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| Clinical data | |
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| Other names | 2,5-DMA; 2,5-Dimethoxy-α-methylphenethylamine; DMA; DMA-4; DOH; NSC-367445 |
| Routes of administration | Oral[1][2] |
| Drug class | Serotonin5-HT2 receptoragonist;Serotonin5-HT2A receptoragonist;Stimulant |
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| Pharmacokinetic data | |
| Duration of action | 6–8 hours[1][2] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.018.673 |
| Chemical and physical data | |
| Formula | C11H17NO2 |
| Molar mass | 195.262 g·mol−1 |
| 3D model (JSmol) | |
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2,5-Dimethoxyamphetamine (2,5-DMA), also known asDMA-4 or asDOH, is apsychoactive drug of thephenethylamine andamphetamine families.[1][2] It is one of thedimethoxyamphetamine (DMA) series ofpositional isomers.[1][2] The drug is notable in being theparent compound of theDOx (4-substituted-2,5-dimethoxyamphetamine) series ofpsychedelic drugs.[1][2] It is takenorally.[1][2][3]
2,5-DMA is said to be inactive as apsychedelic, at least at the doses that have been assessed.[1][2] However, it has been reported to produce somestimulant-like effects, as well assympathomimetic effects andmydriasis.[1][2][3] The dose range is said to be 80 to 160 mgorally and itsduration 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]
| 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-potencyserotonin5-HT2A receptorpartial agonist, with anaffinity (Ki) of 2,502 nM, anEC50Tooltip half-maximal effective concentration of 160 to 3,548 nM (depending on thesignaling cascade and study), and anEmaxTooltip maximal efficacy of 66 to 109%.[8][9][12][13] It has also been assessed at several otherreceptors.[8][9] In a much earlier study, its affinities (Ki) were 1,020 nM at the serotonin5-HT1 receptor and 5,200 nM at the serotonin5-HT2 receptor.[17][18] The drug does not appear to bind to themonoamine transporters, at least at the assessed concentrations (up to 7,000 nM).[8][9] It was inactive at the humantrace 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 as2,5-dimethoxy-4-methylamphetamine (DOM).[8][9]
2,5-DMA produces thehead-twitch response, a behavioral proxy ofpsychedelic effects, in rodents.[7] However, it produces a very weak head-twitch response compared to otherstructurally related psychedelics like DOM,DOET,DOPR, and evenDOBU.[7] In addition, it is lesspotent in comparison.[7] 2,5-DMA substitutes for DOM in rodentdrug discrimination tests, albeit with dramatically lower potency than other DOx drugs.[19] It also substitutes for5-MeO-DMT in rodent drug discrimination tests.[20] These findings suggesting that 2,5-DMA might produce weakhallucinogenic effects at sufficiently high doses.[7][19][20] 2,5-DMA shows no substitution fordextroamphetamine in drug discrimination tests, suggesting that it lackspsychostimulant- oramphetamine-like effects, at least in rodents.[19] Unlike other DOx drugs like DOM, DOPR, DOBU, andDOAM, 2,5-DMA does not producehyperlocomotion in rodents and insteaddose-dependently produces onlyhypolocomotion.[7] On the other hand, it does similarly producehypothermia 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 potentanti-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 ofcalcium 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 likeDOTFM are known.[21]
2,5-DMA crosses theblood–brain barrier in rodents.[7] It showed the lowestbrain/plasma ratio amongDOM and its higherhomologues.[7]
Thechemical synthesis of 2,5-DMA has been described.[1][2][22]
Analogues andderivatives of 2,5-DMA include theDOx series likeDOM,DOB, andDOI,FLY compounds likeDOB-FLY,Bromo-DragonFLY (DOB-DFLY),DOH-5-hemiFLY,25-NB compounds likeDOM-NBOMe,DOB-NBOMe, andDOI-NBOMe, and other compounds liketrimethoxyamphetamines (TMAs) andpentamethoxyamphetamine (PeMA).[1][2]
2,5-DMA was first described in thescientific literature by F. Benington and colleagues by at least 1968.[23][24] Subsequently, it was described in greater detail byAlexander Shulgin in his 1991 bookPiHKAL (Phenethylamines I Have Known and Loved).[1]
2,5-DMA is used byPolaroid Corporation in themanufacturing ofPolaroid film.[3][25][26]
2,5-DMA is acontrolled substance inCanada.[27]
2,5-DMA is aschedule Icontrolled substance in theUnited States.[28]
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.
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), [...]
Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites