# 4-Methylamphetamine > Mediated Wiki article. Canonical URL: https://mediated.wiki/source/4-Methylamphetamine > Markdown URL: https://mediated.wiki/source/4-Methylamphetamine.md > Source: https://en.wikipedia.org/wiki/4-Methylamphetamine > Source revision: 1348368662 > License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/) {{Short description|Stimulant and anorectic drug of the amphetamine class}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = changed | class = [Serotonin-norepinephrine-dopamine releasing agent](/source/Serotonin-norepinephrine-dopamine_releasing_agent); [Stimulant](/source/Stimulant); [Anorectic](/source/Anorectic) | verifiedrevid = 477222632 | IUPAC_name = 1-(4-methylphenyl)propan-2-amine | image = 4-Methylamphetamine structure.svg | image_class = skin-invert-image | width = 235px | image2 = 4-Methylamphetamine molecule ball.png | image_class2 = bg-transparent | width2 = 225px | alt2 = Ball-and-stick model of the 4-methylamphetamine molecule | tradename = Aptrol | pregnancy_category = | legal_CA = Schedule I | legal_UK = Class A | legal_DE = Anlage II | legal_US = [Schedule II (isomer of Methamphetamine)](/source/List_of_Schedule_II_drugs_(US)) | routes_of_administration = Oral, intranasal, injection, | bioavailability = | protein_bound = | metabolism = | elimination_half-life = 6–12 hours | excretion = Urine | CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 64-11-9 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 9E273KL7HS | ATC_prefix = none | PubChem = 199116 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 172349 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 166183 | synonyms = 4-MA; PAL-313; PAL313; p-TAP; Normephedrine | C = 10 | H = 15 | N = 1 | SMILES = NC(Cc1ccc(cc1)C)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C10H15N/c1-8-3-5-10(6-4-8)7-9(2)11/h3-6,9H,7,11H2,1-2H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = ZDHZDWSHLNBTEB-UHFFFAOYSA-N }} '''4-Methylamphetamine''' ('''4-MA''') or '''para-methylamphetamine''', also known by the former proposed brand name '''Aptrol''', is a [stimulant](/source/stimulant) and [anorectic](/source/anorectic) [drug](/source/drug) of the [amphetamine](/source/substituted_amphetamine) family. It is [structurally related](/source/structural_analog) to [mephedrone](/source/mephedrone) (4-methylmethcathinone). == Pharmacology == ===Pharmacodynamics=== ''[In vitro](/source/In_vitro)'', 4-methylamphetamine acts as a [potent](/source/potency_(pharmacology)) and well-balanced [serotonin](/source/serotonin), [norepinephrine](/source/norepinephrine), and [dopamine](/source/dopamine) [releasing agent](/source/releasing_agent) (SNDRA) with {{Abbrlink|EC50|half-maximal effective concentration}} values of 53.4{{nbsp}}nM, 22.2{{nbsp}}nM, and 44.1{{nbsp}}nM at the [serotonin](/source/serotonin_transporter), [norepinephrine](/source/norepinephrine_transporter), and [dopamine transporter](/source/dopamine_transporter)s, respectively.{{cite journal | vauthors = Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL | title = Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 313 | issue = 2 | pages = 848–854 | date = May 2005 | pmid = 15677348 | doi = 10.1124/jpet.104.080101 | s2cid = 12135483 }} [Receptor](/source/Receptor_(biochemistry)) interaction data for 4-methylamphetamine have also been reported.{{cite journal | vauthors = Luethi D, Kolaczynska KE, Docci L, Krähenbühl S, Hoener MC, Liechti ME | title = Pharmacological profile of mephedrone analogs and related new psychoactive substances | journal = Neuropharmacology | volume = 134 | issue = Pt A | pages = 4–12 | date = May 2018 | pmid = 28755886 | doi = 10.1016/j.neuropharm.2017.07.026 | url = }} However, more recent ''[in vivo](/source/in_vivo)'' studies that involved performing [microdialysis](/source/microdialysis) on rats showed a different trend. These studies showed that 4-methylamphetamine is much more potent at elevating serotonin (~18 x baseline) relative to [dopamine](/source/dopamine) (~5 x baseline). The authors speculated that this is because 5-HT release dampens DA release through some mechanism. For example, it was suggested that a possible cause for this could be activation of 5HT2C receptors since this is known to inhibit DA release. In addition there are alternative explanations such as 5-HT release then going on to encourage GABA release, which has an inhibitory effect on DA neurons.