4-HO-DET

Last updated
4-HO-DET
4-HO-DET.svg
4-HO-DET-3d-sticks.png
Clinical data
Other names4-Hydroxy-DET; 4-OH-DET; 4-Hydroxy-N,N-diethyltryptamine; Ethocin; CZ-74; CZ74
Routes of
administration 		Oral [1]
Drug class Serotonin receptor agonist; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Onset of action 30–45 minutes [1]
Duration of action 2–6 hours [1] [2] [3]
Identifiers
  • 3-(2-diethylaminoethyl)-1H-indol-4-ol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C14H20N2O
Molar mass 232.327 g·mol−1
3D model (JSmol)
Melting point 104 to 106 °C (219 to 223 °F)
  • CCN(CC)CCc1c[nH]c2cccc(O)c12
  • InChI=1S/C14H20N2O/c1-3-16(4-2)9-8-11-10-15-12-6-5-7-13(17)14(11)12/h5-7,10,15,17H,3-4,8-9H2,1-2H3 Yes check.svgY
  • Key:OHHYMKDBKJPILO-UHFFFAOYSA-N Yes check.svgY
   (verify)

4-HO-DET, also known as 4-hydroxy-N,N-diethyltryptamine as well as ethocin or CZ-74, is a psychedelic drug of the tryptamine and 4-hydroxytryptamine families related to psilocin (4-HO-DMT). [1] It is taken orally. [1]

Contents

The drug acts as a non-selective serotonin receptor agonist, including of the serotonin 5-HT2A receptor among others. [4] [5] [6] It produces psychedelic-like effects in animals. [5] 4-HO-DET is closely structurally related to other psychedelic tryptamines such as psilocin, diethyltryptamine (DET), and 4-HO-MET. [1] [7] Ethocybin (4-PO-DET; CEY-19) and 4-AcO-DET are assumed to act as prodrugs of 4-HO-DET. [1] [5]

4-HO-DET was first described in the literature by 1963. [8] [9] [5] It was developed at Sandoz by Albert Hofmann and colleagues. [8] [5] The drug was studied in psychedelic-assisted psychotherapy by Hanscarl Leuner and colleagues in the 1960s. [10] [1] [9] Later, it was described further by Alexander Shulgin in his 1997 book TiHKAL (Tryptamines I Have Known and Loved). [1] 4-HO-DET was encountered as a novel designer drug in 2005. [11]

Use and effects

In his book TiHKAL (Tryptamines I Have Known and Loved) and other publications, Alexander Shulgin variably lists the dose range of 4-HO-DET as 10 to 25 mg orally, either as 4-HO-DET itself or as presumed prodrugs like ethocybin (4-PO-DET) or 4-AcO-DET, and its duration as 2 to 6 hours. [1] [12] [2] [13] [14] [10] [3] Threshold effects are said to occur at doses of 5 to 15 mg, whereas loss of contact with reality is said to occur at doses over 30 mg. [15] [2] However, strong effects have also been reported at a dose of 15 mg of ethocybin. [1] A typical dose estimate has been reported to be around 17.5 mg. [12] The onset of 4-HO-DET is described as being around 30 to 45 minutes. [1]

The drug has been reported to be very similar to psilocin and psilocybin in its qualitative effects but to be somewhat shorter in duration, for instance as short as 2 to 3 hours. [16] [2] [10] [3] The effects of 4-HO-DET, either as 4-HO-DET itself or as presumed prodrugs, have been reported to include closed-eye visuals, open-eye visuals such as fire light turning into bursts of color, potential for intense psychedelic visuals, auditory hallucinations, time dilation, temporal and spatial disorientation, body image disturbance, musical immersion, derealization, ego death, feeling like one has ceased to exist, feelings of oneness with the universe or reality, ineffability, "sparkly-ness", powerful emotions including feelings of intense love, peace, acceptance, awe, reverence, and joy, feelings of sadness, uncomfortableness, and feeling overwhelmed. [1]

Other effects included feeling intoxicated, sedation, restlessness, loss of language ability, impaired concentration, compulsion to talk and interact with others, and lack of erotic feelings. [1] At very high doses, effects including temporary psychosis, depersonalization, mystical experiences, delirium, schizophrenia-like behavior, catatonia, and paranoia have been found to occur. [1] Physical effects have been reported to include stomach and abdominal discomfort, appetite loss, jaw tightening, body tremors, motor incoordination, body disturbance, diuretic effects, and increased blood pressure. [1]

