2,5-Dimethoxy-4-ethylamphetamine

Last updated

DOET
DOET structure.png
Clinical data
Other namesDOET; DOEt; DOE; HECATE; Hecate; DMEA; 2,5-Dimethoxy-4-ethylamphetamine; 4-Ethyl-2,5-dimethoxyamphetamine; Dimethoxyethylamphetamine; Ethyldimethoxyamphetamine
Drug class Serotonergic psychedelic; Serotonin 5-HT2 receptor agonist; Antidepressant; Psychic energizer; Cognitive enhancer
Legal status
Legal status
Pharmacokinetic data
Metabolism Oxidation of the 4-position ethyl group [2] [3]
Onset of action 1–3 hours [2] [4] [5] [6]
Duration of action 5–20 hours [5] [7]
Excretion Urine (10–40% unchanged within 24 hours) [2] [4] [5]
Identifiers
  • 1-(4-Ethyl-2,5-dimethoxyphenyl)propan-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C13H21NO2
Molar mass 223.316 g·mol−1
3D model (JSmol)
  • O(c1cc(c(OC)cc1CC(N)C)CC)C
  • 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 Yes check.svgY
  • Key:HXJKWPGVENNMCC-UHFFFAOYSA-N Yes check.svgY
   (verify)

2,5-Dimethoxy-4-ethylamphetamine (DOET) is a psychedelic drug of the phenethylamine, amphetamine, and DOx families. [8] [7] [4] [2] It is closely related to DOM and is a synthetic analogue of the naturally occurring phenethylamine psychedelic mescaline. [2] [9] The drug acts as a selective agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. [10] [11]

Contents

DOET was first discovered by Alexander Shulgin in the 1960s. [12] 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. [12] However, its development was terminated after DOM emerged as a street drug and caused a public health crisis in San Francisco in 1967. [12] [13] Nonetheless, DOET's effects at low doses were extensively characterized in small clinical trials. [2] [5] [14] [15] [6] The psychedelic effects of DOET at higher doses were subsequently described by Shulgin in his book PiHKAL in 1991. [7]

DOET is taken by mouth. [7] [4] [5] It has a slow onset of 1 to 3 hours, a delayed peak of 3 to 5 hours, and a dose-dependent and potentially very long duration of 5 to 20 hours. [7] [16] [2] [4] Effects at low doses include mild euphoria, enhanced self-awareness, and talkativeness, among others. [2] [4] [5] Mild closed-eye visuals can also occur. [15] [6] At higher doses, DOET produces psychedelic effects including heightened emotions, sensory enhancement, rich closed-eye visuals, and open-eye visuals, among others. [7] [6] Physical effects include pupil dilation, increased heart rate, and increased blood pressure. [5] [14] [17]

Effects

In a 1968 clinical trial, DOET at an oral dose of 1.5 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. [2] [4] [5] [14] [17] 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. [2] [5] [14] [17] Some of the effects of DOET in the study resembled those of dextroamphetamine, including talkativeness, euphoria, and feeling alert. [5] [14] The subjective effects began 1 to 1.5 hours after dosing, peaked around 3 to 4 hours after administration, and the duration was about 5 to 6 hours. [2] [4] [5] Pupil dilation was also observed, but there were no marked changes in heart rate or blood pressure. [5] [14] [17] There were also changes on cognitive tests of association and serial learning. [2] [5] [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 more potent (with 2.0 mg DOM being indistinguishable from placebo). [5] [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] [4] [15] Once again, there were no hallucinogenic effects, aside from closed-eye visuals in a minority of individuals, and there was no cognitive impairment. [2] [4] [15] New assessed and reported effects included feeling relaxed, feelings of unpleasantness in some, lightheadedness, reduced depressive feelings, and feeling anxious or restless. [4] [15] The feelings of nervousness and restlessness occurred more at the higher doses. [4] [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 like LSD 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] [6] 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] [6] The onset was 1.5 to 3 hours, peak effects were at 4 to 5 hours, and the duration was 6 to 10 hours. [6] 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. [6] No hallucinogenic effects or visual distortions with eyes open occurred, but vivid imagery with eyes closed could be experienced at the higher doses. [6]

