Chemistry:3,4-Methylenedioxyamphetamine

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Short description: Empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family
3,4-Methylenedioxyamphetamine
INN: Tenamfetamine
MDA-2D-skeletal.svg
MDA molecule ball.png
Clinical data
Routes of
administration		Oral, sublingual, insufflation, intravenous
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic (CYP extensively involved)
ExcretionRenal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC10H13NO2
Molar mass179.219 g·mol−1
3D model (JSmol)
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3,4-Methylenedioxyamphetamine (also known as MDA and sass) is an empathogen-entactogen, psychostimulant, 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,[1] the product of hepatic N-dealkylation,[2] of MDMA (ecstasy). It is also a common adulterant of illicitly produced MDMA.[3][4]


Uses

Medical

MDA currently has no accepted medical use.

Recreational

MDA is bought, sold, and used as a recreational 'love drug', due to its enhancement of mood and empathy.[5] A recreational dose of MDA is sometimes cited as being between 100 and 160 mg.[6]

Adverse effects

MDA can produce serotonergic neurotoxic effects in rodents,[7][8] thought to be activated by initial metabolism of MDA.[2] In addition, MDA activates a response of the neuroglia, though this subsides after use.[7]

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).[9]

Pharmacology

Pharmacodynamics

MDA is a substrate of the serotonin, norepinephrine, dopamine, and vesicular monoamine transporters, as well as a TAAR1 agonist,[10] and for these reasons acts as a reuptake inhibitor and releasing agent of serotonin, norepinephrine, and dopamine (that is, it is an SNDRA).[11] It is also an agonist of the serotonin 5-HT2A,[12] 5-HT2B,[13] and 5-HT2C receptors[14] and shows affinity for the α2A-, α2B-, and α2C-adrenergic receptors and serotonin 5-HT1A and 5-HT7 receptors.[15]

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 empathogen-entactogen effects, release of dopamine and norepinephrine is responsible for its psychostimulant effects, dopamine release is necessary for its euphoriant (rewarding and addictive) effects, and direct agonism of the serotonin 5-HT2A receptor is causative of its psychedelic effects.

Pharmacokinetics

The duration of the drug has been reported as about 6 to 8 hours.[6]

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:

Synthesis of MDA and related analogs from safrole

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.[26][27][28]

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.[19] It was first ingested in July 1930 by Gordon Alles who later licensed the drug to Smith, Kline & French.[29] 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.[30][31]

Society and culture

MDA as prepared for recreational use

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.[32] 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."[32]

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".[6]

A 2019 double-blind study administered both MDA and MDMA to healthy volunteers. The study found that MDA shared many properties with MDMA including entactogen and stimulant effects, but generally lasted longer and produced greater increases in psychedelic-like effects like complex imagery, synesthesia, and spiritual experiences.[33]

