Chemistry:Escaline

From HandWiki

Escaline (E), also known as 3,5-dimethoxy-4-ethoxyphenethylamine, is a psychedelic drug of the phenethylamine and scaline families related to mescaline.[1] It is the 4-ethoxy analogue of mescaline (3,4,5-trimethoxyphenethylamine) and the phenethylamine (non-α-methyl) analogue of 3C-E (3,5-dimethoxy-4-ethoxyamphetamine).[1] The drug has been encountered as a novel designer drug.[2]

Use and effects

In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists escaline's dose range as 40 to 60 mg orally.[1][3] The duration is stated to be 8 to 12 hours, whereas the onset is not described.[1] Escaline is approximately 5- to 8-fold more potent than mescaline.[4]

The effects of escaline have been described relatively limitedly but have been reported to include sensory enhancement without an intellectual component, little synthesis of external sensory inputs like music or visual stimuli, easy fantasy, rational thinking and insight, pleasantness, powerful and complex intoxication, pain relief, muscle tension, motor incoordination to the extent of not being able to walk or tie one's shoelaces, body tension that outweighed the desired psychoactive effects, tachycardia, dehydration, nightmares, and next-day hangover symptoms such as tiredness and low energy.[1]

Interactions

Pharmacology

Pharmacodynamics

Escaline activities
Target Affinity (Ki, nM)
5-HT1A >10,000 (Ki)
372–724 (EC50)
23–40% (Emax)
5-HT1B >10,000 (Ki)
513–1,410 (EC50)
62–98% (Emax)
5-HT1D 724 (Ki)
117–2,690 (EC50)
56–100% (Emax)
5-HT1E >10,000 (Ki)
4,370–7,590 (EC50)
73–113% (Emax)
5-HT1F ND (Ki)
182–3,470 (EC50)
20–72% (Emax)
5-HT2A 216–>10,000 (Ki)
107–2,140 (EC50)
62–108% (Emax)
5-HT2B 148–551 (Ki)
257–708 (EC50)
53–105% (Emax)
5-HT2C 177–4,366 (Ki)
741–2,450 (EC50)
68–112% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A >10,000
5-HT6 >10,000
5-HT7 >10,000
α1A–α1D >10,000
α2A 2,450
α2B >10,000
α2C 4,790
β1–β3 >10,000
D1, D2 >10,000
D3 380
D4 525 (Ki)
1,290–6,610 (EC50)
24–88% (Emax)
D5 >10,000
H1–H4 >10,000
M1–M5 >10,000
TAAR1 ND
I1 ND
σ1, σ2 >10,000
SERT >10,000 (Ki)
ND (IC50)
NET >10,000 (Ki)
ND (IC50)
DAT >10,000 (Ki)
ND (IC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [5][6][7]

The comprehensive receptor interactions of escaline have been described.[5] It acts as an agonist of the serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, and 5-HT2C receptors, among other actions.[5] The drug is also an agonist of the dopamine D4 receptor, though not of any other dopamine receptors.[5] Besides escaline, the receptor interactions of various escaline analogues and derivatives have been described.[8]

Escaline produces the head-twitch response, a behavioral proxy of psychedelic-like effects, in rodents.[9][3] It partially substitutes for LSD in rodent drug discrimination tests.[10][9][7] The drug is unusual among serotonergic psychedelics in only partially rather than fully substituting for LSD.[10][9][7]

Chemistry

Synthesis

The chemical synthesis of escaline has been described.[1]

Analogues

Analogues of escaline include mescaline, proscaline, allylescaline, methallylescaline, 3C-E, and 3-methoxy-4-ethoxyphenethylamine (MEPEA; 3-desmethoxyescaline), among others.[1]

History

Escaline was first described in the scientific literature by George S. Grace in 1934.[11] Subsequently, it was also described by F. Benington and colleagues in 1954.[12] It was later further described by Otakar Leminger in 1972.[13] Then, it was studied by David E. Nichols and colleagues, who prepared a series of mescaline analogues that included escaline, proscaline, and isoproscaline and published their work in 1977.[14][15]

Society and culture

Canada

Escaline is not a controlled substance in Canada as of 2025.[16]

Sweden

Escaline is illegal in Sweden as of 26 January 2016.[17]

