2,5-Dimethoxy-4-ethylamphetamine

{{Short description|Psychedelic drug}} {{For|the book|The Design of Everyday Things}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 477211641 | drug_name = DOET | image = DOET structure.svg | image_class = skin-invert-image | width = 225px | image2 = DOET ball-and-stick structure.png | image_class2 = bg-transparent | width2 = 185px

| tradename = | pregnancy_category = | routes_of_administration = | class = Serotonin 5-HT2 receptor agonist; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen; Stimulant; Antidepressant; Psychic energizer; Cognitive enhancer | ATC_prefix = None | ATC_suffix =

| legal_AU = Schedule 9 | legal_BR = F2 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-07-25}}</ref> | legal_CA = Schedule I | legal_DE = Anlage I | legal_UN = P I | legal_US = Schedule I | legal_UK = Class A

| bioavailability = | protein_bound = | onset = 1–3{{nbsp}}hours<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderUngerBlatchley1974" /> | metabolism = Oxidation of the 4-position ethyl group<ref name="Shulgin1978" /><ref name="TanseyEstevezHo1975" /> | elimination_half-life = | duration_of_action = 5–20{{nbsp}}hours<ref name="SnyderFaillaceWeingartner1968" /><ref name="PiHKAL" /> | excretion = Urine (10–40% unchanged within 24{{nbsp}}hours)<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderFaillaceWeingartner1968" />

| CAS_number_Ref = {{cascite|correct|cas}} | CAS_number = 22004-32-6 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 9SK6K682UL | PubChem = 27402 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB01467 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 25499 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 8224 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = C22714 | synonyms = DOET; DOEt; DOE; HECATE; Hecate; DMEA; 4-Ethyl-2,5-dimethoxyamphetamine; 2,5-Dimethoxy-4-ethylamphetamine; Dimethoxyethylamphetamine; Ethyldimethoxyamphetamine

| IUPAC_name = 1-(4-Ethyl-2,5-dimethoxyphenyl)propan-2-amine | C = 13 | H = 21 | N = 1 | O = 2 | SMILES = O(c1cc(c(OC)cc1CC(N)C)CC)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HXJKWPGVENNMCC-UHFFFAOYSA-N }}

'''DOET''', also known as '''4-ethyl-2,5-dimethoxyamphetamine''' or as '''Hecate''', is a psychedelic drug of the phenethylamine, amphetamine, and DOx families.<ref name="ShulginManningDaley2011">{{cite book | vauthors = Shulgin A, Manning T, Daley PF | chapter=#56. DOET (2,5-Dimethoxy-4-ethylamphetamine) | title=The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher=Transform Press | location=Berkeley | volume=1 | year=2011 | isbn=978-0-9630096-3-0 | pages=106–110 | chapter-url=https://archive.org/details/shulgin-index-vol-1/page/106/mode/1up?view=theater }}</ref><ref name="PiHKAL" /><ref name="WillsErickson2012">{{cite book | vauthors = Wills B, Erickson T | chapter = Psychoactive Phenethylamine, Piperazine, and Pyrrolidinophenone Derivatives | veditors = Barceloux DG | title=Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants | publisher=Wiley | date=9 March 2012 | isbn=978-0-471-72760-6 | doi=10.1002/9781118105955.ch10 | pages=156–192 }}</ref><ref name="Shulgin1978">{{cite book | veditors = Iversen LL, Iversen SD, Snyder SH | vauthors = Shulgin AT | title=Stimulants | chapter=Psychotomimetic Drugs: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_6 | pages=243–333 | chapter-url=https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 | url=https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261 }}</ref> It is closely related to DOM and is a synthetic analogue of the naturally occurring phenethylamine psychedelic mescaline.<ref name="Shulgin1978" /><ref name="HassanBoschSingh2017" /> The drug is the derivative of DOM in which the methyl group at the 4 position has been replaced with a ethyl group.<ref name="PiHKAL" /> It is taken orally.<ref name="PiHKAL" /><ref name="WillsErickson2012" /><ref name="SnyderFaillaceWeingartner1968" /> DOET has a slow onset of 1 to 3{{nbsp}}hours, a delayed peak of 3 to 5{{nbsp}}hours, and a dose-dependent and potentially very long duration of 5 to 20{{nbsp}}hours.<ref name="PiHKAL" /><ref name="Bonson2005" /><ref name="Shulgin1978" /><ref name="WillsErickson2012" />

Effects of DOET at low doses include mild euphoria, enhanced self-awareness, and talkativeness, among others.<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderFaillaceWeingartner1968" /> Mild closed-eye visuals can also occur.<ref name="SnyderWeingartnerFaillace1971" /><ref name="SnyderUngerBlatchley1974" /> At higher doses, DOET produces psychedelic effects including heightened emotions, sensory enhancement, rich closed-eye visuals, and open-eye visuals, among others.<ref name="PiHKAL" /><ref name="SnyderUngerBlatchley1974" /> Physical effects include pupil dilation, increased heart rate, and increased blood pressure.<ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="WeingartnerSnyderFaillace1970" /> It acts as a selective agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.<ref name="LuethiGlatfelterPottie2025" /><ref name="LuethiRudinHoener2022" /><ref name="Ray2010" />

DOET was first discovered by Alexander Shulgin in the 1960s.<ref name="Baggott2023">{{cite journal | vauthors = Baggott MJ | title=Learning about STP: A Forgotten Psychedelic from the Summer of Love | journal=History of Pharmacy and Pharmaceuticals | volume=65 | issue=1 | date=1 October 2023 | issn=2694-3034 | doi=10.3368/hopp.65.1.93 | doi-access=free | pages=93–116 | url=https://hopp.uwpress.org/content/wphopp/65/1/93.full.pdf | access-date=26 January 2025}}</ref> It was clinically studied at low and sub-hallucinogenic doses for potential use as a pharmaceutical drug acting as a "psychic energizer" by Dow Chemical Company in the 1960s.<ref name="Baggott2023" /> However, its development was terminated after DOM emerged as a street drug and caused a small public health crisis in San Francisco in 1967.<ref name="Baggott2023" /><ref name="TroutDaley2024" /> Nonetheless, DOET's effects at low doses were extensively characterized in small clinical trials.<ref name="Shulgin1978" /><ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="SnyderWeingartnerFaillace1971" /><ref name="SnyderUngerBlatchley1974" /> The psychedelic effects of DOET at higher doses were subsequently described by Shulgin in his book ''PiHKAL'' (''Phenethylamines I Have Known and Loved'') in 1991.<ref name="PiHKAL">{{cite book |url=https://erowid.org/library/books_online/pihkal/pihkal066.shtml |title=PiHKAL: A Chemical Love Story |vauthors=Shulgin A, Shulgin A |date=September 1991 |publisher=Transform Press |isbn=0-9630096-0-5 |location=United States |pages=978}}</ref>

