# 3,4-Methylenedioxyamphetamine

3,4-Methylenedioxyamphetamine (MDA) is an empathogen-entactogen, stimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.
MDA is rarely sought as a recreational drug compared to other amphetamines; however, it remains widely used due to it being a primary metabolite, the product of hepatic N-dealkylation, of MDMA. It is also a common adulterant of illicitly produced MDMA.

## Uses
### Medical

MDA currently has no accepted medical use.

### Recreational

MDA is bought, sold, and used as a recreational drug due to its enhancement of mood and empathy. A recreational dose of MDA is sometimes cited as being between 100 and 160 mg. It produces MDMA-like effects, including entactogen and psychedelic effects.

## 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 cardiac effects and subsequent hemorrhaging in the brain (stroke).

## Pharmacology
### Pharmacodynamics

Activities of MDA :
| Target | Affinity (K$_i$, nM) |
| SERTTooltip Serotonin transporter | 5,600–>10,000 (K$_i$) 478–4,900 (IC$_{50}$Tooltip half-maximal inhibitory concentration) 160–162 (EC$_{50}$Tooltip Half-maximal effective concentration) (rat) |
| NETTooltip Norepinephrine transporter | 13,000 (K$_i$) 150–420 (IC$_{50}$) 47–108 (EC$_{50}$) (rat) |
| DATTooltip Dopamine transporter | >26,000 (K$_i$) 890–20,500 (IC$_{50}$) 106–190 (EC$_{50}$) (rat) |
| 5-HT$_{1A}$ | 3,762–>10,000 |
| 5-HT$_{1B}$ | >10,000 |
| 5-HT$_{1D}$ | >10,000 |
| 5-HT$_{1E}$ | >10,000 |
| 5-HT$_{1F}$ | ND |
| 5-HT$_{2A}$ | 3,200–>10,000 (K$_i$) 630–1,767 (EC$_{50}$) 57–99% (E$_{max}$Tooltip maximal efficacy) |
| 5-HT$_{2B}$ | 91–100 (K$_i$) 190–850 (EC$_{50}$) 51–80% (E$_{max}$) |
| 5-HT$_{2C}$ | 3,000–6,418 (K$_i$) 98–4,800 (EC$_{50}$) 79–118% (E$_{max}$) |
| 5-HT$_3$ | >10,000 |
| 5-HT$_4$ | ND |
| 5-HT$_{5A}$ | >10,000 |
| 5-HT$_6$ | >10,000 |
| 5-HT$_7$ | 3,548 |
| α$_{1A}$ | 8,700–>10,000 |
| α$_{1B}$ | >10,000 |
| α$_{1D}$ | ND |
| α$_{2A}$ | 1,100–2,600 |
| α$_{2B}$ | 690 |
| α$_{2C}$ | 229 |
| β$_1$, β$_2$ | >10,000 |
| D$_1$–D$_5$ | >10,000–>20,000 |
| H$_1$–H$_4$ | >10,000–>13,000 |
| M$_1$–M$_5$ | ND |
| nACh | ND |
| TAAR1 | 220–250 (K$_i$) (rat) 740 (EC$_{50}$) (rat) 86% (E$_{max}$) (rat) 160–180 (K$_i$) (mouse) 580 (EC$_{50}$) (mouse) 102% (E$_{max}$) (rat) 3,600 (EC$_{50}$) (human) 11% (E$_{max}$) (human) |
| I$_1$ | >10,000 |
| σ$_1$, σ$_2$ | ND |
| 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 SNDRATooltip serotonin–norepinephrine–dopamine releasing agent). It is also an agonist of the serotonin 5-HT$_{2A}$, 5-HT$_{2B}$, and 5-HT$_{2C}$ receptors and shows affinity for the α$_{2A}$-, α$_{2B}$-, and α$_{2C}$-adrenergic receptors and serotonin 5-HT$_{1A}$ and 5-HT$_7$ receptors.
The (S)-optical isomer of MDA is more potent than the (R)-optical isomer as a psychostimulant, possessing greater affinity for the three monoamine transporters.
In terms of the subjective and behavioral effects of MDA, it is thought that serotonin release is required for its empathogenic effects, dopamine release is required for its euphoriant (rewarding and addictive) effects, dopamine and norepinephrine release is required for its psychostimulant effects, and direct agonism of the serotonin 5-HT$_{2A}$ receptor is required for its mild psychedelic effects.
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.
Activities of MDMA, its enantiomers, and related compounds :
| Compound | Monoamine release (EC$_{50}$Tooltip half-maximal effective concentration, nM) | Monoamine release (EC$_{50}$Tooltip half-maximal effective concentration, nM) | Monoamine release (EC$_{50}$Tooltip half-maximal effective concentration, nM) |
| Compound | Serotonin | Norepinephrine | Dopamine |
| Amphetamine | ND | ND | ND |
| (S)-Amphetamine (d) | 698–1,765 | 6.6–7.2 | 5.8–24.8 |
| (R)-Amphetamine (l) | ND | 9.5 | 27.7 |
| Methamphetamine | ND | ND | ND |
| (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: ||||