United States

Escaline is a Schedule I controlled substance (DEA #7930) in the United States with the reason cited being that it is a positional isomer of 3,4,5-trimethoxyamphetamine (TMA).[18][19]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Shulgin, Alexander; Shulgin, Ann (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN 0-9630096-0-5. OCLC 25627628. http://www.erowid.org/library/books_online/pihkal/pihkal.shtml.  https://erowid.org/library/books_online/pihkal/pihkal072.shtml
  2. ↑ "E (Эскалин) (Escaline)" (in ru). https://aipsin.com/newsubstance/181/. 
  3. ↑ 3.0 3.1 "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. 
  4. ↑ "Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors". ChemMedChem 3 (9): 1299–1309. September 2008. doi:10.1002/cmdc.200800133. PMID 18666267. https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/files/1981-Structure%E2%80%93Activity-Relationships-of-Phenylalkylamines-asAgonist-Ligands-for-5-HT2A-Receptors807f.pdf. 
  5. ↑ 5.0 5.1 5.2 5.3 "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics". Neuron. July 2025. doi:10.1016/j.neuron.2025.06.012. PMID 40683247. https://www.cell.com/cms/10.1016/j.neuron.2025.06.012/attachment/7d8365fe-51f3-4a28-bf40-9999bec837f6/mmc11.pdf. Retrieved 2025-07-25. 
  6. ↑ Braden MR (2007). Towards a Biophysical Understanding of Hallucinogen Action (Ph.D. thesis). Purdue University. ProQuest 304838368.
  7. ↑ 7.0 7.1 7.2 "Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives". J Med Chem 40 (19): 2997–3008. September 1997. doi:10.1021/jm970219x. PMID 9301661. 
  8. ↑ "Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines". Frontiers in Pharmacology 12. 2021. doi:10.3389/fphar.2021.794254. PMID 35222010. PMC 8865417. https://pmc.ncbi.nlm.nih.gov/articles/PMC8865417/pdf/fphar-12-794254.pdf. 
  9. ↑ 9.0 9.1 9.2 "Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice". Journal of Psychopharmacology 33 (3): 406–414. March 2019. doi:10.1177/0269881119826610. PMID 30789291. PMC 6848748. https://www.researchgate.net/publication/331263972. 
  10. ↑ 10.0 10.1 "Dark Classics in Chemical Neuroscience: Mescaline". ACS Chemical Neuroscience 9 (10): 2448–2458. October 2018. doi:10.1021/acschemneuro.8b00215. PMID 29847089. https://shaunlacob.com/wp-content/uploads/2020/12/DC-MESCALINE.pdf. "In the case of the 3,4,5- trioxygenated compounds, binding studies at 5-HT2A and 5-HT2C receptors revealed somewhat higher affinities than mescaline but, in phosphoinositide hydrolysis assays (only for 5-HT2A), lower efficacies relative to serotonin and the full agonist mescaline (60 and 45%, respectively). More striking, however, was the observation that the new compounds did not fully substitute for LSD in LSD-trained rats, and at doses well above the mescaline EC50, only 50 and 29% appropriate responding was recorded. In view of this unexpected result, 3,5-dimethoxy-4-ethoxyphenethylamine (escaline), which is considerably more potent than mescaline in humans,128 was also tested. It was found to have about twice the affinity of mescaline for 5-HT2A receptors and was a complete agonist with very similar functional potency, but again it failed to substitute completely for LSD in the drug discrimination experiments.". 
  11. ↑ Grace, George S. (1934). "The Action of Mescaline and Some Related Compounds". The Journal of Pharmacology and Experimental Therapeutics 50 (4): 359–372. doi:10.1016/S0022-3565(25)07327-6. 
  12. ↑ "Synthesis of 4-Hydroxy- and 4-Ethoxy-3,5-dimethoxy-β-phenethylamines 1". Journal of the American Chemical Society 76 (21): 5555–5556. 1954. doi:10.1021/ja01650a084. ISSN 0002-7863. Bibcode: 1954JAChS..76.5555B. 
  13. ↑ Otakar Leminger (1972). "Příspěvek k chemii v jádře alkoxylovaných β-fenoetylaminů – II: O některých v jádře alkoxylovaných β-fenoetylaminech, resp. jejich sulfátech". Chemický Průmysl 22: 553–557. https://isomerdesign.com/bitnest/external/ChemickyPrumysl/22.553. Retrieved 17 February 2026. 
  14. ↑ "Lipophilicity and serotonin agonist activity in a series of 4-substituted mescaline analogues". Journal of Medicinal Chemistry 20 (2): 299–301. February 1977. doi:10.1021/jm00212a022. PMID 836502. 
  15. ↑ "Directional lipophilic character in a series of psychotomimetic phenethylamine derivatives". Life Sciences 21 (4): 569–575. August 1977. doi:10.1016/0024-3205(77)90099-6. PMID 904435. 
  16. ↑ "Controlled Drugs and Substances Act". https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html. 
  17. ↑ "31 nya ämnen kan klassas som narkotika eller hälsofarlig vara" (in Swedish). Folkhälsomyndigheten. November 2015. http://www.folkhalsomyndigheten.se/nyheter-och-press/nyhetsarkiv/2015/november/31-nya-amnen-kan-klassas-som-narkotika-eller-halsofarlig-vara/. 
  18. ↑ "Controlled Substances - Alphabetical Order". Diversion Control Division, Drug Enforcement Administration. U.S. Department of Justice. December 2024. https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf. 
  19. ↑ Drug Enforcement Administration (3 December 2007). "Definition of “Positional Isomer” as It Pertains to the Control of Schedule I Controlled Substances". https://www.federalregister.gov/documents/2007/12/03/E7-23413/definition-of-positional-isomer-as-it-pertains-to-the-control-of-schedule-i-controlled-substances. 



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