{{Short description|Psychedelic drug}} {{for|the internet domain|.fm}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Drugbox | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 477211798 | drug_name = DOTFM | image = DOTFM.svg | image_class = skin-invert-image | width = 225px
<!-- Clinical data --> | tradename = | pregnancy_category = | routes_of_administration = Oral<ref name="Trachsel_2012" /><ref name="Trachsel_2013" /> | class =
<!-- Legal status --> | legal_CA = Schedule I | legal_UK = Class A | legal_status =
<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | onset = | elimination_half-life = | duration_of_action = Unknown<ref name="Trachsel_2012" /><ref name="Trachsel_2013" /> | excretion =
<!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 159277-07-3 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = NLH3FWZ9T4 | CAS_supplemental = <br /> {{CAS|159277-12-0}} (hydrochloride) | ATC_prefix = | ATC_suffix = | PubChem = 10400521 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 8575959 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 6620 | synonyms = 2,5-Dimethoxy-4-trifluoromethylamphetamine; 4-Trifluoromethyl-2,5-dimethoxyamphetamine; DOTFM; 3C-TFM
<!-- Chemical data --> | IUPAC_name = (''RS'')-1-[2,5-Dimethoxy-4-(trifluoromethyl)phenyl]propan-2-amine | C=12 | H=16 | F=3 | N=1 | O=2 | SMILES = FC(F)(F)c1cc(OC)c(cc1OC)CC(N)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C12H16F3NO2/c1-7(16)4-8-5-11(18-3)9(12(13,14)15)6-10(8)17-2/h5-7H,4,16H2,1-3H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = WPGOTSORDNBMHP-UHFFFAOYSA-N }}
'''DOTFM''', also known as '''2,5-dimethoxy-4-trifluoromethylamphetamine''', is a psychedelic drug of the phenethylamine, amphetamine, and DOx families related to DOM.<ref name="Shulgin_2011" /><ref name="Trachsel_2012" /><ref name="Trachsel_2013" /><ref name="Nichols_1994" /> It is the α-methylated analogue of 2C-TFM.<ref name="Shulgin_2011" /><ref name="Trachsel_2013" /> The drug is the most potent known DOx psychedelic.<ref name="Trachsel_2012" /><ref name="Trachsel_2013" />
==Use and effects== According to Daniel Trachsel, DOTFM is active as a psychedelic in humans at doses of 0.3 to 1{{nbsp}}mg (300–1,000{{nbsp}}μg) orally and its duration is not listed.<ref name="Trachsel_2012">{{cite journal | vauthors = Trachsel D | title = Fluorine in psychedelic phenethylamines | journal = Drug Test Anal | volume = 4 | issue = 7–8 | pages = 577–590 | date = 2012 | pmid = 22374819 | doi = 10.1002/dta.413 | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=c7b41be36b1f580a264a752521d151e6e2d9409d | url-access = subscription | quote = The 4-trifluoromethyl derivative 2C-TFM (34) was identified as a potent 5-HT2A/C receptor agonist by Nichols et al. in 1994.[28] Together with its a-methyl congener DOTFM (35) it is among the most potent simple phenethylamines at these binding sites, showing comparable or slightly higher binding affinities than DOB (29) and DOI (30).[28] Compared to DOB (29) and DOI (30), both compounds 34 and 35 turned out to be of equal, or slightly increased potency in DD studies (rats, training drug: LSD).[28] Within the context of a DD study, this was the first time for a 2C derivative to be found equally potent to the potent 3C derivatives DOB (29) and DOI (30). In humans, initial experiments seem to be consistent with high potencies (34: 3–5 mg; 35: 0.3 mg or more. A.T. Shulgin, personal communication in 2003).[4] }}</ref><ref name="Trachsel_2013">{{cite book | vauthors = Trachsel D, Lehmann D, Enzensperger C | title = Phenethylamine: von der Struktur zur Funktion | location = Solothurn | year = 2013 | trans-title = Phenethylamines: From Structure to Function | edition = 1 | publisher = Nachtschatten-Verlag | series = Nachtschatten-Science | isbn = 978-3-03788-700-4 | oclc = 858805226 | url = https://books.google.com/books?id=-Us1kgEACAAJ | language = de }}</ref> It is the most potent psychedelic of the DOx family, followed by DOB, which has a dose range of 1 to 3{{nbsp}}mg orally.<ref name="Trachsel_2012" /><ref name="Trachsel_2013" />
==Interactions== {{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes}}
==Pharmacology== ===Pharmacodynamics=== DOTFM acts as an agonist at the serotonin 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors.<ref name="Nichols_1994" /> In drug discrimination tests in rats, DOTFM fully substituted for LSD and was slightly more potent than DOI.<ref name="Nichols_1994" /> In addition, (''R'')-DOTFM robustly induces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents, with equivalent potency as (''R'')-DOI.<ref name="Flanagan_2024" /> The drug is around twice as potent as 2C-TFM in animal studies.