==Use and effects== In his book ''PiHKAL'' (''Phenethylamines I Have Known and Loved''), Alexander Shulgin lists DOET's dose as 2 to 6{{nbsp}}mg orally and its duration as 14 to 20{{nbsp}}hours.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /> In experience reports of DOET at doses of 1 to 7{{nbsp}}mg orally in different individuals, 1{{nbsp}}mg produced relaxation but no psychedelic effects; 2.5{{nbsp}}mg produced both open- and closed-eye visuals; 4{{nbsp}}mg produced mood-energizing effects but very little or no hallucinogenic effect; 6{{nbsp}}mg produced sensory enhancement, rich closed-eye visuals, and no open-eye visual movement; and 7{{nbsp}}mg produced strong feelings with themes of love, eroticism, and divinity, openness, not much visually, closed-eye visuals, and body load symptoms.<ref name="PiHKAL" /> There was considerable variation between individuals in terms of subjective effects.<ref name="PiHKAL" /> Shulgin has described both DOET and DOM as being effective antidepressants at lower doses and DOET as being a cognitive enhancer at modest doses.<ref name="Shulgin1972">{{cite book | veditors=Mulé, SJ, Brill H | vauthors = Shulgin AT | chapter=Hallucinogens, CNS Stimulants, And Cannabis | title=Chemical and Biological Aspects of Drug Dependence | publisher=CRC Press | date=1972 | isbn=978-0-87819-011-9 | doi=10.1201/9780429260629-16 | pages=163–176 | chapter-url=https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=8d86c9d6e58771ccef891e76483b86fceee153f8 | url=https://books.google.com/books?id=-edsAAAAMAAJ}}</ref><ref name="PiHKAL" /> DOET, also known as Hecate, is one of Shulgin's "ten classic ladies", a series of methylated DOM derivatives.<ref name="PiHKAL" /><ref name="GerGer2011">{{cite journal | vauthors = Ger A, Ger D | title = Triple Goddess of the Night | journal = British Neuroscience Association Bulletin | volume = 63 | pages = 28–30 | url = https://isomerdesign.com/bitnest/external/BNAB/63.30 }}</ref>

In a 1968 clinical trial, DOET at an oral dose of 1.5{{nbsp}}mg (as the hydrochloride salt) produced mild euphoria and enhanced self-awareness, but no hallucinogenic effects (in terms of perceptual distortions or hallucinations/open-eye visuals), marked behavioral changes, or intellectual impairment.<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderFaillaceWeingartner1968">{{cite journal | vauthors = Snyder SH, Faillace LA, Weingartner H | title = DOM (STP), a new hallucinogenic drug, and DOET: effects in normal subjects | journal = Am J Psychiatry | volume = 125 | issue = 3 | pages = 113–120 | date = September 1968 | pmid = 4385937 | doi = 10.1176/ajp.125.3.357 | url = }}</ref><ref name="SnyderFaillace1969">{{cite journal | vauthors = Snyder SH, Faillace LA, Weingartner H | title = A new psychotropic agent. Psychological and physiological effects of 2,5-dimethoxy-4-ethyl amphetamine (DOET) in man | journal = Arch Gen Psychiatry | volume = 21 | issue = 1 | pages = 95–101 | date = July 1969 | pmid = 4389442 | doi = 10.1001/archpsyc.1969.01740190097014 | url = }}</ref><ref name="WeingartnerSnyderFaillace1970">{{cite journal | vauthors = Weingartner H, Snyder SH, Faillace LA, Markley H | title=Altered free associations: Some cognitive effects of DOET (2, 5-dimethoxy-4-ethylamphetamine) | journal=Behavioral Science | volume=15 | issue=4 | date=1970 | doi=10.1002/bs.3830150402 | pages=297–303}}</ref> Other reported effects included feeling high, feelings of insight, feelings of pleasantness, body image awareness, impatience, slight difficulty concentrating, talkativeness, racing thoughts, mild closed-eye visuals, time dilation in some, feeling alert, and feeling "washed out" after the drug.<ref name="Shulgin1978" /><ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="WeingartnerSnyderFaillace1970" /> Some of the effects of DOET in the study resembled those of dextroamphetamine, including talkativeness, euphoria, and feeling alert.<ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /> The subjective effects began 1 to 1.5{{nbsp}}hours after dosing, peaked around 3 to 4{{nbsp}}hours after administration, and the duration was about 5 to 6{{nbsp}}hours.<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderFaillaceWeingartner1968" /> Pupil dilation was also observed, but there were no marked changes in heart rate or blood pressure.<ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="WeingartnerSnyderFaillace1970" /> There were also changes on cognitive tests of association and serial learning.<ref name="Shulgin1978" /><ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="WeingartnerSnyderFaillace1970" /> The effects of DOET were similar to those of low doses of DOM (2.7–3.3{{nbsp}}mg) but DOET appeared to be more potent (with 2.0{{nbsp}}mg DOM being indistinguishable from placebo).<ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" />

