2,5-Dimethoxy-4-ethylamphetamine

Psychedelic drug the book The Design of Everyday Things vanc 6 verified verified 477211641 DOET DOET structure.svg skin-invert-image 225px DOET ball-and-stick structure.png bg-transparent 185px Serotonin 5-HT2 receptor agonist; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen; Stimulant; Antidepressant; Psychic energizer; Cognitive enhancer None Schedule 9 F2 Anvisa Brazilian Health Regulatory Agency 2023-07-24 RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 live 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 2023-08-27 2023-08-27 Diário Oficial da União pt-BR 2023-07-25 Schedule I Anlage I P I Schedule I Class A 1–3hours Oxidation of the 4-position ethyl group 5–20hours Urine (10–40% unchanged within 24hours) correct cas 22004-32-6 correct FDA 9SK6K682UL 27402 correct drugbank DB01467 correct chemspider 25499 correct EBI 8224 correct kegg C22714 DOET; DOEt; DOE; HECATE; Hecate; DMEA; 4-Ethyl-2,5-dimethoxyamphetamine; 2,5-Dimethoxy-4-ethylamphetamine; Dimethoxyethylamphetamine; Ethyldimethoxyamphetamine 1-(4-Ethyl-2,5-dimethoxyphenyl)propan-2-amine 13 21 1 2 O(c1cc(c(OC)cc1CC(N)C)CC)C correct chemspider 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 correct chemspider 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. Shulgin A, Manning T, Daley PF #56. DOET (2,5-Dimethoxy-4-ethylamphetamine) The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds Transform Press Berkeley 1 2011 978-0-9630096-3-0 106–110 https://archive.org/details/shulgin-index-vol-1/page/106/mode/1up?view=theater Wills B, Erickson T Psychoactive Phenethylamine, Piperazine, and Pyrrolidinophenone Derivatives Barceloux DG Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants Wiley 9 March 2012 978-0-471-72760-6 10.1002/9781118105955.ch10 156–192 Iversen LL, Iversen SD, Snyder SH Shulgin AT Stimulants Psychotomimetic Drugs: Structure-Activity Relationships Springer US Boston, MA 1978 978-1-4757-0512-6 10.1007/978-1-4757-0510-2_6 243–333 https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261 It is closely related to DOM and is a synthetic analogue of the naturally occurring phenethylamine psychedelic mescaline. The drug is the derivative of DOM in which the methyl group at the 4 position has been replaced with a ethyl group. It is taken orally. DOET has a slow onset of 1 to 3hours, a delayed peak of 3 to 5hours, and a dose-dependent and potentially very long duration of 5 to 20hours. Effects of DOET at low doses include mild euphoria, enhanced self-awareness, and talkativeness, among others. Mild closed-eye visuals can also occur. At higher doses, DOET produces psychedelic effects including heightened emotions, sensory enhancement, rich closed-eye visuals, and open-eye visuals, among others. Physical effects include pupil dilation, increased heart rate, and increased blood pressure. It acts as a selective agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. DOET was first discovered by Alexander Shulgin in the 1960s. Baggott MJ Learning about STP: A Forgotten Psychedelic from the Summer of Love History of Pharmacy and Pharmaceuticals 65 1 1 October 2023 2694-3034 10.3368/hopp.65.1.93 free 93–116 https://hopp.uwpress.org/content/wphopp/65/1/93.full.pdf 26 January 2025 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. However, its development was terminated after DOM emerged as a street drug and caused a small public health crisis in San Francisco in 1967. Nonetheless, DOET's effects at low doses were extensively characterized in small clinical trials. 