Para-Methoxymethamphetamine

{{Short description|Stimulant and entactogen designer drug}} {{DISPLAYTITLE:''para''-Methoxymethamphetamine}} {{Use dmy dates|date=March 2020}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | verifiedrevid = 449584234 | drug_name = PMMA | image = PMMA structure.svg | image_class = skin-invert-image | width = 250px | image2 = PMMA ball-and-stick structure.png | image_class2 = bg-transparent | width2 = 250px

| tradename = | class = Serotonin–norepinephrine releasing agent; Monoamine oxidase inhibitor | routes_of_administration = Oral<ref name="PiHKAL" />

| legal_AU =  | legal_BR = F2 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-07-25}}</ref> | legal_CA = Schedule I | legal_DE = Anlage I | legal_US = Schedule 1 | legal_US_comment = | legal_UK = Class A

| bioavailability = | protein_bound = | metabolism = CYP2D6, [https://link.springer.com/article/10.1186/s13321-018-0324-5] [https://www.sciencedirect.com/science/article/abs/pii/S009095562405431X] | metabolites = Pholedrine [https://zenodo.org/records/13235312], para-methoxyamphetamine, 4-hydroxyamphetamine, 3,4-dihydroxymethamphetamine, oxilofrine [https://www.sciencedirect.com/science/article/abs/pii/S009095562405431X] [https://www.sciencedirect.com/science/article/abs/pii/S1570023202010188] | onset = ≤1 hour<ref name="PiHKAL" /> | elimination_half-life = | duration_of_action = "Short"<ref name="PiHKAL" /> | excretion =  | index_label = | index2_label = | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 22331-70-0 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 037U5SR9KL | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = C22810 | PubChem = 90766 | ChemSpiderID = 81951 | synonyms = PMMA; ''p''-Methoxymethamphetamine; ''para''-Methoxy-''N''-methylamphetamine; 4-Methoxy-''N''-methylamphetamine; 4-MMA; Methyl-MA; 4-PMDA

| IUPAC_name = 1-(4-Methoxyphenyl)-''N''-methylpropan-2-amine | C = 11 | H = 17 | N = 1 | O = 1 | SMILES = CC(CC1=CC=C(C=C1)OC)NC | SMILES2 = C1=CC(=CC=C1CC(C)NC)OC | StdInChI = 1S/C11H17NO/c1-9(12-2)8-10-4-6-11(13-3)7-5-10/h4-7,9,12H,8H2,1-3H3 | StdInChIKey = UGFMBZYKVQSQFX-UHFFFAOYSA-N }}

'''''para''-Methoxymethamphetamine''' ('''PMMA'''), also known as '''4-methoxy-''N''-methylamphetamine''' ('''4-MMA'''), is a serotonergic drug of the amphetamine family related to ''para''-methoxyamphetamine (PMA).<ref name="PiHKAL">{{CitePiHKAL}}</ref><ref name="ShulginManningDaley2011" /> It is the 4-methoxy analogue of methamphetamine.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" />

Little is known about the pharmacological properties, metabolism, and toxicity of PMMA; because of its structural similarity to PMA, which has known toxicity in humans, it is thought to have considerable potential to cause harmful side effects or death in overdose.<ref>{{cite journal | vauthors = Becker J, Neis P, Röhrich J, Zörntlein S | title = A fatal paramethoxymethamphetamine intoxication | journal = Legal Medicine | volume = 5 | pages = S138-41 | date = March 2003 | pmid = 12935573 | doi = 10.1016/s1344-6223(02)00096-2 | series = 5 | issue = Suppl 1 }}</ref> In the early 2010s, a number of deaths in users of the drug MDMA (ecstasy) were linked to misrepresented tablets and capsules of PMMA.<ref>{{Cite web | url = https://vancouversun.com/news/five-bc-deaths-linked-to-lethal-chemical-pmma| title = Five B.C. deaths linked to lethal chemical PMMA | work = vancouversun | date = 10 January 2012 | publisher = Vancouver Sun}}</ref>

