2,5-Dimethoxyamphetamine

vanc 6 2,5-DMA.svg skin-invert-image 175px 2,5-Dimethoxyamphetamine ball-and-stick structure.png bg-transparent 175px Oral Serotonin 5-HT2 receptor agonist; Serotonin 5-HT2A receptor agonist; Stimulant None 1 hour 5–8hours 2801-68-5 62787 DB01465 56526 OIM1536TQQ C22738 8642 2,5-DMA; 2,5-Dimethoxy-α-methylphenethylamine; DMA; DMA-4; DOH; NSC-367445 1-(2,5-dimethoxyphenyl)propan-2-amine 11 17 1 2 CC(CC1=C(C=CC(=C1)OC)OC)N 1S/C11H17NO2/c1-8(12)6-9-7-10(13-2)4-5-11(9)14-3/h4-5,7-8H,6,12H2,1-3H3 LATVFYDIBMDBSY-UHFFFAOYSA-N 2,5-Dimethoxyamphetamine (2,5-DMA), also known as DMA-4 or as DOH, is a psychoactive drug of the phenethylamine and amphetamine families. Shulgin AT, Shulgin A #54 2,5-DMA; DMA; 2,5-DIMETHOXYAMPHETAMINE PiHKAL: A Chemical Love Story Berkeley, CA 1991 Transform Press 978-0-9630096-0-9 1st 25627628 https://www.erowid.org/library/books_online/pihkal/pihkal054.shtml Shulgin A, Manning T, Daley PF #36. 2,5-DMA The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds Berkeley 1 2011 Transform Press 978-0-9630096-3-0 https://archive.org/details/shulgin-index-vol-1/page/57/mode/1up?view=theater It is one of the dimethoxyamphetamine (DMA) series of positional isomers. The drug is notable in being the parent compound of the DOx (4-substituted-2,5-dimethoxyamphetamine) series of psychedelic drugs. It is taken orally. Use and effects In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists 2,5-DMA's dose as 80 to 160mg orally and its duration is 6 to 8hours. Information on the qualitative effects of 2,5-DMA is said to be very sparse. According to Shulgin, it produced threshold effects or a "plus-one" on the Shulgin Rating Scale at a dose of 80mg orally, with the effects being completely physical and including tremors, some cardiovascular effects, and no sensory effects. He opted not to try higher doses. Other reports were also reviewed in PiHKAL. According to a report from South America, a dose of 75mg produced a largely pleasant intoxication, including increased interest in one's surroundings, but with no perceptual changes, no overt stimulation, and no physiological effects aside from slight pupil dilation. One other report of 250mg 2,5-DMA tartrate, which would be equivalent to somewhere in the range of 150 to 200mg of the hydrochloride salt, produced some "speedy" or amphetamine-like effects but no sensory changes. In an earlier review, Shulgin reported that 2,5-DMA produced stimulant-like effects at a dose of 50mg, with effects including vertigo, a "closed visual field", slight muscular incoordination, modest central intoxication, slightly increased blood pressure, and "extreme hyperactivity". The onset was reported to be 1hour and peak effects after 2hours, with a total duration of 5hours. 2,5-DMA has been encountered as a novel designer drug, with capsules of 200mg of the hydrobromide salt, equivalent to 170mg of the hydrochloride salt. It was initially misrepresented as mescaline or MDA before being named DMA. According to Shulgin, this might be an effective dose level that has not been formally clinically explored. Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Pharmacology Pharmacodynamics + 2,5-DMA activities Target Affinity (Ki, nM) 5-HT1A 2,583–6,017 5-HT1B 8,435 (rat) 5-HT1D ND No data 5-HT1E ND No data 5-HT1F ND No data 5-HT2A 211–5,200 (Ki)160–3,548 (EC50 half-maximal effective concentration)58–109% (Emax maximal efficacy) 5-HT2B 1,039 (Ki)3,390–93,320 (EC50 half-maximal effective concentration)93–94% (Emax maximal efficacy) 5-HT2C 104–>10,000 (Ki)124–3,144 (EC50 half-maximal effective concentration)76–103% (Emax maximal efficacy) 5-HT3 ND No data 5-HT4 ND No data 5-HT5A ND No data 5-HT6 ND No data 5-HT7 ND No data α1A 5,363 α1B–α1D ND No data α2A 4,385 α2B–α2C ND No data β1, β2 ND No data D1 ND No data D2 >13,000 D3–D5 ND No data H1–H4 ND No data M1–M5 ND No data TAAR1 >30,000 (EC50 half-maximal effective concentration) (human) I1 ND No data σ1, σ2 ND No data SERT Serotonin transporter >7,000 (Ki)ND No data (IC50 half-maximal inhibitory concentration)ND No data (EC50 half-maximal effective concentration) NET Norepinephrine transporter >8,000 (Ki)ND No data (IC50 half-maximal inhibitory concentration)ND No data (EC50 half-maximal effective concentration) DAT Dopamine transporter >8,000 (Ki)ND No data (IC50 half-maximal inhibitory concentration)ND No data (EC50 half-maximal effective concentration) MAO-A Monoamine oxidase A >100,000 (IC50 half-maximal inhibitory concentration) MAO-B Monoamine oxidase B >100,000 (IC50 half-maximal inhibitory concentration) Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: Kᵢ Database 15 March 2025 PDSP https://pdsp.unc.edu/kidb2/kidb/web/kis-results/index?KisResultsSearch%5Binput_receptors%5D=&KisResultsSearch%5Binput_sources%5D=&KisResultsSearch%5Binput_species%5D=&KisResultsSearch%5Binput_hot_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=12958&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=15598&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=12962&KisResultsSearch%5Binput_citations%5D=&KisResultsSearch%5BsearchType%5D=&KisResultsSearch%5Bki_val_from%5D=&KisResultsSearch%5Bki_val_to%5D=&KisResultsSearch%5Bcustom_ki_val%5D=&KisResultsSearch%5Binput_receptors%5D=&KisResultsSearch%5Binput_sources%5D=&KisResultsSearch%5Binput_species%5D=&KisResultsSearch%5Binput_hot_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=688&KisResultsSearch%5Binput_citations%5D=&KisResultsSearch%5BsearchType%5D=&KisResultsSearch%5Bki_val_from%5D=&KisResultsSearch%5Bki_val_to%5D=&KisResultsSearch%5Bcustom_ki_val%5D= 15 March 2025 Liu T BindingDB BDBM50005251 (+/-)2-(2,5-Dimethoxy-phenyl)-1-methyl-ethylamine::1-(2,5-dimethoxyphenyl)propan-2-amine::2,5-dimethoxy-4-bromoamphetamine::2-(2,5-Dimethoxy-phenyl)-1-methyl-ethylamine::2-(2,5-Dimethoxy-phenyl)-1-methyl-ethylamine(2,5-DMA)::CHEMBL8642::DMA BindingDB https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50005251 15 March 2025 Nelson DL, Lucaites VL, Wainscott DB, Glennon RA Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors Naunyn-Schmiedeberg's Archives of Pharmacology 359 1 1–6 January 1999 9933142 10.1007/pl00005315 Luethi D, Glatfelter GC, Pottie E, Sellitti F, Maitland AD, Gonzalez NR, Kryszak LA, Jackson SN, Hoener MC, Stove CP, Liechti ME, Smieško M, Baumann MH, Simmler LD, Rudin D The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects Mol Psychiatry November 2025 41193673 10.1038/s41380-025-03325-1 https://www.nature.com/articles/s41380-025-03325-1.pdf Hemanth P, Nistala P, Nguyen VT, Eltit JM, Glennon RA, Dukat M Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors Frontiers in Pharmacology 14 2023 36762110 9902381 10.3389/fphar.2023.1101290 free 1101290 Dowd CS, Herrick-Davis K, Egan C, DuPre A, Smith C, Teitler M, Glennon RA 1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes as 5-HT(2A) partial agonists Journal of Medicinal Chemistry 43 16 3074–3084 August 2000 10956215 10.1021/jm9906062 Acuña-Castillo C, Villalobos C, Moya PR, Sáez P, Cassels BK, Huidobro-Toro JP Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors British Journal of Pharmacology 136 4 510–519 June 2002 12055129 1573376 10.1038/sj.bjp.0704747 Runyon SP, Mosier PD, Roth BL, Glennon RA, Westkaemper RB Potential modes