Chemistry:Diethyltryptamine

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Diethyltryptamine (DET), also known as N,N-diethyltryptamine or T-9, is a psychedelic drug of the tryptamine family closely related to DMT, 4-HO-DET, and 5-MeO-DET.[1][2]

The drug acts as a non-selective serotonin receptor agonist, including of the serotonin 5-HT2A receptor among others.[3][4] It has not been found to occur endogenously.[5] It is a close structural homologue of dimethyltryptamine (DMT) and dipropyltryptamine (DPT).

DET was first synthesized in 1956 by Stephen Szára and subsequently described in material published in 1957.[6] More systematic studies were reported later by Szára and colleagues[7] and independently by Böszörményi and colleagues.[8] It is relatively uncommon compared to other psychedelic tryptamines.[citation needed]

Use and effects

DET have been described to be administered in doses of 44 to 400 mg orally, 40 to 90 mg smoked, 60 to 100 mg intramuscularly, 40 mg subcutaneously and 60 mg intravenously.[1][9] Its duration of action is 2 to 4 hours.[1][9]

Most common reported effects include: slight generalized tremors to gross athletic movements, visual distortion, hypersensitivity to light, visual hallucinations, auditory perceptual distortions and olfactory hallucinations.[10]

Interactions

Pharmacology

Pharmacodynamics

DET activities
Target Affinity (Ki, nM)
5-HT1A 370 (Ki)
138 (EC50)
98% (Emax)
5-HT2A 530 (Ki)
68–612a (EC50)
41a–90% (Emax)
5-HT2C 970 (Ki)
660a (EC50)
106%a (Emax)
SERT 1,200 (Ki)
254–258 (IC50)
NET >10,000 (IC50)
DAT >10,000 (IC50)

Similarly to other classic psychedelics, DET acts as a non-selective serotonin receptor agonist, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.[3][4][11] The drug has been shown to activate Gq-mediated signaling at the serotonin 5-HT2A receptor with Emax higher than 70%[12] and to produce the head-twitch response in rodents which is a behavioral proxy of psychedelic-like effects.[9][12]

DET is a very weak reversible monoamine oxidase inhibitor (MAOI), with IC50 values of 59 μM for serotonin and 5,000 μM for tryptamine as substrates.[13] Injections of 30 mg/kg to rats resulted in 67% reduction of brain MAO-A activity 15 minutes after administration.[13] The substance may also act as a serotonin reuptake inhibitor, with low affinity but moderate potency.[4] It shows no activity as a norepinephrine or dopamine reuptake inhibitor.[4]

Pharmacokinetics

DET demonstrates significant resistance to metabolism by monoamine oxidase A (MAO-A) compared to DMT. This may be due to the increased steric bulk of the N-ethyl substituents relative to the respective methyl groups of DMT which results in metabolic stability sufficient for oral activity.[13][14] This is also true for many other tryptamines with larger nitrogen substituents.[1]

The drug similarly to DMT is rapidly absorbed from the intraperitoneal cavity and quickly distributed through plasma, liver and brain. Most of the substance had disappeared from the aforementioned tissues 30 minutes from administration, except in the brain, where it could still be detected at 60 minutes.[13]

Likewise to DMT the substance is metabolized through 6-hydroxylation and N-dealkylation to form the corresponding intermediates.[15] These metabolites were found to be excreted in urine of about 20% of the administered dose as the glucoronide conjugate, of which the parent compound can be detected by chromatographic analysis at low concentrations (3-5%). Hepatic 6-hydroxylation of the indole ring, yields a minor, psychoactively inactive metabolite 6-hydroxy-DET (6-HO-DET) in similar concentration, with additional hydroxylation possible at alternative positions. Repeated administration of DET - second exposure one to two weeks after the first; resulted in significant metabolic changes. The unchanged drug excreted after a later exposure was significantly lower, while the excretion of the metabolites which were measured in this case were higher than at the first exposure to DET.[7][15]

Chemistry

DET, also known as N,N-diethyltryptamine, is a synthetic compound in the tryptamine class, structurally related to the endogenous neurotransmitter serotonin and the naturally occurring psychedelic compounds dimethyltryptamine (DMT) and dipropyltryptamine (DPT).[2] It is the ethyl analogue of DMT.[10]

Synthesis

The chemical synthesis of DET has been described.[1][16][17]