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] [6] However, Alexander Shulgin has stated that DOET is psychedelic at doses of 3 mg and above. [8] In PiHKAL, Shulgin listed the dosage of DOET as 2 to 6 mg and its duration as 14 to 20 hours. [7] [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 of love, eroticism, and divinity, openness, not much visually, closed-eye visuals, and body load symptoms. [7] There was considerable variation in subjective effects between individuals. [7] Shulgin has described both DOET and DOM as being effective antidepressants at lower doses and DOET as being a cognitive enhancer at modest doses. [20] [7]

In line with notions that DOET is a "psychic energizer", the related drug DOPR has shown pro-motivational effects in rodents at sub-hallucinogenic doses [21] [22] and the related drug Ariadne has reportedly shown pro-motivational effects in monkeys despite being non-hallucinogenic. [23]

Pharmacology

Pharmacodynamics

DOET activities
Target Affinity (Ki, nM)
5-HT1A 14.4–9,727
5-HT1B 2,801
5-HT1D 6,615
5-HT1E 3,552
5-HT1F ND
5-HT2A 12–100 (Ki)
0.34–8.1 (EC50 Tooltip half-maximal effective concentration)
99–112% (Emax Tooltip maximal efficacy)
5-HT2B 29 (Ki)
68 (EC50)
73% (Emax)
5-HT2C 101–108 (Ki)
9.2 (EC50)
82% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A >10,000
5-HT6 >10,000
5-HT7 1,225
α1A–α1B >10,000
α1D ND
α2A 1,277
α2B 574
α2C 1,447
β1 5,723
β2 2,195
D1–D5 >10,000
H1–H4 >10,000
M1, M3–M4 ND
M2–M5 >10,000
TAAR1 >10,000 (EC50)
I1 >10,000
σ1 9,780
σ2 9,560
SERT Tooltip Serotonin transporter>10,000 (Ki)
NET Tooltip Norepinephrine transporter>10,000 (Ki)
DAT Tooltip 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: [24] [25] [11] [10] [26] [27] [28]

DOET acts as a selective serotonin 5-HT2 receptor agonist, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. [10] [11] In one study, its affinities (Ki) were 12 nM for the serotonin 5-HT2A receptor, 108 nM for the serotonin 5-HT2C receptor (9-fold lower than for 5-HT2A), and 9,727 nM for the serotonin 5-HT1A receptor (811-fold lower than for 5-HT2A). [10] The drug's EC50 Tooltip half-maximal effective concentration for activation of the serotonin 5-HT2A receptor was 1.7 to 8.1 nM depending on the intracellular signaling cascade, while its Emax Tooltip maximal efficacy was 99%. [10] At the serotonin 5-HT2B receptor, its EC50 was 68 nM (8- to 40-fold lower than for 5-HT2A) and its Emax was 73%. [10] 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. [10] [11] 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. [26] [10] In contrast to many other amphetamines, but like other DOx drugs, DOET does not bind to the monoamine transporters. [10] [11]

DOET produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents. [29] As with other psychedelics, DOET shows a biphasic or inverted U-shaped dose–response curve for production of the HTR. [29] The drug induces the HTR to a similar maximal extent as other related psychedelics like DOM and DOI. [29] 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. [30] [31] [32] [33] DOET produces hyperlocomotion in mice. [34] [35] [36] 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. [34] [35] [36] DOET produces serotonin receptor-dependent pressor and hyperthermic effects in rodents. [36]

