2,5-Dimethoxyamphetamine

2,5-Dimethoxyamphetamine
Clinical data
Other names2,5-DMA; 2,5-Dimethoxy-α-methylphenethylamine; DMA; DMA-4; DOH; NSC-367445
Routes of
administration		Oral[1][2]
Drug classSerotonin 5-HT2 receptor agonist; Serotonin 5-HT2A receptor agonist; Stimulant
ATC code
  • None
Pharmacokinetic data
Duration of action6–8 hours[1][2]
Identifiers
  • 1-(2,5-dimethoxyphenyl)propan-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.018.673
Chemical and physical data
FormulaC11H17NO2
Molar mass195.262 g·mol−1
3D model (JSmol)
  • CC(CC1=C(C=CC(=C1)OC)OC)N
  • InChI=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
  • Key: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.[1][2] It is one of the dimethoxyamphetamine (DMA) series of positional isomers.[1][2] The drug is notable in being the parent compound of the DOx (4-substituted-2,5-dimethoxyamphetamine) series of psychedelic drugs.[1][2] It is taken orally.[1][2][3]

Use and effects

2,5-DMA is said to be inactive as a psychedelic, at least at the doses that have been assessed.[1][2] However, it has been reported to produce some stimulant-like effects, as well as sympathomimetic effects and mydriasis.[1][2][3] The dose range is said to be 80 to 160 mg orally and its duration is 6 to 8 hours.[1][2] However, it has also been said to be active with stimulant-like effects at a dose of 50 mg.[3]

Interactions

See also: Psychedelic drug § Interactions, and 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
5-HT1E ND
5-HT1F ND
5-HT2A 211–5,200 (Ki)
160–3,548 (EC50Tooltip half-maximal effective concentration)
58–109% (EmaxTooltip maximal efficacy)
5-HT2B 1,039 (Ki)
3,390–93,320 (EC50)
93–94% (Emax)
5-HT2C 104–>10,000 (Ki)
124–3,144 (EC50)
76–103% (Emax)
5-HT3 ND
5-HT4 ND
5-HT5A ND
5-HT6 ND
5-HT7 ND
α1A 5,363
α1B–α1D ND
α2A 4,385
α2B–α2C ND
β1, β2 ND
D1 ND
D2 >13,000
D3–D5 ND
H1–H4 ND
M1–M5 ND
TAAR1 >30,000 (EC50) (human)
I1 ND
σ1, σ2 ND
SERTTooltip Serotonin transporter >7,000 (Ki)
ND (IC50Tooltip half-maximal inhibitory concentration)
ND (EC50)
NETTooltip Norepinephrine transporter >8,000 (Ki)
ND (IC50)
ND (EC50)
DATTooltip Dopamine transporter >8,000 (Ki)
ND (IC50)
ND (EC50)
MAO-ATooltip Monoamine oxidase A >100,000 (IC50)
MAO-BTooltip Monoamine oxidase B >100,000 (IC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [4][5][6][7][8][9][10]
[11][12][13][14][15][16]

2,5-DMA is a low-potency serotonin 5-HT2A receptor partial agonist, with an affinity (Ki) of 2,502 nM, an EC50Tooltip half-maximal effective concentration of 160 to 3,548 nM (depending on the signaling cascade and study), and an EmaxTooltip maximal efficacy of 66 to 109%.[8][9][12][13] It has also been assessed at several other receptors.[8][9] In a much earlier study, its affinities (Ki) were 1,020 nM at the serotonin 5-HT1 receptor and 5,200 nM at the serotonin 5-HT2 receptor.[17][18] The drug does not appear to bind to the monoamine transporters, at least at the assessed concentrations (up to 7,000 nM).[8][9] It was inactive at the human trace amine-associated receptor 1 (TAAR1).[8][9] 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).[8][9]

2,5-DMA produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.[7] However, it produces a very weak head-twitch response compared to other structurally related psychedelics like DOM, DOET, DOPR, and even DOBU.[7] In addition, it is less potent in comparison.[7] 2,5-DMA substitutes for DOM in rodent drug discrimination tests, albeit with dramatically lower potency than other DOx drugs.[19] It also substitutes for 5-MeO-DMT in rodent drug discrimination tests.[20] These findings suggesting that 2,5-DMA might produce weak hallucinogenic effects at sufficiently high doses.[7][19][20] 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.[19] 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.[7] On the other hand, it does similarly produce hypothermia at higher doses.[7]

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.[13][21] 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 = 3,548 nM; Emax = 109.0%).[13] 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.[21]

Pharmacokinetics

2,5-DMA crosses the blood–brain barrier in rodents.[7] It showed the lowest brain/plasma ratio among DOM and its higher homologues.[7]

Chemistry

Synthesis

The chemical synthesis of 2,5-DMA has been described.[1][2][22]

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).[1][2] Methoxamine (β-hydroxy-2,5-DMA) is another derivative of 2,5-DMA.[2]

History

2,5-DMA was first described in the scientific literature by F. Benington and colleagues by at least 1968.[23][24] Subsequently, it was described in greater detail by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved).[1]

Society and culture

Manufacturing

2,5-DMA is used by Polaroid Corporation in the manufacturing of Polaroid film.[3][25][26]

Canada

2,5-DMA is a controlled substance in Canada.[27]

United States

2,5-DMA is a schedule I controlled substance in the United States.[28]

