MDA has a long history of psychotherapeutic and recreational use that predates that ofMDMA, dating back to at least the mid-1960s.[3][6][4] It has been described as the first entactogen.[2] MDA has also been described as probably the most popularanalogue of MDMA.[6] In most countries, the drug is acontrolled substance and its possession and sale are illegal.
The dose range of MDA given inAlexander Shulgin's bookPiHKAL (Phenethylamines I Have Known and Loved) and other sources is 80 to 160mg.[5][3] A wider recreational dose range for MDA of 20 to 200mg or more, with a typical dose estimate of 90mg, has also been reported.[10] The dose range of MDA is very similar to that of MDMA.[5][3][10][2]
MDA shares most of MDMA's qualitative and emotional effects, including entactogenic and stimulant effects.[3][12][2] However, it has been said to be slightly less stimulating than MDMA.[3][2] In addition, MDA'shallucinogenic effects are much greater than those of MDMA, although still less than those of classical psychedelics likepsilocybin.[3][11][2] Another difference between the two drugs is that MDA appears to produce a more introverted and emotionally intense prosocial state, while MDMA encourages a more extroverted and gregarious prosocial state.[2]
In terms of the individualenantiomers of MDA, (R)-MDA produces psychedelic effects and some entactogenic effects, while (S)-MDA is non-hallucinogenic, produces similar entactogenic effects as theracemate, and has considerable stimulant effects.[11][12][5] High doses ofenantiopure (R)-MDA, in the range of 120 to 200mg, are described as closely resembling the effects ofLSD, for instance doses of 200 to 400μg.[12][13] Enantiopure (R)-MDA at high doses produces more robust psychedelic effects than typical doses of racemic MDA.[12][13][5]
Theduration of MDA is about 5 to 8hours and is about 2hours longer than that of MDMA (3–6hours).[3][2] Shulgin originally gave a duration of MDA of 8 to 12hours inPiHKAL, but he later revised this down to only 3 to 6hours.[5] A modern clinical study gave a duration of 6 to 8hours.[2]
In addition to its actions as a monoamine releasing agent, MDA is a potent high-efficacypartial agonist orfull agonist of the rodent TAAR1.[24][25] Conversely, MDA is much weaker in terms ofpotency as an agonist of the human TAAR1.[24][25][31] Moreover, MDA acts as a very weak partial agonist orantagonist of the human TAAR1 rather than as an efficacious agonist.[24][25] TAAR1 activation is thought to auto-inhibit and constrain the effects of amphetamines that act as TAAR1 agonists, for instance MDMA in rodents.[32][33][34][35]
In terms of the subjective and behavioral effects of MDA, it is thought thatserotonin release is required for its entactogenic effects,dopamine release is required for itseuphoriant (rewarding andaddictive) effects, dopamine andnorepinephrine release are required for itspsychostimulant effects, and direct agonism of the serotonin 5-HT2A receptor is required for its mild psychedelic effects.[3] The entactogenic effects of drugs like MDA are thought to dependent on a precise balance of serotonin and dopamine release as well as serotonin receptor agonism.[38][39][40][41][2] The longer duration of MDA compared to MDMA appears to be related topharmacodynamics as opposed topharmacokinetics, for instance the effects of MDA depending relatively more on serotonin 5-HT2A receptor agonism than on serotonin release.[2]
MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDA and major metabolites of MDMA, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10% those of the parent drug.[64][65][66]
TheUnited States Army also experimented with the drug, code named EA-1298, while working to develop atruth drug or incapacitating agent.Harold Blauer died in January 1953 after being intravenously injected, without his knowledge or consent, with 450 mg of the drug as part ofProject MKUltra.[71] MDA was patented as anataractic bySmith, Kline & French in 1960, and as ananorectic under the trade name "Amphedoxamine" in 1961. MDA began to appear on the recreational drug scene around 1963 to 1964. It was then inexpensive and readily available as aresearch chemical from several scientific supply houses. Several researchers, includingClaudio Naranjo and Richard Yensen, have explored MDA in the field ofpsychotherapy.[72][73]
MDA is schedule 9 prohibited substance under thePoisons Standards.[77] A schedule 9 substance is listed as a "Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities."[77]
^Monte AP, Marona-Lewicka D, Cozzi NV, Nichols DE (November 1993). "Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine".Journal of Medicinal Chemistry.36 (23):3700–3706.doi:10.1021/jm00075a027.PMID8246240.