Analogues

Analogues of DET include dimethyltryptamine (DMT), dipropyltryptamine (DPT), methylethyltryptamine (MET), ethylpropyltryptamine (EPT), 4-HO-DET, 5-HO-DET, 6-HO-DET, 4-AcO-DET, ethocybin (4-PO-DET or CEY-19), 6F-DET, and 2-Me-DET.[1]

History

DET was first synthesized and administered intramuscularly in a 60 mg dose by Stephen Szára in 1956. It was subsequently described in his material published in 1957.[6] More systematic studies were reported later by Szara and colleagues and independently by Böszörményi and colleagues.[8][7] Early research began as a search for “psychosis mimics” in psychiatry, then expanded into broader psychedelic and structure–activity studies. Selection of study subjects for some of these studies was criticized by Alexander Shulgin in his 1997 book TiHKAL (Tryptamines I Have Known and Loved) for its "oppressive research environment".[1] For many years, based on early clinical reports and private communications, Shulgin maintained that DET exhibited psychoactive effects only when administered via parenteral routes. He eventually revised his view, ultimately acknowledging that the substance is also orally active.[1]

Initially, DET was not classified as a controlled substance, and some early clinical and experimental psychopharmacological research used it without scheduling restrictions. By the late 1960s and early 1970s, however, increasing regulatory attention led to tighter controls and this led to DET getting placed in Schedule I internationally by the Convention on Psychotropic Substances.[18]

Modern research on DET remains limited compared to dimethyltryptamine (DMT), due to its status as a controlled substance and the predominance of focus on other tryptamines with greater prevalence in traditional or clinical contexts. Most recent studies and reviews refer to DET primarily in comparative molecular pharmacology, assessing its receptor binding and signaling at serotonin receptors.[3][4]

Society and culture

International

DET is listed under Schedule I of the United Nations 1971 Convention on Psychotropic Substances, placing it under international control.[18] This means that countries that are parties to the Convention are required to regulate DET production, distribution, and use, restricting it to scientific and very limited medical purposes. Possession and trade of DET without appropriate authorization is prohibited under international law.

Australia

DET is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[19] 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.

Research

Psychosis model

Early studies of DET as well as other psychedelics were focused on their presumed psychotomimetic properties.[20] Researchers theorized that abnormal metabolites of endogenous chemicals such as tryptamine, serotonin, and tryptophan could be the explanation for mental disorders such as schizophrenia, or psychosis.[21] DET, along with other synthetic psychedelics, was administered to both patients and healthy volunteers to understand its effects and as a possible biological model for psychosis. With the progression of science and pharmacological understanding, this belief has been dismissed by most researchers.[22][23]