See also

References

  1. ^ a b c d e f g h i j k l Shulgin AT, Shulgin A (1991). "#54 2,5-DMA; DMA; 2,5-DIMETHOXYAMPHETAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN 978-0-9630096-0-9. OCLC 25627628.
  2. ^ a b c d e f g h i j k l Shulgin A, Manning T, Daley PF (2011). "#36. 2,5-DMA". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. ISBN 978-0-9630096-3-0.
  3. ^ a b c d Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN 978-1-4757-0512-6. 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.
  4. ^ "Kᵢ Database". PDSP. 15 March 2025. Retrieved 15 March 2025.
  5. ^ 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. Retrieved 15 March 2025.
  6. ^ Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (January 1999). "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. doi:10.1007/pl00005315. PMID 9933142.
  7. ^ a b c d e f g h i Luethi D, Glatfelter GC, Pottie E, Sellitti F, Maitland AD, Gonzalez NR, et al. (November 2025). "The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects" (PDF). Mol Psychiatry. doi:10.1038/s41380-025-03325-1. PMID 41193673.
  8. ^ a b c d e f Luethi D, Rudin D, Hoener MC, Liechti ME (2022). "Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines". The FASEB Journal. 36 (S1) fasebj.2022.36.S1.R2691. doi:10.1096/fasebj.2022.36.S1.R2691. ISSN 0892-6638.
  9. ^ a b c d e f Rudin D, Luethi D, Hoener MC, Liechti ME (2022). "Structure-activity Relation of Halogenated 2,5-Dimethoxyamphetamines Compared to their α‑Desmethyl (2C) Analogues". The FASEB Journal. 36 (S1) fasebj.2022.36.S1.R2121. doi:10.1096/fasebj.2022.36.S1.R2121. ISSN 0892-6638.
  10. ^ Hemanth P, Nistala P, Nguyen VT, Eltit JM, Glennon RA, Dukat M (2023). "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 1101290. doi:10.3389/fphar.2023.1101290. PMC 9902381. PMID 36762110.
  11. ^ Dowd CS, Herrick-Davis K, Egan C, DuPre A, Smith C, Teitler M, et al. (August 2000). "1-[4-(3-Phenylalkyl)phenyl]-2-aminopropanes as 5-HT(2A) partial agonists". Journal of Medicinal Chemistry. 43 (16): 3074–3084. doi:10.1021/jm9906062. PMID 10956215.
  12. ^ a b Pottie E, Cannaert A, Stove CP (October 2020). "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. Bibcode:2020ArTox..94.3449P. doi:10.1007/s00204-020-02836-w. hdl:1854/LU-8687071. PMID 32627074.
  13. ^ a b c d Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD (April 2021). "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. doi:10.1021/acsptsci.0c00063. PMC 8033619. PMID 33860179. 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), [...]
  14. ^ Acuña-Castillo C, Villalobos C, Moya PR, Sáez P, Cassels BK, Huidobro-Toro JP (June 2002). "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. doi:10.1038/sj.bjp.0704747. PMC 1573376. PMID 12055129.
  15. ^ Runyon SP, Mosier PD, Roth BL, Glennon RA, Westkaemper RB (November 2008). "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. doi:10.1021/jm800771x. PMC 3088499. PMID 18847250.
  16. ^ Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Frontiers in Pharmacology. 10 1590. doi:10.3389/fphar.2019.01590. PMC 6989591. PMID 32038257.
  17. ^ Glennon RA (January 1987). "Central serotonin receptors as targets for drug research". Journal of Medicinal Chemistry. 30 (1): 1–12. doi:10.1021/jm00384a001. PMID 3543362. Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
  18. ^ Shannon M, Battaglia G, Glennon RA, Titeler M (June 1984). "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. doi:10.1016/0014-2999(84)90333-9. PMID 6479216.
  19. ^ a b c Glennon RA (1989). "Stimulus properties of hallucinogenic phenalkylamines and related designer drugs: formulation of structure-activity relationships" (PDF). NIDA Research Monograph. 94: 43–67. PMID 2575229. Archived from the original (PDF) on May 11, 2023.
  20. ^ a b Glennon RA, Young R, Rosecrans JA, Kallman MJ (1980). "Hallucinogenic agents as discriminative stimuli: a correlation with serotonin receptor affinities". Psychopharmacology. 68 (2): 155–158. doi:10.1007/BF00432133. PMID 6776558.
  21. ^ a b Hamilton Morris (14 November 2021). "PODCAST 33: An interview with Dr. Charles D. Nichols". The Hamilton Morris Podcast (Podcast). Patreon. Event occurs at 48:22–53:56. Retrieved 20 January 2025.
  22. ^ Trachsel D, Lehmann D, Enzensperger C (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. ISBN 978-3-03788-700-4. OCLC 858805226. Archived from the original on 21 August 2025.
  23. ^ Benington F, Morin RD (July 1968). "The chemorelease of norepinephrine from mouse hearts by substituted amphetamines". J Med Chem. 11 (4): 896–897. doi:10.1021/jm00310a048. PMID 5677681.
  24. ^ Shulgin AT, Sargent T, Naranjo C (February 1969). "Structure--activity relationships of one-ring psychotomimetics". Nature. 221 (5180): 537–541. Bibcode:1969Natur.221..537S. doi:10.1038/221537a0. PMID 5789297.
  25. ^ "Erowid Psychoactive Vault : DEA Federal Register". erowid.org. Retrieved 10 May 2025.
  26. ^ "Manufacturer of Controlled Substances; Notice of Registration". Federal Register. 25 April 2000. Retrieved 10 May 2025.
  27. ^ "Controlled Drugs and Substances Act". Department of Justice Canada. Retrieved 19 January 2026.
  28. ^ Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026) (PDF), United States: U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division, January 2026
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