{{cite journal | vauthors = Di Giovanni G, Esposito E, Di Matteo V | title = Role of serotonin in central dopamine dysfunction | journal = CNS Neuroscience & Therapeutics | volume = 16 | issue = 3 | pages = 179–194 | date = June 2010 | pmid = 20557570 | pmc = 6493878 | doi = 10.1111/j.1755-5949.2010.00135.x }} In animal studies, 4-MA was shown to have the lowest rate of self-administration out of a range of similar drugs tested (the others being [3-methylamphetamine](/source/3-methylamphetamine), [4-fluoroamphetamine](/source/4-fluoroamphetamine), and [3-fluoroamphetamine](/source/3-fluoroamphetamine)), likely as a result of having the highest potency for releasing serotonin relative to dopamine.{{cite journal | vauthors = Baumann MH, Clark RD, Woolverton WL, Wee S, Blough BE, Rothman RB | title = In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 337 | issue = 1 | pages = 218–225 | date = April 2011 | pmid = 21228061 | pmc = 3063744 | doi = 10.1124/jpet.110.176271 }} 4-MA produces the [head-twitch response](/source/head-twitch_response) in rodents similarly to [''para''-chloroamphetamine](/source/para-chloroamphetamine) (PCA).{{cite journal | vauthors = Ogren SO, Ross SB | title = Substituted amphetamine derivatives. II. Behavioural effects in mice related to monoaminergic neurones | journal = Acta Pharmacol Toxicol (Copenh) | volume = 41 | issue = 4 | pages = 353–368 | date = October 1977 | pmid = 303437 | doi = 10.1111/j.1600-0773.1977.tb02674.x | url = }} {| class="wikitable" style="font-size:small;" |+ {{Nowrap|[Monoamine release](/source/Monoamine_releasing_agent) of 4-methylamphetamine and related agents ({{Abbrlink|EC50|Half maximal effective concentration}}, nM)}} |- ! Compound !! data-sort-type="number" | {{abbrlink|NE|Norepinephrine}} !! data-sort-type="number" | {{abbrlink|DA|Dopamine}} !! data-sort-type="number" | {{abbrlink|5-HT|Serotonin}} !! Ref |- | [Dextroamphetamine](/source/Dextroamphetamine) || 6.6–10.2 || 5.8–24.8 || 698–1,765 || {{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | s2cid = 15573624 }}{{cite journal | vauthors = Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW | title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products | journal = Neuropsychopharmacology | volume = 38 | issue = 4 | pages = 552–562 | date = March 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken [NJ] | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}{{cite book | vauthors = Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB | chapter = Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substrates | title = Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc | series = NIDA Res Monogr | volume = 180 | pages = 1–476 (252) | date = 1999 | pmid = 11680410 | doi = | url = https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261 | archive-url = https://archive.today/20241208071605/https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261 | archive-date = December 8, 2024 | quote = RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.