Interactions

Pharmacology

Pharmacodynamics

4-HO-DET activities
TargetAffinity (Ki, nM)
5-HT1A 396–1,840 (Ki)
1,030 (EC50 Tooltip half-maximal effective concentration)
80% (Emax Tooltip maximal efficacy)
5-HT1B 2,242
5-HT1D 585
5-HT1E 568
5-HT2A 269–400 (Ki)
6.5–296a (EC50)
80a–100% (Emax)
5-HT2B 73 (Ki)
6.3 (EC50)
71% (Emax)
5-HT2C 388–436 (Ki)
151a–264 (EC50)
80–83%a (Emax)
5-HT5A 1,429
5-HT6 230
5-HT7A 826
α2A–α2C IA
D2–D5 IA
H1 1,079
H2 9,984
M4 IA
σ1 IA
σ2 3,026
NR2B 8,720
SERT Tooltip Serotonin transporter1,411–1,800 (Ki)
383 ( IC50 )
DAT Tooltip Dopamine transporterIA
Notes: The smaller the value, the more avidly drug interacts with the site. Footnotes:a = Stimulation of IP1 Tooltip inositol phosphate formation. Sources: [4] [5] [6] [17]

4-HO-DET acts as a potent non-selective serotonin receptor agonist, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. [4] [5] [6] It may also act as a serotonin reuptake inhibitor, with low affinity but moderate potency. [4] The drug showed no significant activity at various other assessed targets, including adrenergic receptors (α2A-, α2B, α2C), dopamine receptors (D2–D5), muscarinic acetylcholine receptors (M4), and the dopamine transporter (DAT). [6]

It induces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. [5] Its potency for inducing the head-twitch response in mice is approximately 2-fold lower than that of psilocin. [5]

Chemistry

4-HO-DET, also known as 4-hydroxy-N,N-diethyltryptamine, is a substituted tryptamine and 4-hydroxytryptamine. [1] It is the 4-hydroxy derivative of N,N-diethyltryptamine (DET) and is a close analogue of psilocin (4-hydroxy-N,N-dimethyltryptamine; 4-HO-DMT). [1]

Synthesis

The chemical synthesis of 4-HO-DET has been described. [1]

Analogues

4-HO-DET is the N,N-diethyl analogue of psilocin (4-HO-DMT). [1] Other analogues of 4-HO-DET include diethyltryptamine (DET), 5-MeO-DET, 4-HO-DPT, 4-HO-MET, 4-HO-EPT, and 5-HO-DET, among others. [1] The acetate ester of 4-HO-DET is known as 4-AcO-DET and the phosphate ester is known as ethocybin (4-PO-DET or CEY-19). [1] [5] These compounds are assumed to be prodrugs of 4-HO-DET, as has been shown with the acetate and phosphate esters of other methylated tryptamines such as psilocin (e.g., psilocybin (4-PO-DMT) and 4-AcO-DMT). [1] [18] [5]

History

4-HO-DET was first described in the literature by 1963. [8] [9] It was developed by Albert Hofmann and Franz Troxler at Sandoz in the 1950s and went by the developmental code name CZ-74. [8] [5] [3] Along with its presumed prodrug ethocybin (4-PO-DET; CEY-19), 4-HO-DET was one of the earliest structurally modified or synthetic psychedelic tryptamines to be developed. [16] [3] It was used along with ethocybin in clinical studies of psychedelic-assisted psychotherapy by the German researchers Hanscarl Leuner and Gerhard Baer in the 1960s. [10] [1] [9] The drug was synthesized and studied, along with many other 4-hydroxytryptamines, by David Repke and colleagues in the 1970s and 1980s. [19] [20] It was later additionally described by Alexander Shulgin in his 1997 book TiHKAL (Tryptamines I Have Known and Loved). [1] 4-HO-DET was encountered as a novel designer drug in Europe in 2005. [11]

Society and culture

Finland

Scheduled in the "government decree on psychoactive substances banned from the consumer market". [21]

Sweden

Sveriges riksdags health ministry Statens folkhälsoinstitut classified 4-HO-DET as "health hazard" under the act Lagen om förbud mot vissa hälsofarliga varor (translated Act on the Prohibition of Certain Goods Dangerous to Health) as of Nov 1, 2005, in their regulation SFS 2005:733 listed as 4-hydroxi-N,N-diethyltryptamin (4-HO-DET), making it illegal to sell or possess. [22]

