3,4-Methylenedioxyamphetamine (MDA) is an entactogen, stimulant, and psychedelic drug of the amphetamine and MDxx families that is encountered mainly as a recreational drug. It is usually taken orally.

In terms of its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA) and a serotonin 5-HT2 receptor agonist, including of the serotonin 5-HT2A receptor. It has a duration of 5 to 8hours or around 6hours typically.

MDA has a long history of psychotherapeutic and recreational use that predates that of MDMA, dating back to at least the mid-1960s. It has been described as the first entactogen. MDA has also been described as probably being the most popular analogue of MDMA. In most countries, the drug is a controlled substance and its possession and sale are illegal.

Use and effects MDA is bought, sold, and used as a recreational drug due to the compound's ability to uplift mood and increase empathy. It produces MDMA-like effects, including entactogenic and stimulant effects, as well as mild psychedelic effects.

The dose range of MDA given in Alexander Shulgin's book PiHKAL (Phenethylamines I Have Known and Loved) and other sources is 80 to 160mg. A wider recreational dose range for MDA of 20 to 200mg or more, with a typical dose estimate of 90mg, has also been reported. The dose range of MDA is very similar to that of MDMA.

The effects of MDA include euphoria, empathy, emotional amplification, relaxation, feeling at peace with the world, increased introspection, self-awareness, and acceptance, authenticity, clarity of thought, a desire to communicate with others and relate personal issues, and emotional bonding with others. These effects led to MDA being called the "love drug" or "hug drug". MDA also produces mild psychedelic effects, including brightened colors, closed-eye visuals or complex mental imagery, synaesthesia, and rarely mild hallucinations. It does not produce profound sensory disruption or overt hallucinations. The drug has also been found to produce mystical or spiritual experiences.

MDA shares most of MDMA's qualitative and emotional effects, including entactogenic and stimulant effects. However, it has been said to be slightly less stimulating than MDMA. Conversely, a clinical study found that it was more stimulating than MDMA. In addition, MDA's hallucinogenic effects are much greater than those of MDMA, although still less than those of classical psychedelics like psilocybin. 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. MDA tends to produce more anxiety and fear than MDMA.

MDA produces sympathomimetic effects such as increased heart rate and blood pressure, among other physiological effects.

In terms of the individual enantiomers of MDA, (R)-MDA produces psychedelic effects and some entactogenic effects, while (S)-MDA is non-hallucinogenic, produces similar entactogenic effects as the racemate, and has considerable stimulant effects. High doses of enantiopure (R)-MDA, in the range of 120 to 200mg, are described as closely resembling the effects of a 200 to 400μg dose of LSD-25. Enantiopure (R)-MDA at high doses produces more robust psychedelic effects than typical doses of racemic MDA.

The duration of MDA is about 5 to 8hours and is about 2hours longer than that of MDMA (3–6hours). Shulgin originally gave a duration of MDA of 8 to 12hours in PiHKAL, but he later revised this down to only 3 to 6hours. Modern clinical studies have given an average duration of 6 to 8hours with a range of 0.9 to 10hours. The drug's onset is 0.7hours (range 0.3 to 1.1hours) and its time to peak effects is 2.0hours (range 1.0 to 3.5hours).

Side effects Side effects of MDA include sympathomimetic effects like increased heart rate and blood pressure as well as increased cortisol and prolactin levels.

Overdose Symptoms of acute toxicity may include agitation, sweating, increased blood pressure and heart rate, dramatic increase in body temperature, convulsions, and death. Death is usually caused by cardiotoxicity. A 450mg intravenous injection of MDA was found to result in death in one case.

Interactions

Pharmacology Pharmacodynamics

+ Target Affinity (Ki, nM) 5,600–>10,000 (Ki)478–4,900 ()160–162 () (rat) 13,000 (Ki)150–420 ()47–108 () (rat) >26,000 (Ki)890–20,500 ()106–190 () (rat) 5-HT1A 3,762–>10,000 5-HT1B >10,000 5-HT1D >10,000 5-HT1E >10,000 5-HT1F 5-HT2A 3,200–>10,000 (Ki)630–1,767 ()57–99% () 5-HT2B 91–100 (Ki)190–850 ()51–80% () 5-HT2C 3,000–6,418 (Ki)98–4,800 ()79–118% () 5-HT3 >10,000 5-HT4 5-HT5A >10,000 5-HT6 >10,000 5-HT7 3,548 α1A 8,700–>10,000 α1B >10,000 α1D α2A 1,100–2,600 α2B 690 α2C 229 β1, β2 >10,000 D1–D5 >10,000–>20,000 H1–H4 >10,000–>13,000 M1–M5 nACh TAAR1 220–250 (Ki) (rat)740 () (rat)86% () (rat)160–180 (Ki) (mouse)580 () (mouse)102% () (rat)3,600 () (human)11% () (human) I1 >10,000 σ1, σ2 Notes: The smaller the value, the more avidly the drug binds to the site. Proteins are human unless otherwise specified. Refs:

MDA is a substrate of the serotonin, norepinephrine, dopamine, and vesicular monoamine transporters, and in relation to this, acts as a reuptake inhibitor and releasing agent of serotonin, norepinephrine, and dopamine (that is, it is an ). It is also an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors and shows affinity for the α2A-, α2B-, and α2C-adrenergic receptors and serotonin 5-HT1A and 5-HT7 receptors.