}} |- | [Dextromethamphetamine](/source/Dextromethamphetamine) || 12.3–14.3 || 8.5–40.4 || 736–1,292 || {{cite journal | vauthors = Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV | title = The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue | journal = Neuropsychopharmacology | volume = 37 | issue = 5 | pages = 1192–1203 | date = April 2012 | pmid = 22169943 | pmc = 3306880 | doi = 10.1038/npp.2011.304 }} |- | 4-Methylamphetamine || 22.2 || 44.1 || 53.4 || {{cite journal | vauthors = Forsyth AN | date = 22 May 2012 | title = Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | website = ScholarWorks@UNO | url = https://scholarworks.uno.edu/td/1436/ | access-date = 4 November 2024 }} |- | [4-Methylmethamphetamine](/source/4-Methylmethamphetamine) (mephedrine) || 66.9 || 41.3 || 67.4 || {{cite journal | vauthors = Solis E, Partilla JS, Sakloth F, Ruchala I, Schwienteck KL, De Felice LJ, Eltit JM, Glennon RA, Negus SS, Baumann MH | date = September 2017 | title = N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability | journal = Neuropsychopharmacology | volume = 42 | issue = 10 | pages = 1950–1961 | doi = 10.1038/npp.2017.98 | pmc = 5561352 | pmid = 28530234 }}{{cite thesis | vauthors = Sakloth F | date = 11 December 2015 | title = Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action | website = VCU Scholars Compass | doi = 10.25772/AY8R-PW77 }} |- | [4-Methylcathinone](/source/4-Methylcathinone) (normephedrone) || 100 || 220 || 210 || {{cite journal | vauthors = Mayer FP, Wimmer L, Dillon-Carter O, Partilla JS, Burchardt NV, Mihovilovic MD, Baumann MH, Sitte HH | title = Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters | journal = Br J Pharmacol | volume = 173 | issue = 17 | pages = 2657–2668 | date = September 2016 | pmid = 27391165 | pmc = 4978154 | doi = 10.1111/bph.13547 | url = }}{{cite journal | vauthors = Hutsell BA, Baumann MH, Partilla JS, Banks ML, Vekariya R, Glennon RA, Negus SS | title = Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats | journal = Eur Neuropsychopharmacol | volume = 26 | issue = 2 | pages = 288–297 | date = February 2016 | pmid = 26738428 | pmc = 5331761 | doi = 10.1016/j.euroneuro.2015.12.010 | url = }}{{cite book | vauthors = Glennon RA, Dukat M | title = Neuropharmacology of New Psychoactive Substances (NPS) | chapter = Structure-Activity Relationships of Synthetic Cathinones | series = Current Topics in Behavioral Neurosciences | volume = 32 | pages = 19–47 | date = 2017 | pmid = 27830576 | pmc = 5818155 | doi = 10.1007/7854_2016_41 | isbn = 978-3-319-52442-9 | chapter-url = }} |- | [4-Methylmethcathinone](/source/4-Methylmethcathinone) (mephedrone) || 58–62.7 || 49.1–51 || 118.3–122 || {{cite journal | vauthors = Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB | title = The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes | journal = Psychopharmacology | volume = 236 | issue = 3 | pages = 915–924 | date = March 2019 | pmid = 30341459 | pmc = 6475490 | doi = 10.1007/s00213-018-5063-9 }}{{cite journal | vauthors = Walther D, Shalabi AR, Baumann MH, Glennon RA | title = Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents | journal = ACS Chem Neurosci | volume = 10 | issue = 1 | pages = 740–745 | date = January 2019 | pmid = 30354055 | pmc = 8269283 | doi = 10.1021/acschemneuro.8b00524 | url = }}{{cite journal | vauthors = Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, Cozzi NV, Partilla JS, Baumann MH, Negus SS | title = Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues | journal = Br J Pharmacol | volume = 172 | issue = 10 | pages = 2433–2444 | date = May 2015 | pmid = 25438806 | pmc = 4409897 | doi = 10.1111/bph.13030 | url = }} |- | colspan="5" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more strongly the drug releases the neurotransmitter. The [assay](/source/bioassay)s were done in rat brain [synaptosome](/source/synaptosome)s and human [potencies](/source/potency_(pharmacology)) may be different. See also [Monoamine releasing agent § Activity profiles](/source/Monoamine_releasing_agent) for a larger table with more compounds. '''Refs:''' {{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = European Journal of Pharmacology | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 }}{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }} |} == Natural occurrence == 4-Methylamphetamine occurs naturally as an alkaloid in [Thymus quinquecostatus](/source/Thymus_quinquecostatus) plants, although its content even in young leaves is quite low {{cite journal | vauthors = Jing H, Liu J, Liu H, Xin H | date = 2014 | title = Histochemical investigation and kinds of alkaloids in leaves of different developmental stages in Thymus quinquecostatus | journal = TheScientificWorldJournal | volume = 2014 | article-number = 839548 | doi = 10.1155/2014/839548 | pmc = 4102088 | pmid = 25101324 | doi-access = free }} In addition to it, there are related amphetamine structures or [phenylpropanoids](/source/Phenylpropanoid).