of interaction of 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives with the 5-HT2A receptor: a ligand structure-affinity relationship, receptor mutagenesis and receptor modeling investigation Journal of Medicinal Chemistry 51 21 6808–6828 November 2008 18847250 3088499 10.1021/jm800771x Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK Amphetamine Derivatives as Monoamine Oxidase Inhibitors Frontiers in Pharmacology 10 2019 32038257 6989591 10.3389/fphar.2019.01590 free 1590 2,5-DMA is a low-potency serotonin 5-HT2A receptor partial agonist, with an affinity (Ki) of 2,502nM, an EC50 half-maximal effective concentration of 160 to 3,548nM (depending on the signaling cascade and study), and an Emax maximal efficacy of 66 to 109%. Luethi D, Rudin D, Hoener MC, Liechti ME Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines The FASEB Journal 36 S1 2022 10.1096/fasebj.2022.36.S1.R2691 0892-6638 fasebj.2022.36.S1.R2691 free https://www.researchgate.net/publication/360369275 Rudin D, Luethi D, Hoener MC, Liechti ME Structure-activity Relation of Halogenated 2,5-Dimethoxyamphetamines Compared to their α‑Desmethyl (2C) Analogues The FASEB Journal 36 S1 2022 10.1096/fasebj.2022.36.S1.R2121 fasebj.2022.36.S1.R2121 0892-6638 free https://www.researchgate.net/publication/360423277 Pottie E, Cannaert A, Stove CP In vitro structure-activity relationship determination of 30 psychedelic new psychoactive substances by means of β-arrestin 2 recruitment to the serotonin 2A receptor Archives of Toxicology 94 10 3449–3460 October 2020 32627074 10.1007/s00204-020-02836-w free 2020ArTox..94.3449P 1854/LU-8687071 It has also been assessed at several other receptors. In a much earlier study, its affinities (Ki) were 1,020nM at the serotonin 5-HT1 receptor and 5,200nM at the serotonin 5-HT2 receptor. Glennon RA Central serotonin receptors as targets for drug research Journal of Medicinal Chemistry 30 1 1–12 January 1987 3543362 10.1021/jm00384a001 Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites Shannon M, Battaglia G, Glennon RA, Titeler M 5-HT1 and 5-HT2 binding properties of derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA) European Journal of Pharmacology 102 1 23–29 June 1984 6479216 10.1016/0014-2999(84)90333-9 The drug does not appear to bind to the monoamine transporters, at least at the assessed concentrations (up to 7,000nM). It was inactive at the human trace amine-associated receptor 1 (TAAR1). 2,5-DMA shows dramatically reduced potency as a serotonin 5-HT2A receptor agonist compared to the DOx drugs, such as 2,5-dimethoxy-4-methylamphetamine (DOM). 2,5-DMA produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. However, it produces a very weak head-twitch response compared to other structurally related psychedelics like DOM, DOET, DOPR, and even DOBU. In addition, it is less potent in comparison. 2,5-DMA substitutes for DOM in rodent drug discrimination tests, albeit with dramatically lower potency than other DOx drugs. Glennon RA Stimulus properties of hallucinogenic phenalkylamines and related designer drugs: formulation of structure-activity relationships NIDA Research Monograph 94 43–67 1989 2575229 https://archives.nida.nih.gov/sites/default/files/monograph94.pdf#page=54 dead https://web.archive.org/web/20230511144224/https://archives.nida.nih.gov/sites/default/files/monograph94.pdf#page=54 May 11, 2023 It also substitutes for 5-MeO-DMT in rodent drug discrimination tests. Glennon RA, Young R, Rosecrans JA, Kallman MJ Hallucinogenic agents as discriminative stimuli: a correlation with serotonin receptor affinities Psychopharmacology 68 2 155–158 1980 6776558 10.1007/BF00432133 These findings suggesting that 2,5-DMA might produce weak hallucinogenic effects at sufficiently high doses. 