6-Hydroxy-DET

Last updated

6-Hydroxy-DET
6-HO-DET structure.png
Clinical data
Other names6-HO-DET; 6-OH-DET; 6-HDET; 6-Hydroxydiethyltryptamine; 6-Hydroxy-N,N-diethyltryptamine
Routes of
administration 		Intramuscular injection [1] [2]
Drug class Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Pharmacokinetic data
Onset of action 1 hour [1] [2]
Duration of action 3–4 hours [1] [2]
Identifiers
  • 3-[2-(diethylamino)ethyl]-1H-indol-6-ol
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C14H20N2O
Molar mass 232.327 g·mol−1
3D model (JSmol)
  • CCN(CC)CCC1=CNC2=C1C=CC(=C2)O
  • InChI=1S/C14H20N2O/c1-3-16(4-2)8-7-11-10-15-14-9-12(17)5-6-13(11)14/h5-6,9-10,15,17H,3-4,7-8H2,1-2H3
  • Key:BOLBZNHQIHKGON-UHFFFAOYSA-N

6-Hydroxy-DET, or 6-HO-DET, also known as 6-hydroxy-N,N-diethyltryptamine, is a possible psychedelic drug of the tryptamine family related to dimethyltryptamine (DMT). [1] [3] It is the 6-hydroxy derivative of diethyltryptamine (DET). [1] [3] The drug is a notable metabolite of DET. [1] [3]

Contents

Use and effects

According to Alexander Shulgin in his book TiHKAL (Tryptamines I Have Known and Loved), 6-HO-DET has been reported to be active at a dose of 10 mg by intramuscular injection. [1] [2] Lower doses of 1 to 2 mg were inactive, whereas 5 mg produced threshold effects. [2] The drug at a dose of 10 mg was said to produce psychedelic effects very similar to those with 60 mg diethyltryptamine (DET), with these effects starting after 1 hour and lasting 2 to 3 hours. [1] [2] Based on this report, the drug would be about 5 to 6 times more potent than DET in humans. [2] However, this report of 6-HO-DET's properties and effects is a second-hand early account in a single subject provided by Stephen Szara and colleagues and has not been replicated. [1] [2] Moreover, it is seemingly inconsistent with the inactivity of the closely related compounds 6-HO-DMT, 6-MeO-DMT, and 6-fluoro-DET. [1] [4] [5]

Interactions

Pharmacology

Pharmacodynamics

The effects of 6-HO-DET in animals have been studied. [2] [6] It was found to be much more potent than diethyltryptamine (DET) in terms of producing behavioral effects in rodents. [2] [6] [7]

Pharmacokinetics

Alexander Shulgin has noted that 6-HO-DET may have poor blood–brain barrier permeability due to its exposed hydroxyl group and consequent polarity analogously to bufotenin (5-HO-DMT). [1]

Chemistry

Properties

The predicted log P of 6-HO-DET is 3.1. [8] For comparison, the predicted log P of 6-HO-DMT is 2.4, [9] of 4-HO-DET is 2.7, [10] of 5-HO-DET is 1.9, [11] and of bufotenin (5-HO-DMT) is 1.2. [12]

Analogues

Analogues of 6-HO-DET include diethyltryptamine (DET), 6-hydroxytryptamine (6-HT or 6-HO-T), 6-HO-DMT, 6-MeO-DMT, 6-fluoro-DET, psilocin (4-HO-DMT), 4-HO-DET, bufotenin (5-HO-DMT), 5-HO-DET, 5-HO-DPT, and 5-HO-DiPT, among others. [1]