PMMA is a serotonin–norepinephrine releasing agent (SNRA)<ref name="Glennon2017" /><ref name="GlennonYoung2011" /><ref name="Vekariya2012" /><ref name="MatsumotoMaenoKato2014" /> as well as potent monoamine oxidase inhibitor (MAOI).<ref name="Reyes-ParadaIturriaga-VasquezCassels2019" /> It has a reduced tendency to produce severe hyperthermia at low doses compared to PMA,<ref>{{Cite journal | vauthors = Glennon RA, Young R, Dukat M, Cheng Y | title = Initial characterization of PMMA as a discriminative stimulus | journal = Pharmacology, Biochemistry, and Behavior | volume = 57 | issue = 1–2 | pages = 151–8 | year = 1997 | pmid = 9164566 | doi = 10.1016/S0091-3057(96)00306-1 | s2cid = 28758326 }}</ref><ref>{{cite journal | vauthors = Rangisetty JB, Bondarev ML, Chang-Fong J, Young R, Glennon RA | title = PMMA-stimulus generalization to the optical isomers of MBDB and 3,4-DMA | journal = Pharmacology, Biochemistry, and Behavior | volume = 69 | issue = 1–2 | pages = 261–7 | year = 2001 | pmid = 11420094 | doi = 10.1016/S0091-3057(01)00530-5 | s2cid = 41953749 }}</ref> but at higher doses, side effects and risk of death become similar to those of PMA.<ref>{{cite journal | vauthors = Johansen SS, Hansen AC, Müller IB, Lundemose JB, Franzmann MB | title = Three fatal cases of PMA and PMMA poisoning in Denmark | journal = Journal of Analytical Toxicology | volume = 27 | issue = 4 | pages = 253–6 | year = 2003 | pmid = 12820749 | doi = 10.1093/jat/27.4.253 | s2cid = 42519181 | doi-access = free }}</ref>

The synthesis and effects of PMMA were described by American experimental chemist Alexander Shulgin in his book ''PiHKAL'', where it is referred to by the name "methyl-MA", as the ''N''-methylated form of 4-MA (PMA).<ref name="PiHKAL" />

==Use and effects== According to Alexander Shulgin in his book ''PiHKAL'' (''Phenethylamines I Have Known and Loved''), the effects of PMMA at a dose of 110{{nbsp}}mg orally included tachycardia, compulsive yawning, and nystagmus, among others.<ref name="PiHKAL" /> It was said to have some of the physical side effects of the entactogen MDMA but none of its central effects.<ref name="PiHKAL" /> No psychedelic-like effects were mentioned.<ref name="PiHKAL" />