In addition to its actions as a monoamine releasing agent, MDA is a potent high-efficacy partial agonist or full agonist of the rodent TAAR1. Conversely, MDA is much weaker in terms of potency as an agonist of the human TAAR1. Moreover, MDA acts as a very weak partial agonist or antagonist of the human TAAR1 rather than as an efficacious agonist. TAAR1 activation is thought to auto-inhibit and constrain the effects of amphetamines that act as TAAR1 agonists, for instance MDMA in rodents.

MDA fully substitutes for MDMA in rodent drug discrimination tests. However, its prosocial effects in rodents are said to not fully resemble those of MDMA.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. MDA also substitutes for stimulants like dextroamphetamine and cocaine in drug discrimination tests. The (S)-optical isomer of MDA is more potent than the (R)-optical isomer as a psychostimulant, possessing greater activity at the monoamine transporters. MDA and (R)-MDA but not (S)-MDA fully substitute for serotonergic psychedelics including DOM, LSD, and mescaline. Similarly, MDA and (R)-MDA produce the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. However, the head-twitch response they produce is very weak in magnitude compared to other related psychedelics such as the DOx drugs. On the other hand, the response is more similar in magnitude to that of Ariadne.

In terms of the subjective and behavioral effects of MDA, it is thought that serotonin release is required for its entactogenic effects, dopamine release is required for its euphoriant (rewarding and addictive) effects, dopamine and norepinephrine release are required for its psychostimulant effects, and direct agonism of the serotonin 5-HT2A receptor is required for its mild psychedelic effects. The entactogenic effects of drugs like MDA are thought to be dependent on a precise balance of serotonin and dopamine release as well as serotonin receptor agonism. The longer duration of MDA compared to MDMA appears to be related to pharmacodynamics as opposed to pharmacokinetics, for instance the effects of MDA depending relatively more on serotonin 5-HT2A receptor agonism than on serotonin release.

MDA can produce serotonergic neurotoxic effects in rodents. This might in part be due to metabolism of MDA. In addition, MDA activates a response of the neuroglia, though this subsides after use.

+ Activities of MDMA, its enantiomers, and related compounds Compound Monoamine release (, nM) Serotonin Norepinephrine Dopamine Amphetamine (S)-Amphetamine (d) 698–1,765 6.6–7.2 5.8–24.8 (R)-Amphetamine (l) 9.5 27.7 Methamphetamine (S)-Methamphetamine (d) 736–1,292 12.3–13.8 8.5–24.5 (R)-Methamphetamine (l) 4,640 28.5 416 MDA 160 108 190 (S)-MDA (d) 100 50 98 (R)-MDA (l) 310 290 900 MDMA 49.6–72 54.1–110 51.2–278 (S)-MDMA (d) 74 136 142 (R)-MDMA (l) 340 560 3,700 MDEA 47 2,608 622 MBDB 540 3,300 >100,000 MDAI 114 117 1,334 Notes: The smaller the value, the more strongly the compound produces the effect. Refs: + Compound 5-HT2A 5-HT2B 5-HT2C EC50 (nM) Emax EC50 (nM) Emax EC50 (nM) Emax Serotonin 53 92% 1.0 100% 22 91% MDA 1,700 57% 190 80% (S)-MDA (d) 18,200 89% 100 81% 7,400 73% (R)-MDA (l) 5,600 95% 150 76% 7,400 76% MDMA 6,100 55% 2,000–>20,000 32% (S)-MDMA (d) 10,300 9% 6,000 38% 2,600 53% (R)-MDMA (l) 3,100 21% 900 27% 5,400 27% Notes: The smaller the Kact or EC50 value, the more strongly the compound produces the effect. Refs:

Pharmacokinetics The pharmacokinetics of MDA have been studied. Its duration of action has been reported to be about 6 to 8hours. The duration of MDA is longer than that of MDMA, about 8hours for MDA versus 6hours for MDMA. The elimination half-life of MDA is 10.9hours. Differences in the duration of MDA versus MDMA may be due pharmacodynamics rather than pharmacokinetics.

Chemistry MDA is a substituted methylenedioxylated phenethylamine and amphetamine derivative. In relation to other phenethylamines and amphetamines, it is the 3,4-methylenedioxy and α-methyl derivative of phenethylamine, the 3,4-methylenedioxy derivative of amphetamine, and the N-desmethyl derivative of MDMA. The compound is a racemic mixture of (S)- and (R)-enantiomers, (S)-MDA and (R)-MDA.

It is a common contaminant of illicitly produced MDMA.

Synonyms In addition to 3,4-methylenedioxyamphetamine, MDA is also known by other chemical synonyms such as the following:

α-Methyl-3,4-methylenedioxy-β-phenylethylamine 1-(3,4-Methylenedioxyphenyl)-2-propanamine 1-(1,3-Benzodioxol-5-yl)-2-propanamine

Synthesis MDA is typically synthesized from essential oil derived chemicals such as safrole or piperonal. Common approaches from these precursors include:

Bromination of safrole's alkene functional group followed by amine alkylation procedure a:

Detection in body fluids 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.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.R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, California, 2011, pp. 1078–1080.

Analogues and derivatives Analogues of MDA include its positional isomer 2,3-methylenedioxyamphetamine (2,3-MDA) and others. MDMA is the N-methyl derivative of MDA. Some other analogues of MDA include 5-APB, 6-APB, 5-APDB, 6-APDB, 5-APBT, 6-APBT, and SDA (3T-MDA), among others.

MDA constitutes part of the core structure of the β-adrenergic receptor agonist protokylol.

History