^abcBaggott MJ, Siegrist J, Coyle JR, Flower K, Galloway G, Mendelson J (2010). "Poster Session III (PIII 1-84): PIII-09 Pharmacodynamic Effects of 3,4-Methylenedioxyamphetamine (MDA)".Clinical Pharmacology & Therapeutics.87 (Suppl 1): S68–S95 (S70).doi:10.1038/clpt.2009.277.ISSN0009-9236.In a placebo-controlled, double-blind, within-subjects study, 12 individuals received a single 98 mg/70 kg bw dose of MDA. This is the molar equivalent of 105 mg/ 70 kg bw MDMA, a well-studied dose. [...] MDA increased cortisol by 16.39 ug/dL (95%CI: 13.03-19.74, P < 1e-3) and prolactin by 18.37 ng/mL (95%CI: 7.39-29.35, P < 1e-3). These hormonal changes are comparable to those seen after MDMA. Heart rate increased by 9.05 bpm (95%CI: 6.10-11.99, P < 1e-5) and blood pressure increased by 18.98 / 12.73 mm Hg (Systolic 95%CI: 16.47 - 21.49, P < 1e-7; Diastolic 95%CI: 10.82 - 14.63, P < 1e-4). [...] There were robust self-report VAS changes in both MDMA-like (e.g., "closeness to others") and hallucinogen-like (e.g., "familiar things seem unfamiliar", time distortions, closed-eye visuals) effects that were generally similar to those seen after MDMA. [...] MDA is a psychoactive sympathomimetic phenethylamine with effects similar to MDMA. Although differences may exist in the magnitude of physiological effects, the overall profiles appear remarkably similar.
^abcdefgNichols DE (1986). "Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens".J Psychoactive Drugs.18 (4):305–313.doi:10.1080/02791072.1986.10472362.PMID2880944.
^abYensen R, Di Leo FB, Rhead JC, Richards WA, Soskin RA, Turek B, Kurland AA (October 1976). "MDA-assisted psychotherapy with neurotic outpatients: a pilot study".J Nerv Ment Dis.163 (4):233–245.doi:10.1097/00005053-197610000-00002.PMID972325.
^Nash JF,Roth BL, Brodkin JD, Nichols DE, Gudelsky GA (August 1994). "Effect of the R(−) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors".Neuroscience Letters.177 (1–2):111–115.doi:10.1016/0304-3940(94)90057-4.PMID7824160.S2CID41352480.
^Espinoza S, Gainetdinov RR (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1".Taste and Smell. Topics in Medicinal Chemistry. Vol. 23. Cham: Springer International Publishing. pp. 175–194.doi:10.1007/7355_2014_78.ISBN978-3-319-48925-4.Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission.
^Kuropka P, Zawadzki M, Szpot P (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse".Hum Psychopharmacol.38 (3) e2866.doi:10.1002/hup.2866.PMID36866677.Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 2016). The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).
^Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (January 2013)."Pharmacological characterization of designer cathinones in vitro".Br J Pharmacol.168 (2):458–470.doi:10.1111/j.1476-5381.2012.02145.x.PMC3572571.PMID22897747.β-Keto-analogue cathinones also exhibited approximately 10-fold lower affinity for the TA1 receptor compared with their respective non-β-keto amphetamines. [...] Activation of TA1 receptors negatively modulates dopaminergic neurotransmission. Importantly, methamphetamine decreased DAT surface expression via a TA1 receptor-mediated mechanism and thereby reduced the presence of its own pharmacological target (Xie and Miller, 2009). MDMA and amphetamine have been shown to produce enhanced DA and 5-HT release and locomotor activity in TA1 receptor knockout mice compared with wild-type mice (Lindemann et al., 2008; Di Cara et al., 2011). Because methamphetamine and MDMA auto-inhibit their neurochemical and functional effects via TA1 receptors, low affinity for these receptors may result in stronger effects on monoamine systems by cathinones compared with the classic amphetamines.
^Sáez-Briones P, Castro V, Maass M, Mundaca E, Villagra M, Díaz-Véliz G. Modelo animal de interacción social: administración aguda de MDMA (3-4-metilendioximetanfetamina “Extasis”) y algunos de sus análogos en ratas Sprague-Dawley. Rev. Farmacol. Chile. 2011;4: 72.