In contrast to (''R'')-DOI, which has extraordinarily potent serotonin 5-HT<sub>2A</sub> receptor-mediated anti-inflammatory effects,<ref name="Nichols_2017">{{cite journal | vauthors = Nichols DE, Johnson MW, Nichols CD | title = Psychedelics as Medicines: An Emerging New Paradigm | journal = Clinical Pharmacology and Therapeutics | volume = 101 | issue = 2 | pages = 209–219 | date = February 2017 | pmid = 28019026 | doi = 10.1002/cpt.557 }}</ref><ref name="Yu_2008">{{cite journal | vauthors = Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD | title = Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 2 | pages = 316–323 | date = November 2008 | pmid = 18708586 | doi = 10.1124/jpet.108.143461 }}</ref> DOTFM shows no anti-inflammatory effects.<ref name="Flanagan_2022">{{cite journal | vauthors = Flanagan TW, Billac G, Nichols CD | title = Differential Regulation of Inflammatory Responses Following 5-HT 2 Receptor Activation in Pulmonary Tissues | journal = The FASEB Journal | volume = 36 | issue = S1 | date = 2022 | doi = 10.1096/fasebj.2022.36.S1.R2617 | issn = 0892-6638 | article-number = fasebj.2022.36.S1.R2617 | doi-access = free }}</ref> The differences between the drugs in this regard appear to be due to differences in functional selectivity at the serotonin 5-HT<sub>2A</sub> receptor.<ref name="Flanagan_2022" /><ref name="Flanagan_2024">{{cite journal | vauthors = Flanagan TW, Foster TP, Galbato TE, Lum PY, Louie B, Song G, Halberstadt AL, Billac GB, Nichols CD | title = Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression | journal = ACS Pharmacology & Translational Science | volume = 7 | issue = 2 | pages = 478–492 | date = February 2024 | pmid = 38357283 | pmc = 10863441 | doi = 10.1021/acsptsci.3c00297 | quote = The effects of (R)-DOTFM were examined in the head-twitch response (HTR) assay. (R)-DOTFM produced a strong HTR with a potent ED 50 of 0.60 μmol/kg. These values are equivalent to (R)-DOI, as previously determined. }}</ref>
==Chemistry== ===Synthesis=== The chemical synthesis of DOTFM has been described.<ref name="Shulgin_2011" /><ref name="Nichols_1994" />
===Analogues=== Analogues of DOTFM include 2C-TFM, 4C-TFM (TFM-Ariadne; 4C-DOTFM), DOTFE, TFMFly (DOTFM-FLY), and 25TFM-NBOMe, among others.
==History== DOTFM was first synthesized in 1994 by a team at Purdue University led by David E. Nichols.<ref name="Nichols_1994">{{cite journal | vauthors = Nichols DE, Frescas S, Marona-Lewicka D, Huang X, Roth BL, Gudelsky GA, Nash JF | title = 1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: a potent serotonin 5-HT2A/2C agonist | journal = Journal of Medicinal Chemistry | volume = 37 | issue = 25 | pages = 4346–4351 | date = December 1994 | pmid = 7996545 | doi = 10.1021/jm00051a011 | author5-link = Bryan Roth }}</ref> The threshold dose in humans was reported by Alexander Shulgin in his 2011 book ''The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds'', who cited personal communication with an anonymous individual in 2003 as the source for the information.<ref name="Shulgin_2011">{{cite book | vauthors = Shulgin A, Manning T, Daley P | title = The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | location = Berkeley | volume = 1 | year = 2011 | publisher = Transform Press | isbn = 978-0-9630096-3-0 | quote = Threshold oral activity [of DOTFM] reported in humans at 300 µg (Anon., 2003). }}</ref><ref name="Trachsel_2012" /> Subsequently, Daniel Trachsel described a wider dose range in 2013, although did not report its duration.<ref name="Trachsel_2013" />
==Society and culture== ===Legal status=== ====Canada==== DOTFM is a controlled substance in Canada under phenethylamine blanket-ban language.<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>
==See also== * DOx (psychedelics) * 2C-iBu (ELE-02) * 5-HT<sub>2A</sub> receptor § Anti-inflammatory effects
== References == {{Reflist}}
==External links== * [https://isomerdesign.com/pihkal/explore/5381 DOTFM - Isomer Design] * [https://archive.org/details/shulgin-index-vol-1/page/133/mode/1up DOTFM - The Shulgin Index]
{{Psychedelics}} {{Serotonin receptor modulators}} {{Phenethylamines}}
{{DEFAULTSORT:Dimethoxy-4-trifluoromethylamphetamine, 2,5-}}
Category:5-HT2A agonists Category:5-HT2C agonists Category:Daniel Trachsel Category:David E. Nichols Category:DOx (psychedelics) Category:Psychedelic phenethylamines Category:Substances discovered in the 1990s Category:Trifluoromethyl compounds