Pharmacokinetics

In terms of effects in humans, the onset of lower doses of DOET and its individual enantiomers (0.75–4 mg) is 1 to 3 hours, peak effects occur after 3 to 5 hours, and the duration is 5 to 10 hours. [2] [4] [5] [14] [15] [6] At higher doses of DOET (2 to 6 mg), the duration was reported to be 14 to 20 hours. [7] [8] DOET, like other DOx drugs, has an unusually slow onset and long duration. [16] In rodents, DOET is metabolized by oxidation of the ethyl group at the 4 position. [2] [3] It appears to be metabolized more quickly than DOM. [2] In humans, DOET is excreted 10 to 40% in urine unchanged within 24 hours. [2] [4] [5] The greatest excretion rate occurred between 3 and 6 hours. [2] [5]

Chemistry

DOET, also known as 2,5-dimethoxy-4-ethylamphetamine or as 2,5-dimethoxy-4-ethyl-α-methylphenethylamine, is a substituted phenethylamine and amphetamine and is a member of the DOx group of drugs. [8] [7] [4] [2] It is structurally related to the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine). [2] [9] Analogues of DOET include other DOx drugs such as DOM, DOPR, DOBU, DOAM, DOB, and DOI. [2] The α-desmethyl or phenethylamine analogue of DOET is 2C-E. [8] [7] Ariadne is the α-ethyl or phenylisobutylamine analogue of DOM. [37] [7]

History

DOET was discovered by Alexander Shulgin in the 1960s. [12] He assessed DOET after synthesizing DOM in 1963 and discovering DOM's psychedelic effects in 1964. [12] [38] [39] [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 included positive mood, talkativeness, and disinhibition 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 intense lethargy followed by profound depression 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 at Dow 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 with clinical trials for potential use as a pharmaceutical drug. [12] Shulgin and the company filed a patent for DOET in 1966, which was published in 1970. [12] [38] [8] [40] Dow Chemical Company tasked neuroscientist Solomon H. Snyder at Johns Hopkins University with clinically studying DOET. [12]

In 1967, DOM emerged as a street drug and LSD replacement with the name "STP" in San Francisco and caused a public health crisis. [12] [13] This occurred after LSD distributor Owsley Stanley learned of DOM from Shulgin and began distributing very-high-dose DOM tablets for free. [12] [13] LSD had become illegal in California in 1966 and an alternative had been sought by Stanley. [12] The DOET tablets he distributed could have very long durations (up to 3–4 days) and resulted in intense experiences, worrying physical side effects, and hospitalizations. [12] DOM was first described in the media and scientific literature in 1967 as a result of the crisis. [12] [41] [5] The drug became illegal in the United States in 1968. [12] It is unclear why Shulgin told Stanley about DOM and risked his professional career as well as the DOET clinical 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. [5] Snyder continued to be interested in DOET as a potential medicine, but it was never further developed. [5] Snyder conducted and published a series of three clinical trials of low-dose DOET between 1968 and 1974. [5] [14] [17] [15] [6] In these trials, he compared DOET with DOM, dextroamphetamine, and placebo. [5] [14] [15] [6] 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. [5] [14] [15] Snyder also studied the individual enantiomers of DOET. [2] [19] [6] Shulgin first discussed DOET in publications in 1969 and 1970. [38] [12] [42] [43] DOET became a Schedule I controlled substance in the United States in February 1973. [44]

Ariadne (4C-D, 4C-DOM, BL-3912, Dimoxamine), the α-ethyl or phenylisobutylamine analogue of DOM, was developed by Shulgin in the 1970s. [37] [7] He found it to be psychoactive and to produce "the alert of a psychedelic, with none of the rest of the package". [7] [37] This threshold psychoactivity without psychedelic effects was reminiscent of low doses of DOET. [7] [37] 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. [7] [37] 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. [8] [37] [7] (R)-Ariadne (BL-3912A) completed phase 2 clinical trials and showed promising initial clinical benefits. [37] However, further clinical development was halted for strategic economic reasons. [37] 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. [37]

