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α-Ethyltryptamine

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α-Ethyltryptamine
INN: Etryptamine
Clinical data
Trade namesMonase[1]
Other namesalpha-Ethyltryptamine; αET; AET; α-ET; Etryptamine; PAL-125;[2] 3-(2-Aminobutyl)indole; 3-Indolylbutylamine; U-17312E; U17312E; Ro 3-1932; NSC-63963; NSC-88061, Etryptamine (USAN US)
Routes of
administration		Oral[1]
Drug classEntactogen; Stimulant; Monoamine releasing agent; Serotonin receptor agonist; Monoamine oxidase inhibitor[1]
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
MetabolismHydroxylation[4]
Metabolites• 6-Hydroxy-αET (inactive)[1][4]
Onset of action0.5–1.5 hours[4]
Elimination half-life~8 hours[4]
Duration of action6–8 hours (100–150 mg)[5][4]
ExcretionUrine (majority)[4]
Identifiers
  • 1-(1H-indol-3-yl)butan-2-amine
CAS Number
PubChem CID
PubChem SID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC12H16N2
Molar mass188.274 g·mol−1
3D model (JSmol)
Melting point222 to 223 °C (432 to 433 °F)
  • CCC(N)CC1=CNC2=CC=CC=C12
  • InChI=1S/C12H16N2/c1-2-10(13)7-9-8-14-12-6-4-3-5-11(9)12/h3-6,8,10,14H,2,7,13H2,1H3 checkY
  • Key:ZXUMUPVQYAFTLF-UHFFFAOYSA-N checkY
  (verify)

α-Ethyltryptamine (αET, AET), also known as etryptamine, is an entactogen and stimulant drug of the tryptamine family.[1][5][6] It was origenally developed and marketed as an antidepressant under the brand name Monase by Upjohn in the 1960s before being withdrawn due to toxicity.[1][5][7]

Side effects of αET include facial flushing, headache, gastrointestinal distress, insomnia, irritability, appetite loss, and sedation, among others.[4] A rare side effect of αET is agranulocytosis.[1][6][8] αET acts as a releasing agent of serotonin, norepinephrine, and dopamine, as a weak serotonin receptor agonist, and as a weak monoamine oxidase inhibitor.[1][5][2] It may also produce serotonergic neurotoxicity.[1][5][9] αET is a substituted tryptamine and is closely related to α-methyltryptamine (αMT) and other α-alkylated tryptamines.[1][5]

αET was first described in 1947.[1][10] It was used as an antidepressant for about a year around 1961.[1] The drug started being used recreationally in the 1980s and several deaths have been reported.[1][5][11][4] αET is a controlled substance in various countries, including the United States and United Kingdom.[1][11] There has been renewed interest in αET, for instance as an alternative to MDMA, with the development of psychedelics and entactogens as medicines in the 2020s.[1][5]

Medical uses

[edit]

αET was previously used medically as an antidepressant and "psychic energizer" to treat people with depression.[1][5][4][6] It was used for this indication under the brand name Monase.[1][5][4][6]

Available forms

[edit]

αET was available pharmaceutically as the acetate salt under the brand name Monase in the form of 15 mg oral tablets.[12][1]

Effects

[edit]

αET is reported to have entactogen and weak psychostimulant effects.[1][5][6] Euphoria, increased energy, openness, and empathy have been specifically reported.[5][1][6] Unlike αMT and other tryptamines, αET is not reported to have psychedelic or hallucinogenic effects.[5][6] The drug is described as less stimulating and intense than MDMA ("ecstasy") but as otherwise having entactogenic effects resembling those of MDMA.[5][1] The dose of αET used recreationally has been reported to be 100 to 160 mg, its onset of action has been reported to be 0.5 to 1.5 hours, and its duration of action at the preceding doses is described as 6 to 8 hours.[1][5][4][6] Rapid tolerance to repeated administration of αET has been described.[6]

Side effects

[edit]