In a subsequent 1971 clinical trial, DOET hydrochloride at oral doses of 0.75 to 4{{nbsp}}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.<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderWeingartnerFaillace1971">{{cite journal | vauthors = Snyder SH, Weingartner H, Faillace LA | title = DOET (2,5-dimethoxy-4-ethylamphetamine), a new psychotropic drug. Effects of varying doses in man | journal = Arch Gen Psychiatry | volume = 24 | issue = 1 | pages = 50–55 | date = January 1971 | pmid = 4923215 | doi = 10.1001/archpsyc.1971.01750070052006 | url = }}</ref> Once again, there were no hallucinogenic effects, aside from closed-eye visuals in a minority of individuals, and there was no cognitive impairment.<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderWeingartnerFaillace1971" /> New assessed and reported effects included feeling relaxed, feelings of unpleasantness in some, lightheadedness, reduced depressive feelings, and feeling anxious or restless.<ref name="WillsErickson2012" /><ref name="SnyderWeingartnerFaillace1971" /> The feelings of nervousness and restlessness occurred more at the higher doses.<ref name="WillsErickson2012" /><ref name="SnyderWeingartnerFaillace1971" /> DOET appeared to show a greater apparent separation between threshold and hallucinogenic doses than had been documented for other psychedelics.<ref name="SnyderWeingartnerFaillace1971" /><ref name="StanridgeHowellGylys1976" /> Other psychedelics like LSD and DOM show a 2- to 3-fold separation, whereas DOET showed an at least 5-fold separation.<ref name="SnyderWeingartnerFaillace1971" /><ref name="StanridgeHowellGylys1976" /> 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.<ref name="SnyderWeingartnerFaillace1971" /><ref name="StanridgeHowellGylys1976">{{cite journal | vauthors = Standridge RT, Howell HG, Gylys JA, Partyka RA, Shulgin AT | title = Phenylakylamines with potential psychotherapeutic utility. 1. 2-Amino-1-(2,5-dimethoxy-4-methylphenyl)butane | journal = J Med Chem | volume = 19 | issue = 12 | pages = 1400–1404 | date = December 1976 | pmid = 1003425 | doi = 10.1021/jm00234a010 | url = https://erowid.org/archive/rhodium/pdf/shulgin/shulgin.4c-dom.pdf | quote = Interestingly, DOM and DOET both produced subjective effects of mild euphoria and enhanced self-awareness; however, DOM demonstrated clear-cut psychotomimetic-hallucinogenic effects at twice the minimal detectable dose, while DOET exhibited none of these at five times the minimal dosage. Shulgin and co-workers had noted similar potential with low dosages of DOB14 and 3,4-methylenedioxyamphetamine.15 }}</ref>

A third and final 1974 clinical trial assessed oral doses of 1 to 4{{nbsp}}mg (''S'')-(+)-DOET, 1 to 2{{nbsp}}mg (''R'')-(−)-DOET, and 2 to 4{{nbsp}}mg (''RS'')-(±)-DOET.<ref name="Shulgin1978" /><ref name="AndersonBraunBraun1978">{{cite journal | vauthors = Anderson GM, Braun G, Braun U, Nichols DE, Shulgin AT | title = Absolute configuration and psychotomimetic activity | journal = NIDA Research Monograph | volume = | issue = 22 | pages = 8–15 | date = 1978 | pmid = 101890 | doi = | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=2ab674b010611df18c029a78f6d17e52dba5f82f }}</ref><ref name="SnyderUngerBlatchley1974">{{cite journal | vauthors = Snyder SH, Unger S, Blatchley R, Barfknecht CF | title = Stereospecific actions of DOET (2,5-dimethoxy-4-ethylamphetamine) in man | journal = Arch Gen Psychiatry | volume = 31 | issue = 1 | pages = 103–106 | date = July 1974 | pmid = 4599412 | doi = 10.1001/archpsyc.1974.01760130079013 | url = }}</ref> It was found that 1{{nbsp}}mg (''R'')-(−)-DOET was equivalent to 4{{nbsp}}mg (''S'')-(+)-DOET in producing psychoactive effects and hence that (''R'')-(−)-DOET was about 4{{nbsp}}times as potent as (''S'')-(+)-DOET.<ref name="Shulgin1978" /><ref name="AndersonBraunBraun1978" /><ref name="SnyderUngerBlatchley1974" /> The onset was 1.5 to 3{{nbsp}}hours, peak effects were at 4 to 5{{nbsp}}hours, and the duration was 6 to 10{{nbsp}}hours.<ref name="SnyderUngerBlatchley1974" /> The subjective effects were similar to the earlier trials, but new reported effects included enhanced perception of all senses, difficult-to-describe cognitive alteration, relaxed well-being, and heightened emotions with rapid mood changes.<ref name="SnyderUngerBlatchley1974" /> No hallucinogenic effects or visual distortions with eyes open occurred, but vivid imagery with eyes closed could be experienced at the higher doses.<ref name="SnyderUngerBlatchley1974" />

Based on the preceding clinical trials, DOET does not produce clear hallucinogenic effects, aside from closed-eye visuals, at doses of up to 4{{nbsp}}mg orally.<ref name="Shulgin1978" /><ref name="SnyderWeingartnerFaillace1971" /><ref name="SnyderUngerBlatchley1974" /> However, Shulgin has stated that DOET is psychedelic at doses of 3{{nbsp}}mg and above orally.<ref name="ShulginManningDaley2011" />

In line with notions that DOET is a "psychic energizer" at lower doses, the related psychedelic DOPR has shown pro-motivational effects in rodents at sub-hallucinogenic doses<ref name="NobackKentonKlein2025">{{cite journal | vauthors = Noback M, Kenton JA, Klein AK, Hughes ZA, Kruegel AC, Schmid Y, Halberstadt AL, Young JW | title = Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice | journal = Neuropharmacology | volume = 268 | issue = | article-number = 110334 | date = February 2025 | pmid = 39900138 | doi = 10.1016/j.neuropharm.2025.110334 | url = | doi-access = free }}</ref><ref name="NobackKentonKlein2022">{{cite journal | vauthors = Noback M, Kenton J, Klein A, Hughes Z, Kruegel A, Young J | title = ACNP 61st Annual Meeting: Poster Abstracts P541 - P809: P572. 2,5-Dimethoxy-4-Propylamphetamine (DOPR) Increased Effortful Motivation in Mice | journal = Neuropsychopharmacology | volume = 47 | issue = Suppl 1 | pages = 371–520 (390–390) | date = December 2022 | pmid = 36456695 | pmc = 9714408 | doi = 10.1038/s41386-022-01486-z | url = }}</ref> and the related drug Ariadne (4C-DOM) has reportedly shown pro-motivational effects in monkeys despite being non-hallucinogenic.<ref name="PiHKAL1991-ARIADNE">{{cite book | author1 = Alexander T. Shulgin | author2 = Ann Shulgin | chapter = #8 ARIADNE; 4C-DOM; BL-3912; DIMOXAMINE; 1-(2,5- DIMETHOXY-4-METHYLPHENYL)-2-AMINOBUTANE; 2,5- DIMETHOXY-a-ETHYL-4-METHYLPHENETHYLAMINE | pages = 475–480 | chapter-url = https://www.erowid.org/library/books_online/pihkal/pihkal008.shtml | title = PiHKAL: A Chemical Love Story | date = 1991 | publisher = Transform Press | edition = 1st | location = Berkeley, CA | isbn = 978-0-9630096-0-9 | oclc = 25627628 | url = https://books.google.com/books?id=O8AdHBGybpcC | quote = His company did many animal tests, one of which showed that it was not hallucinogenic (a cat whose tail erected dramatically with DOM did nothing with ARIADNE) and another that showed re-motivation (some old maze-running monkeys who had decided not to run any more mazes changed their minds with ARIADNE).}}</ref> ASR-2001 (2CB-5PrO), a non-hallucinogenic analogue of the related psychedelic 2C-B, is under development for use as a stimulant-like medication for the treatment of psychiatric disorders.<ref name="Busby2023">{{cite web | vauthors = Busby M | title=The Heirs to a Vault of Novel Psychedelics Take a Trip Into the Unknown | website=DoubleBlind Mag | date=2 November 2023 | url=https://doubleblindmag.com/sasha-shulgin-legacy/ | access-date=19 April 2025}}</ref><ref name="Busby2025">{{cite web | vauthors = Busby M | title=What Happens When You Inherit 500 Psychedelic Compounds? | website=DoubleBlind Mag | date=30 March 2025 | url=https://doubleblindmag.com/what-happens-when-you-inherit-500-psychedelic-compounds/ | access-date=19 April 2025}}</ref><ref name="Kargbo2025">{{cite journal | vauthors = Kargbo RB | title = Innovative Approaches in Psychedelics, AI, and Communication: A Multi-Domain Perspective | journal = ACS Med Chem Lett | volume = 16 | issue = 4 | pages = 514–516 | date = April 2025 | pmid = 40236531 | doi = 10.1021/acsmedchemlett.5c00114 | pmc = 11995231 | url = }}</ref><ref name="Goldstein2023">{{cite web | vauthors = Goldstein L | title=Pioneering Psychedelics Scientist Alexander "Sasha" Shulgin's Legacy Lives On Via New Compounds And Research | website=Benzinga | date=10 July 2023 | url=https://www.benzinga.com/markets/cannabis/23/07/33171977/pioneering-psychedelics-scientist-alexander-sasha-shulgins-legacy-lives-on-via-new-compounds-and | access-date=19 April 2025}}</ref><ref name="WO2024243599A1">{{cite patent | country = WO | number = 2024243599A1 | invent1 = Mark J. Martini | invent2 = Nicholas V. Cozzi | invent3 = Paul F. Daley | invent4 = Thomas Szabo | status = patent | title = Asymmetric phenylalkylamines | pubdate = 28 November 2024 | gdate = | fdate = 28 May 2024 | pridate = | assign1 = Alexander Shulgin Research Institute | url = https://patents.google.com/patent/WO2024243599A1/ }}</ref>