References

  1. ↑ "Effects of (+/-)3,4-methylenedioxymethamphetamine, (+/-)3,4-methylenedioxyamphetamine and methamphetamine on temperature and activity in rhesus macaques". Neuroscience 142 (2): 515–525. October 2006. doi:10.1016/j.neuroscience.2006.06.033. PMID 16876329. 
  2. ↑ 2.0 2.1 "Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition". Therapeutic Drug Monitoring 26 (2): 137–144. April 2004. doi:10.1097/00007691-200404000-00009. PMID 15228154. 
  3. ↑ "EcstasyData.org: Test Result Statistics: Substances by Year". EcstasyData.org. http://www.ecstasydata.org/stats_substance_by_year.php. 
  4. ↑ "Trans European Drug Information" (in en). http://idpc.net/profile/Trans-european-drug-information. 
  5. ↑ "Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine". Journal of Medicinal Chemistry 36 (23): 3700–3706. November 1993. doi:10.1021/jm00075a027. PMID 8246240. 
  6. ↑ 6.0 6.1 6.2 "Investigating the mechanisms of hallucinogen-induced visions using 3,4-methylenedioxyamphetamine (MDA): a randomized controlled trial in humans". PLOS ONE 5 (12): e14074. December 2010. doi:10.1371/journal.pone.0014074. PMID 21152030. Bibcode: 2010PLoSO...514074B. 
  7. ↑ 7.0 7.1 "Glial cell response to 3,4-(+/-)-methylenedioxymethamphetamine and its metabolites". Toxicological Sciences 138 (1): 130–138. March 2014. doi:10.1093/toxsci/kft275. PMID 24299738. 
  8. ↑ "The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs". CMAJ 165 (7): 917–928. October 2001. PMID 11599334. 
  9. ↑ How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall. 1996. 
  10. ↑ "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry 19 (23): 7044–7048. December 2011. doi:10.1016/j.bmc.2011.10.007. PMID 22037049. 
  11. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. https://zenodo.org/record/1235860. 
  12. ↑ Serotonin–dopamine Interaction: Experimental Evidence and Therapeutic Relevance. Elsevier. 2008. pp. 294–. ISBN 978-0-444-53235-0. https://books.google.com/books?id=mPkKtA15KM8C&pg=PA294. 
  13. ↑ "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety 8 (3): 317–329. May 2009. doi:10.1517/14740330902931524. PMID 19505264. 
  14. ↑ "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. August 1994. doi:10.1016/0304-3940(94)90057-4. PMID 7824160. 
  15. ↑ "Psychedelics and the human receptorome". PLOS ONE 5 (2): e9019. February 2010. doi:10.1371/journal.pone.0009019. PMID 20126400. Bibcode: 2010PLoSO...5.9019R. 
  16. ↑ "[Production of some amphetamine derivatives]". Acta Poloniae Pharmaceutica 18: 471–478. 1961. PMID 14477621. 
  17. ↑ 17.0 17.1 17.2 The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds (1st ed.). Berkeley, CA: Transform Press. 2011. p. 165. ISBN 9780963009630. https://books.google.com/books?id=68-huAAACAAJ&q=9780963009630. 
  18. ↑ "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. 1986. PMID 2875058. 
  19. ↑ 19.0 19.1 "Über Oxyphenyl-alkylamine und Dioxyphenyl-alkylamine". Berichte der Deutschen Chemischen Gesellschaft 41 (1): 189–197. 1910. doi:10.1002/cber.19100430126. https://zenodo.org/record/1426387. 
  20. ↑ "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. January 1970. doi:10.1021/jm00295a007. PMID 5412110. 
  21. ↑ "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. 1974. doi:10.1039/C39740000307. 
  22. ↑ "Synthesis of Phenethylamine Derivatives as Hallucinogen". Japanese Journal of Toxicology and Environmental Health 38 (6): 571–580. 1992. doi:10.1248/jhs1956.38.571. https://www.jstage.jst.go.jp/article/jhs1956/38/6/38_6_571/_pdf/-char/en. Retrieved 20 June 2014. 
  23. ↑ PiHKAL: A Chemical Love Story. Lafayette, CA: Transform Press. 1991. ISBN 9780963009609. https://books.google.com/books?id=O8AdHBGybpcC&q=9780963009609. 
  24. ↑ "7. β-3 : 4-Methylenedioxyphenylisopropylamine". J. Chem. Soc.: 15–16. 1943. doi:10.1039/JR9430000015. ISSN 0368-1769. 
  25. ↑ https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3973132
  26. ↑ 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.
  27. ↑ "Disposition of MDMA and metabolites in human sweat following controlled MDMA administration". Clinical Chemistry 55 (3): 454–462. March 2009. doi:10.1373/clinchem.2008.117093. PMID 19168553. 
  28. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, California, 2011, pp. 1078–1080.
  29. ↑ "The First MDA trip and the measurement of 'mystical experience' after MDA, LSD, and Psilocybin". Psychedelic research. 18 July 2008. http://psychedelicresearch.org/?p=45. 
  30. ↑ "Evaluation of 3,4-methylenedioxyamphetamine (MDA) as an adjunct to psychotherapy". Medicina et Pharmacologia Experimentalis. International Journal of Experimental Medicine 17 (4): 359–364. 1967. doi:10.1159/000137100. PMID 5631047. 
  31. ↑ "MDA-assisted psychotherapy with neurotic outpatients: a pilot study". The Journal of Nervous and Mental Disease 163 (4): 233–245. October 1976. doi:10.1097/00005053-197610000-00002. PMID 972325. 
  32. ↑ 32.0 32.1 Poisons Standard (October 2015) comlaw.gov.au
  33. ↑ "Effects of the Psychedelic Amphetamine MDA (3,4-Methylenedioxyamphetamine) in Healthy Volunteers". Journal of Psychoactive Drugs 51 (2): 108–117. 2019-03-15. doi:10.1080/02791072.2019.1593560. PMID 30967099. 

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