Mushroom production

Although DET is a synthetic compound with no known natural sources, it has been used in conjunction with the mycelium of Psilocybe cubensis to biosynthetically produce the chemicals ethocybin (4-PO-DET) and ethocin (4-HO-DET). Isolation of the alkaloids resulted in 3.3% ethocybin and 0.01-0.8% ethocin.[5]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "#3 DET". Transform Press. September 2024. https://isomerdesign.com/pihkal/read/tk/3. 
  2. ↑ 2.0 2.1 "Erowid DET Vault : Chemistry". http://www.erowid.org/chemicals/det/det_chemistry.shtml. 
  3. ↑ 3.0 3.1 3.2 Cite error: Invalid <ref> tag; no text was provided for refs named Blough_2014
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Cite error: Invalid <ref> tag; no text was provided for refs named Kozell_2023
  5. ↑ 5.0 5.1 "Biotransformation of tryptamine derivatives in mycelial cultures of Psilocybe". Journal of Basic Microbiology 29 (6): 347–352. 1989. doi:10.1002/jobm.3620290608. PMID 2614674. 
  6. ↑ 6.0 6.1 Psychotropic Drugs: The Comparison of the Psychotic Effect of Tryptamine Derivatives with the Effects of Mescaline and LSD-25 in Self-Experiments (Book chapter). Amsterdam: Elsevier. 1957. pp. 460–467. 
  7. ↑ 7.0 7.1 7.2 "Psychological effects and metabolism of N,N-diethyltryptamine in man". Archives of General Psychiatry 15 (3): 320–329. September 1966. doi:10.1001/archpsyc.1966.01730150096014. PMID 5330062. 
  8. ↑ 8.0 8.1 "Observations on the psychotogenic effect of N-N diethyltryptamine, a new tryptamine derivative". The Journal of Mental Science 105 (438): 171–181. January 1959. doi:10.1192/bjp.105.438.171. PMID 13641966. 
  9. ↑ 9.0 9.1 9.2 "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology 167. May 2020. doi:10.1016/j.neuropharm.2019.107933. PMID 31917152. PMC 9191653. http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Serotonergic%20Psychedelics%2020/Halberstadt%2020%20Neuropharm%20potency%20of%20hallucinogens%20%20head-twitch.pdf. "Table 4 Human potency data for selected hallucinogens. [...]". 
  10. ↑ 10.0 10.1 "Toxicology and Analysis of Psychoactive Tryptamines". International Journal of Molecular Sciences 21 (23): 9279. December 2020. doi:10.3390/ijms21239279. PMID 33291798. 
  11. ↑ "Behavioral effects of N,N-diethyltryptamine: absence of antagonism by xylamidine tosylate". The Journal of Pharmacology and Experimental Therapeutics 169 (1): 7–16. September 1969. doi:10.1016/S0022-3565(25)28342-2. PMID 5306645. 
  12. ↑ 12.0 12.1 "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nature Communications 14 (1). December 2023. doi:10.1038/s41467-023-44016-1. PMID 38102107. Bibcode: 2023NatCo..14.8221W. 
  13. ↑ 13.0 13.1 13.2 13.3 "The effect of diethyltryptamine and its derivatives on monoamine oxidase". Biochemical Pharmacology 13 (8): 1151–1156. August 1964. doi:10.1016/0006-2952(64)90116-9. PMID 14222512. 
  14. ↑ Wallach J, Dybek M, "Fluorinated tryptamine compounds, analogues thereof, and methods using same", US patent 20240286998, issued 29 August 2024
  15. ↑ 15.0 15.1 "Discussion of the fate and metabolism of some hallucinogenic indolealkylamines". Pharmacology, Behavior, and Clinical Aspects, Proceedings of a Symposium held at the College of Physicians and Surgeons, Columbia University, New York. Biological Role of Indolealkylamine Derivates - Proceedings of a Symposium held at The College of Physicians and Surgeons, Columbia University, New York, New York, 10–12 May 1967. 6. Academic Press. 1968. 230–1. doi:10.1016/s1054-3589(08)60321-x. ISBN 978-0-12-032906-9. 
  16. ↑ "Synthesis and Pharmacological Activity of Fluorinated Tryptamine Derivatives". Journal of Medicinal Chemistry 6 (6): 716–719. November 1963. doi:10.1021/jm00342a019. PMID 14184932. 
  17. ↑ "Synthesis of Deuterium Labeled Tryptamine Derivatives" (in en). Journal of the Chinese Chemical Society 54 (5): 1363–1368. 2007. doi:10.1002/jccs.200700194. ISSN 2192-6549. https://onlinelibrary.wiley.com/doi/abs/10.1002/jccs.200700194. 
  18. ↑ 18.0 18.1 "List of psychotropic substances under international control". August 2003. http://www.incb.org/pdf/e/list/green.pdf. 
  19. ↑ "Poisons Standard". Federal Register of Legislation. Australian Government. October 2015. https://www.comlaw.gov.au/Details/F2015L01534. 
  20. ↑ "Psilocybin and diethyltryptamine: Two tryptamine hallucinogens.". Neuro-psychopharm. 2: 226–229. 1960. http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=2633. 
  21. ↑ "Effects of LSD-25, n,n-dimethyltryptamine (DMT), and N,N-diethyltryptamine (DET) on the photic evoked responses in the unanesthetized rabbit". Archives Internationales de Pharmacodynamie et de Therapie 154 (2): 474–483. April 1965. PMID 5839429. http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=2360. 
  22. ↑ "Psychosis and psychedelics: Historical entanglements and contemporary contrasts" (in EN). Transcultural Psychiatry 59 (5): 592–609. October 2022. doi:10.1177/13634615221129116. PMID 36300247. 
  23. ↑ "Reconsidering evidence for psychedelic-induced psychosis: an overview of reviews, a systematic review, and meta-analysis of human studies". Molecular Psychiatry 30 (3): 1223–1255. March 2025. doi:10.1038/s41380-024-02800-5. PMID 39592825. 

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