MDA
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Collated from PsychonautWiki, TripSit, Pharmacology, PiHKAL. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as MDA, Sass, Sally, Tenamfetamine, 3,4-METHYLENEDIOXYAMPHETAMINEPW
A stimulant and empathogen. Similar to MDMA but typically produces more visuals than MDMA. Known to be more neurotoxic than MDMA, and is a minor metabolite of MDMA. Duration and onset similar to MDMA. The common Marquis reagent test cannot differentiate MDA and MDMA.TS
Oral
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 20 mg | 40–60 mg | 60–100 mg | 100–145 mg | 145 mg+ |
| Onset | 30–90 minutes |
|---|---|
| Come-up | 15–45 minutes |
| Peak | 2.5–4 hours |
| Offset | 2–3 hours |
| Total | 5–8 hours |
| After-effects | 4–48 hours |
Unsafe interactionsPW
Caution / uncertainPW
🧬 Receptor activityPH
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| 5-hydroxytryptamine receptor 2A | — | Ki 387 nM | CHEMBL | Target5-hydroxytryptamine receptor 2A Action— AffinityKi 387 nM SourceCHEMBL |
| Sodium-dependent noradrenaline transporter | — | Ki 704 nM | CHEMBL | TargetSodium-dependent noradrenaline transporter Action— AffinityKi 704 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 2C | — | Ki 2100 nM | CHEMBL | Target5-hydroxytryptamine receptor 2C Action— AffinityKi 2100 nM SourceCHEMBL |
| Serotonin 2 (5-HT2) receptor | — | Ki 2190 nM | CHEMBL | TargetSerotonin 2 (5-HT2) receptor Action— AffinityKi 2190 nM SourceCHEMBL |
| Sodium-dependent serotonin transporter | — | Ki 2306 nM | CHEMBL | TargetSodium-dependent serotonin transporter Action— AffinityKi 2306 nM SourceCHEMBL |
| Sodium-dependent dopamine transporter | — | Ki 2425 nM | CHEMBL | TargetSodium-dependent dopamine transporter Action— AffinityKi 2425 nM SourceCHEMBL |
Mechanism of actionPH
Phenylethylamines act on the peripheral and central nervous system by alpha- and beta-adrenergic stimulation. These compounds may also have varying degrees of serotonergic and dopaminergic activity, depending on structural similarity to mescaline. /Phenylethylamines/
The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of 3H-5-HT and 3H-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of 3H-5-HT and 3H-DA in vitro. The release of 3H-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both 3H-5-HT and 3H-DA. ... Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using 3H-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. ...
The effect of the R(-) and S(+) isomers of 3,4-methylenedioxyamphetamine (MDA) and its N-methyl analog 3,4-methylenedioxymethamphetamine (MDMA) on [3H]inositol monophosphate accumulation was studied in cells expressing either 5-HT2A or 5-HT2C receptors. The isomers of MDA produced a concentration dependent increase in phosphatidyl inositol (PI) hydrolysis at the 5-HT2A receptors, with the R(-) isomer of MDA being more potent than the S(+) at the 5-HT2A receptor. The R(-) and S(+) isomers of MDMA were significantly less efficacious at the 5-HT2A receptor as compared to MDA; S(+)MDMA had no effect. At the 5-HT2C receptor, both R(-) and S(+)MDA were equipotent at stimulating PI hydrolysis, with the S(+) isomer of MDMA being more efficacious at the 5-HT2C receptor compared with the R(-) isomer. In all cases at both the 5-HT2A and 5-HT2C receptors, the affinities of the isomers of MDMA and MDA were at least 2-3 orders of magnitude less than 5-HT. Despite the weak effect of these compounds at the 5-HT2A and 5-HT2C receptors, these substituted amphetamines do possess intrinsic activity which may contribute to their neurotoxic effects when administered at high doses.
