin in his bookPiHKAL in 1991.^[6]

DOET is takenby mouth.^[6][3][4] It has a slowonset of 1 to 3 hours, a delayedpeak of 3 to 5 hours, and adose-dependent and potentially very longduration of 5 to 20 hours.^{[6][16][2][3]} Effects at low doses include mildeuphoria, enhancedself-awareness, andtalkativeness, among others.^[2][3][4] Mildclosed-eye visuals can also occur.^[15][5] At higher doses, DOET produces psychedelic effects includingheightened emotions,sensory enhancement, rich closed-eye visuals, andopen-eye visuals, among others.^[6][5] Physical effects includepupil dilation, increasedheart rate, and increasedblood pressure.^[4][14][17]

In a 1968clinical trial, DOET at anoral dose of 1.5 mg (as thehydrochloridesalt) produced mildeuphoria and enhancedself-awareness, but nohallucinogenic effects (in terms of perceptual distortions orhallucinations/open-eye visuals), marked behavioral changes, orintellectual impairment.^{[2][3][4][14][17]} Other reported effects included feelinghigh, feelings ofinsight, feelings ofpleasantness,body image awareness,impatience, slightdifficulty concentrating,talkativeness,racing thoughts, mildclosed-eye visuals,time dilation in some, feelingalert, and feeling "washed out" after the drug.^{[2][4][14][17]} Some of the effects of DOET in the study resembled those ofdextroamphetamine, including talkativeness, euphoria, and feeling alert.^[4][14] The subjective effects began 1 to 1.5 hours after dosing,peaked around 3 to 4 hours after administration, and theduration was about 5 to 6 hours.^[2][3][4]Pupil dilation was also observed, but there were no marked changes inheart rate orblood pressure.^[4][14][17] There were also changes oncognitive tests ofassociation andserial learning.^{[2][4][14][17]} The effects of DOET were similar to those of low doses of DOM (2.7–3.3 mg) but DOET appeared to be morepotent (with 2.0 mg DOM being indistinguishable fromplacebo).^[4][14]

In a subsequent 1971 clinical trial, DOET hydrochloride at oral doses of 0.75 to 4 mg again produced pupil dilation (dose-dependent), mild euphoria, feelings of enhanced self-awareness, and many of the other effects observed in the previous trial.^[2][3][15] Once again, there were no hallucinogenic effects, aside from closed-eye visuals in a minority of individuals, and there was nocognitive impairment.^[2][3][15] New assessed and reported effects included feelingrelaxed, feelings ofunpleasantness in some,lightheadedness, reduceddepressive feelings, and feelinganxious orrestless.^[3][15] The feelings ofnervousness and restlessness occurred more at the higher doses.^[3][15] DOET appeared to show a greater apparent separation between threshold and hallucinogenic doses than had been documented for other psychedelics.^[15][18] Other psychedelics likeLSD and DOM show a 2- to 3-fold separation, whereas DOET showed an at least 5-fold separation.^[15][18] The lesser influence of DOET on perceptual processes than equivalent doses of DOM was in spite of the greater potency of DOET than DOM in producing subjective effects in general.^[15][18]

A third and final 1974 clinical trial assessed oral doses of 1 to 4 mg (S)-(+)-DOET, 1 to 2 mg (R)-(–)-DOET, and 2 to 4 mg (RS)-(±)-DOET.^[2][19][5] It was found that 1 mg (R)-(–)-DOET was equivalent to 4 mg (S)-(+)-DOET in producing psychoactive effects and hence that (R)-(–)-DOET was about 4 times as potent as (S)-(+)-DOET.^[2][19][5] The onset was 1.5 to 3 hours, peak effects were at 4 to 5 hours, and the duration was 6 to 10 hours.^[5] The subjective effects were similar to the earlier trials, but new reported effects includedenhanced perception of allsenses, difficult-to-describecognitive alteration, relaxedwell-being, andheightened emotions with rapidmood changes.^[5] No hallucinogenic effects orvisual distortions with eyes open occurred, butvivid imagery with eyes closed could be experienced at the higher doses.^[5]