==Pharmacology== ===Pharmacodynamics=== PMMA is a monoamine releasing agent (MRA).<ref name="Glennon2017" /><ref name="GlennonYoung2011" /><ref name="Vekariya2012" /><ref name="MatsumotoMaenoKato2014">{{cite journal | vauthors = Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, Nagao M, Aoki Y | title = 5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis | journal = Eur Neuropsychopharmacol | volume = 24 | issue = 8 | pages = 1362–1370 | date = August 2014 | pmid = 24862256 | doi = 10.1016/j.euroneuro.2014.04.009 | url = }}</ref> The drug's {{Abbrlink|EC50|half-maximal effective concentration}} values for induction of monoamine release in rat brain synaptosomes have been reported for the individual enantiomers of PMMA.<ref name="Glennon2017">{{cite journal | vauthors = Glennon RA | title = The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse | journal = J Med Chem | volume = 60 | issue = 7 | pages = 2605–2628 | date = April 2017 | pmid = 28244748 | pmc = 5824997 | doi = 10.1021/acs.jmedchem.7b00085 | url = | quote = Table 5. Action of MDMA, MDA, and PMMA as Releasing Agents at the Serotonin (SERT), Dopamine (DAT), and Norepinephrine (NET) Transporters18,59,60 [...] a Data, although from different publications, were obtained from the same laboratory.}}</ref><ref name="GlennonYoung2011">{{cite book | vauthors=Glennon RA, Young R | title=Drug Discrimination | chapter=Drug Discrimination and Mechanisms of Drug Action | publisher=Wiley | date=5 August 2011 | isbn=978-0-470-43352-2 | doi=10.1002/9781118023150.ch6 | pages=183–216 | quote=PMMA is a 5-HT releasing agent. S(+)PMMA is a potent releaser of 5-HT (EC50 = 41 nM) and NE (EC50 = 147 nM) with reduced activity as a releaser of DA (EC50 = 1,000 nM); the R(−)isomer of PMMA is a releaser of 5-HT (EC50 = 134 nM) with reduced potency for release of NE (EC50 = 1,600 nM) and DA (EC50 > 14,000 nM) (R.B. Rothman, unpublished data).}}</ref><ref name="Vekariya2012">{{cite thesis | vauthors = Vekariya R | degree = Master of Science | publisher = Virginia Commonwealth University | title=Towards Understanding the Mechanism of Action of Abused Cathinones | via = VCU Theses and Dissertations | date=2012 | doi=10.25772/AR93-7024 | page=}}</ref> In the case of (''S'')-PMMA, they were 41{{nbsp}}nM for serotonin, 147{{nbsp}}nM for norepinephrine, and 1,000{{nbsp}}nM for dopamine, whereas for (''R'')-PMMA, they were 134{{nbsp}}nM for serotonin, >14,000{{nbsp}}nM for norepinephrine, and 1,600{{nbsp}}nM for dopamine.<ref name="Glennon2017" /><ref name="GlennonYoung2011" /><ref name="Vekariya2012" /> Hence, PMMA appears to be a serotonin–norepinephrine releasing agent (SNRA) with weak effects on dopamine release.<ref name="Glennon2017" /><ref name="GlennonYoung2011" /><ref name="Vekariya2012" /><ref name="MatsumotoMaenoKato2014" /> The drug has been found to strongly release serotonin and to weakly release dopamine in the brain in rodents ''in vivo''.<ref name="MatsumotoMaenoKato2014" />

In addition to its MRA activity, PMMA is a potent monoamine oxidase A (MAO-A) inhibitor.<ref name="Reyes-ParadaIturriaga-VasquezCassels2019">{{cite journal | vauthors = Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK | title = Amphetamine Derivatives as Monoamine Oxidase Inhibitors | journal = Front Pharmacol | volume = 10 | issue = | article-number = 1590 | date = 2019 | pmid = 32038257 | pmc = 6989591 | doi = 10.3389/fphar.2019.01590 | doi-access = free | url = }}</ref> Its {{Abbrlink|IC50|half-maximal inhibitory concentration}} for MAO-A inhibition has been reported to be 1,700{{nbsp}}nM.<ref name="Reyes-ParadaIturriaga-VasquezCassels2019" /> This is several-fold less potent than the related agents ''para''-methoxyamphetamine (PMA) and 4-methylthioamphetamine (4-MTA).<ref name="Reyes-ParadaIturriaga-VasquezCassels2019" />

PMMA is said to lack affinity for the serotonin 5-HT2A receptor.<ref name="Glennon2017" /> In one study, its affinities were >20,000{{nbsp}}nM for the serotonin 5-HT1A receptor, 13,600{{nbsp}}nM for the serotonin 5-HT2A receptor, and >13,000{{nbsp}}nM for the serotonin 5-HT2C receptor.<ref name="SimmlerRickliHoener2014">{{cite journal | vauthors = Simmler LD, Rickli A, Hoener MC, Liechti ME | title = Monoamine transporter and receptor interaction profiles of a new series of designer cathinones | journal = Neuropharmacology | volume = 79 | issue = | pages = 152–160 | date = April 2014 | pmid = 24275046 | doi = 10.1016/j.neuropharm.2013.11.008 | url = }}</ref> On the other hand, PMMA shows much higher affinities for the mouse and rat trace amine-associated receptor 1 (TAAR1).<ref name="SimmlerRickliHoener2014" />