==Interactions== {{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes}}

==Pharmacology== ===Pharmacodynamics=== {| class="wikitable floatright" style="font-size:small;" |+ {{Nowrap|DOET activities}} |- ! Target !! Affinity (Ki, nM) |- | 5-HT1A || 14–9,727 |- | 5-HT1B || 2,801 |- | 5-HT1D || 6,615 |- | 5-HT1E || 3,552 |- | 5-HT1F || {{Abbr|ND|No data}} |- | 5-HT2A || 12–100 (Ki) 0.34–31 ({{Abbrlink|EC50|half-maximal effective concentration}}) 88–112% ({{Abbrlink|Emax|maximal efficacy}}) |- | 5-HT2B || 29–174 (Ki) 68–236 ({{Abbr|EC50|half-maximal effective concentration}}) 73–108% ({{Abbr|Emax|maximal efficacy}}) |- | 5-HT2C || 101–108 (Ki) 0.57–17.0 ({{Abbr|EC50|half-maximal effective concentration}}) 82–102% ({{Abbr|Emax|maximal efficacy}}) |- | 5-HT3 || >10,000 |- | 5-HT4 || {{Abbr|ND|No data}} |- | 5-HT5A || >10,000 |- | 5-HT6 || >10,000 |- | 5-HT7 || 1,225 |- | α1A || 4,006–>10,000 |- | α1B || >10,000 |- | α1D || {{Abbr|ND|No data}} |- | α2A || 1,277–>4,970 |- | α2B || 574 |- | α2C || 1,447 |- | β1 || 5,723 |- | β2 || 2,195 |- | D1–D5 || >10,000 |- | H1–H4 || >10,000 |- | M1, M3, M4 || {{Abbr|ND|No data}} |- | M2, M5 || >10,000 |- | TAAR1 || >30,000 ({{Abbr|EC50|half-maximal effective concentration}}) |- | I1 || >10,000 |- | σ1 || 9,780 |- | σ2 || 9,560 |- | {{Abbrlink|SERT|Serotonin transporter}} || >10,000 (Ki) |- | {{Abbrlink|NET|Norepinephrine transporter}} || >10,000 (Ki) |- | {{Abbrlink|DAT|Dopamine transporter}} || >10,000 (Ki) |- class="sortbottom" | colspan="2" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. '''Refs:''' <ref name="PDSPKiDatabase">{{cite web | title=PDSP Database | website=UNC | url=https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=doet&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | language=zu | access-date=27 January 2025}}</ref><ref name="BindingDB">{{cite web | vauthors = Liu T | title=BindingDB BDBM81965 1-(4-ethyl-2,5-dimethoxyphenyl)propan-2-amine::CAS_62066::CHEMBL8224::DOET,(-)::NSC_62066 | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=81965 | access-date=5 November 2024}}</ref><ref name="Ray2010" /><ref name="LuethiGlatfelterPottie2025">{{cite journal | vauthors = Luethi D, Glatfelter GC, Pottie E, Sellitti F, Maitland AD, Gonzalez NR, Kryszak LA, Jackson SN, Hoener MC, Stove CP, Liechti ME, Smieško M, Baumann MH, Simmler LD, Rudin D | title = The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects | journal = Mol Psychiatry | volume = 31| issue = 3| pages = 1799–1809| date = November 2025 | pmid = 41193673 | doi = 10.1038/s41380-025-03325-1 | pmc = 12916490 | url = https://www.nature.com/articles/s41380-025-03325-1.pdf}}</ref><ref name="LuethiRudinHoener2022" /><ref name="LewinMillerGilmour2011" /><ref name="ÅstrandGuerrieriVikingsson2020">{{cite journal | vauthors = Åstrand A, Guerrieri D, Vikingsson S, Kronstrand R, Green H | title = In vitro characterization of new psychoactive substances at the μ-opioid, CB1, 5HT1A, and 5-HT2A receptors-On-target receptor potency and efficacy, and off-target effects | journal = Forensic Science International | volume = 317 | article-number = 110553 | date = December 2020 | pmid = 33160102 | doi = 10.1016/j.forsciint.2020.110553 | doi-access = free }}</ref><ref name="vanWijngaardenSoudijn1997">{{cite book | vauthors = van Wijngaarden I, Soudijn W | title=Pharmacochemistry Library | chapter=5-HT2A, 5-HT2B and 5-HT2C receptor ligands | publisher=Elsevier | volume=27 | date=1997 | isbn=978-0-444-82041-9 | doi=10.1016/s0165-7208(97)80013-x | pages=161–197}}</ref><ref name="WallachCaoCalkins2023">{{cite journal | vauthors = Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD | title = Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential | journal = Nat Commun | volume = 14 | issue = 1 | article-number = 8221 | date = December 2023 | pmid = 38102107 | pmc = 10724237 | doi = 10.1038/s41467-023-44016-1 | bibcode = 2023NatCo..14.8221W }}</ref> |}

