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3,4-Methylenedioxyamphetamine

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3,4-Methylenedioxyamphetamine
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{{distinguish|text=MDMA (methylenedioxymethamphetamine) or 2,3-methylenedioxyamphetamine}}
Not to be confused with malondialdehyde, a different chemical that is also abbreviated as MDA.
{{Use dmy dates|date=April 2016}}{{Drugbox| Verifiedfields = changed| Watchedfields = changed| verifiedrevid = 646873547| IUPAC_name = 1-(2H-1,3-Benzodioxol-5-yl)propan-2-amine| image = MDA-2D-skeletal.svg| image2 = MDA molecule ball.png| drug_name = | INN = Tenamfetamine | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = S9| legal_CA = Schedule I| legal_DE = Anlage I| legal_UK = Class A| legal_US = Schedule I| legal_UN = Psychotropic Schedule I| routes_of_administration = Oral, sublingual, insufflation, intravenous| bioavailability = | protein_bound =
Liver>Hepatic (CYP extensively involved)| elimination_half-life =Kidney>Renalcorrect|CAS}}| CAS_number = 4764-17-4changed|FDA}}| UNII = XJZ28FJ27W| CAS_supplemental =| ATC_prefix = None| ATC_suffix = | PubChem = 1614correct|drugbank}}| DrugBank = DB01509correct|chemspider}}| ChemSpiderID = 1555correct|EBI}}| ChEMBL = 6731
| C=10 | H=13 | N=1 | O=2| molecular_weight = 179.22 g/mol| smiles = NC(C)CC1=CC2=C(C=C1)OCO2
correct|chemspider}}| StdInChI = 1S/C10H13NO2/c1-7(11)4-8-2-3-9-10(5-8)13-6-12-9/h2-3,5,7H,4,6,11H2,1H3correct|chemspider}}| StdInChIKey = NGBBVGZWCFBOGO-UHFFFAOYSA-N}}3,4-Methylene{{wbr}}dioxy{{wbr}}amphetamine (MDA), is an empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In terms of pharmacology, MDA acts most importantly as a serotonin-norepinephrine-dopamine releasing agent (SNDRA). Due to its euphoriant and hallucinogenic effects, the drug is a controlled substance and its possession and sale are illegal in most countries.MDA is rarely sought after as a recreational drug compared to other drugs in the amphetamine family; however, it remains an important and widely used drug due to it being a primary metabolite,JOURNAL, Crean, R. D., Davis, S. A., Von Huben, S. N., Lay, C. C., Katner, S. N., Taffe, M. A., 2006-10-13, Effects of (±)3,4-methylenedioxymethamphetamine, (±)3,4-methylenedioxyamphetamine and methamphetamine on temperature and activity in rhesus macaques, Neuroscience, 142, 2, 515–525, 10.1016/j.neuroscience.2006.06.033, 1853374, 16876329, the product of hepatic N-dealkylation,JOURNAL, de la Torre, R, Farre, M, Roset, Pn, Pizzaro, N, Abanades, S, Segura, M, Segura, M, Camí, J, 2004, Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition., 15228154, Therapeutic Drug Monitoring, 26, 2, 137–144, 10.1097/00007691-200404000-00009, of MDMA (ecstasy), In addition, it is not uncommon to find MDA as an adulterant of illicitly produced MDMA.WEB,weblink EcstasyData.org: Test Result Statistics: Substances by Year, EcstasyData.org, www.ecstasydata.org, 2017-06-27, WEB,weblink Trans European Drug Information, idpc.net, en, 2017-06-27, {{TOC limit|3}}

Uses

Medical

MDA currently has no accepted medical use.

Recreational

Although illegal, MDA is bought, sold, and used as a recreational 'love drug', due to its enhancement of mood and empathy.JOURNAL, Monte AP, Marona-Lewicka D, Cozzi NV, Nichols DE, Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine, Journal of Medicinal Chemistry, 1993, 36, 23, 3700–3706, 8246240, 10.1021/jm00075a027, A recreational dose of MDA is sometimes cited as being between 100 and 160 mg.