Based on the preceding clinical trials, DOET does not produce clear hallucinogenic effects, aside from closed-eye visuals, at doses of up to 4 mg.^[2][15][5] However,Alexander Shulgin has stated that DOET is psychedelic at doses of 3 mg and above.^[8] InPiHKAL, Shulgin listed the dosage of DOET as 2 to 6 mg and its duration as 14 to 20 hours.^[6][8] In experience reports of 1 to 7 mg DOET in different individuals, 1 mg produced relaxation but no psychedelic effects; 2.5 mg produced both open- and closed-eye visuals; 4 mg produced mood-energizing effects but very little or no hallucinogenic effect; 6 mg produced sensory enhancement, rich closed-eye visuals, and no open-eye visual movement; and 7 mg produced strong feelings with themes oflove,eroticism, anddivinity,openness, not much visually, closed-eye visuals, andbody load symptoms.^[6] There was considerable variation in subjective effects between individuals.^[6] Shulgin has described both DOET and DOM as being effectiveantidepressants at lower doses and DOET as being acognitive enhancer at modest doses.^[20][6]

In line with notions that DOET is a "psychic energizer", the related psychedelicDOPR has shownpro-motivational effects in rodents at sub-hallucinogenic doses^[21][22] and the related drugAriadne (4C-DOM) has reportedly shown pro-motivational effects in monkeys despite being non-hallucinogenic.^[23]ASR-2001 (2CB-5PrO), a non-hallucinogenic analogue of the related psychedelic2C-B, is under development for use as astimulant-likemedication for the treatment ofpsychiatric disorders.^{[24][25][26][27][28]}

DOET acts as aselectiveserotonin5-HT₂ receptoragonist, including of the serotonin5-HT_2A,5-HT_2B, and5-HT_2C receptors.^[10][11][35] In one study, itsaffinities (K_i) were 12 nM for the serotonin 5-HT_2A receptor, 108 nM for the serotonin 5-HT_2C receptor (9-fold lower than for 5-HT_2A), and 9,727 nM for the serotonin5-HT_1A receptor (811-fold lower than for 5-HT_2A).^[10] The drug'sEC₅₀Tooltip half-maximal effective concentration for activation of the serotonin 5-HT_2A receptor was 1.7 to 8.1 nM depending on theintracellular signaling cascade, while itsE_maxTooltip maximal efficacy was 99%.^[10] At the serotonin 5-HT_2B receptor, itsEC₅₀ was 68 nM (8- to 40-fold lower than for 5-HT_2A) and itsE_max was 73%.[10] DOET is afull agonist of the serotonin 5-HT_2A receptor and a high-efficacypartial agonist of the serotonin 5-HT_2B and 5-HT_2C receptors.^[10][11] The drug is a very weak or inactive agonist of the humantrace amine-associated receptor 1 (TAAR1) and is inactive at therhesus monkey TAAR1.^[31][10] In contrast to many other amphetamines, but like otherDOx drugs, DOET does not bind to themonoamine transporters.^[10][11]

DOET produces thehead-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents.^[36] As with other psychedelics, DOET shows a biphasic orinverted U-shapeddose–response curve for production of the HTR.^[36] The drug induces the HTR to a similar maximal extent as other related psychedelics likeDOM andDOI.^[36] DOET substitutes for thephenethylamine psychedelicsmescaline and DOM, partially substitutes for thetryptamine psychedelic5-MeO-DMT, and does not substitute for thepsychostimulantdextroamphetamine in animaldrug discrimination tests.^{[37][38][39][40]} DOET produceshyperlocomotion in mice.^[41][42][43] However, like other psychedelics, it shows a biphasic or inverted U-shaped dose–response curve, increasinglocomotor activity at low to moderate doses and reducing it at high doses.^[41][42][43] DOET producesserotonin receptor-dependentpressor andhyperthermic effects in rodents.^[43]