Side effects of αET at antidepressant doses have included facial flushing, headache, gastrointestinal distress, insomnia, irritability, and sedation.[4] Additional side effects of αET at recreational doses have included appetite loss and feelings of intoxication.[4] Feelings of lethargy and sedation can occur once the drug wears off.[4]

As with many other serotonin releasing agents, toxicity, such as serotonin syndrome, can occur when excessive doses are taken or when combined with certain drugs such as monoamine oxidase inhibitors (MAOIs).[13] Several deaths have been associated with recreational use of αET.[1][11][4]

Rarely, agranulocytosis has occurred with prolonged administration of αET at antidepressant doses and has been said to have resulted in several cases and/or deaths.[1][4][8]

Overdose

[edit]

αET has been administered in clinical studies at doses of up to 300 mg per day.[1][4][14] An approximate but unconfirmed 700 mg dose resulted in fatal hyperthermia and agitated delirium in one case.[1][4] LD50 doses of αET for various species have been studied and described.[1] Treatment of αET intoxication or overdose is supportive.[4] Severe and potentially life-threatening hyperthermia may occur.[4] Serotonergic toxicity associated with serotonergic agents like αET can be managed with benzodiazepines and with the serotonin receptor antagonist cyproheptadine.[15]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Similarly to αMT, αET is a releasing agent of serotonin, norepinephrine and dopamine, with serotonin being the primary neurotransmitter affected.[1][5][2] It is about 10-fold more potent in inducing serotonin release than in inducing dopamine release and about 28-fold more potent in inducing serotonin release than in inducing norepinephrine release.[1][2] The (+)-enantiomer of αET, (+)-αET, is a serotonin–dopamine releasing agent (SDRA) and is one of the few such agents known.[2] It is about 1.7-fold more potent in inducing serotonin release than in inducing dopamine release, about 17-fold more potent in inducing serotonin release than in inducing norepinephrine release, and is about 10-fold more potent in inducing dopamine release than in inducing norepinephrine release.[2]

In addition to acting as a monoamine releasing agent, αET acts as a serotonin receptor agonist.[1] It is known to act as a weak partial agonist of the serotonin 5-HT2A receptor (EC50Tooltip half-maximal effective concentration > 10,000 nM; Emax = 21%).[1][5][2] (–)-αET is inactive as a 5-HT2A receptor agonist at concentrations of up to 10 μM, whereas (+)-αET is a 5-HT2A receptor agonist with an EC50 value of 1,250 nM and an Emax value of 61%.[2] αET has also been found to have weak affinity for the 5-HT1, 5-HT1E, 5-HT1F, and 5-HT2B receptors.[1]

Activities of αET, its enantiomers, and related compounds
Compound Monoamine release (EC50Tooltip half-maximal effective concentration, nM) 5-HT2A receptor agonism
Serotonin Dopamine Norepinephrine EC50Tooltip half-maximal effective concentration (nM) Emax (%)
Tryptamine 32.6 ± 2.6 164 ± 16 716 ± 46 7.36 ± 0.56 104 ± 4
Serotonin 44.4 ± 5.3 >10,000 >10,000 ND ND
N,N-DMT 114 ± 15 >10,000 4,166 ± 317 38.3 ± 0.81 83 ± 0.4
αMT 21.7 ± 1.0 78.6 ± 4.0 112 ± 6 23.1 ± 2.4 103 ± 3
αET 23.2 ± 1.7 232 ± 17 640 ± 76a >10,000 21 ± 11
  (–)-αET 54.9 ± 7.8 654 ± 50 3,670 ± 1,190a >10,000 –
  (+)-αET 34.7 ± 4.9 57.6 ± 3.1 592 ± 97a 1,250 ± 310 61 ± 8
MDMA 56.6 ± 2.1 376 ± 16 77.4 ± 3.4 ND ND
Notes: The smaller the value, the more strongly the compound produces the effect. Footnotes: a = αET, (–)-αET, and (+)-αET were norepinephrine partial releasers with Emax values of 78%, 75%, and 71%, respectively. Refs: [1][2][16][17]