History

6-HO-DET was first described in the scientific literature by Stephen Szara and colleagues by 1962. [2] It was identified as a major active metabolite of diethyltryptamine (DET). [3] [2] In addition, they found that excretion of 6-HO-DET with DET administration correlated with DET's hallucinogenic effects and that 6-HO-DET was much more potent than DET in humans based on preliminary observations. [2] Consequently, Szara and colleagues theorized that 6-hydroxylation of psychedelic tryptamines like dimethyltryptamine (DMT), DET, and α-methyltryptamine (AMT) was importantly involved in their hallucinogenic effects. [3] [2] [6] [13] [14] However, this hypothesis was later found to be incorrect and was abandoned. [14] [1] [3]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 Shulgin A, Shulgin A (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN   0-9630096-9-9. OCLC   38503252. "6-HO-DET has been observed to be a minor human metabolite of DET, with the excretion of about 20% of the administered dose as the glucoronide conjugate. In a study with normal and schizophrenic patients, a positive correlation was observed between the amount of 6-HO-DET excreted and the intensity of the experience. Also, there was a suggestion that the schizophrenics produced greater amounts of this metabolite. This led to a hypothesis that perhaps it was an active factor in the generation of the intoxicated state. In principle, as with bufotenine, that bare, exposed polar hydroxyl group should make its entry to the brain quite difficult. But, on the other hand, if it were generated there from DET after it had gotten into the brain, entry would not be a concern and the lipophilic barrier could serve to make its exit difficult. Then, if it were an effective compound, it might well be a long acting one. There is an early report of the self-administration intramuscularly, within a single subject, of 10 milligrams 6-HO-DET with the description of what appeared to be DET-like effects from about the second to fourth hour. Although this report suggested that it was several times more potent than DET, it has never been replicated and it does not jibe too well with the 6-HO-DMT report below."
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Szara S, Hearst E (1962). "The 6-Hydroxylation of Tryptamines Derivatives: A Way of Producing Psychoactive Metabolites". Annals of the New York Academy of Sciences. 96 (1): 134–141. Bibcode:1962NYASA..96..134S. doi:10.1111/j.1749-6632.1962.tb50108.x. ISSN   0077-8923. This correlation between metabolic transformation rates and psychological effect is suggestive. It strengthens our notion that metabolically formed 6-HDET most likely plays a role in producing the psychological effects. A more stringent test would be to give the metabolite directly to the same subjects, as was done in the animal experiments. Unfortunately we did not have enough synthetic 6-HDET to do extensive human studies, so the senior author tried it out himself. Both 1 and 2 mg. of 6-HDET had no noticeable effect. At 5 mg. there was only a very faint short-lasting perceptual disturbance. Then, on the fourth attempt, 10 mg. of 6-HDET was administered. No obvious effect on behavior occurred in the first hour, but then typical psychotomimetic disturbances began to appear. For the next 2 or 3 hours hallucinogenic effects were observed that were very similar to the effect of 60 mg. of DET. These experiments lead us to believe that 6-HDET in man is 5 to 6 times more active psychotropically than DET, but more extended studies will be necessary to establish the exact form of the relationship.
  3. 1 2 3 4 5 6 Shulgin AT (1976). "Psychotomimetic Agents". In Gordon M (ed.). Psychopharmacological Agents: Use, Misuse and Abuse. Medicinal Chemistry: A Series of Monographs. Vol. 4. Academic Press. pp. 59–146. doi:10.1016/b978-0-12-290559-9.50011-9. ISBN   978-0-12-290559-9. Much interest became concentrated on tryptamines substituted in the 6 position, when it was found that [DMT], [DET] (Szara, 1961b), and [AMT] (Szara, 1961a) were in part metabolized by hydroxylation at this position. The observation of a good correlation between the psychological changes associated with [DET] and the level of [6-HO-DET] excreted suggested that this hydroxylation product might indeed by the active form of the original drug (Szara et al., 1966). In fact, animal studies with [6-HO-DMT] suggested that the compound was indeed more potent that its parent (Szara and Hearst, 1962). However, animal studies with a number of N-methyl analogs were not consistent with this. [6-HO-5-MeO-DMT] appeared to be less potent than [5-MeO-DMT] (Taborsky et al., 1966) and [6-HO-5-MeO-T] was less potent than [5-MeO-T] (Taborsky et al., 1965). In animal studies (Uyeno, 1969) as well as human studies (Rosenberg et al., 1963), [6-HO-DMT] was inactive at 1 mg/kg, whereas [DMT] is clinically effective at this dosage. This metabolically available site (6 position) was blocked with a fluoro-group in a number of these N,N-dialkyltryptamines. [6-Fluoro-DMT] was again found to be less active than the parent [DMT] in animal studies (Kalir and Szara, 1966). However, clinical studies with [6-fluoro-DET] has shown that it produces most of the somatic effects of the comparison drug [DPT] without any of the psychological changes. It is proposed as an "active placebo" in controlling experiments with possible hallucinogenics (Faillace et al., 1967). The present evidence indicates that chemical substitution on the 6 position of the tryptamine system destroys the psychotomimetic potential of the compound.
  4. ↑ Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chemical Reviews. 124 (1): 124–163. doi:10.1021/acs.chemrev.3c00375. PMID   38033123. Nevertheless, substitutions at positions 6 or 7 were reported to reduce or even abolish the binding ability to 5-HT2 receptors. For example, 6-OMe-DMT (35, Ki = 7300 nM) and 7-OMe-DMT (36, Ki = 5400 nM) exhibited reduced affinity compared to that of DMT (Ki = 1200 nM) at [3H]-ketanserin-labeled 5-HT2Rs.124
  5. ↑ Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, et al. (December 2023). "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nature Communications. 14 (1) 8221. Bibcode:2023NatCo..14.8221W. doi:10.1038/s41467-023-44016-1. PMC   10724237 . PMID   38102107.
  6. 1 2 3 Szara S, Hearst E, Putney F (1962). "Metabolism and behavioural action of psychotropic tryptamine homologues" . International Journal of Neuropharmacology. 1 (1–3): 111–117. doi:10.1016/0028-3908(62)90015-1 . Retrieved 8 April 2025.
  7. ↑ Kalir A, Szara S (May 1966). "Synthesis and pharmacological activity of alkylated tryptamines". Journal of Medicinal Chemistry. 9 (3): 341–344. doi:10.1021/jm00321a017. PMID   5960901.
  8. ↑ "3-(2-(Diethylamino)ethyl)-1H-indol-6-ol". PubChem. Retrieved 5 November 2025.
  9. ↑ "3-(2-(Dimethylamino)ethyl)-1H-indol-6-ol". PubChem. Retrieved 5 November 2025.
  10. ↑ "4-Hydroxy-N,N-diethyltryptamine". PubChem. Retrieved 5 November 2025.
  11. ↑ "Indole, 3-(2-(diethylamino)ethyl)-5-hydroxy-". PubChem. Retrieved 5 November 2025.
  12. ↑ "Bufotenine". PubChem. Retrieved 5 November 2025.
  13. ↑ Szara S, Rockland LH, Rosenthal D, Handlon JH (September 1966). "Psychological effects and metabolism of N,N-diethyltryptamine in man". Archives of General Psychiatry. 15 (3): 320–329. doi:10.1001/archpsyc.1966.01730150096014. PMID   5330062.
  14. 1 2 Taborsky RG, Delvigs P, Page IH (August 1966). "6-hydroxylation: effect on the psychotropic potency of tryptamines". Science. 153 (3739): 1018–1020. Bibcode:1966Sci...153.1018T. doi:10.1126/science.153.3739.1018. PMID   5917552.
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