In rodents, PMMA produces hyperlocomotion, no changes in locomotor activity, and/or catatonia, and has effects that are said to differ from those of amphetamine-like stimulants.<ref name="ShulginManningDaley2011">{{cite book | vauthors = Shulgin A, Manning T, Daley P | title=The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher=Transform Press | location=Berkeley | volume=1 | year=2011 | isbn=978-0-9630096-3-0 | url=https://books.google.com/books?id=68-huAAACAAJ | access-date=2 November 2024}}</ref><ref name="Glennon1999">{{cite journal | vauthors = Glennon RA | title = Arylalkylamine drugs of abuse: an overview of drug discrimination studies | journal = Pharmacol Biochem Behav | volume = 64 | issue = 2 | pages = 251–256 | date = October 1999 | pmid = 10515299 | doi = 10.1016/s0091-3057(99)00045-3 | url = }}</ref><ref name="Glennon2017" /> It has been said not to have amphetamine-like properties in rodents even at high doses.<ref name="ShulginManningDaley2011" /><ref name="Glennon1999" /><ref name="Glennon2017" /> Similarly, PMMA did not substitute for the psychedelic DOM.<ref name="Glennon1999" /> On the other hand, in contrast to PMA, PMMA fully substituted for MDMA in drug discrimination tests in rodents, despite not having MDMA-like psychoactive effects in humans.<ref name="ShulginManningDaley2011" /><ref name="Glennon2017" /><ref name="PiHKAL" /> In any case, PMMA is said to lack the amphetamine- or stimulant-like properties of MDMA.<ref name="Glennon1999" /><ref name="Glennon2017" />

