Escaline

{{Short description|Psychedelic phenthylamine drug}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 408945247 | drug_name = | image = Escaline2DACS.svg | image_class = skin-invert-image | width = 235px | image2 = Escaline-3d-sticks.png | image_class2 = bg-transparent | width2 = 225px

<!-- Clinical data --> | pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA = | licence_EU = | DailyMedID = | licence_US = | pregnancy_AU = | pregnancy_category = | dependency_liability = | addiction_liability = | routes_of_administration = Oral<ref name="PiHKAL" /> | class = Serotonin receptor modulator; Serotonin 5-HT_2A receptor agonist; Serotonergic psychedelic; Hallucinogen | ATC_prefix = None | ATC_suffix =

<!-- Legal status --> | legal_status =

<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = 8–12 hours<ref name="PiHKAL" /> | excretion =

<!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 39201-82-6 | CAS_supplemental = | PubChem = 38240 | PubChemSubstance = | IUPHAR_ligand = | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 35053 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = Q13F1C1N8I | KEGG = | ChEBI = | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 319415 | NIAID_ChemDB = | PDB_ligand = | synonyms = E; 3,5-Dimethoxy-4-ethoxyphenethylamine; 4-Ethoxy-3,5-dimethoxyphenethylamine

<!-- Chemical data --> | IUPAC_name = 2-(4-ethoxy-3,5-dimethoxyphenyl)ethan-1-amine | C=12 | H=19 | N=1 | O=3 | SMILES = NCCC1=CC(OC)=C(OCC)C(OC)=C1 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C12H19NO3/c1-4-16-12-10(14-2)7-9(5-6-13)8-11(12)15-3/h7-8H,4-6,13H2,1-3H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = RHOGRSKNWDNCDN-UHFFFAOYSA-N

<!-- Physical data --> | melting_point = 165 | melting_high = 166 | melting_notes = (hydrochloride) }}

'''Escaline''' ('''E'''), also known as '''3,5-dimethoxy-4-ethoxyphenethylamine''', is a psychedelic drug of the phenethylamine and scaline families related to mescaline.<ref name="PiHKAL">{{CitePiHKAL}} https://erowid.org/library/books_online/pihkal/pihkal072.shtml</ref> 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).<ref name="PiHKAL" /> The drug has been encountered as a novel designer drug.<ref name="Aipsin">{{cite web | title=E (Эскалин) (Escaline) | website=АИПСИН | url=https://aipsin.com/newsubstance/181/ | language=ru | access-date=6 January 2026}}</ref>

==Use and effects== In his book ''PiHKAL'' (''Phenethylamines I Have Known and Loved''), Alexander Shulgin lists escaline's dose range as 40 to 60{{nbsp}}mg orally.<ref name="PiHKAL" /><ref name="HalberstadtChathaKlein2020" /> The duration is stated to be 8 to 12{{nbsp}}hours, whereas the onset is not described.<ref name="PiHKAL" /> Escaline is approximately 5- to 8-fold more potent than mescaline.<ref name="BlaazerSmidKruse2008">{{cite journal | vauthors = Blaazer AR, Smid P, Kruse CG | title = Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors | journal = ChemMedChem | volume = 3 | issue = 9 | pages = 1299–1309 | date = September 2008 | pmid = 18666267 | doi = 10.1002/cmdc.200800133 | url = https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/files/1981-Structure%E2%80%93Activity-Relationships-of-Phenylalkylamines-asAgonist-Ligands-for-5-HT2A-Receptors807f.pdf | archive-url = https://web.archive.org/web/20190721062032/https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/files/1981-Structure%E2%80%93Activity-Relationships-of-Phenylalkylamines-asAgonist-Ligands-for-5-HT2A-Receptors807f.pdf | archive-date = 21 July 2019 }}</ref>