United States

4-HO-DET is unscheduled in the United States, but purchase, sale, or possession for human consumption could be prosecuted under the Federal Analogue Act. [23]

Research

4-HO-DET, under the code name CZ-74 and along with ethocybin (CEY-19), has been studied in psychedelic-assisted psychotherapy. [10] [1] [9]

See also

References

  1. 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 Shulgin A, Shulgin A (September 1997). "#16 4-HO-DET". Isomer Design. Transform Press. Retrieved 28 November 2023.
  2. 1 2 3 4 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. Although the N-dealkylated homologs are as yet untested clinically, the N,N-diethyl homologs of psilocybin and of psilocin have been studied in man (Leunder and Baer, 1965). These compounds [CEY-19, (XXXIII); CZ-74, (XXXIV)] in dosages of from 5 to 20 mg appear to resemble psilocybin in the qualitative nature of their action but to be of shorter duration. Maximum effects are obtained in an hour, and 2 hours later the subject is for the most part recovered, thus providing a valuable time course for psychiatric therapy.
  3. 1 2 3 4 5 Ross S, Franco S, Reiff C, Agin-Liebes G (9 March 2021). "Psilocybin". In Grob CS, Grigsby J (eds.). Handbook of Medical Hallucinogens. Guilford Publications. pp. 181–214. ISBN   978-1-4625-4544-5. Sandoz began manufacturing and distributing pure synthetic psilocybin pills (under the name Indocybin) to curious physicians and researchers around the world and would do so until recalling the drug in 1965 due to a growing political backlash in the United States (Hofmann, 2005). Sandoz also produced two synthetic drugs derived from mushroom-extracted psilocybin, CZ-74 (4-hydroxy-N,N-diethyltryptamine) and CEY-19 (4-phosphoryloxy-N,N-diethyltryptamine), both of which are shorter (approximately 3 hours in duration) acting than psilocybin (Baer, 1967). [...]
  4. 1 2 3 4 Kozell LB, Eshleman AJ, Swanson TL, Bloom SH, Wolfrum KM, Schmachtenberg JL, et al. (April 2023). "Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2A Receptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter". The Journal of Pharmacology and Experimental Therapeutics. 385 (1): 62–75. doi:10.1124/jpet.122.001454. PMC   10029822 . PMID   36669875.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 Klein AK, Chatha M, Laskowski LJ, Anderson EI, Brandt SD, Chapman SJ, et al. (April 2021). "Investigation of the Structure-Activity Relationships of Psilocybin Analogues". ACS Pharmacology & Translational Science. 4 (2): 533–542. doi:10.1021/acsptsci.0c00176. PMC   8033608 . PMID   33860183. Following the isolation of psilocybin and psilocin by Hofmann and colleagues in 1957,34 various 4-substituted tryptamines were reported in the literature. For example, Hofmann synthesized 4-hydroxy-N,N-diethyltryptamine (CZ-74, 4-HO-DET) and 4-phosphoryloxy-N,N-diethyltryptamine (CEY-19).75 Similar to psilocybin and psilocin, CEY-19 and CZ-74 have equivalent molar potencies in humans.3,50
  6. 1 2 3 4 Glatfelter GC, Naeem M, Pham DN, Golen JA, Chadeayne AR, Manke DR, Baumann MH (April 2023). "Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice". ACS Pharmacology & Translational Science. 6 (4): 567–577. doi:10.1021/acsptsci.2c00222. PMC   10111620 . PMID   37082754.
  7. ↑ Greene SL (2021). "Tryptamines". In Dargan PI, Wood DM (eds.). Novel Psychoactive Substances: Classification, Pharmacology and Toxicology (Second ed.). London, United Kingdom: Academic Press. p. 499. ISBN   978-0-12-819030-2.
  8. 1 2 3 4 USpatent 3075992,Hofmann, Albert; Troxler, Franz.,"Esters of indoles",issued 1963-1-29
  9. 1 2 3 4 5 Leuner H, Baer G (1965). "Two new short-acting hallucinogens of the psilocybin group". Neuropsychopharmacology. 4: 471–474. Archived from the original on 2025-04-22.