{{cite journal | vauthors = Guo J, Li L, Liu Z, Zhou Y, Wang J, Yang Z | date = September 2023 | title = Multi-dimensional preparation of Thymus quinquecostatus Celak. by normal-phase flash chromatography coupled to counter-current chromatography | journal = Journal of Chromatography. A | volume = 1706 | article-number = 464238 | doi = 10.1016/j.chroma.2023.464238 | pmid = 37506459 }} == Society and culture == More than a dozen deaths were reported throughout Europe in 2012-2013 after consumption of amphetamine ('speed') contaminated with 4-methylamphetamine.{{cite journal | vauthors = Blanckaert P, van Amsterdam J, Brunt T, van den Berg J, Van Durme F, Maudens K, van Bussel J | title = 4-Methyl-amphetamine: a health threat for recreational amphetamine users | journal = Journal of Psychopharmacology | volume = 27 | issue = 9 | pages = 817–822 | date = September 2013 | pmid = 23784740 | doi = 10.1177/0269881113487950 | s2cid = 35436194 | url = https://www.researchgate.net/publication/240306373_4-Methyl-amphetamine_A_health_threat_for_recreational_amphetamine_users }}{{cite journal | vauthors = Coppola M, Mondola R | title = 4-methylamphetamine (4-MA): chemistry, pharmacology and toxicology of a new potential recreational drug | journal = Mini Reviews in Medicinal Chemistry | volume = 13 | issue = 14 | pages = 2097–2101 | date = December 2013 | pmid = 24195663 | doi = 10.2174/13895575113136660106 }} == Research == 4-MA was investigated as an [appetite suppressant](/source/appetite_suppressant) in 1952 and was even given a trade name, Aptrol, but development was apparently never completed.{{cite journal | vauthors = Gelvin EP, McGavack TH | title = 2-Amino-1-(p-methylphenyl)-propane (aptrol) as an anorexigenic agent in weight reduction | journal = New York State Journal of Medicine | volume = 52 | issue = 2 | pages = 223–226 | date = January 1952 | pmid = 14890975 }} More recently it has been reported as a novel [designer drug](/source/designer_drug). == See also == * [Substituted amphetamine](/source/Substituted_amphetamine) * [1-(4-Methylphenyl)-2-aminobutane](/source/1-(4-Methylphenyl)-2-aminobutane) * [2-Methylamphetamine](/source/2-Methylamphetamine) * [3-Methylamphetamine](/source/3-Methylamphetamine) * [4-Methyl-''N''-methylamphetamine](/source/4-Methylmethamphetamine) * [4-Methyl-''N''-methylcathinone](/source/4-Methylmethcathinone) * [4-Methylphenmetrazine](/source/4-Methylphenmetrazine) * [3-Methoxy-4-methylamphetamine](/source/3-Methoxy-4-methylamphetamine) * [3,4-Dimethylamphetamine](/source/3%2C4-Dimethylamphetamine) * [4-Ethylamphetamine](/source/4-Ethylamphetamine) == References == {{Reflist}} ==External links== * [https://isomerdesign.com/pihkal/explore/221 4-Methylamphetamine - Isomer Design] * [https://archive.org/details/shulgin-index-vol-1/page/275/mode/1up?view=theater PMeA (4-Methylamphetamine) - The Shulgin Index] {{Stimulants}} {{Anorectics}} {{Monoamine releasing agents}} {{Serotonin receptor modulators}} {{Phenethylamines}} {{DEFAULTSORT:Methylamphetamine, 4-}} Category:5-HT2A agonists Category:5-HT2B agonists Category:Anorectics Category:Serotonin-norepinephrine-dopamine releasing agents Category:Stimulants Category:Substituted amphetamines --- Adapted from the Wikipedia article [4-Methylamphetamine](https://en.wikipedia.org/wiki/4-Methylamphetamine) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/4-Methylamphetamine?action=history)). 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