Pharmacokinetics
AbsorptionPH
... This paper describes for the first time an evaluation of the concentrations of methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) found in five fatalities admitted to hospital where both antemortem and postmortem blood samples were available. Admission MDMA and MDA concentrations ranged between 0.55 and 4.33 mg/L and 0 and 0.10 mg/L, respectively, in antemortem serum/plasma. Postmortem blood MDMA and MDA concentrations ranged between 0.47 and 28.39 mg/L and 0.02 and 1.33 mg/L, respectively. Postmortem concentrations were higher than corresponding antemortem concentrations in all 5 cases with postmortem/antemortem ratios between 1.1 and 6.6 for MDMA and 1.5 and 13.3 for MDA. Differences in concentrations were also observed between anatomical sites, with central sites (e.g., heart) having much higher concentrations than peripheral sites (e.g., femoral). Overall, MDMA and MDA appear to exhibit postmortem redistribution and concentrations measured in postmortem specimens (even from peripheral sites) are not directly comparable with antemortem findings close to or prior to death.
Data ... reported /here/ include postmortem distribution of methylenedioxymethamphetamine (MDMA) and methylenedioxyamphetamine (MDA) in heart blood, gastric content, urine, and bile specimens from 20 fatal cases; other drugs found in the heart blood from these 20 cases; and the distribution of MDMA and MDA in 25 antemortem urine and 6 hair specimens. The MDA/MDMA concentration ratio observed in a limited number of hair specimens (n=6) are consistent and appear to be higher than those found in other specimens. Compared to other commonly abused drugs (e.g., cocaine and heroin), the "drug/metabolite" concentration ratio (MDMA/MDA) in hair is not significantly different from the ratios derived from other specimens, such as urine and blood. This observation is consistent with the relative drug/metabolite incorporation rates reported for cocaine/benzoylecgonine, tetrahydrocannabinol/tetrahydrocannabinoic acid, and MDMA/MDA.
MetabolismPH
The phase I and II metabolites of the designer drugs methylenedioxyamphetamine (MDA), R,S-methylenedioxymethamphetamine (MDMA), R,S-methylenedioxyethylamphetamine (MDE), R, S-benzodioxazolylbutanamine (BDB) and R, S-N-methyl-benzodioxazolylbutanamine (MBDB) were identified by gas chromatography-mass spectrometry (GC-MS) or liquid chromotography-mass spectrometry (LC-MS) in urine and liver microsomes of humans and rats. Two overlapping pathways could be postulated: (1) demethylenation followed by catechol-O-methyl-transferase (COMT) catalyzed methylation and/or glucuronidation/sulfatation; (2) N-dealkylation, deamination and only for MDA, MDMA, MDE oxidation to the corresponding benzoic acid derivatives conjugated with glycine. Demethylenation was mainly catalyzed by CYP2D1/6 or CYP3A2/4, but also by CYP independent mechanisms. In humans, MDMA and MBDB could also be demethylenated by CYP1A2. N-demethylation was mainly catalyzed by CYP1A2, N-deethylation by CYP3A2/4. ...
The two major metabolites of (+/-)3,4-methylenedioxyamphetamine (MDA), alpha-methyldopamine (alpha-MeDA) and 3-O-methyl-alpha-methyldopamine (3-O-Me-alpha-MeDA), were administered to rats intracerebroventricularly and into brain parenchyma. In addition, their precursors, (alpha-MeDOPA and 3-O-Me-alpha-MeDOPA, respectively) were administered systemically, individually and in combination. None of these treatments produced a lasting depletion of brain serotonin (5-HT). These findings suggest that neither of MDA's major metabolites mediate its toxic effects on 5-HT neurons and that either a minor metabolite is responsible or that alternate mechanisms are involved.