  10. 1 2 3 4 5 Passie T (7 November 2022). "History of the Use of Hallucinogens in Psychiatric Treatment". In Grob CS, Grigsby J (eds.). Handbook of Medical Hallucinogens. Guilford Publications. pp. 95–118. ISBN   978-1-4625-5189-7. Psycholytic therapy underwent a number of modifications during its active years. Some European therapists experimented with shorter-acting psilocybin derivatives such as CZ-74 (4-hydroxy-N,N-diethyltryptamine, also known as 4-HO-DET; Baer, 1967; Shulgin & Shulgin, 2014), which has a duration of 4—6 hours and is phenomenologically similar to LSD; CEY-19 (phosphoryloxy-N,N-diethyltryptamine, also known as 4-PO-DET or ethocybin), which has a duration of 2—4 hours and is also similar to LSD, and the mescaline derivative 2-CD (2,5-dimethoxy-4-methylphenethylamine; Schlichting, 1989). Therapists in the United States experimented with the short-acting dipropyltrytamine (DP T) in psycholytic therapy (Soskin, 1975; Soskin, Grof, & Richards, 1973), as well as in psychedelic therapy (Richards, Rhead, DiLeo, Yensen, & Kurland, 1977).
  11. 1 2 "EMCDDA–Europol Annual Report on the implementation of Council Decision 2005/387/JHA". European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).
  12. 1 2 Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD (May 2020). "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species" (PDF). Neuropharmacology. 167 107933. doi:10.1016/j.neuropharm.2019.107933. PMC   9191653 . PMID   31917152. Table 4 Human potency data for selected hallucinogens. [...]
  13. ↑ Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs". NIDA Research Monograph. 146: 74–91. PMID   8742795.
  14. ↑ Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN   978-0-12-433951-4.
  15. ↑ Glennon RA, Rosecrans JA (1982). "Indolealkylamine and phenalkylamine hallucinogens: a brief overview". Neuroscience and Biobehavioral Reviews. 6 (4): 489–497. doi:10.1016/0149-7634(82)90030-6. PMID   6757811.
  16. 1 2 Nichols DE (2018). Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN   978-3-662-55878-2. PMID   28401524. One of the earliest modifications of the tryptamines to be studied for psychoactive effects was the N,N-diethyl analogue of psilocin (CZ-74, 16). Both CZ-74 and its O-phosphoryl derivative CEY 19 (17) were studied in humans. Qualitatively, these compounds were very similar to psilocin and psilocybin, respectively, but had somewhat reduced durations of action (Leuner and Baer 1965).
  17. ↑ McKenna DJ, Repke DB, Lo L, Peroutka SJ (March 1990). "Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes". Neuropharmacology. 29 (3): 193–198. doi:10.1016/0028-3908(90)90001-8. PMID   2139186.
  18. ↑ Nichols DE (February 11, 1999). "Improvements to the Synthesis of Psilocybin and a Facile Method for Preparing the O-Acetyl Prodrug of Psilocin" . Synthesis. 1999 (6): 935–938. doi:10.1055/s-1999-3490. S2CID   32044725.
  19. ↑ Repke DB, Ferguson WJ, Bates DK (1977). "Psilocin analogs. 1. Synthesis of 3‐[2‐(dialkylamino)ethyl] ‐and 3‐[2‐(cycloalkylamino)ethyl] indol‐4‐ols". Journal of Heterocyclic Chemistry. 14 (1): 71–74. doi: 10.1002/jhet.5570140113 . ISSN   0022-152X . Retrieved 16 October 2025.
  20. ↑ Repke DB, Ferguson WJ (1982). "Psilocin analogs. III. Synthesis of 5‐methoxy‐ and 5‐hydroxy‐1,2,3,4‐tetrahydro‐9 H ‐pyrido[3,4‐ b ]indoles". Journal of Heterocyclic Chemistry. 19 (4): 845–848. doi:10.1002/jhet.5570190428. ISSN   0022-152X . Retrieved 16 October 2025.
  21. ↑ "Valtioneuvoston asetus kuluttajamarkkinoilta kielletyistä psykoaktiivisista aineista" [Government Decree on psychoactive substances banned from the consumer market]. Finlex (in Finnish). Finnish Ministry of Justice. 19 December 2014.
  22. ↑ "Förordning om ändring i förordningen (1999:58) om förbud mot vissa hälsofarliga varor;" [Ordinance amending the ordinance (1999: 58) on the prohibition of certain dangerous goods;](PDF). Svensk författningssamling (Swedish Code of Statutes) (in Swedish). 6 October 2005. Archived from the original (PDF) on 26 June 2021. Retrieved 6 September 2013.
  23. ↑ "21 U.S. Code § 841 - Prohibited acts A", LII / Legal Information Institute, retrieved 2016-08-02
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