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.https://erowid.org/library/books_online/pihkal/pihkal066.shtml PiHKAL: A Chemical Love Story Shulgin A, Shulgin A September 1991 Transform Press 0-9630096-0-5 United States 978 Use and effects In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists DOET's dose as 2 to 6mg orally and its duration as 14 to 20hours. In experience reports of DOET at doses of 1 to 7mg orally in different individuals, 1mg produced relaxation but no psychedelic effects; 2.5mg produced both open- and closed-eye visuals; 4mg produced mood-energizing effects but very little or no hallucinogenic effect; 6mg produced sensory enhancement, rich closed-eye visuals, and no open-eye visual movement; and 7mg produced strong feelings with themes of love, eroticism, and divinity, openness, not much visually, closed-eye visuals, and body load symptoms. There was considerable variation between individuals in terms of subjective effects. Shulgin has described both DOET and DOM as being effective antidepressants at lower doses and DOET as being a cognitive enhancer at modest doses.Mulé, SJ, Brill H Shulgin AT Hallucinogens, CNS Stimulants, And Cannabis Chemical and Biological Aspects of Drug Dependence CRC Press 1972 978-0-87819-011-9 10.1201/9780429260629-16 163–176 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=8d86c9d6e58771ccef891e76483b86fceee153f8 https://books.google.com/books?id=-edsAAAAMAAJ DOET, also known as Hecate, is one of Shulgin's "ten classic ladies", a series of methylated DOM derivatives. Ger A, Ger D Triple Goddess of the Night British Neuroscience Association Bulletin 63 28–30 https://isomerdesign.com/bitnest/external/BNAB/63.30 In a 1968 clinical trial, DOET at an oral dose of 1.5mg (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. Snyder SH, Faillace LA, Weingartner H DOM (STP), a new hallucinogenic drug, and DOET: effects in normal subjects Am J Psychiatry 125 3 113–120 September 1968 4385937 10.1176/ajp.125.3.357 Snyder SH, Faillace LA, Weingartner H A new psychotropic agent. Psychological and physiological effects of 2,5-dimethoxy-4-ethyl amphetamine (DOET) in man Arch Gen Psychiatry 21 1 95–101 July 1969 4389442 10.1001/archpsyc.1969.01740190097014 Weingartner H, Snyder SH, Faillace LA, Markley H Altered free associations: Some cognitive effects of DOET (2, 5-dimethoxy-4-ethylamphetamine) Behavioral Science 15 4 1970 10.1002/bs.3830150402 297–303 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. Some of the effects of DOET in the study resembled those of dextroamphetamine, including talkativeness, euphoria, and feeling alert. The subjective effects began 1 to 1.5hours after dosing, peaked around 3 to 4hours after administration, and the duration was about 5 to 6hours. Pupil dilation was also observed, but there were no marked changes in heart rate or blood pressure. There were also changes on cognitive tests of association and serial learning. The effects of DOET were similar to those of low doses of DOM (2.7–3.3mg) but DOET appeared to be more potent (with 2.0mg DOM being indistinguishable from placebo). In a subsequent 1971 clinical trial, DOET hydrochloride at oral doses of 0.75 to 4mg again produced pupil dilation (dose-dependent), mild euphoria, feelings of enhanced self-awareness, and many of the other effects observed in the previous trial. Snyder SH, Weingartner H, Faillace LA DOET (2,5-dimethoxy-4-ethylamphetamine), a new psychotropic drug. Effects of varying doses in man Arch Gen Psychiatry 24 1 50–55 January 1971 4923215 10.1001/archpsyc.1971.01750070052006 Once again, there were no hallucinogenic effects, aside from closed-eye visuals in a minority of individuals, and there was no cognitive impairment. New assessed and reported effects included feeling relaxed, feelings of unpleasantness in some, lightheadedness, reduced depressive feelings, and feeling anxious or restless. The feelings of nervousness and restlessness occurred more at the higher doses. DOET appeared to show a greater apparent separation between threshold and hallucinogenic doses than had been documented for other psychedelics. Other psychedelics like LSD and DOM show a 2- to 3-fold separation, whereas DOET showed an at least 5-fold separation. 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. Standridge RT, Howell HG, Gylys JA, Partyka RA, Shulgin AT Phenylakylamines with potential psychotherapeutic utility. 1. 2-Amino-1-(2,5-dimethoxy-4-methylphenyl)butane J Med Chem 19 12 1400–1404 December 1976 1003425 10.1021/jm00234a010 https://erowid.org/archive/rhodium/pdf/shulgin/shulgin.4c-dom.pdf 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 A third and final 1974 clinical trial assessed oral doses of 1 to 4mg (S)-(+)-DOET, 1 to 2mg (R)-(−)-DOET, and 2 to 4mg (RS)-(±)-DOET. Anderson GM, Braun G, Braun U, Nichols DE, Shulgin AT Absolute configuration and psychotomimetic activity NIDA Research Monograph 22 8–15 1978 101890 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=2ab674b010611df18c029a78f6d17e52dba5f82f Snyder SH, Unger S, Blatchley R, Barfknecht CF Stereospecific actions of DOET (2,5-dimethoxy-4-ethylamphetamine) in man Arch Gen Psychiatry 31 1 103–106 July 1974 4599412 10.1001/archpsyc.1974.01760130079013 It was found that 1mg (R)-(−)-DOET was equivalent to 4mg (S)-(+)-DOET in producing psychoactive effects and hence that (R)-(−)-DOET was about 4times as potent as (S)-(+)-DOET. The onset was 1.5 to 3hours, peak effects were at 4 to 5hours, and the duration was 6 to 10hours. 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. No hallucinogenic effects or visual distortions with eyes open occurred, but vivid imagery with eyes closed could be experienced at the higher doses. Based on the preceding clinical trials, DOET does not produce clear hallucinogenic effects, aside from closed-eye visuals, at doses of up to 4mg orally. However, Shulgin has stated that DOET is psychedelic at doses of 3mg and above orally. 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 Noback M, Kenton JA, Klein AK, Hughes ZA, Kruegel AC, Schmid Y, Halberstadt AL, Young JW Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice Neuropharmacology 268 110334 February 2025 39900138 10.1016/j.neuropharm.2025.110334 free Noback M, Kenton J, Klein A, Hughes Z, Kruegel A, Young J ACNP 61st Annual Meeting: Poster Abstracts P541 - P809: P572. 2,5-Dimethoxy-4-Propylamphetamine (DOPR) Increased Effortful Motivation in Mice Neuropsychopharmacology 47 Suppl 1 371–520 (390–390) December 2022 36456695 9714408 10.1038/s41386-022-01486-z and the related drug Ariadne (4C-DOM) has reportedly shown pro-motivational effects in monkeys despite being non-hallucinogenic. Alexander T. Shulgin Ann Shulgin #8 ARIADNE; 4C-DOM; BL-3912; DIMOXAMINE; 1-(2,5- DIMETHOXY-4-METHYLPHENYL)-2-AMINOBUTANE; 2,5- DIMETHOXY-a-ETHYL-4-METHYLPHENETHYLAMINE 475–480 https://www.erowid.org/library/books_online/pihkal/pihkal008.shtml PiHKAL: A Chemical Love Story 1991 Transform Press 1st Berkeley, CA 978-0-9630096-0-9 25627628 https://books.google.com/books?id=O8AdHBGybpcC 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). 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. Busby M The Heirs to a Vault of Novel Psychedelics Take a Trip Into the Unknown DoubleBlind Mag 2 November 2023 https://doubleblindmag.com/sasha-shulgin-legacy/ 19 April 2025 Busby M What Happens When You Inherit 500 Psychedelic Compounds? DoubleBlind Mag 30 March 2025 https://doubleblindmag.com/what-happens-when-you-inherit-500-psychedelic-compounds/ 19 April 2025 Kargbo RB Innovative Approaches in Psychedelics, AI, and Communication: A Multi-Domain Perspective ACS Med Chem Lett 16 4 514–516 April 2025 40236531 10.1021/acsmedchemlett.5c00114 11995231 Goldstein L Pioneering Psychedelics Scientist Alexander "Sasha" Shulgin's Legacy Lives On Via New Compounds And Research Benzinga 10 July 2023 https://www.benzinga.com/markets/cannabis/23/07/33171977/pioneering-psychedelics-scientist-alexander-sasha-shulgins-legacy-lives-on-via-new-compounds-and 19 April 2025 11 July 2023 https://web.archive.org/web/20230711121547/https://www.benzinga.com/markets/cannabis/23/07/33171977/pioneering-psychedelics-scientist-alexander-sasha-shulgins-legacy-lives-on-via-new-compounds-and