2,5-DMA shows no substitution for dextroamphetamine in drug discrimination tests, suggesting that it lacks psychostimulant- or amphetamine-like effects, at least in rodents. Unlike other DOx drugs like DOM, DOPR, DOBU, and DOAM, 2,5-DMA does not produce hyperlocomotion in rodents and instead dose-dependently produces only hypolocomotion. On the other hand, it does similarly produce hypothermia at higher doses. Though 2,5-DMA appears to be inactive or of very low potency as a psychedelic in humans, it is a highly potent anti-inflammatory drug similarly to other DOx and 2C drugs. Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore ACS Pharmacology & Translational Science 4 2 488–502 April 2021 33860179 8033619 10.1021/acsptsci.0c00063 The nature of the 4-position substituent of phenethylamine psychedelics has been previously linked to 5-HT2 receptor selectivity as well as agonist properties at 5-HT2 receptors.40 Analysis of the 4-position demonstrated that the identity of the moiety at this position was rather flexible. Fully efficacious substitutions at the 4-position included the halogens iodine and bromine (R)-DOI (Figure 3), 2C-B (Figure 7A), methoxy (TMA-2) (Figure 7G), short-chain hydrocarbons (R)-DOM (Figure 7H), (R)-DOET) (Figure 7I), and a branched hydrocarbon (DOiBu) (Figure 7J). [...] In a comparison of PenH-AUC values determined for each drug as a proxy measure of anti-inflammatory efficacy (Figure 8A) to either EC50 or EMax for calcium mobilization downstream of 5- HT2A receptor activation (Table 1), [...] PODCAST 33: An interview with Dr. Charles D. Nichols 14 November 2021 https://www.patreon.com/posts/podcast-33-with-58708009 The Hamilton Morris Podcast Patreon Hamilton Morris 48:22–53:56 20 January 2025 This was in spite of it being of very low potency as a serotonin 5-HT2A receptor agonist in terms of calcium mobilization in the study (EC50 half-maximal effective concentration = 3,548nM; Emax maximal efficacy = 109.0%). Based on the preceding findings, Charles D. Nichols has said that both fully anti-inflammatory non-psychedelic compounds like 2,5-DMA and fully psychedelic non-anti-inflammatory compounds like DOTFM are known. Pharmacokinetics 2,5-DMA crosses the blood–brain barrier in rodents. It showed the lowest brain/plasma ratio among DOM and its higher homologues. Chemistry Synthesis The chemical synthesis of 2,5-DMA has been described. Trachsel D, Lehmann D, Enzensperger C Phenethylamine: von der Struktur zur Funktion Solothurn 2013 Phenethylamines: From Structure to Function 1 Nachtschatten-Verlag Nachtschatten-Science 978-3-03788-700-4 858805226 https://books.google.com/books?id=-Us1kgEACAAJ de https://web.archive.org/web/20251113135159/https://books.google.com/books?id=-Us1kgEACAAJ 13 November 2025 26 November 2025 bot: unknown Analogues and derivatives Analogues and derivatives of 2,5-DMA include the DOx series like DOM, DOB, and DOI, FLY compounds like DOB-FLY, Bromo-DragonFLY (DOB-DFLY), DOH-5-hemiFLY, 25-NB compounds like DOM-NBOMe, DOB-NBOMe, and DOI-NBOMe, and other compounds like trimethoxyamphetamines (TMAs) and pentamethoxyamphetamine (PeMA). Methoxamine (β-hydroxy-2,5-DMA) is another derivative of 2,5-DMA. History 2,5-DMA was first described in the scientific literature by F. Benington and colleagues by at least 1968. Benington F, Morin RD The chemorelease of norepinephrine from mouse hearts by substituted amphetamines J Med Chem 11 4 896–897 July 1968 5677681 10.1021/jm00310a048 Shulgin AT, Sargent T, Naranjo C