Shulgin first synthesized 2C-E, the α-desmethyl or phenethylamine analogue of DOET, in 1977. [45] [46] Shulgin first published reports describing the psychedelic effects of higher doses of DOET in PiHKAL in 1991. [7] 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] [5] [14] [6] Shulgin also described 2C-E as producing robust psychedelic effects in PiHKAL, though with much higher doses required than DOET. [7]

Society and culture

Names

DOET was originally named DOE by Alexander Shulgin. [7] [8] However, he subsequently recalled that this was also an acronym for desoxyephedrine (methamphetamine). [7] As a result, he changed his name for the drug from DOE to DOET or DOEt. [7] [8] Other names that Shulgin has given DOET have included HECATE or Hecate (after the Greek goddess) and DMEA (short for dimethoxyethylamphetamine). [7] [8]

Internationally, DOET is a Schedule I controlled drug; under the Convention on Psychotropic Substances, it is legal only for medical uses or scientific research. [47]

United States

DOET is classified as a Schedule I substance in the United States and is similarly controlled in other parts of the world. [44] [47]

Australia

DOET is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). [48] 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. [48]

References

  1. ↑ Anvisa (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] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN   978-1-4757-0512-6.
  3. 1 2 Tansey LW, Estevez VS, Ho BT (1975). "Metabolic study of 2,5-dimethoxy-4-ethylamphetamine (DOET) in rats". Proc West Pharmacol Soc. 18: 362. PMID   1182040.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Wills B, Erickson T (9 March 2012). "Psychoactive Phenethylamine, Piperazine, and Pyrrolidinophenone Derivatives". In Barceloux DG (ed.). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. Wiley. pp. 156–192. doi:10.1002/9781118105955.ch10. ISBN   978-0-471-72760-6.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Snyder SH, Faillace LA, Weingartner H (September 1968). "DOM (STP), a new hallucinogenic drug, and DOET: effects in normal subjects". Am J Psychiatry. 125 (3): 113–120. doi:10.1176/ajp.125.3.357. PMID   4385937.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Snyder SH, Unger S, Blatchley R, Barfknecht CF (July 1974). "Stereospecific actions of DOET (2,5-dimethoxy-4-ethylamphetamine) in man". Arch Gen Psychiatry. 31 (1): 103–106. doi:10.1001/archpsyc.1974.01760130079013. PMID   4599412.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Shulgin A, Shulgin A (September 1991). PiHKAL: A Chemical Love Story. United States: Transform Press. p. 978. ISBN   0-9630096-0-5.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 Shulgin A, Manning T, Daley PF (2011). "#56. DOET (2,5-Dimethoxy-4-ethylamphetamine)". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley: Transform Press. pp. 106–110. ISBN   978-0-9630096-3-0.
  9. 1 2 Hassan Z, Bosch OG, Singh D, Narayanan S, Kasinather BV, Seifritz E, et al. (2017). "Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs". Front Psychiatry. 8: 152. doi: 10.3389/fpsyt.2017.00152 . PMC   5563308 . PMID   28868040. 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).
  10. 1 2 3 4 5 6 7 8 9 Luethi D, Rudin D, Hoener MC, Liechti ME (2022). "Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines". The FASEB Journal. 36 (S1). doi: 10.1096/fasebj.2022.36.S1.R2691 . ISSN   0892-6638.
  11. 1 2 3 4 5 Ray TS (February 2010). "Psychedelics and the human receptorome". PLOS ONE. 5 (2): e9019. Bibcode:2010PLoSO...5.9019R. doi: 10.1371/journal.pone.0009019 . PMC   2814854 . PMID   20126400.