{| class="wikitable" style="font-size:small;" |+ {{Nowrap|Monoamine release of {{Abbrlink|PMMA|para-methoxymethamphetamine}} and related agents ({{Abbrlink|EC50|Half maximal effective concentration}}, nM)}} |- ! Compound !! {{abbrlink|5-HT|Serotonin}} !! {{abbrlink|NE|Norepinephrine}} !! {{abbrlink|DA|Dopamine}} !! Ref |- | ''d''-Amphetamine || 698–1,765 || 6.6–7.2 || 5.8–24.8 || <ref name="RothmanBaumannDersch2001">{{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 | url = }}</ref><ref name="BaumannPartillaLehner2013">{{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 | year = 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}</ref> |- | ''d''-Methamphetamine || 736–1,292 || 12.3–13.8 || 8.5–24.5 || <ref name="RothmanBaumannDersch2001" /><ref name="BaumannAyestasPartilla2012">{{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 | year = 2012 | pmid = 22169943 | pmc = 3306880 | doi = 10.1038/npp.2011.304 }}</ref> |- | 2-Methoxyamphetamine || {{Abbr|ND|No data}} || 473 || 1,478 || <ref name="Blough2008">{{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 }}</ref> |- | 3-Methoxyamphetamine || {{Abbr|ND|No data}} || 58.0 || 103 || <ref name="Blough2008" /> |- | ''para''-Methoxyamphetamine (PMA) || {{Abbr|ND|No data}} || 166 || 867 || <ref name="Blough2008" /><ref name="Vekariya2012" /> |- | {{Abbrlink|PMMA|para-Methoxymethamphetamine}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} |- | {{nbsp}}{{nbsp}}(''S'')-PMMA || 41 || 147 || 1,000 || <ref name="Glennon2017"/><ref name="GlennonYoung2011"/><ref name="Vekariya2012" /> |- | {{nbsp}}{{nbsp}}(''R'')-PMMA || 134 || >14,000 || 1,600 || <ref name="Glennon2017" /><ref name="GlennonYoung2011" /><ref name="Vekariya2012" /> |- | 4-Methylamphetamine (4-MA) || 53.4 || 22.2 || 44.1 || <ref name="WeeAndersonBaumann2005">{{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 }}</ref><ref name="Forsyth2012">{{cite thesis | vauthors = Forsyth AN | degree = Ph.D. | title=Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | publisher = University of New Orleans | via = ScholarWorks@UNO | date=22 May 2012 | url=https://scholarworks.uno.edu/td/1436/ | access-date=4 November 2024}}</ref><ref name="Blough2008" /> |- | 4-Methylmethamphetamine (4-MMA) || 67.4 || 66.9 || 41.3 || <ref name="SolisPartillaSakloth2017">{{cite journal | vauthors = Solis E, Partilla JS, Sakloth F, Ruchala I, Schwienteck KL, De Felice LJ, Eltit JM, Glennon RA, Negus SS, Baumann MH | 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 | date = September 2017 | pmid = 28530234 | pmc = 5561352 | doi = 10.1038/npp.2017.98 | url = }}</ref><ref name="Sakloth2015">{{cite thesis | vauthors = Sakloth F | degree = Ph.D. | title=Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action | work = Theses and Dissertations | publisher = Virginia Commonwealth University | via = VCU Scholars Compass | date=11 December 2015 | doi=10.25772/AY8R-PW77 | url=https://scholarscompass.vcu.edu/etd/4041/ | access-date=24 November 2024}}</ref> |- | ''para''-Chloroamphetamine (PCA) || 28.3 || 23.5–26.2 || 42.2–68.5 || <ref name="Forsyth2012" /><ref name="Blough2008" /><ref name="FitzgeraldGannonWalther2024">{{cite journal | vauthors = Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE | title = Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones | journal = Neuropharmacology | volume = 245 | issue = | article-number = 109827 | date = March 2024 | pmid = 38154512 | doi = 10.1016/j.neuropharm.2023.109827 | pmc = 10842458 | url = }}</ref><ref name="Nicole2022">{{cite thesis | vauthors = Nicole L | degree = Ph.D. | publisher = University of Arkansas for Medical Sciences | title=In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones | date=2022 | url=https://www.proquest.com/docview/2711781450 | access-date=5 December 2024 | id = {{ProQuest|2711781450}} | quote = FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]}}</ref> |- | ''para''-Chloromethamphetamine (PCMA) || 29.9 || 36.5 || 54.7 || <ref name="FitzgeraldGannonWalther2024" /><ref name="Nicole2022" /> |- | Methedrone (4-MeO-MC) || 120–195 || 111 || 506–881 || <ref name="BaumannWaltersNiello2018">{{cite journal | vauthors = Baumann MH, Walters HM, Niello M, Sitte HH | title = Neuropharmacology of Synthetic Cathinones | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 252 | issue = | pages = 113–142 | date = 2018 | pmid = 30406443 | pmc = 7257813 | doi = 10.1007/164_2018_178 | isbn = 978-3-030-10560-0 | url = }}</ref><ref name="BloughDeckerLandavazo2019">{{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 }}</ref><ref name="Shalabi2017">{{cite thesis | vauthors = Shalabi AR | degree = Ph.D. | publisher = Virginia Commonwealth University | title=Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters | work = Theses and Dissertations | via = VCU Scholars Compass | date=14 December 2017 | doi=10.25772/M4E1-3549 | url=https://scholarscompass.vcu.edu/etd/5176/ | access-date=24 November 2024}}</ref><ref name="WaltherShalabiBaumann2019">{{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 = }}</ref><ref name="BonanoBanksKolanos2015">{{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 = }}</ref> |- | Mephedrone (4-MMC) || 118.3–122 || 58–62.7 || 49.1–51 || <ref name="BaumannAyestasPartilla2012" /><ref name="BaumannPartillaLehner2013" /><ref name="BloughDeckerLandavazo2019" /><ref name="WaltherShalabiBaumann2019" /><ref name="BonanoBanksKolanos2015" /> |- | 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 assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. '''Refs:''' <ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = Eur J Pharmacol | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 | url = }}</ref><ref name="RothmanBaumann2006">{{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 | url = https://zenodo.org/record/1235860 }}</ref> |}

==Chemistry== ===Synthesis=== The chemical synthesis of PMMA has been described.<ref name="PiHKAL" />

===Detection=== PMMA can be detected with reagent testing kits.{{Citation needed|date=February 2026}}

===Analogues=== Analogues of PMMA include ''para''-methoxyamphetamine (PMA), ''para''-methoxy-''N''-ethylamphetamine (PMEA), 4-methylthio-''N''-methylamphetamine (4-MTMA), 4-methyl-''N''-methylamphetamine (4-MMA; mephedrine), ''para''-chloro-''N''-methylamphetamine (PCMA), 4-fluoro-''N''-methylamphetamine (4-FMA), methoxyphenamine (2-methoxy-''N''-methylamphetamine; OMMA), 3-methoxy-''N''-methylamphetamine (MMMA), and methedrone (4-methoxymethcathinone; bk-PMMA), among others.<ref name="PiHKAL" /><ref name="ShulginManningDaley2011" />

