3,4-Methylenedioxyamphetamine

Use and effects

MDA is bought, sold, and used as a recreational drug due to its enhancement of mood and 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. In any case, the drug has still 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 produces more negative "bad drug effects" and fear than MDMA.

Besides its psychoactive effects, 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 LSD, for instance doses of 200 to 400μg. 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 cardiac effects and subsequent hemorrhaging in the brain (stroke). A 450mg intravenous injection of MDA was found to result in death in one case.

Interactions

Pharmacology

Pharmacodynamics

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. 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 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.

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, α-methyl derivative of β-phenylethylamine, the 3,4-methylenedioxy derivative of amphetamine, and the N-desmethyl derivative of MDMA.

It is a common adulterant 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 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 hydroxylamine. 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.

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

MDA was first synthesized by Carl Mannich and W. Jacobsohn in 1910. However, he did not subsequently describe these effects until 1959. Alles 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. However, it was found to be detrimental in people with Parkinson's disease. The drug was described as having analeptic effects in humans in 1953. From 1949 to 1957, more than five hundred human subjects were given MDA in an investigation of its potential use as an antidepressant or appetite suppressant 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.

Matthew J. Baggott and colleagues conducted some of the first modern clinical studies of MDA in humans and published their findings in the 2010s.

Society and culture

Names

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."

Canada

MDA is a Schedule I controlled substance in Canada.

European Union

MDA is individually classified by countries in the European Union, but generally the countries follow the Convention on Psychotropic Substances.

United States

MDA is a Schedule I controlled substance in the United States.

Research

MDA has been studied in entactogen-assisted psychotherapy.

References

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