In terms of effects in humans, theonset of lower doses of DOET and its individualenantiomers (0.75–4 mg) is 1 to 3 hours,peak effects occur after 3 to 5 hours, and theduration is 5 to 10 hours.^{[2][3][4][14][15][5]} At higher doses of DOET (2 to 6 mg), the duration was reported to be 14 to 20 hours.^[6][8] DOET, like otherDOx drugs, has an unusually slow onset and long duration.^[16] In rodents, DOET ismetabolized byoxidation of theethyl group at the 4 position.^[2][7] It appears to be metabolized more quickly thanDOM.^[2] In humans, DOET isexcreted 10 to 40% inurine unchanged within 24 hours.^[2][3][4] The greatest excretion rate occurred between 3 and 6 hours.^[2][4]

DOET, also known as 2,5-dimethoxy-4-ethylamphetamine or as 2,5-dimethoxy-4-ethyl-α-methylphenethylamine, is asubstituted phenethylamine andamphetamine and is a member of theDOx group of drugs.^[8][6][3][2] It isstructurally related to thenaturally occurring phenethylamine psychedelicmescaline (3,4,5-trimethoxyphenethylamine).^[2][9]Analogues of DOET include otherDOx drugs such asDOM,DOPR,DOBU,DOAM,DOB, andDOI.^[2] The α-desmethyl or phenethylamine analogue of DOET is2C-E.^[8][6]Ariadne is the α-ethyl orphenylisobutylamine analogue of DOM.^[44][6]

DOET was discovered byAlexander Shulgin in the 1960s.^[12] He assessed DOET aftersynthesizing DOM in 1963 and discovering DOM'spsychedelic effects in 1964.^{[12][45][46][8]} Shulgin found that DOET was a remarkable "psychic energizer" at low doses without producing psychedelic effects at these doses.^[12] The effects that he experienced includedpositive mood,talkativeness, anddisinhibition that lasted the whole day.^[12] In contrast to Shulgin however, a friend and colleague of Shulgin's that he had try DOET a month later only experienced intenselethargy followed by profounddepression after taking the drug.^[12] Nonetheless, Shulgin's enthusiasm was not dissuaded, and he felt that the drug should be exploited.^[12] Shulgin was working atDow Chemical Company at the time, and he pitched DOET to the company.^[12] They selected DOET as a promising compound and decided to move forward withclinical trials for potential use as apharmaceutical drug.^[12] Shulgin and the company filed apatent for DOET in 1966, which was published in 1970.^{[12][45][8][47]} Dow Chemical Company taskedneuroscientistSolomon H. Snyder atJohns Hopkins University with clinically studying DOET.^[12]

In 1967,DOM emerged as astreet drug andLSD replacement with the name "STP" inSan Francisco and caused apublic health crisis.^[12][13] This occurred after LSD distributorOwsley Stanley learned of DOM from Shulgin and began distributing very-high-dose DOMtablets for free.^[12][13] LSD had become illegal inCalifornia in 1966 and an alternative had been sought by Stanley.^[12] The DOET tablets he distributed could have very longdurations (up to 3–4 days) and resulted in intense experiences, worrying physicalside effects, andhospitalizations.^[12] DOM was first described in the media andscientific literature in 1967 as a result of the crisis.^[12][48][4] The drug became illegal in theUnited States in 1968.^[12] It is unclear why Shulgin told Stanley about DOM and risked his professional career as well as the DOETclinical development.^[12][13] However, it might have been because Shulgin felt that DOM was a promising compound but was not being further pursued by Dow Chemical Company and would otherwise be forgotten.^[12][13]