^de la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, et al. (April 2004). "Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition".Therapeutic Drug Monitoring.26 (2):137–144.doi:10.1097/00007691-200404000-00009.PMID15228154.
^Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates".Current Topics in Medicinal Chemistry.6 (17):1845–1859.doi:10.2174/156802606778249766.PMID17017961.
^Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain".European Journal of Pharmacology.559 (2–3):132–137.doi:10.1016/j.ejphar.2006.11.075.PMID17223101.
^Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA (August 1994). "Effect of the R(-) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors".Neurosci Lett.177 (1–2):111–115.doi:10.1016/0304-3940(94)90057-4.PMID7824160.
^abcBaggott MJ, Li L, Galloway GP, Scheidweiler KB, Barnes AJ, Huestis MA, Mendelson J (2012). "Poster Session III (PIII 1-110): PIII-110: Pharmacokinetics of Oral 3,4-Methylenedioxyamphetamine in Humans".Clinical Pharmacology & Therapeutics.91 (Suppl 1):S96 –S135.doi:10.1038/clpt.2011.363.ISSN0009-9236.Knowledge of MDA and HMA kinetics in humans is limited to data from MDMA administration studies where minimal formation of these compounds likely leads to inaccurate parameter estimation. We administered a single [98 mg/70 kg body weight] oral dose of MDA to participants in a controlled setting to characterize plasma MDA pharmacokinetics for the first time. [...] Cmax and AUC0-∞ for MDA were 229 ± 39 ng/mL (mean ± SD) and 3636 ± 958 for MDA and 92 ± 61 ng/mL and 1544 ± 741 for the metabolite HMA. Total MDA clearance was 30267 ± 8214 mL/min. There was considerable between-subject variation in metabolite exposure: HMA Cmax and AUC varied over 7-fold and 4-fold, respectively, between the highest and lowest individuals. [...] Pharmacokinetics of MDA resemble those of an iso-molar dose of MDMA, suggesting differences in duration of acute effects between MDA and MDMA are not due to kinetic differences.
^Noggle FT, DeRuiter J, Long MJ (1986). "Spectrophotometric and liquid chromatographic identification of 3,4-methylenedioxyphenylisopropylamine and its N-methyl and N-ethyl homologs".Journal of the Association of Official Analytical Chemists.69 (4):681–686.PMID2875058.
^Ho BT, McIsaac WM, An R, Tansey LW, Walker KE, Englert LF, Noel MB (January 1970). "Analogs of alpha-methylphenethylamine (amphetamine). I. Synthesis and pharmacological activity of some methoxy and/or methyl analogs".Journal of Medicinal Chemistry.13 (1):26–30.doi:10.1021/jm00295a007.PMID5412110.
^Butterick JR, Unrau AM (1974). "Reduction of β-nitrostyrene with sodium bis-(2-methoxyethoxy)-aluminium dihydride. A convenient route to substituted phenylisopropylamines".Journal of the Chemical Society, Chemical Communications.8 (8):307–308.doi:10.1039/C39740000307.
^Kolbrich EA, Goodwin RS, Gorelick DA, Hayes RJ, Stein EA, Huestis MA. Plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine after controlled oral administration to young adults. Ther. Drug Monit. 30: 320–332, 2008.
^Benzenhöfer U, Passie T (August 2010). "Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin".Addiction.105 (8):1355–61.doi:10.1111/j.1360-0443.2010.02948.x.PMID20653618.
^Naranjo C, Shulgin AT, Sargent T (1967). "Evaluation of 3,4-methylenedioxyamphetamine (MDA) as an adjunct to psychotherapy".Medicina et Pharmacologia Experimentalis. International Journal of Experimental Medicine.17 (4):359–364.doi:10.1159/000137100.PMID5631047.
^Yensen R, Di Leo FB, Rhead JC, Richards WA, Soskin RA, Turek B, Kurland AA (October 1976). "MDA-assisted psychotherapy with neurotic outpatients: a pilot study".The Journal of Nervous and Mental Disease.163 (4):233–245.doi:10.1097/00005053-197610000-00002.PMID972325.S2CID41155810.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages. See also:Receptor/signaling modulators