Structure--activity relationships of one-ring psychotomimetics Nature 221 5180 537–541 February 1969 5789297 10.1038/221537a0 1969Natur.221..537S Subsequently, it was described in greater detail by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). Society and culture Manufacturing 2,5-DMA is used by Polaroid Corporation in the manufacturing of Polaroid film. Shulgin AT Iversen LL, Iversen SD, Snyder SH Psychotomimetic Drugs: Structure-Activity Relationships Stimulants 243–333 1978 10.1007/978-1-4757-0510-2_6 Springer US Boston, MA 978-1-4757-0512-6 https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261 3.1.4. 2,5-Dimethoxyphenylisopropylamine This third positional isomer of dimethoxyphenylisopropylamine (32, 2,5-DMA, 2,5-dimethoxyamphetamine) has a potency in man of some eight times that of mescaline (Shulgin et al., 1969), being effective as an intoxicant at an oral dose of about 50 mg. At this level the drug's effects are closer to a stimulant than a psychotomimetic. There is a sudden onset of action just over an hour following ingestion, which is characterized by vertigo, a closed visual field, and slight muscular incoordination (Shulgin, 1963, unpublished data). Over the following 2 hr there is a modest central intoxication, which is accompanied by a slightly elevated blood pressure and extreme hyperactivity. The syndrome is dissipated at 5 hr. [...] Although 2,5-DMA has no medical utility and has thus been classified as a Schedule I drug by the Drug Enforcement Administration, there is a considerable demand for it as a chemical in the photographic industry. The manufacturing quota for it, for a single year's production, is 45,000,000 g as the free base (Anon., 1976), and this magnitude of commercial production, in addition to the inexpensive availability of the synthetic precursor 1-(2,5-dimethoxyphenyl)-2-nitropropene, may have accounted for its appearance in high purity and broad availability in the period prior to its legal proscription. Erowid Psychoactive Vault : DEA Federal Register erowid.org https://erowid.org/freedom/law/federal_register/57.FR.59845.shtml 10 May 2025 Manufacturer of Controlled Substances; Notice of Registration 25 April 2000 Federal Register https://www.federalregister.gov/documents/2000/04/25/00-10210/manufacturer-of-controlled-substances-notice-of-registration 10 May 2025 Legal status Canada 2,5-DMA is a controlled substance in Canada.Controlled Drugs and Substances Act Department of Justice Canada https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html 19 January 2026 United States 2,5-DMA is a schedule I controlled substance in the United States. Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026) January 2026 U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division United States https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf See also Dimethoxyamphetamine Substituted methoxyphenethylamine DOx (psychedelics) Stimulant § Serotonin 5-HT2A receptor agonists Motivation-enhancing drug § Serotonin 5-HT2A receptor agonists 2,5-Dimethoxyphenethylamine (2C-H) 2,4,5-Trimethoxyamphetamine (2,4,5-TMA, TMA-2, or DOMeO) 5-HT2A receptor § Anti-inflammatory effects References External links 2,5-DMA - Isomer Design 2,5-DMA - PsychonautWiki 2,5-DMA - PiHKAL - Erowid 2,5-DMA - PiHKAL - Isomer Design 2,5-DMA - The Shulgin Index Category:5-HT2A agonists Category:5-HT2B agonists Category:5-HT2C agonists Category:Anti-inflammatory agents Category:DOx (psychedelics) Category:PiHKAL Category:Psychedelic phenethylamines Category:Serotonin receptor agonists Category:Stimulants Category:Sympathomimetics Category:Dimethoxyphenyl compounds