3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are ring-substituted amphetamine derivatives with stimulant and hallucinogenic properties. The recreational use of these amphetamines, especially MDMA, is prevalent despite warnings of irreversible damage to the central nervous system. MDA and MDMA are primarily serotonergic neurotoxicants. Because (1) neither MDA nor MDMA produces neurotoxicity when injected directly into brain, (2) intracerebroventricular (i.c.v.) administration of some major metabolites of MDA and MDMA fails to reproduce their neurotoxicity, (3) alpha-methyldopamine (alpha-MeDA) and N-methyl-alpha-MeDA are metabolites of both MDA and MDMA, (4) alpha-MeDA and N-methyl-alpha-MeDA are readily oxidized to the corresponding ortho-quinones, which can undergo conjugation with glutathione (GSH), and (5) quinone thioethers exhibit a variety of toxicologic activities, /the investigators/ initiated studies on the potential role of thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA in the neurotoxicity of MDA and MDMA. /These/ studies have revealed that the thioether conjugates stimulate the acute release of serotonin, dopamine, and norepinephrine and produce a behavioral response commensurate with the "serotonin syndrome." Direct injection of the conjugates into rat brain also produces long-term depletions in serotonin (5-HT) concentrations, elevations in GFAP expression, and activation of microglial cells. The data are consistent with the view that thioether metabolites of alpha-MeDA and N-methyl-alpha-MeDA contribute to the neurotoxicity of the parent amphetamines.
3,4-Methylenedioxyamphetamine (MDA) and 3,4-methyl-enedioxymethamphetamine (MDMA, ecstasy) are widely abused amphetamine derivatives that target the serotonin system. The serotonergic neurotoxicity of MDA and MDMA seems dependent on their systemic metabolism. 5-(Glutathion-S-yl)-alpha-methyldopamine [5-(GSyl)-alpha-MeDA] and 2,5-bis(glutathion-S-yl)-alpha-methyldopamine [2,5-bis(GSyl)-alpha-MeDA], metabolites of MDA and MDMA, are also selective serotonergic neurotoxicants and produce behavioral and neurochemical changes similar to those seen with MDA and MDMA. 5-(GSyl)-alpha-MeDA and 2,5-bis(GSyl)-alpha-MeDA are more potent than MDA and MDMA (K(i) = 69, 50, 107, and 102 microM, respectively) at inhibiting 5-hy-droxytryptamine (serotonin) transport into SK-N-MC cells transiently transfected with the human serotonin transporter (hSERT). Moreover, 5-(GSyl)-alpha-MeDA and 2,5-bis(GSyl)-alpha-MeDA simultaneously stimulated dopamine (DA) transport into the hSERT-expressing cells, an effect attenuated by fluoxetine, indicating that stimulated DA transport was hSERT-dependent. Finally, 5-(GSyl)-alpha-MeDA and 2,5-bis(GSyl)-alpha-MeDA, and to a lesser extent MDA and MDMA, induced a concentration and time-dependent increase in reactive oxygen species (ROS) in both hSERT and human dopamine transporter-transfected cells. Fluoxetine attenuated the increase in ROS generation in hSERT-expressing cells. The results are consistent with the view that the serotonergic neurotoxicity of MDA and MDMA may be mediated by the metabolism-dependent stimulation of DA transport into hSERT-expressing cells and ROS generation by redox active catechol-thioether metabolites and DA.
Metabolites of 3,4-methylenedioxyamphetamine in the urine of dogs and monkeys were separated by gas-liquid chromatography as their trifluoroacetyl and/or n-butyl ether derivatives and identified by comparison of the chromatographic and mass spectrometric behavior of these derivatives with those of synthetic compounds. The metabolites identified in dog and monkey urine were alpha-methyldopamine, 3-O-methyl-alpha-methyldopamine, and 3,4-dihydroxybenzyl methyl ketone. The monkey urine also contained 3,4-methylenedioxybenzyl methyl ketone and 3,4-methylenedioxybenzoic acid present as a glucuronide and/or sulfate conjugate, whereas the dog urine had 3-methoxy-4-hydroxybenzoic acid present as a conjugate other than glucuronide and sulfate. The phenolic metabolites in both species were present free and as glucuronide and/or sulfate conjugates.
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