==History== PMMA was first described in the scientific literature by at least 1984.<ref name="Clark1984">{{cite journal | last=Clark | first=Cc | title=The Identification of Methoxy- N -Methylamphetamines | journal=Journal of Forensic Sciences | volume=29 | issue=4 | date=1 October 1984 | issn=0022-1198 | doi=10.1520/JFS11772J | pages=1056–1071 | url=https://dl.astm.org/jofs/article/29/4/1056/8311/The-Identification-of-Methoxy-N-Methylamphetamines | access-date=26 February 2026}}</ref>

==Society and culture== ===Recreational use=== [[File:PMMA tablets.jpg|thumb|200px|left|Tablets of PMMA recovered by the U.S. Drug Enforcement Administration]]

PMMA has been found in tablets and capsules of the MDMA sold as "ecstasy". A number of deaths have been attributed to tablets sold as ecstasy that contained other substances, such as PMMA's structural analog, PMA.<ref>{{cite journal | vauthors = Refstad S | title = Paramethoxyamphetamine (PMA) poisoning; a 'party drug' with lethal effects | journal = Acta Anaesthesiologica Scandinavica | volume = 47 | issue = 10 | pages = 1298–9 | date = November 2003 | pmid = 14616331 | doi = 10.1046/j.1399-6576.2003.00245.x | s2cid = 28006785 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lamberth PG, Ding GK, Nurmi LA | title = Fatal paramethoxy-amphetamine (PMA) poisoning in the Australian Capital Territory | journal = The Medical Journal of Australia | volume = 188 | issue = 7 | pages = 426 | date = April 2008 | pmid = 18393753 | doi = 10.5694/j.1326-5377.2008.tb01695.x | s2cid = 11987961 }}</ref> Death can occur when an ecstasy user believes they are consuming recreational doses of MDMA, when they are in fact consuming a lethal dose of another substance with similar effects. PMA is of particular concern because it not only causes a release of serotonin but also acts as a monoamine oxidase inhibitor (MAOI); if it is used in combination with MDMA or another MDMA-like substance, serotonin syndrome can result.<ref>{{cite journal | vauthors = Green AL, El Hait MA | title = p-Methoxyamphetamine, a potent reversible inhibitor of type-A monoamine oxidase in vitro and in vivo | journal = The Journal of Pharmacy and Pharmacology | volume = 32 | issue = 4 | pages = 262–6 | date = April 1980 | pmid = 6103055 | doi = 10.1111/j.2042-7158.1980.tb12909.x | s2cid = 42213032 }}</ref>

====Deaths==== In January 2011, the Norwegian Broadcasting Corporation reported that Norway had seen 12 deaths related to PMMA over the course of six months. In March 2011, Dutch media reported that there had been four deaths in the province of Limburg since November 2010.<ref>{{cite web|title=PMMA deaths in Holland|url=https://translate.google.com/translate?js=n&prev=_t&hl=en&ie=UTF-8&layout=2&eotf=1&sl=nl&tl=en&u=http%3A%2F%2Fwww.nu.nl%2Fbinnenland%2F2535695%2Fpinkpopgangers-moeten-uitkijken-met-xtc.html|publisher=nu.nl|access-date=8 June 2011}}</ref> In April 2011, Icelandic media reported the death of a young woman that may have been connected to PMMA.{{Citation needed|date=February 2012}}

In 2011, four deaths were recorded in Scotland as a result of ecstasy tablets which also contained PMMA.<ref>{{cite web | url = https://www.bbc.co.uk/news/uk-scotland-16224849 | title = Warning over ecstasy pills that raise overdose risk | date = 16 December 2011 | publisher = BBC News | url-status = live | archive-url = https://web.archive.org/web/20120425143045/http://www.bbc.co.uk/news/uk-scotland-16224849 | archive-date = 25 April 2012}}</ref>

In January 2012, a number of ecstasy-related deaths in Canada in the previous year were linked to PMMA overdoses. In the single year, approximately 45 exposures occurred, resulting in 21 deaths. Cases were centred primarily in Calgary and Vancouver.<ref>{{cite web | url = https://theprovince.com/life/Rare+chemical+found+fatal+ecstasy/5998482/story.html | archive-url = https://web.archive.org/web/20120117004747/http://www.theprovince.com/life/Rare+chemical+found+fatal+ecstasy/5998482/story.html | url-status = dead | archive-date = 17 January 2012 | publisher = The Province | date = 15 January 2012 | access-date = 12 January 2012 | title = Rare chemical found in fatal ecstasy}}</ref><ref>{{cite web | url = http://www.nantonnews.com/ArticleDisplay.aspx?e=3446181 | publisher = Nanton News | title = Overdose death investigated | date = 24 January 2012 }}{{Dead link|date=June 2025 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref>{{cite web |url=https://calgaryherald.com/news/alberta/Update+Seized+substances+sent+testing+after+suspected+overdose+SAIT/6037966/story.html |work=Calgary Herald|title=Seized substances sent for testing after suspected overdose |access-date=24 January 2012 |url-status=dead |archive-url=https://web.archive.org/web/20120127040640/http://www.calgaryherald.com/news/alberta/Update+Seized+substances+sent+testing+after+suspected+overdose+SAIT/6037966/story.html |archive-date=27 January 2012}}</ref><ref>{{cite web | url = https://vancouversun.com/touch/story.html?id=5980841 | title = Tainted ecstasy linked to five Calgary deaths could be from B.C. | publisher = Vancouver Sun | date = 12 January 2012 | access-date = 12 January 2012 | url-status = live | archive-url = https://web.archive.org/web/20130304085614/http://www.vancouversun.com/touch/story.html?id=5980841 | archive-date = 4 March 2013}}</ref><ref>{{cite web |title=Authorities renew warning about street drugs |url=http://newsroom.calgary.ca/pr/calgary/authorities-renew-warning-about-221684.aspx |publisher=The City of Calgary Newsroom |access-date=11 January 2012 |url-status=dead |archive-url=https://web.archive.org/web/20120115072845/http://newsroom.calgary.ca/pr/calgary/authorities-renew-warning-about-221684.aspx |archive-date=15 January 2012}}</ref><ref>{{cite web|title=Ecstasy laced with meth in overdose cases|url=https://www.cbc.ca/news/canada/calgary/ecstasy-laced-with-meth-blamed-in-5-calgary-deaths-1.1162942|access-date=12 January 2012|url-status=live|archive-url=https://web.archive.org/web/20120112020050/http://www.cbc.ca/news/canada/calgary/story/2012/01/11/calgary-ecstasy-meth-deaths.html|archive-date=12 January 2012}}</ref>

In September 2012, the deaths of two men in County Cork, Ireland, have been linked to PMMA overdoses.<ref>{{cite web | url = http://www.irishtimes.com/newspaper/ireland/2012/0913/1224323959421.html | title = Dangerous drug linked to Kinsale deaths | work = Irish Independent| date = 13 September 2012 | access-date = 13 September 2012 | url-status = live | archive-url = https://web.archive.org/web/20120913021332/http://www.irishtimes.com/newspaper/ireland/2012/0913/1224323959421.html | archive-date = 13 September 2012}}</ref> In the same month, the death of a man in Queensland, Australia was attributed to PMMA.<ref>{{cite web | url = http://www.news.com.au/national/queensland-police-investigate-three-deaths-linked-to-poison-pill-ecstasy-overdoses/story-fndo4ckr-1226468070006 | title = Queensland Police investigate three deaths linked to 'poison pill' ecstasy overdoses | publisher = news.com.au | date = 9 September 2012 | access-date = 30 September 2012}}</ref>