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.<ref name="PiHKAL" />

==Interactions== {{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes}}

==Pharmacology== ===Pharmacodynamics=== {| class="wikitable floatleft" style="font-size:small;" |+ {{Nowrap|Escaline activities}} |- ! Target !! Affinity (K_i, nM) |- | 5-HT_1A || >10,000 (K_i)<br />372–724 ({{Abbrlink|EC₅₀|half-maximal effective concentration}})<br />23–40% ({{Abbrlink|E_max|maximal efficacy}}) |- | 5-HT_1B || >10,000 (K_i)<br />513–1,410 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />62–98% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT_1D || 724 (K_i)<br />117–2,690 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />56–100% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT_1E || >10,000 (K_i)<br />4,370–7,590 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />73–113% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT_1F || {{Abbr|ND|No data}} (K_i)<br />182–3,470 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />20–72% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT_2A || 216–>10,000<!-- 611 --> (K_i)<br />107–2,140<!-- 275 --> ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />62–108% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT_2B || 148–551 (K_i)<br />257–708 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />53–105% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT_2C || 177–4,366<!-- 1,950 --> (K_i)<br />741–2,450 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />68–112% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT₃ || >10,000 |- | 5-HT₄ || {{Abbr|ND|No data}} |- | 5-HT_5A || >10,000 |- | 5-HT₆ || >10,000 |- | 5-HT₇ || >10,000 |- | α_1A–α_1D || >10,000 |- | α_2A || 2,450 |- | α_2B || >10,000 |- | α_2C || 4,790 |- | β₁–β₃ || >10,000 |- | D₁, D₂ || >10,000 |- | D₃ || 380 |- | D₄ || 525 (K_i)<br />1,290–6,610 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />24–88% ({{Abbr|E_max|maximal efficacy}}) |- | D₅ || >10,000 |- | H₁–H₄ || >10,000 |- | M₁–M₅ || >10,000 |- | TAAR₁ || {{Abbr|ND|No data}} |- | I₁ || {{Abbr|ND|No data}} |- | σ₁, σ₂ || >10,000 |- | {{Abbrlink|SERT|Serotonin transporter}} || >10,000 (K_i)<br />{{Abbr|ND|No data}} ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}}) |- | {{Abbrlink|NET|Norepinephrine transporter}} || >10,000 (K_i)<br />{{Abbr|ND|No data}} ({{Abbr|IC₅₀|half-maximal inhibitory concentration}}) |- | {{Abbrlink|DAT|Dopamine transporter}} || >10,000 (K_i)<br />{{Abbr|ND|No data}} ({{Abbr|IC₅₀|half-maximal inhibitory concentration}}) |- class="sortbottom" | colspan="2" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. '''Refs:''' <ref name="JainGumpperSlocum2025" /><!-- Note: Only affinities and 5-HT1A/1B/1D/1E/1F + 5-HT2A/2B/2C + D4 EC50/Emax added so far for Jain et al. (2025) --><ref name="Braden_2007">{{cite thesis | vauthors = Braden MR | title = Towards a Biophysical Understanding of Hallucinogen Action | date = 2007 | degree = Ph.D. | publisher = Purdue University | id = {{ProQuest | 304838368}}|url=https://web.archive.org/web/20250121164406/https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=9a30faca37ad48466b87a192ccd542401dc24012}}</ref><ref name="MonteWaldmanMarona-Lewicka1997" /> |}

The comprehensive receptor interactions of escaline have been described.<ref name="JainGumpperSlocum2025">{{cite journal | vauthors = Jain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, Suomivuori CM, Huang XP, Shub L, DiBerto JF, Kim K, DeLeon C, Krumm BE, Fay JF, Keiser M, Hauser AS, Dror RO, Shoichet B, Gloriam DE, Nichols DE, Roth BL | title = The polypharmacology of psychedelics reveals multiple targets for potential therapeutics | journal = Neuron | volume = | issue = | pages = | date = July 2025 | pmid = 40683247 | doi = 10.1016/j.neuron.2025.06.012 | url = https://www.cell.com/cms/10.1016/j.neuron.2025.06.012/attachment/7d8365fe-51f3-4a28-bf40-9999bec837f6/mmc11.pdf | archive-date = 2025-07-25 | access-date = 2025-07-25 | archive-url = https://web.archive.org/web/20250725061718/https://www.cell.com/cms/10.1016/j.neuron.2025.06.012/attachment/7d8365fe-51f3-4a28-bf40-9999bec837f6/mmc11.pdf | url-status = bot: unknown }}</ref> It acts as an agonist of the serotonin 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors, among other actions.<ref name="JainGumpperSlocum2025" /> The drug is also an agonist of the dopamine D₄ receptor, though not of any other dopamine receptors.<ref name="JainGumpperSlocum2025" /> Besides escaline, the receptor interactions of various escaline analogues and derivatives have been described.<ref name="KolaczynskaLuethiTrachsel2021">{{cite journal | vauthors = Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, Liechti ME | title = Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines | journal = Frontiers in Pharmacology | volume = 12 | issue = | article-number = 794254 | date = 2021 | pmid = 35222010 | pmc = 8865417 | doi = 10.3389/fphar.2021.794254 | doi-access = free | url = https://pmc.ncbi.nlm.nih.gov/articles/PMC8865417/pdf/fphar-12-794254.pdf }}</ref>