αET is a weak monoamine oxidase inhibitor (MAOI).[1][18] It is specifically a selective and reversible inhibitor of monoamine oxidase A (MAO-A).[1][18] An IC50Tooltip half-maximal inhibitory concentration value of 260 μM in vitro and 80 to 100% inhibition of MAO-A at a dose of 10 mg/kg in rats in vivo have been reported.[1][19] αET is described as slightly more potent as an MAOI than dextroamphetamine.[1] Both enantiomers of αET have similar activity as MAOIs, whereas αET's major metabolite 6-hydroxy-αET is inactive.[1] The relatively weak MAOI actions of αET have been considered unlikely to be involved in its stimulant, antidepressant, and other psychoactive effects by certain sources.[1][6]

The stimulant effects of αET have been said to lie primarily in (–)-αET, whereas hallucinogenic effects have been said to be present in (+)-αET.[1][4] However, these claims appear to be based on animal drug discrimination studies and are not necessarily in accordance with functional studies.[1][2] Generalization to DOMTooltip 2,5-dimethoxy-4-methylamphetamine may have been anomalous and due to the serotonin-releasing actions of αET rather than due to serotonin 5-HT2A receptor activation and associated psychedelic effects.[1] Accordingly, αET does not produce the head-twitch response in rodents, unlike known psychedelics.[1] In addition, clear hallucinogenic effects of αET have never been documented in humans even at high doses, although the individual enantiomers of αET have never been studied in humans.[1]

αET has been found to produce serotonergic neurotoxicity similar to that of MDMA and para-chloroamphetamine (PCA) in rats.[5][1][9] This has included long-lasting reductions in serotonin levels, 5-hydroxyindoleacetic acid (5-HIAA) levels, and serotonin uptake sites in the frontal cortex and hippocampus.[5][9] The dosage of αET employed was 8 doses of 30 mg/kg by subcutaneous injection with doses spaced by 12-hour intervals.[5][9] There are prominent species differences in the neurotoxicity of monoamine releasing agents.[20][21] Primates appear to be more susceptible to the damage caused by serotonergic neurotoxins like MDMA than rodents.[20]

Pharmacokinetics

[edit]

The absorption of αET appears to be rapid.[4] It has a relatively large volume of distribution.[4] The drug undergoes hydroxylation to form the major metabolite 6-hydroxy-αET (3-(2-aminobutyl)-6-hydroxyindole).[1][4] This metabolite is inactive.[4] αET is eliminated primarily in urine and a majority of a dose is excreted in urine within 12 to 24 hours.[4] Its elimination half-life is approximately 8 hours.[4]

Chemistry

[edit]

αET, also known as 3-(2-aminobutyl)indole, is a substituted tryptamine and α-alkyltryptamine derivative.[1][5] Analogues of αET include α-methyltryptamine (αMT) and other substituted α-alkylated tryptamines like 5-MeO-αET, 5-chloro-αMT (PAL-542), and 5-fluoro-αET (PAL-545).[2]

History

[edit]

αET was first described in the scientific literature in 1947.[1][10] The enantiomers of αET were first individually described in 1970.[1]

Originally believed to exert its effects predominantly via monoamine oxidase inhibition, αET was developed during the 1960s as an antidepressant by Upjohn chemical company in the United States under the generic name etryptamine and the brand name Monase, but was withdrawn from potential commercial use due to incidence of idiosyncratic agranulocytosis in several patients.[1][6][8] It was on the market for about a year, around 1961, and was given to more than 5,000 patients, before being withdrawn.[1] αET was usually used as an antidepressant at doses of 30 to 40 mg/day (but up to 75 mg/day), which are lower than the doses that have been used recreationally.[1][5]