Dow Chemical Company terminated its clinical research program on DOET due to the DOM public health crisis.^[12] DOET was subsequently first described in the scientific literature by Snyder and colleagues in 1968.^[4] Snyder continued to be interested in DOET as a potential medicine, but it was never further developed.^[4] Snyder conducted and published a series of threeclinical trials of low-dose DOET between 1968 and 1974.^{[4][14][17][15][5]} In these trials, he compared DOET with DOM,dextroamphetamine, andplacebo.^{[4][14][15][5]} As with Shulgin, he found DOET to produceamphetamine-like mildeuphoria and talkativeness, among other effects, without producing significanthallucinogenic effects at the assessed doses.^[4][14][15] Snyder also studied the individualenantiomers of DOET.^[2][19][5] Shulgin first discussed DOET in publications in 1969 and 1970.^{[45][12][49][50]} DOET became aSchedule Icontrolled substance in theUnited States in February 1973.^[51]

Ariadne (4C-D, 4C-DOM, BL-3912, Dimoxamine), the α-ethyl orphenylisobutylamineanalogue of DOM, was developed by Shulgin in the 1970s.^[44][6] He found it to bepsychoactive and to produce "the alert of a psychedelic, with none of the rest of the package".^[6][44] This threshold psychoactivity without psychedelic effects was reminiscent of low doses of DOET.^[6][44] However, in contrast to DOET and otherDOx drugs like DOM, Ariadne remained completely non-hallucinogenic even at very high doses, showing a hardceiling to its psychoactive effects and a lack ofrecreational potential.^[6][44] Ariadne was patented and developed by Shulgin andBristol Laboratories for potential use as anantidepressant and for a variety of other clinical indications in the 1970s.^[8][44][6] (R)-Ariadne (BL-3912A) completedphase 2 clinical trials and showed promising initial clinical benefits.^[44] However, further clinical development was halted for strategic economic reasons.^[44] In 2023, Ariadne was found to exhibit reduced-efficacypartial agonism of the serotonin 5-HT_2A receptor compared to DOM, and this was considered to account for its dramatically reduced hallucinogenic potential.^[44]

Shulgin first synthesized2C-E, the α-desmethyl orphenethylamine analogue of DOET, in 1977.^[52][53] Shulgin first published reports describing the psychedelic effects of higher doses of DOET inPiHKAL in 1991.^[6] Prior to this, no reports had clearly been published of hallucinogenic effects of DOET, although Snyder had observed some closed-eye visuals with low-dose DOET in his clinical trials.^{[2][4][14][5]} Shulgin also described 2C-E as producing robust psychedelic effects in PiHKAL, though with much higher doses required than DOET.^[6]

DOET was originally named DOE byAlexander Shulgin.^[6][8] However, he subsequently recalled that this was also an acronym fordesoxyephedrine (methamphetamine).^[6] As a result, he changed his name for the drug from DOE to DOET or DOEt.^[6][8] Other names that Shulgin has given DOET have included HECATE or Hecate (after theGreek goddess) and DMEA (short for dimethoxyethylamphetamine).^[6][8]

Internationally, DOET is a Schedule I controlled drug; under theConvention on Psychotropic Substances, it is legal only for medical uses or scientific research.^[54]

DOET is classified as aSchedule I substance in the United States and is similarly controlled in other parts of the world.^[51][54]

DOET is considered a Schedule 9 prohibited substance in Australia under thePoisons Standard (October 2015).^[55] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.^[55]

• DOx

• DOET - Isomer Design
• DOET Experience Reports - Erowid
• DOET - PiHKAL - Erowid
• DOET - PiHKAL - Isomer Design
• DOET: Exploring This Rare DOX Psychedelic - Tripsitter

• Drugs not assigned an ATC code
• 5-HT2A agonists
• 5-HT2B agonists
• 5-HT2C agonists
• Abandoned drugs
• Alexander Shulgin
• Designer drugs
• DOx (psychedelics)
• Experimental antidepressants
• Experimental hallucinogens
• Nootropics
• Pro-motivational agents
• Psychedelic phenethylamines
• TAAR1 agonists

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