dead WO 2024243599A1 Mark J. Martini Nicholas V. Cozzi Paul F. Daley Thomas Szabo patent Asymmetric phenylalkylamines 28 November 2024 28 May 2024 Alexander Shulgin Research Institute https://patents.google.com/patent/WO2024243599A1/ Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Pharmacology Pharmacodynamics + 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 ND No data 5-HT2A 12–100 (Ki)0.34–31 (EC50 half-maximal effective concentration)88–112% (Emax maximal efficacy) 5-HT2B 29–174 (Ki)68–236 (EC50 half-maximal effective concentration)73–108% (Emax maximal efficacy) 5-HT2C 101–108 (Ki)0.57–17.0 (EC50 half-maximal effective concentration)82–102% (Emax maximal efficacy) 5-HT3 >10,000 5-HT4 ND No data 5-HT5A >10,000 5-HT6 >10,000 5-HT7 1,225 α1A 4,006–>10,000 α1B >10,000 α1D 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 ND No data M2, M5 >10,000 TAAR1 >30,000 (EC50 half-maximal effective concentration) I1 >10,000 σ1 9,780 σ2 9,560 SERT Serotonin transporter >10,000 (Ki) NET Norepinephrine transporter >10,000 (Ki) DAT Dopamine transporter >10,000 (Ki) Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: PDSP Database UNC 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 zu 27 January 2025 Liu T BindingDB BDBM81965 1-(4-ethyl-2,5-dimethoxyphenyl)propan-2-amine::CAS_62066::CHEMBL8224::DOET,(-)::NSC_62066 BindingDB https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=81965 5 November 2024 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 The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects Mol Psychiatry 31 3 1799–1809 November 2025 41193673 10.1038/s41380-025-03325-1 12916490 https://www.nature.com/articles/s41380-025-03325-1.pdf Åstrand A, Guerrieri D, Vikingsson S, Kronstrand R, Green H 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 Forensic Science International 317 110553 December 2020 33160102 10.1016/j.forsciint.2020.110553 free van Wijngaarden I, Soudijn W Pharmacochemistry Library 5-HT2A, 5-HT2B and 5-HT2C receptor ligands Elsevier 27 1997 978-0-444-82041-9 10.1016/s0165-7208(97)80013-x 161–197 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 Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential Nat Commun 14 1 8221 December 2023 38102107 10724237 10.1038/s41467-023-44016-1 free 2023NatCo..14.8221W DOET acts as a selective serotonin 5-HT2 receptor agonist, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. Luethi D, Rudin D, Hoener MC, Liechti ME Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines The FASEB Journal 36 S1 2022 0892-6638 10.1096/fasebj.2022.36.S1.R2691 fasebj.2022.36.S1.R2691 free https://www.researchgate.net/publication/360369275 Ray TS Psychedelics and the human receptorome PLOS ONE 5 2 e9019 February 2010 20126400 2814854 10.1371/journal.pone.0009019 free 2010PLoSO...5.9019R Glennon RA Central serotonin receptors as targets for drug research J Med Chem 30 1 1–12 January 1987 3543362 10.1021/jm00384a001 Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites In one study, its affinities (Ki) were 12nM for the serotonin 5-HT2A receptor, 108nM for the serotonin 5-HT2C receptor (9-fold lower than for 5-HT2A), and 9,727nM for the serotonin 5-HT1A receptor (811-fold lower than for 5-HT2A). The drug's EC50 half-maximal effective concentration for activation of the serotonin 5-HT2A receptor was 1.7 to 8.1nM depending on the intracellular signaling cascade, while its Emax maximal efficacy was 99%. At the serotonin 5-HT2B receptor, its EC50 half-maximal effective concentration was 68nM (8- to 40-fold lower than for 5-HT2A) and its Emax maximal efficacy was 73%. 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. 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. Lewin AH, Miller GM, Gilmour B Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class Bioorganic & Medicinal Chemistry 19 23 7044–7048 December 2011 22037049 3236098 10.1016/j.bmc.2011.10.007 In contrast to many other amphetamines, but like other DOx drugs, DOET does not bind to the monoamine transporters. DOET produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents. Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species Neuropharmacology 167 107933 May 2020 31917152 9191653 10.1016/j.neuropharm.2019.107933 As with other psychedelics, DOET shows a biphasic or inverted U-shaped dose–response curve for production of the HTR. The drug induces the HTR to a similar maximal extent as other related psychedelics like DOM and DOI. 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. Winter JC 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 Psychopharmacologia 44 1 29–32 October 1975 1197576 10.1007/BF00421179 Silverman PB, Ho BT The discriminative stimulus properties of 2,5-dimethoxy-4-methylamphetamine (DOM): differentiation from amphetamine Psychopharmacology (Berl) 68 3 209–215 1980 6771804 10.1007/BF00428105 Glennon RA, Doot DL, Young R DOM and related 2,5-dimethoxy-4-alkylphenylisopropylamines: behavioral and serotonin receptor properties Pharmacol Biochem Behav 14 3 287–292 March 1981 7232455 10.1016/0091-3057(81)90392-0 Glennon RA, Young R, Rosecrans JA A comparison of the behavioral effects of DOM homologs Pharmacol Biochem Behav 16 4 557–559 April 1982 7071089 10.1016/0091-3057(82)90414-2 DOET produces hyperlocomotion in mice. Halberstadt AL, Geyer MA Behavioral Neurobiology of Psychedelic Drugs Effect of Hallucinogens on Unconditioned Behavior Current Topics in Behavioral Neurosciences 36 159–199 2018 28224459 5787039 10.1007/7854_2016_466 978-3-662-55878-2 Halberstadt AL, Powell SB, Geyer MA Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice Neuropharmacology 70 218–227 July 2013 23376711 3934507 10.1016/j.neuropharm.2013.01.014 Huang J, Ho BT Some pharmacological actions of 2,5-dimethoxy-4-ethylamphetamine (DOET) in rats and mice J Pharm Pharmacol 27 1 18–22 January 1975 235610 10.1111/j.2042-7158.1975.tb09372.x 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. DOET produces serotonin receptor-dependent pressor and hyperthermic effects in rodents. Pharmacokinetics In terms of effects in humans, the onset of lower doses of DOET and its individual enantiomers (0.75–4mg) is 1 to 3hours, peak effects occur after 3 to 5hours, and the duration is 5 to 10hours. At higher doses of DOET (2 to 6mg), the duration was reported to be 14 to 20hours. DOET, like other DOx drugs, has an unusually slow onset and long duration.Katherine R. Bonson Hallucinogenic Drugs 294–307 Encyclopedia of Life Sciences Wiley 9 September 2005 978-0-470-01617-6 10.1002/9780470015902.a0000166.pub2 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. The drug crosses the blood–brain barrier in rodents. DOET is metabolized by oxidation of the ethyl group at the 4 position in rodents. Tansey LW, Estevez VS, Ho BT Metabolic study of 2,5-dimethoxy-4-ethylamphetamine (DOET) in rats Proc West Pharmacol Soc 18 362 1975 1182040 It appears to be metabolized more quickly than DOM. In humans, DOET is excreted 10 to 40% in urine unchanged within 24hours. The greatest excretion rate occurred between 3 and 6hours. 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. It is structurally related to the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine). Hassan Z, Bosch OG, Singh D, Narayanan S, Kasinather BV, Seifritz E, Kornhuber J, Quednow BB, Müller CP Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs Front Psychiatry 8 152 2017 28868040 5563308 10.3389/fpsyt.2017.00152 free 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). Synthesis The chemical synthesis of DOET has been described. Analogues Analogues of DOET include other DOx drugs such as DOM, DOPR, DOBU, DOAM, DOB, DOI, DOEF, and DOTFE, among others. The α-desmethyl or phenethylamine analogue of DOET is 2C-E. Ariadne is the α-ethyl or phenylisobutylamine analogue of DOM. History DOx#History DOET was