### Pharmacokinetics

The pharmacokinetics of MDA have been studied. Its duration of action has been reported to be about 6 to 8 hours. The duration of MDA is longer than that of MDMA, about 8 hours for MDA versus 6 hours for MDMA. The elimination half-life of MDA is 10.9 hours. 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, α-methyl derivative of β-phenylethylamine, the 3,4-methylenedioxy derivative of amphetamine, and the N-desmethyl derivative of 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 oils such as safrole or piperonal. Common approaches from these precursors include:
* Reaction of safrole's alkene functional group with a halogen containing mineral acid followed by amine alkylation.
* Wacker oxidation of safrole to yield 3,4-methylenedioxyphenylpropan-2-one (MDP2P) followed by reductive amination or via reduction of its oxime.
* Henry reaction of piperonal with nitroethane followed by nitro compound reduction.
* Darzens reaction on heliotropin was also done by J. Elks, et al. This gives MDP2P, which was then subjected to a Leuckart reaction.
* The "two dogs" or "dopeboy" clandestine method, starting with helional as a precursor. First, an oxime is created using hydoxylamine. Then, a Beckmann rearrangement is performed with nickel acetate to form the amide. Then a Hofmann rearrangement is done to form the freebase amine of MDA. Then it is purified with an acid base extraction.

### 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.

### Derivatives

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

## History

MDA was first synthesized by Carl Mannich and W. Jacobsohn in 1910. It was first ingested in July 1930 by Gordon Alles who later licensed the drug to Smith, Kline & French. MDA was first used in animal tests in 1939, and human trials began in 1941 in the exploration of possible therapies for Parkinson's disease. From 1949 to 1957, more than five hundred human subjects were given MDA in an investigation of its potential use as an antidepressant and/or anorectic by Smith, Kline & French. The United States Army also experimented with the drug, code named EA-1298, while working to develop a truth 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 of Project MKUltra. MDA was patented as an ataractic by Smith, Kline & French in 1960, and as an anorectic 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 a research chemical from several scientific supply houses. Several researchers, including Claudio Naranjo and Richard Yensen, have explored MDA in the field of psychotherapy.
The International Nonproprietary Name (INN) tenamfetamine was recommended by the World Health Organization (WHO) in 1986. It was recommended in the same published list in which the INN of 2,5-dimethoxy-4-bromoamphetamine (DOB), brolamfetamine, was recommended. These events suggest that MDA and DOB were under development as potential pharmaceutical drugs at the time. The Multidisciplinary Association for Psychedelic Studies (MAPS) was also founded in 1986.

## Society and culture
### Name

When MDA was under development as a potential pharmaceutical drug, it was given the International Nonproprietary Name (INN) of tenamfetamine.

### Legal status
#### Australia

MDA is schedule 9 prohibited substance under the Poisons Standards. 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."

#### United States

MDA is a Schedule I controlled substance in the US.

## Research

In 2010, the ability of MDA to invoke mystical experiences and alter vision in healthy volunteers was studied. The study concluded that MDA is a "potential tool to investigate mystical experiences and visual perception".
A 2019 double-blind study administered both MDA and MDMA to healthy volunteers. The study found that MDA shared many properties with MDMA including entactogenic and stimulant effects, but generally lasted longer and produced greater increases in psychedelic-like effects like complex imagery, synesthesia, and spiritual experiences.

### Adverse effects

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