Adverse effects

MDA produces serotonergic neurotoxic effects,JOURNAL, Herndon, Joseph M., Cholanians, Aram B., Lau, Serrine S., Monks, Terrence J., March 2014, Glial Cell Response to 3,4-(±)-Methylenedioxymethamphetamine and Its Metabolites, Toxicological Sciences, 138, 1, 130–138, 10.1093/toxsci/kft275, 1096-6080, 3930364, 24299738, JOURNAL, Kalant, Harold, 2001-10-02, The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs, CMAJ: Canadian Medical Association Journal, 165, 7, 917–928, 0820-3946, 81503, 11599334, thought to be activated by initial metabolism of MDA. In addition, MDA activates a response of the neuroglia, though this subsides after use.

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).Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.{{mcn|date=January 2015}}

Interactions

{{Empty section|date=April 2017}}

Pharmacology

Pharmacodynamics

MDA is a substrate of the serotonin, norepinephrine, dopamine, and vesicular monoamine transporters, as well as a TAAR1 agonist,JOURNAL, Lewin AH, Miller GM, Gilmour B, Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class, Bioorg. Med. Chem., 19, 23, 7044–8, December 2011, 22037049, 3236098, 10.1016/j.bmc.2011.10.007, and for these reasons acts as a reuptake inhibitor and releasing agent of serotonin, norepinephrine, and dopamine (that is, it is an {{abbrlink|SNDRA|serotonin-norepinephrine-dopamine releasing agent}}).JOURNAL, Rothman RB, Baumann MH, Therapeutic potential of monoamine transporter substrates, Curr Top Med Chem, 6, 17, 1845–59, 2006, 17017961, 10.2174/156802606778249766, It is also an agonist of the serotonin 5-HT2A,BOOK, Giuseppe Di Giovanni, Vincenzo Di Matteo, Ennio Esposito, Serotonin-dopamine Interaction: Experimental Evidence and Therapeutic Relevance,weblink 2008, Elsevier, 978-0-444-53235-0, 294–, 5-HT2B,JOURNAL, Rothman, Richard B, Baumann, Michael H, Serotonergic drugs and valvular heart disease, Expert Opinion on Drug Safety, 8, 3, 2009, 317–329, 1474-0338, 10.1517/14740330902931524, 19505264, 2695569, and 5-HT2C receptorsJOURNAL, Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA, 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, 111–5, 1994, 7824160, 10.1016/0304-3940(94)90057-4, and shows affinity for the α2A-, α2B-, and α2C-adrenergic receptors and serotonin 5-HT1A and 5-HT7 receptors.JOURNAL, Manzoni, Olivier Jacques, Ray, Thomas S., Psychedelics and the Human Receptorome, PLoS ONE, 5, 2, 2010, e9019, 1932-6203, 10.1371/journal.pone.0009019, 20126400, 2814854, 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.{{Medical citation needed|date=March 2017}}

Pharmacokinetics

The duration of the drug has been reported as about 6 to 8 hours.JOURNAL, Baggott, MJ, Siegrist, JD, Galloway, GP, Robertson, LC, Coyle, JR, Mendelson, JE, 2010, Investigating the Mechanisms of Hallucinogen-Induced Visions Using 3,4-Methylenedioxeamphetamine (MDA): A Randomized Controlled Trial in Humans, PLOS ONE, 5, 12, e14074, 10.1371/journal.pone.0014074, 21152030, 2996283,