Escaline produces the head-twitch response, a behavioral proxy of psychedelic-like effects, in rodents.<ref name="HalberstadtChathaChapman2019">{{cite journal | vauthors = Halberstadt AL, Chatha M, Chapman SJ, Brandt SD | title = Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice | journal = Journal of Psychopharmacology | volume = 33 | issue = 3 | pages = 406–414 | date = March 2019 | pmid = 30789291 | pmc = 6848748 | doi = 10.1177/0269881119826610 | url = https://www.researchgate.net/publication/331263972 }}</ref><ref name="HalberstadtChathaKlein2020">{{cite journal | vauthors = Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD | title = Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species | journal = Neuropharmacology | volume = 167 | issue = | article-number = 107933 | date = May 2020 | pmid = 31917152 | pmc = 9191653 | doi = 10.1016/j.neuropharm.2019.107933 | url = http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Serotonergic%20Psychedelics%2020/Halberstadt%2020%20Neuropharm%20potency%20of%20hallucinogens%20%20head-twitch.pdf }}</ref> It partially substitutes for LSD in rodent drug discrimination tests.<ref name="CasselsSáez-Briones2018">{{cite journal | vauthors = Cassels BK, Sáez-Briones P | title = Dark Classics in Chemical Neuroscience: Mescaline | journal = ACS Chemical Neuroscience | volume = 9 | issue = 10 | pages = 2448–2458 | date = October 2018 | pmid = 29847089 | doi = 10.1021/acschemneuro.8b00215 | url = https://shaunlacob.com/wp-content/uploads/2020/12/DC-MESCALINE.pdf | quote = 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. }}</ref><ref name="HalberstadtChathaChapman2019" /><ref name="MonteWaldmanMarona-Lewicka1997">{{cite journal | vauthors = Monte AP, Waldman SR, Marona-Lewicka D, Wainscott DB, Nelson DL, Sanders-Bush E, Nichols DE | title = Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives | journal = J Med Chem | volume = 40 | issue = 19 | pages = 2997–3008 | date = September 1997 | pmid = 9301661 | doi = 10.1021/jm970219x | url = }}</ref> The drug is unusual among serotonergic psychedelics in only partially rather than fully substituting for LSD.<ref name="CasselsSáez-Briones2018" /><ref name="HalberstadtChathaChapman2019" /><ref name="MonteWaldmanMarona-Lewicka1997" />

==Chemistry== ===Synthesis=== The chemical synthesis of escaline has been described.<ref name="PiHKAL" />

===Analogues=== Analogues of escaline include mescaline, proscaline, allylescaline, methallylescaline, 3C-E, and 3-methoxy-4-ethoxyphenethylamine (MEPEA; 3-desmethoxyescaline), among others.<ref name="PiHKAL" />