DOET acts as a selective serotonin 5-HT2 receptor agonist, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.<ref name="LuethiGlatfelterPottie2025" /><ref name="LuethiRudinHoener2022">{{cite journal | vauthors = Luethi D, Rudin D, Hoener MC, Liechti ME | title=Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines | journal=The FASEB Journal | volume=36 | issue=S1 | date=2022 | issn=0892-6638 | doi=10.1096/fasebj.2022.36.S1.R2691 | article-number=fasebj.2022.36.S1.R2691 | doi-access=free | url=https://www.researchgate.net/publication/360369275 }}</ref><ref name="Ray2010">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 |article-number=e9019 | date = February 2010 | pmid = 20126400 | pmc = 2814854 | doi = 10.1371/journal.pone.0009019 | doi-access = free | bibcode = 2010PLoSO...5.9019R }}</ref><ref name="Glennon1987">{{cite journal | vauthors = Glennon RA | title = Central serotonin receptors as targets for drug research | journal = J Med Chem | volume = 30 | issue = 1 | pages = 1–12 | date = January 1987 | pmid = 3543362 | doi = 10.1021/jm00384a001 | url = | quote = Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites}}</ref> In one study, its affinities (Ki) were 12{{nbsp}}nM for the serotonin 5-HT2A receptor, 108{{nbsp}}nM for the serotonin 5-HT2C receptor (9-fold lower than for 5-HT2A), and 9,727{{nbsp}}nM for the serotonin 5-HT1A receptor (811-fold lower than for 5-HT2A).<ref name="LuethiRudinHoener2022" /> The drug's {{Abbrlink|EC50|half-maximal effective concentration}} for activation of the serotonin 5-HT2A receptor was 1.7 to 8.1{{nbsp}}nM depending on the intracellular signaling cascade, while its {{Abbrlink|Emax|maximal efficacy}} was 99%.<ref name="LuethiRudinHoener2022" /> At the serotonin 5-HT2B receptor, its {{Abbr|EC50|half-maximal effective concentration}} was 68{{nbsp}}nM (8- to 40-fold lower than for 5-HT2A) and its {{Abbr|Emax|maximal efficacy}} was 73%.<ref name="LuethiRudinHoener2022" /> DOET is a full agonist of the serotonin 5-HT2A receptor and a high-efficacy partial agonist of the serotonin 5-HT2B and 5-HT2C receptors.<ref name="LuethiRudinHoener2022" /><ref name="Ray2010" /> The drug is a very weak or inactive agonist of the human trace amine-associated receptor 1 (TAAR1) and is inactive at the rhesus monkey TAAR1.<ref name="LewinMillerGilmour2011">{{cite journal | vauthors = Lewin AH, Miller GM, Gilmour B | title = Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journal = Bioorganic & Medicinal Chemistry | volume = 19 | issue = 23 | pages = 7044–7048 | date = December 2011 | pmid = 22037049 | pmc = 3236098 | doi = 10.1016/j.bmc.2011.10.007 }}</ref><ref name="LuethiRudinHoener2022" /> In contrast to many other amphetamines, but like other DOx drugs, DOET does not bind to the monoamine transporters.<ref name="LuethiRudinHoener2022" /><ref name="Ray2010" />

DOET produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents.<ref name="LuethiGlatfelterPottie2025" /><ref name="HalberstadtChathaKlein2020">{{cite journal | vauthors = Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD | title = Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species | journal = Neuropharmacology | volume = 167 | issue = | article-number = 107933 | date = May 2020 | pmid = 31917152 | pmc = 9191653 | doi = 10.1016/j.neuropharm.2019.107933 | url = }}</ref> As with other psychedelics, DOET shows a biphasic or inverted U-shaped dose–response curve for production of the HTR.<ref name="LuethiGlatfelterPottie2025" /><ref name="HalberstadtChathaKlein2020" /> The drug induces the HTR to a similar maximal extent as other related psychedelics like DOM and DOI.<ref name="LuethiGlatfelterPottie2025" /><ref name="HalberstadtChathaKlein2020" /> DOET substitutes for the phenethylamine psychedelics mescaline and DOM, partially substitutes for the tryptamine psychedelic 5-MeO-DMT, and does not substitute for the psychostimulant dextroamphetamine in animal drug discrimination tests.<ref name="Winter1975">{{cite journal | vauthors = Winter JC | title = The effects of 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-ethylamphetamine (DOET), d-amphetamine, and cocaine in rats trained with mescaline as a discriminative stimulus | journal = Psychopharmacologia | volume = 44 | issue = 1 | pages = 29–32 | date = October 1975 | pmid = 1197576 | doi = 10.1007/BF00421179 | url = }}</ref><ref name="SilvermanHo1980">{{cite journal | vauthors = Silverman PB, Ho BT | title = The discriminative stimulus properties of 2,5-dimethoxy-4-methylamphetamine (DOM): differentiation from amphetamine | journal = Psychopharmacology (Berl) | volume = 68 | issue = 3 | pages = 209–215 | date = 1980 | pmid = 6771804 | doi = 10.1007/BF00428105 | url = }}</ref><ref name="GlennonDootYoung1981">{{cite journal | vauthors = Glennon RA, Doot DL, Young R | title = DOM and related 2,5-dimethoxy-4-alkylphenylisopropylamines: behavioral and serotonin receptor properties | journal = Pharmacol Biochem Behav | volume = 14 | issue = 3 | pages = 287–292 | date = March 1981 | pmid = 7232455 | doi = 10.1016/0091-3057(81)90392-0 | url = }}</ref><ref name="GlennonYoungRosecrans1982">{{cite journal | vauthors = Glennon RA, Young R, Rosecrans JA | title = A comparison of the behavioral effects of DOM homologs | journal = Pharmacol Biochem Behav | volume = 16 | issue = 4 | pages = 557–559 | date = April 1982 | pmid = 7071089 | doi = 10.1016/0091-3057(82)90414-2 | url = }}</ref> DOET produces hyperlocomotion in mice.<ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | chapter-url = }}</ref><ref name="HalberstadtPowellGeyer2013">{{cite journal | vauthors = Halberstadt AL, Powell SB, Geyer MA | title = Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice | journal = Neuropharmacology | volume = 70 | issue = | pages = 218–227 | date = July 2013 | pmid = 23376711 | pmc = 3934507 | doi = 10.1016/j.neuropharm.2013.01.014 | url = }}</ref><ref name="HuangHo1975">{{cite journal | vauthors = Huang J, Ho BT | title = Some pharmacological actions of 2,5-dimethoxy-4-ethylamphetamine (DOET) in rats and mice | journal = J Pharm Pharmacol | volume = 27 | issue = 1 | pages = 18–22 | date = January 1975 | pmid = 235610 | doi = 10.1111/j.2042-7158.1975.tb09372.x | url = }}</ref> However, like other psychedelics, it shows a biphasic or inverted U-shaped dose–response curve, increasing locomotor activity at low to moderate doses and reducing it at high doses.<ref name="HalberstadtGeyer2018" /><ref name="HalberstadtPowellGeyer2013" /><ref name="HuangHo1975" /> DOET produces serotonin receptor-dependent pressor and hyperthermic effects in rodents.<ref name="HuangHo1975" />