discovered by Alexander Shulgin in the 1960s. He assessed DOET after synthesizing DOM in 1963 and discovering DOM's psychedelic effects in 1964. Canal CE, Morgan D Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model Drug Test Anal 4 7–8 556–576 2012 22517680 3722587 10.1002/dta.1333 Alexander Theodore Shulgin (1925-2014) openDemocracy 9 June 2014 https://www.opendemocracy.net/en/alexander-theodore-shulgin-19252014/ 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. Shulgin found that DOET was a remarkable "psychic energizer" at low doses without producing psychedelic effects at these doses. The effects that he experienced included positive mood, talkativeness, and disinhibition that lasted the whole day. 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. Nonetheless, Shulgin's enthusiasm was not dissuaded, and he felt that the drug should be exploited. Shulgin was working at Dow Chemical Company at the time, and he pitched DOET to the company. They selected DOET as a promising compound and decided to move forward with clinical trials for potential use as a pharmaceutical drug. Shulgin and the company filed a patent for DOET in 1966, which was published in 1970.phenethylamines and their pharmacologically-acceptable salts Google Patents 1970 https://patents.google.com/patent/US3547999A/en 26 January 2025 Dow Chemical Company tasked neuroscientist Solomon H. Snyder at Johns Hopkins University with clinically studying DOET. 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. Trout K, Daley PF The origin of 2,5-dimethoxy-4-methylamphetamine (DOM, STP) Drug Test Anal 16 12 1496–1508 December 2024 38419183 10.1002/dta.3667 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 This occurred after LSD distributor Owsley Stanley learned of DOM from Shulgin and began distributing very-high-dose DOM tablets for free. LSD had become illegal in California in 1966 and an alternative had been sought by Stanley. The DOET tablets he distributed could have very long durations (up to 3–4days) and resulted in intense experiences, worrying physical side effects, and hospitalizations. DOM was first described in the media and scientific literature in 1967 as a result of the crisis. Snyder SH, Faillace L, Hollister L 2,5-dimethoxy-4-methyl-amphetamine (STP): a new hallucinogenic drug Science 158 3801 669–670 November 1967 4860952 10.1126/science.158.3801.669 1967Sci...158..669S The drug became illegal in the United States in 1968. It is unclear why Shulgin told Stanley about DOM and risked his professional career as well as the DOET clinical development. 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. Dow Chemical Company terminated its clinical research program on DOET due to the DOM public health crisis. DOET was subsequently first described in the scientific literature by Snyder and colleagues in 1968. Snyder continued to be interested in DOET as a potential medicine, but it was never further developed. Snyder conducted and published a series of three clinical trials of low-dose DOET between 1968 and 1974. In these trials, he compared DOET with DOM, dextroamphetamine, and placebo. 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. Snyder also studied the individual enantiomers of DOET. Shulgin first discussed DOET in publications in 1969 and 1970. Shulgin AT Psychotomimetic Agents Related to the Catecholamines Journal of Psychedelic Drugs 2 2 1969 0022-393X 10.1080/02791072.1969.10524409 14–19 Alexander Shulgin Chemistry and Structure-Activity Relationships of the Psychotomimetics D. H. Efron Psychotomimetic Drugs Raven Press New York 21–41 1970 https://www.erowid.org/library/books_online/psychotomimetic_drugs.pdf#page=23 DOET became a Schedule I controlled substance in the United States in February 1973. Shulgin AT Basic Pharmacology and Effects 67–137 Laing RR Hallucinogens: A Forensic Drug Handbook Elsevier Science Forensic Drug Handbook Series 2003 978-0-12-433951-4 https://books.google.com/books?id=l1DrqgobbcwC https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6 1 February 2025 Ariadne (4C-D, 4C-DOM, BL-3912, Dimoxamine), the α-ethyl or phenylisobutylamine analogue of DOM, was developed by Shulgin in the 1970s. 