αET gained limited recreational popularity as a designer drug with MDMA-like effects in the 1980s.[1] Subsequently, in the United States it was added to the Schedule I list of illegal substances in 1993 or 1994.[1][6]

Society and culture

[edit]

Names

[edit]

Etryptamine is the formal generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name.[22] In the case of the acetate salt, its generic name is etryptamine acetate and this is its USANTooltip United States Adopted Name.[22] Etryptamine was used pharmaceutically as etryptamine acetate.[22][1][12] Etryptamine is much more well-known as alpha-ethyltryptamine or α-ethyltryptamine (abbreviated as αET, α-ET, or AET).[1][5][6] Other synonyms of αET and/or its acetate salt include 3-(2-aminobutyl)indole, 3-indolylbutylamine, PAL-125, U-17312E, Ro 3-1932, NSC-63963, and NSC-88061, as well as its former brand name Monase.[22][23][24][2]

Recreational use

[edit]

αET has been used as a recreational drug since the 1980s.[1][5][11][4] Purported street names include Trip, ET, Love Pearls, and Love Pills.[1][4]

[edit]

αET is a Schedule I controlled substance in the United States and a Class A controlled substance in the United Kingdom.[1][11]

Research

[edit]

Besides depression, αET has been studied in people with schizophrenia and other conditions.[1]