===Pharmacokinetics=== In terms of effects in humans, the onset of lower doses of DOET and its individual enantiomers (0.75–4{{nbsp}}mg) is 1 to 3{{nbsp}}hours, peak effects occur after 3 to 5{{nbsp}}hours, and the duration is 5 to 10{{nbsp}}hours.<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="SnyderWeingartnerFaillace1971" /><ref name="SnyderUngerBlatchley1974" /> At higher doses of DOET (2 to 6{{nbsp}}mg), the duration was reported to be 14 to 20{{nbsp}}hours.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /> DOET, like other DOx drugs, has an unusually slow onset and long duration.<ref name="Bonson2005">{{cite book | author=Katherine R. Bonson | chapter=Hallucinogenic Drugs | pages=294–307 | title=Encyclopedia of Life Sciences | publisher=Wiley | date=9 September 2005 | isbn=978-0-470-01617-6 | doi=10.1002/9780470015902.a0000166.pub2 | quote = In the mid-1960s, structure–activity relationship investigations led to the synthesis of a new phenethylamine hallucinogen, 2,5-dimethoxy-4-methylamphetamine (DOM). [...] A threshold dose of DOM ranges from 3 to 10 mg orally. An extensive family of DOM derivatives have been synthesised, including DOB (substituting bromine at the 4-position), DOI (substituting an iodine group at the 4-position), and DOET (substituting an ethyl group at the 4-position) (Shulgin and Shulgin, 1991a,1991b). These drugs have a long onset time (up to 2 h) and their effects can persist for 15–20 h. The unusually long duration is related to their chemical structure. The presence of an alpha-methyl group on the phenethylamine physically prevents enzymatic degradation of the drug, extending the time the drug acts in the body. }}</ref> The drug crosses the blood–brain barrier in rodents.<ref name="LuethiGlatfelterPottie2025" /> DOET is metabolized by oxidation of the ethyl group at the 4 position in rodents.<ref name="Shulgin1978" /><ref name="TanseyEstevezHo1975">{{cite journal | vauthors = Tansey LW, Estevez VS, Ho BT | title = Metabolic study of 2,5-dimethoxy-4-ethylamphetamine (DOET) in rats | journal = Proc West Pharmacol Soc | volume = 18 | issue = | pages = 362 | date = 1975 | pmid = 1182040 | doi = | url = }}</ref> It appears to be metabolized more quickly than DOM.<ref name="Shulgin1978" /> In humans, DOET is excreted 10 to 40% in urine unchanged within 24{{nbsp}}hours.<ref name="Shulgin1978" /><ref name="WillsErickson2012" /><ref name="SnyderFaillaceWeingartner1968" /> The greatest excretion rate occurred between 3 and 6{{nbsp}}hours.<ref name="Shulgin1978" /><ref name="SnyderFaillaceWeingartner1968" />

==Chemistry== DOET, also known as 4-ethyl-2,5-dimethoxyamphetamine or as 4-ethyl-2,5-dimethoxy-α-methylphenethylamine, is a substituted phenethylamine and amphetamine and is a member of the DOx group of drugs.<ref name="ShulginManningDaley2011" /><ref name="PiHKAL" /><ref name="WillsErickson2012" /><ref name="Shulgin1978" /> It is structurally related to the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine).<ref name="Shulgin1978" /><ref name="HassanBoschSingh2017">{{cite journal | vauthors = Hassan Z, Bosch OG, Singh D, Narayanan S, Kasinather BV, Seifritz E, Kornhuber J, Quednow BB, Müller CP | title = Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs | journal = Front Psychiatry | volume = 8 | issue = | article-number = 152 | date = 2017 | pmid = 28868040 | pmc = 5563308 | doi = 10.3389/fpsyt.2017.00152 | doi-access = free | url = | quote = The next, even though less accidental, producer of NPS hallucinogens was Alexander T. Shulgin, who synthesized hundreds of novel hallucinogenic tryptamines and phenylethylamines in his home laboratory. He described the synthesis of these compounds and also their psychotomimetic effects experienced in self-experiments in detail in his books PIHKAL and TIHKAL (199, 200). He created several dimethoxy-substituted phenylethylamines, such as DOM, 2,5-dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-iodoamphetamine (DOI), and 2,5-dimethoxy-4-ethylamphetamine (DOET), which all display strong hallucinogenic properties. These drugs usually have much longer durations of action (12–30 h) and are much more potent agonists at 5-HT2A-Rs (50- to 175-fold) compared to their related phenylethylamine derivative mescaline (duration of action: 4–8 h) (189, 199, 200). }}</ref>

===Synthesis=== The chemical synthesis of DOET has been described.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" />

===Analogues=== Analogues of DOET include other DOx drugs such as DOM, DOPR, DOBU, DOAM, DOB, DOI, DOEF, and DOTFE, among others.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /><ref name="Shulgin1978" /> The α-desmethyl or phenethylamine analogue of DOET is 2C-E.<ref name="ShulginManningDaley2011" /><ref name="PiHKAL" /> Ariadne is the α-ethyl or phenylisobutylamine analogue of DOM.<ref name="CunninghamBockSerrano2023" /><ref name="PiHKAL" />