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 Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs ACS Chemical Neuroscience 14 1 119–135 January 2023 36521179 10147382 10.1021/acschemneuro.2c00597 He found it to be psychoactive and to produce "the alert of a psychedelic, with none of the rest of the package". This threshold psychoactivity without psychedelic effects was reminiscent of low doses of DOET. 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. 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. (R)-Ariadne (BL-3912A) completed phase 2 clinical trials and showed promising initial clinical benefits. However, further clinical development was halted for strategic economic reasons. 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. Shulgin first synthesized 2C-E, the α-desmethyl or phenethylamine analogue of DOET, in 1977. Darie IF, Praisler M, Negoita C 2C-x and DOx hallucinogens: A systematic review Annals of the "Dunarea de Jos" University of Galati Fascicle II Mathematics Physics Theoretical Mechanics 44 1 12 November 2021 2668-7151 10.35219/ann-ugal-math-phys-mec.2021.1.07 free 46–52 https://www.gup.ugal.ro/ugaljournals/index.php/math/article/download/4925/4350 26 January 2025Alexander Shulgin Alexander Shulgin Pharmacology Notes II (The Shulgin Lab Books) Erowid https://erowid.org/library/books_online/shulgin_labbooks/shulgin_pharmacology_notebook9_searchable.pdf 236 Lafayette, CA, USA 1980 Shulgin first published reports describing the psychedelic effects of higher doses of DOET in PiHKAL in 1991. 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. Shulgin also described 2C-E as producing robust psychedelic effects in PiHKAL, though with much higher doses required than DOET. Society and culture Names DOET was originally named DOE by Alexander Shulgin. However, he subsequently recalled that this was also an acronym for desoxyephedrine (methamphetamine). As a result, he changed his name for the drug from DOE to DOET or DOEt. Other names that Shulgin has given DOET have included HECATE or Hecate (after the Greek goddess) and DMEA (short for dimethoxyethylamphetamine). 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.http://www.incb.org/pdf/e/list/green.pdf List of psychotropic substances under international control August 2003 https://web.archive.org/web/20070302130637/http://www.incb.org/pdf/e/list/green.pdf March 2, 2007 Australia DOET is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534 Therapeutics Goods Administration Australian Government 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. Canada DOET is a controlled substance in Canada.Controlled Drugs and Substances Act Department of Justice Canada https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html 19 January 2026 United States DOET is classified as a Schedule I substance in the United States. See also DOx (psychedelics) Stimulant § Serotonin 5-HT2A receptor agonists Motivation-enhancing drug § Serotonin 5-HT2A receptor agonists References External links DOET - Isomer Design DOET Experience Reports - Erowid DOET - PiHKAL - Erowid DOET - PiHKAL - Isomer Design DOET - The Shulgin Index DOET: Exploring This Rare DOX Psychedelic - Tripsitter Category:5-HT2A agonists Category:5-HT2B agonists Category:5-HT2C agonists Category:Abandoned drugs Category:Alexander Shulgin Category:Anti-inflammatory agents Category:Antidepressants Category:Designer drugs Category:DOx (psychedelics) Category:Experimental antidepressants Category:Experimental hallucinogens Category:Nootropics Category:PiHKAL Category:Pro-motivational agents Category:Psychedelic phenethylamines Category:Stimulants Category:TAAR1 agonists