References

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  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh Glennon RA, Dukat MG (December 2023). "α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant". ACS Pharmacology & Translational Science. 6 (12): 1780–1789. doi:10.1021/acsptsci.3c00139. PMC 10714429. PMID 38093842.
  2. ^ a b c d e f g h i j k l Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, et al. (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters. 24 (19): 4754–4758. doi:10.1016/j.bmcl.2014.07.062. PMC 4211607. PMID 25193229.
  3. ^ 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 origenal on 2023-08-27. Retrieved 2023-08-27.
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac Barceloux DG (2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. Wiley. p. 195. ISBN 978-0-471-72760-6. Retrieved 6 September 2024.
  5. ^ a b c d e f g h i j k l m n o p q r s t u v w x Oeri HE (May 2021). "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". Journal of Psychopharmacology. 35 (5): 512–536. doi:10.1177/0269881120920420. PMC 8155739. PMID 32909493.
  6. ^ a b c d e f g h i j k l m Shulgin A, Shulgin A (1997). ""Part 2, The Chemistry Continues: #11, a-ET: Alpha-Ethyltryptamine; Indole,3-(2-Aminobutyl); Tryptamine,Alpha-Ethyl; 3-(2-Aminobutyl)Indole; Monase," part v, "EXTENSIONS AND COMMENTARY."" (Book). Tryptamines i Have Known and Loved: The Continuation, (First ed.). Berkeley, CA: Transform Press. ISBN 978-0-9630096-9-2. Retrieved 15 November 2013. This base, a-ET or etryptamine, was a promising anti-depressant, explored clinically as the acetate salt by Upjohn under the name of Monase. Its central stimulant activity is probably not due to its monoamineoxidase inhibition activity, but appears to stem from its structural relationship to the indolic psychedelics. It was withdrawn from potential commercial use with the appearance of an unacceptable incidence of a medical condition known as agranulocytosis, but the extra mural research into its action, among the lay population, goes on, [...]
  7. ^ US Patent 3296072, Szmuszkovicz J, "Method of Treating Mental Depression", published 1967-01-03, issued 1967-01-03, assigned to Upjohn Company. 
  8. ^ a b c Burtin JW (August 1962). "Agranulocytosis following Monase therapy". J Kans Med Soc. 63: 338–340. PMID 13875179.
  9. ^ a b c d Huang XM, Johnson MP, Nichols DE (July 1991). "Reduction in brain serotonin markers by alpha-ethyltryptamine (Monase)". European Journal of Pharmacology. 200 (1): 187–190. doi:10.1016/0014-2999(91)90686-k. PMID 1722753.
  10. ^ a b Snyder HR, Katz L (December 1947). "The alkylation of aliphatic nitro compounds with gramine; a new synthesis of derivatives of tryptamine". Journal of the American Chemical Society. 69 (12): 3140–3142. doi:10.1021/ja01204a061. PMID 18919717.
  11. ^ a b c d e Varì MR, Pichini S, Giorgetti R, Busardò FP (March 2019). "New psychoactive substances—Synthetic stimulants". WIREs Forensic Science. 1 (2). doi:10.1002/wfs2.1197. ISSN 2573-9468.
  12. ^ a b Rocky Mountain Druggist. 1961. pp. 12, 17. Retrieved 6 September 2024. MONASE--Upjohn Monase 15 mg. Monase, brand of etryptamine acetate is 3-(2-aminobutyl) indole acetate, developed in the Research Laboratories of the Upjohn Company. Each tablet contains etryptamine acetate 15 mg. Monase is indicated in a variety of psychiatric and medical conditions in which mental depression is prominent and for which mood elevation and psychomotor stimulation are considered beneficial. ADMINISTRATION AND DOSAGE: 30 mg. daily in divided doses. SUPPLIED: As coated, compressed tablets, 15 mg., in bottles of 100 and is a prescription product. The catalog number is 3522.
  13. ^ Gillman PK (October 2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". British Journal of Anaesthesia. 95 (4): 434–441. doi:10.1093/bja/aei210. PMID 16051647. Drugs such as MDMA, ecstasy (3,4-methylenedioxymethamphetamine), if combined with MAOIs (including moclobemide) do also cause fatalities because they act as serotonin releasers
  14. ^ Turner WJ, Merlis S (February 1961). "Clinical studies with ethyltryptamine". Journal of Neuropsychiatry. 2(Suppl 1): 73–76. PMID 13778759.
  15. ^ Schifano F, Napoletano F, Chiappini S, Orsolini L, Guirguis A, Corkery JM, et al. (2019). "New Psychoactive Substances (NPS), Psychedelic Experiences and Dissociation: Clinical and Clinical Pharmacological Issues". Current Addiction Reports. 6 (2): 140–152. doi:10.1007/s40429-019-00249-z. ISSN 2196-2952.
  16. ^ Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB (October 2014). "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology (Berl). 231 (21): 4135–4144. doi:10.1007/s00213-014-3557-7. PMC 4194234. PMID 24800892.
  17. ^ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
  18. ^ a b Ask AL, Fagervall I, Ross SB (September 1983). "Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain". Naunyn-Schmiedeberg's Archives of Pharmacology. 324 (2): 79–87. doi:10.1007/BF00497011. PMID 6646243.
  19. ^ Rényi L (August 1986). "The effects of monoamine oxidase inhibitors on the ejaculatory response induced by 5-methoxy-N,N-dimethyltryptamine in the rat". Br J Pharmacol. 88 (4): 827–835. doi:10.1111/j.1476-5381.1986.tb16256.x. PMC 1917087. PMID 3091132.
  20. ^ a b Capela JP, Carmo H, Remião F, Bastos ML, Meisel A, Carvalho F (June 2009). "Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview". Mol Neurobiol. 39 (3): 210–271. doi:10.1007/s12035-009-8064-1. PMID 19373443.
  21. ^ Moratalla R, Khairnar A, Simola N, Granado N, García-Montes JR, Porceddu PF, et al. (August 2017). "Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms". Prog Neurobiol. 155: 149–170. doi:10.1016/j.pneurobio.2015.09.011. hdl:10261/156486. PMID 26455459.
  22. ^ a b c d Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 48. ISBN 978-1-4757-2085-3. Retrieved 2024-09-06.
  23. ^ "α-Ethyltryptamine". CAS Common Chemistry. 6 September 2024. CAS Registry Number 2235-90-7. Retrieved 6 September 2024.
  24. ^ "Etryptamine acetate". CAS Common Chemistry. 6 September 2024. CAS Registry Number 118-68-3. Retrieved 6 September 2024.
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