==History== {{See also|DOx#History}}

DOET was discovered by Alexander Shulgin in the 1960s.<ref name="Baggott2023" /> He assessed DOET after synthesizing DOM in 1963 and discovering DOM's psychedelic effects in 1964.<ref name="Baggott2023" /><ref name="CanalMorgan2012">{{cite journal | vauthors = Canal CE, Morgan D | title = 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 | journal = Drug Test Anal | volume = 4 | issue = 7–8 | pages = 556–576 | date = 2012 | pmid = 22517680 | pmc = 3722587 | doi = 10.1002/dta.1333 | url = }}</ref><ref name="openDemocracy2014">{{cite web | title=Alexander Theodore Shulgin (1925-2014) | website=openDemocracy | date=9 June 2014 | url=https://www.opendemocracy.net/en/alexander-theodore-shulgin-19252014/ | access-date=26 January 2025 | quote=[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. }}</ref><ref name="ShulginManningDaley2011" /> Shulgin found that DOET was a remarkable "psychic energizer" at low doses without producing psychedelic effects at these doses.<ref name="Baggott2023" /> The effects that he experienced included positive mood, talkativeness, and disinhibition that lasted the whole day.<ref name="Baggott2023" /> In contrast to Shulgin however, a friend and colleague of Shulgin's that he had try DOET a month later only experienced intense lethargy followed by profound depression after taking the drug.<ref name="Baggott2023" /> Nonetheless, Shulgin's enthusiasm was not dissuaded, and he felt that the drug should be exploited.<ref name="Baggott2023" /> Shulgin was working at Dow Chemical Company at the time, and he pitched DOET to the company.<ref name="Baggott2023" /> They selected DOET as a promising compound and decided to move forward with clinical trials for potential use as a pharmaceutical drug.<ref name="Baggott2023" /> Shulgin and the company filed a patent for DOET in 1966, which was published in 1970.<ref name="Baggott2023" /><ref name="CanalMorgan2012" /><ref name="ShulginManningDaley2011" /><ref name="US3547999A">{{cite web | title=phenethylamines and their pharmacologically-acceptable salts | website=Google Patents | date=1970 | url=https://patents.google.com/patent/US3547999A/en | access-date=26 January 2025}}</ref> Dow Chemical Company tasked neuroscientist Solomon H. Snyder at Johns Hopkins University with clinically studying DOET.<ref name="Baggott2023" />

In 1967, DOM emerged as a street drug and LSD replacement with the name "STP" in San Francisco and caused a small public health crisis.<ref name="Baggott2023" /><ref name="TroutDaley2024">{{cite journal | vauthors = Trout K, Daley PF | title = The origin of 2,5-dimethoxy-4-methylamphetamine (DOM, STP) | journal = Drug Test Anal | volume = 16 | issue = 12 | pages = 1496–1508 | date = December 2024 | pmid = 38419183 | doi = 10.1002/dta.3667 | url = https://shulginresearch.net/wp-content/uploads/2024/03/The-origin-of-25-dimethoxy-4-methylamphetamine-DOM-STP.-Trout.-Drug-Test.-Anal.-DOI-10.1002-dta.3667-2024.pdf}}</ref> This occurred after LSD distributor Owsley Stanley learned of DOM from Shulgin and began distributing very-high-dose DOM tablets for free.<ref name="Baggott2023" /><ref name="TroutDaley2024" /> LSD had become illegal in California in 1966 and an alternative had been sought by Stanley.<ref name="Baggott2023" /> The DOET tablets he distributed could have very long durations (up to 3–4{{nbsp}}days) and resulted in intense experiences, worrying physical side effects, and hospitalizations.<ref name="Baggott2023" /> DOM was first described in the media and scientific literature in 1967 as a result of the crisis.<ref name="Baggott2023" /><ref name="SnyderFaillaceHollister1967">{{cite journal | vauthors = Snyder SH, Faillace L, Hollister L | title = 2,5-dimethoxy-4-methyl-amphetamine (STP): a new hallucinogenic drug | journal = Science | volume = 158 | issue = 3801 | pages = 669–670 | date = November 1967 | pmid = 4860952 | doi = 10.1126/science.158.3801.669 | bibcode = 1967Sci...158..669S | url = }}</ref><ref name="SnyderFaillaceWeingartner1968" /> The drug became illegal in the United States in 1968.<ref name="Baggott2023" /> It is unclear why Shulgin told Stanley about DOM and risked his professional career as well as the DOET clinical development.<ref name="Baggott2023" /><ref name="TroutDaley2024" /> 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.<ref name="Baggott2023" /><ref name="TroutDaley2024" />

Dow Chemical Company terminated its clinical research program on DOET due to the DOM public health crisis.<ref name="Baggott2023" /> DOET was subsequently first described in the scientific literature by Snyder and colleagues in 1968.<ref name="SnyderFaillaceWeingartner1968" /> Snyder continued to be interested in DOET as a potential medicine, but it was never further developed.<ref name="SnyderFaillaceWeingartner1968" /> Snyder conducted and published a series of three clinical trials of low-dose DOET between 1968 and 1974.<ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="WeingartnerSnyderFaillace1970" /><ref name="SnyderWeingartnerFaillace1971" /><ref name="SnyderUngerBlatchley1974" /> In these trials, he compared DOET with DOM, dextroamphetamine, and placebo.<ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="SnyderWeingartnerFaillace1971" /><ref name="SnyderUngerBlatchley1974" /> As with Shulgin, he found DOET to produce amphetamine-like mild euphoria and talkativeness, among other effects, without producing significant hallucinogenic effects at the assessed doses.<ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="SnyderWeingartnerFaillace1971" /> Snyder also studied the individual enantiomers of DOET.<ref name="Shulgin1978" /><ref name="AndersonBraunBraun1978" /><ref name="SnyderUngerBlatchley1974" /> Shulgin first discussed DOET in publications in 1969 and 1970.<ref name="CanalMorgan2012" /><ref name="Baggott2023" /><ref name="Shulgin1969">{{cite journal | vauthors = Shulgin AT | title=Psychotomimetic Agents Related to the Catecholamines | journal=Journal of Psychedelic Drugs | volume=2 | issue=2 | date=1969 | issn=0022-393X | doi=10.1080/02791072.1969.10524409 | pages=14–19}}</ref><ref name="Shulgin1970">{{cite book | author = Alexander Shulgin | chapter = Chemistry and Structure-Activity Relationships of the Psychotomimetics | editor = D. H. Efron | title = Psychotomimetic Drugs | publisher = Raven Press | location = New York | pages = 21–41 | date = 1970 | url = https://www.erowid.org/library/books_online/psychotomimetic_drugs.pdf#page=23 }}</ref> DOET became a Schedule I controlled substance in the United States in February 1973.<ref name="Shulgin2003">{{cite book | vauthors = Shulgin AT | chapter=Basic Pharmacology and Effects | pages=67–137 | veditors = Laing RR | title=Hallucinogens: A Forensic Drug Handbook | publisher=Elsevier Science | series=Forensic Drug Handbook Series | year=2003 | isbn=978-0-12-433951-4 | url=https://books.google.com/books?id=l1DrqgobbcwC | chapter-url=https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6 | access-date=1 February 2025}}</ref>