==History== Escaline was first described in the scientific literature by George S. Grace in 1934.<ref name="Grace1934">{{cite journal | last=Grace | first=George S. | title=The Action of Mescaline and Some Related Compounds | journal=The Journal of Pharmacology and Experimental Therapeutics | volume=50 | issue=4 | date=1934 | doi=10.1016/S0022-3565(25)07327-6 | pages=359–372}}</ref> Subsequently, it was also described by F. Benington and colleagues in 1954.<ref name="BeningtonMorinClarke1954">{{cite journal | vauthors = Benington F, Morin RD, Clarke LC | title=Synthesis of 4-Hydroxy- and 4-Ethoxy-3,5-dimethoxy-β-phenethylamines 1 | journal=Journal of the American Chemical Society | volume=76 | issue=21 | date=1954 | issn=0002-7863 | doi=10.1021/ja01650a084 | pages=5555–5556| bibcode=1954JAChS..76.5555B }}</ref> It was later further described by Otakar Leminger in 1972.<ref name="Leminger1972">{{cite journal | author = Otakar Leminger | title = Příspěvek k chemii v jádře alkoxylovaných β-fenoetylaminů – II: O některých v jádře alkoxylovaných β-fenoetylaminech, resp. jejich sulfátech | trans-title = A Contribution to the chemistry of alkoxylated phenethylamines – part 2: On some core-alkoxylated β-phenethylamines and their sulfates | journal = Chemický Průmysl | volume = 22 | issue = | date = 1972 | page = 553–557 | url = https://isomerdesign.com/bitnest/external/ChemickyPrumysl/22.553 | archive-url = https://web.archive.org/web/20260217050308/https://isomerdesign.com/bitnest/external/ChemickyPrumysl/22.553 | archive-date = 17 February 2026 | access-date = 17 February 2026 | url-status = bot: unknown }}</ref> 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.<ref name="NicholsDyer1977">{{cite journal | vauthors = Nichols DE, Dyer DC | title = Lipophilicity and serotonin agonist activity in a series of 4-substituted mescaline analogues | journal = Journal of Medicinal Chemistry | volume = 20 | issue = 2 | pages = 299–301 | date = February 1977 | pmid = 836502 | doi = 10.1021/jm00212a022 }}</ref><ref name="NicholsShulginDyer1977">{{cite journal | vauthors = Nichols DE, Shulgin AT, Dyer DC | title = Directional lipophilic character in a series of psychotomimetic phenethylamine derivatives | journal = Life Sciences | volume = 21 | issue = 4 | pages = 569–575 | date = August 1977 | pmid = 904435 | doi = 10.1016/0024-3205(77)90099-6 }}</ref>

==Society and culture== ===Legal status=== ====Canada==== Escaline is not a controlled substance in Canada as of 2025.<ref name="CDSA">{{cite web | title=Controlled Drugs and Substances Act | website=Department of Justice Canada | url=https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html | access-date=19 January 2026}}</ref>

====Sweden==== Escaline is illegal in Sweden as of 26 January 2016.<ref>{{cite web | url=http://www.folkhalsomyndigheten.se/nyheter-och-press/nyhetsarkiv/2015/november/31-nya-amnen-kan-klassas-som-narkotika-eller-halsofarlig-vara/ | title=31 nya ämnen kan klassas som narkotika eller hälsofarlig vara | publisher=Folkhälsomyndigheten | language=Swedish | date=November 2015 | access-date=2024-02-02 | archive-date=2017-08-05 | archive-url=https://web.archive.org/web/20170805220841/https://www.folkhalsomyndigheten.se/nyheter-och-press/nyhetsarkiv/2015/november/31-nya-amnen-kan-klassas-som-narkotika-eller-halsofarlig-vara/ | url-status=live }}</ref>

====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).<ref name="USDOJ">{{cite web| url=https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf| title=Controlled Substances - Alphabetical Order | publisher = U.S. Department of Justice | work = Diversion Control Division, Drug Enforcement Administration | date = December 2024 | access-date=2024-02-02| archive-date=2021-04-21| archive-url=https://web.archive.org/web/20210421180644/https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf| url-status=live}}</ref><ref name="DEA2007">{{cite web | author=Drug Enforcement Administration | title=Definition of “Positional Isomer” as It Pertains to the Control of Schedule I Controlled Substances | website=Federal Register | date=3 December 2007 | url=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}}</ref>

==See also== * Scaline

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/72 Escaline - Isomer Design] * [https://psychonautwiki.org/wiki/Escaline Escaline - PsychonautWiki] * [https://isomerdesign.com/pihkal/explore/72 The Small & Handy Escaline Thread - Bluelight] * [https://erowid.org/library/books_online/pihkal/pihkal072.shtml Escaline - PiHKAL - Erowid] * [https://isomerdesign.com/pihkal/read/pk/72 Escaline - PiHKAL - Isomer Design] * [https://isomerdesign.com/countyourculture/2012/05/04/leminger-allylescaline/ Leminger's Scalines - countyourculture]

{{Psychedelics}} {{Serotonin receptor modulators}} {{Dopamine receptor modulators}} {{Phenethylamines}}

Category:5-HT1A agonists Category:5-HT1B agonists Category:5-HT1D agonists Category:5-HT1E agonists Category:5-HT1F agonists Category:5-HT2A agonists Category:5-HT2B agonists Category:5-HT2C agonists Category:D4 receptor agonists Category:David E. Nichols Category:Designer drugs Category:Ethoxy compounds Category:O-methylated phenols Category:Phenol ethers Category:PiHKAL Category:Psychedelic phenethylamines Category:Scalines