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-demethyl 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.JOURNAL, Muszynski, I.E., Production of some amphetamine derivatives, Acta Poloniae Pharmaceutica, 1961, 18, 471–478, 14477621, BOOK, Shulgin, Alexander, Manning, Tania, Daley, Paul, The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds, 2011, Transform Press, Berkeley, CA, 9780963009630, 165, 1st,weblink
(File:MDA_analogs_from_safrole.png|900px|Synthesis of MDA and related analogs from safrole)
  • Wacker oxidation of safrole to yield 3,4-methylenedioxyphenylpropan-2-one (MDP2P) followed by reductive aminationJOURNAL, Noggle, FT Jr, DeRuiter, J., Long, MJ., Spectrophotometric and liquid chromatographic identification of 3,4-methylenedioxyphenylisopropylamine and its N-methyl and N-ethyl homologs, Journal Association of Official Analytical Chemists, 1986, 69, 4, 681–686, 2875058, or via reduction of its oxime.JOURNAL, Mannich, C., Jacobsohn, W., Mannich, Hr. C., Ãœber Oxyphenyl-alkylamine und Dioxyphenyl-alkylamine, Berichte der Deutschen Chemischen Gesellschaft, 1910, 41, 1, 189–197, 10.1002/cber.19100430126,weblink
  • Henry reaction of piperonal with nitroethane followed by nitro compound reduction.JOURNAL, Ho, Beng-Thong, McIsaac, William M., An, Rong, Tansey, L. Wayne, Walker, Kenneth E., Englert Jr., Leo F., Noel, Michael B., Analogs of a-methylphenethylamine, Journal of Medicinal Chemistry, 1970, 13, 1, 26–30, 10.1021/jm00295a007, 5412110, JOURNAL, Butterick, John R., Unrau, A. M., Reduction of β-nitrostyrene with sodium bis-(2-methoxyethoxy)-aluminium dihydride. A convenient route to substituted phenylisopropylamines, Journal of the Chemical Society, Chemical Communications, 1974, 8, 307–308, 10.1039/C39740000307, 8, JOURNAL, Toshitaka, Ohshita, Hiroaka, Ando, Synthesis of Phenethylamine Derivatives as Hallucinogen, Japanese Journal of Toxicology and Environmental Health, 1992, 38, 6, 571–580,weblink 20 June 2014, BOOK, Shulgin, Alexander, Shulgin, Ann, yes, PiHKAL: A Chemical Love Story, 1991, Transform Press, Lafayette, CA, 9780963009609,weblink
  • Darzens reaction on heliotropin was also done by J. Elks, et al.JOURNAL, Elks, J., Hey, D. H., 7. β-3 : 4-Methylenedioxyphenylisopropylamine, J. Chem. Soc., 0, 1943, 15–16, 0368-1769, 10.1039/JR9430000015, This gives MDP2P, which was then subjected to a Leuckart reaction.

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.JOURNAL, Barnes AJ, De Martinis BS, Gorelick DA, Goodwin RS, Kolbrich EA, Huestis MA, Disposition of MDMA and metabolites in human sweat following controlled MDMA administration, Clinical Chemistry, 55, 3, 454–62, 2009, 19168553, 2669283, 10.1373/clinchem.2008.117093,weblink R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, California, 2011, pp. 1078–1080.

Derivatives

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

History

MDA was first synthesized by C. 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.WEB, The First MDA trip and the measurement of 'mystical experience' after MDA, LSD, and Psilocybin,weblinkweblink" title="archive.is/20120713055811weblink">weblink July 13, 2012, July 18, 2008, Psychedelic research, 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 500 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 BlauerThe History Channel documented details of his death hereweblink See minute 2:38 onward. 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 a cough suppressant by H. D. Brown in 1958, 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.JOURNAL, Naranjo, C., Shulgin, A. T., Sargent, T., 1967, Evaluation of 3, 4-methylenedioxeamphetamine (MDA) as an adjunct to psychotherapy, Pharmacology, 17, 4, 359–364, 10.1159/000137100, JOURNAL, Yensen, R., Di Leo, F. B., Rhead, J. C., Richards, W. A., Soskin, R. A., Turek, B., Kurland, A. A., 1976, MDA-assisted psychotherapy with neurotic outpatients: a pilot study, The Journal of Nervous and Mental Disease, 163, 4, 233–245, 972325, 10.1097/00005053-197610000-00002,

Society and culture

(File:MDA.jpg|thumb|right|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.Poisons Standard (October 2015) comlaw.gov.au 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.

References

{{Reflist|30em}}

External links

{{Entactogens}}{{Hallucinogens}}{{Stimulants}}{{Navboxes| title = Pharmacodynamics| titlestyle = background:#ccccff| list1 = {{Monoamine releasing agents}}{{Serotonin receptor modulators}}{{TAAR ligands}}{{Monoamine neurotoxins}}}}{{Phenethylamines}}{{PiHKAL}}


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