Ariadne (4C-D, 4C-DOM, BL-3912, Dimoxamine), the α-ethyl or phenylisobutylamine analogue of DOM, was developed by Shulgin in the 1970s.<ref name="CunninghamBockSerrano2023">{{cite journal | vauthors = Cunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, Lankri D, Duggan P, Nazarova AL, Cao AB, Calkins MM, Khirsariya P, Hwu C, Katritch V, Chandra SS, McCorvy JD, Sames D | title = Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs | journal = ACS Chemical Neuroscience | volume = 14 | issue = 1 | pages = 119–135 | date = January 2023 | pmid = 36521179 | pmc = 10147382 | doi = 10.1021/acschemneuro.2c00597 }}</ref><ref name="PiHKAL" /> He found it to be psychoactive and to produce "the alert of a psychedelic, with none of the rest of the package".<ref name="PiHKAL" /><ref name="CunninghamBockSerrano2023" /> This threshold psychoactivity without psychedelic effects was reminiscent of low doses of DOET.<ref name="PiHKAL" /><ref name="CunninghamBockSerrano2023" /> However, in contrast to DOET and other DOx drugs like DOM, Ariadne remained completely non-hallucinogenic even at very high doses, showing a hard ceiling to its psychoactive effects and a lack of recreational potential.<ref name="PiHKAL" /><ref name="CunninghamBockSerrano2023" /> Ariadne was patented and developed by Shulgin and Bristol Laboratories for potential use as an antidepressant and for a variety of other clinical indications in the 1970s.<ref name="ShulginManningDaley2011" /><ref name="CunninghamBockSerrano2023" /><ref name="PiHKAL" /> (''R'')-Ariadne (BL-3912A) completed phase 2 clinical trials and showed promising initial clinical benefits.<ref name="CunninghamBockSerrano2023" /> However, further clinical development was halted for strategic economic reasons.<ref name="CunninghamBockSerrano2023" /> In 2023, Ariadne was found to exhibit reduced-efficacy partial agonism of the serotonin 5-HT2A receptor compared to DOM, and this was considered to account for its dramatically reduced hallucinogenic potential.<ref name="CunninghamBockSerrano2023" />

Shulgin first synthesized 2C-E, the α-desmethyl or phenethylamine analogue of DOET, in 1977.<ref name="DariePraisler2021">{{cite journal | vauthors = Darie IF, Praisler M, Negoita C | title= 2C-x and DOx hallucinogens: A systematic review| journal= Annals of the "Dunarea de Jos" University of Galati Fascicle II Mathematics Physics Theoretical Mechanics| volume=44 | issue=1 | date=12 November 2021 | issn=2668-7151 | doi=10.35219/ann-ugal-math-phys-mec.2021.1.07 | doi-access=free | pages=46–52 | url=https://www.gup.ugal.ro/ugaljournals/index.php/math/article/download/4925/4350 | access-date=26 January 2025}}</ref><ref name="Shulgin1980">{{cite book|author=Alexander Shulgin|author-link=Alexander Shulgin|title=Pharmacology Notes II (The Shulgin Lab Books)|publisher=Erowid|url=https://erowid.org/library/books_online/shulgin_labbooks/shulgin_pharmacology_notebook9_searchable.pdf|page=236|place=Lafayette, CA, USA|year=1980}}</ref> Shulgin first published reports describing the psychedelic effects of higher doses of DOET in PiHKAL in 1991.<ref name="PiHKAL" /> 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.<ref name="Shulgin1978" /><ref name="SnyderFaillaceWeingartner1968" /><ref name="SnyderFaillace1969" /><ref name="SnyderUngerBlatchley1974" /> Shulgin also described 2C-E as producing robust psychedelic effects in PiHKAL, though with much higher doses required than DOET.<ref name="PiHKAL" />

==Society and culture==

===Names=== DOET was originally named DOE by Alexander Shulgin.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /> However, he subsequently recalled that this was also an acronym for desoxyephedrine (methamphetamine).<ref name="PiHKAL" /> As a result, he changed his name for the drug from DOE to DOET or DOEt.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" /> Other names that Shulgin has given DOET have included HECATE or Hecate (after the Greek goddess) and DMEA (short for dimethoxyethylamphetamine).<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" />

===Legal status=== ====United Nations==== Internationally, DOET is a Schedule I controlled drug; under the Convention on Psychotropic Substances, it is legal only for medical uses or scientific research.<ref name="INCB">{{Cite report |url=http://www.incb.org/pdf/e/list/green.pdf |title=List of psychotropic substances under international control |date=August 2003|archive-url=https://web.archive.org/web/20070302130637/http://www.incb.org/pdf/e/list/green.pdf|archive-date=March 2, 2007}}</ref>

====Australia==== DOET is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).<ref name="Poisons Standard">{{cite web | title = Poisons Standard | date = October 2015 | url = https://www.comlaw.gov.au/Details/F2015L01534 | work = Therapeutics Goods Administration | publisher = Australian Government }}</ref> 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.<ref name="Poisons Standard" />

====Canada==== DOET is a controlled substance in Canada.<ref name="CDSA">{{cite web | title=Controlled Drugs and Substances Act | website=Department of Justice Canada | url=https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html | access-date=19 January 2026}}</ref>

====United States==== DOET is classified as a Schedule I substance in the United States.<ref name="Shulgin2003" /><ref name="INCB" />

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/66 DOET - Isomer Design] * [https://erowid.org/experiences/subs/exp_DOET.shtml DOET Experience Reports - Erowid] * [https://www.erowid.org/library/books_online/pihkal/pihkal066.shtml DOET - PiHKAL - Erowid] * [https://isomerdesign.com/PiHKAL/read.php?domain=pk&id=66 DOET - PiHKAL - Isomer Design] * [https://tripsitter.com/doet/ DOET: Exploring This Rare DOX Psychedelic - Tripsitter]

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