  12. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Baggott MJ (1 October 2023). "Learning about STP: A Forgotten Psychedelic from the Summer of Love" (PDF). History of Pharmacy and Pharmaceuticals. 65 (1): 93–116. doi: 10.3368/hopp.65.1.93 . ISSN   2694-3034 . Retrieved 26 January 2025.
  13. 1 2 3 4 5 Trout K, Daley PF (December 2024). "The origin of 2,5-dimethoxy-4-methylamphetamine (DOM, STP)". Drug Test Anal. 16 (12): 1496–1508. doi:10.1002/dta.3667. PMID   38419183.
  14. 1 2 3 4 5 6 7 8 9 10 11 12 13 Snyder SH, Faillace LA, Weingartner H (July 1969). "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. doi:10.1001/archpsyc.1969.01740190097014. PMID   4389442.
  15. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Snyder SH, Weingartner H, Faillace LA (January 1971). "DOET (2,5-dimethoxy-4-ethylamphetamine), a new psychotropic drug. Effects of varying doses in man". Arch Gen Psychiatry. 24 (1): 50–55. doi:10.1001/archpsyc.1971.01750070052006. PMID   4923215.
  16. 1 2 Katherine R. Bonson (9 September 2005). "Hallucinogenic Drugs". Encyclopedia of Life Sciences. Wiley. pp. 294–307. doi:10.1002/9780470015902.a0000166.pub2. ISBN   978-0-470-01617-6. In the mid-1960s, structure–activity relationship investigations led to the synthesis of a new phenethylamine hallucinogen, 2,5-dimethoxy-4-methylamphetamine (DOM). (It should be noted that the name amphetamine is simply chemical shorthand for its structure: alpha-methyl-phenethylamine.) 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.
  17. 1 2 3 4 5 6 Weingartner H, Snyder SH, Faillace LA, Markley H (1970). "Altered free associations: Some cognitive effects of DOET (2, 5-dimethoxy-4-ethylamphetamine)". Behavioral Science. 15 (4): 297–303. doi:10.1002/bs.3830150402.
  18. 1 2 3 Standridge RT, Howell HG, Gylys JA, Partyka RA, Shulgin AT (December 1976). "Phenylakylamines with potential psychotherapeutic utility. 1. 2-Amino-1-(2,5-dimethoxy-4-methylphenyl)butane" (PDF). J Med Chem. 19 (12): 1400–1404. doi:10.1021/jm00234a010. PMID   1003425. 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
  19. 1 2 3 Anderson GM, Braun G, Braun U, Nichols DE, Shulgin AT (1978). "Absolute configuration and psychotomimetic activity". NIDA Research Monograph (22): 8–15. PMID   101890.
  20. ↑ Shulgin AT (1972). "Hallucinogens, CNS Stimulants, And Cannabis". Chemical and Biological Aspects of Drug Dependence. CRC Press. pp. 163–176. doi:10.1201/9780429260629-16. ISBN   978-0-429-26062-9.
  21. ↑ Noback M, Kenton JA, Klein AK, Hughes ZA, Kruegel AC, Schmid Y, et al. (February 2025). "Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice". Neuropharmacology. 268: 110334. doi:10.1016/j.neuropharm.2025.110334. PMID   39900138.
  22. ↑ Noback M, Kenton J, Klein A, Hughes Z, Kruegel A, Young J (December 2022). "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). doi:10.1038/s41386-022-01486-z. PMC   9714408 . PMID   36456695.
  23. ↑ Alexander T. Shulgin, Ann Shulgin (1991). "#8 ARIADNE; 4C-DOM; BL-3912; DIMOXAMINE; 1-(2,5- DIMETHOXY-4-METHYLPHENYL)-2-AMINOBUTANE; 2,5- DIMETHOXY-a-ETHYL-4-METHYLPHENETHYLAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. pp. 475–480. ISBN   978-0-9630096-0-9. OCLC   25627628. 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).
  24. ↑ "PDSP Database". UNC (in Zulu). Retrieved 27 January 2025.
  25. ↑ Liu T. "BindingDB BDBM81965 1-(4-ethyl-2,5-dimethoxyphenyl)propan-2-amine::CAS_62066::CHEMBL8224::DOET,(-)::NSC_62066". BindingDB. Retrieved 5 November 2024.
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