In June 2013 a PMMA-related death occurred in the Dutch city of 's-Hertogenbosch.<ref>{{cite web|title=Den Bosch issues a warning for dangerous XTC-pills|url=https://translate.google.com/translate?js=n&prev=_t&hl=en&ie=UTF-8&layout=2&eotf=1&sl=nl&tl=en&u=http%3A%2F%2Fwww.nu.nl%2Fbinnenland%2F3498768%2Fbosch-waarschuwt-gevaarlijke-xtc-pillen.html|publisher=nu.nl|access-date=12 June 2013}}</ref> Two months later, In August 2013, another possibly PMMA-related death occurred in the nearby town of Sliedrecht.<ref>{{cite web | url=http://www.hetkompassliedrecht.nl/lokaal/tiener_overleden_aan_drugssliedrecht__in_sliedrecht_is_zondag_een_meisje_van_zestien_jaar_overleden_2526291.html | title=Tiener overleden aan drugs | access-date=30 August 2013 | url-status=dead | archive-url=https://web.archive.org/web/20130829114721/http://www.hetkompassliedrecht.nl/lokaal/tiener_overleden_aan_drugssliedrecht__in_sliedrecht_is_zondag_een_meisje_van_zestien_jaar_overleden_2526291.html | archive-date=29 August 2013 }}</ref><ref>{{cite web|url=http://www.misdaadjournalist.nl/2013/08/naomi-16-dood-door-roze-xtc-pil/|title=Naomi (16): dood door roze xtc-pil|access-date=26 August 2013|url-status=live|archive-url=https://web.archive.org/web/20130829063908/http://www.misdaadjournalist.nl/2013/08/naomi-16-dood-door-roze-xtc-pil/|archive-date=29 August 2013|date=26 August 2013}}</ref><ref>{{cite web |url=http://www.camilleri.nl/2013/08/waarschuwing-dodelijke-xtc-in-omloop/ |title=Waarschuwing: dodelijke 'XTC' in omloop |access-date=26 August 2013 |url-status=dead |archive-url=https://web.archive.org/web/20130829040737/http://www.camilleri.nl/2013/08/waarschuwing-dodelijke-xtc-in-omloop |archive-date=29 August 2013}}</ref>

In January 2015 in the UK four people died, suspected of taking ecstasy containing PMMA.<ref>{{cite news|url=https://www.bbc.co.uk/news/uk-england-30671300|title=Man charged after ecstasy deaths|date=15 May 2018|url-status=live|archive-url=https://web.archive.org/web/20180513000438/http://www.bbc.co.uk/news/uk-england-30671300|archive-date=13 May 2018|work=BBC News}}</ref> In the same month, in Sweden, another man died from ecstasy laced with PMMA.<ref>{{cite web | url=http://www.aftonbladet.se/nyheter/article20103807.ab | title=Varning för livsfarlig ecstasy | date=2 January 2015 | access-date=4 January 2015 | language=Swedish | url-status=live | archive-url=https://web.archive.org/web/20150105014657/http://www.aftonbladet.se/nyheter/article20103807.ab | archive-date=5 January 2015}}</ref>

In May 2015 a young woman died in Dublin, Ireland, after taking what is suspected to be PMMA.<ref>{{cite web|url=http://www.irishexaminer.com/breakingnews/ireland/dublin-student-dies-after-taking-pmma-tablets-in-nightclub-677531.html|title=Dublin student dies after taking PMMA tablets in nightclub|date=17 May 2015|website=irishexaminer.com|url-status=live|archive-url=https://web.archive.org/web/20150518114230/http://www.irishexaminer.com/breakingnews/ireland/dublin-student-dies-after-taking-pmma-tablets-in-nightclub-677531.html|archive-date=18 May 2015}}</ref>

In April 2016 four young Argentines and one Uruguayan died during a massive rave called "Time Warp" in Buenos Aires and five more were hospitalized. PMMA was found in their bodies. <ref>{{cite news|url=http://www.lanacion.com.ar/1890177-conmocion-por-la-muerte-de-cinco-jovenes-en-una-fiesta-electronica|title=Conmoción por la muerte de cinco jóvenes en una fiesta electrónica | trans-title = Shock over the death of five young people at an electronic party |newspaper=La Nación|language=Spanish|date=17 April 2016|url-status=live|archive-url=https://web.archive.org/web/20160419003155/http://www.lanacion.com.ar/1890177-conmocion-por-la-muerte-de-cinco-jovenes-en-una-fiesta-electronica|archive-date=19 April 2016| vauthors = Himitian E }}</ref>

===Legal status=== ====United Kingdom==== PMMA is controlled as a Schedule 1, Class A drug in the UK.{{citation needed|date=July 2016}}

====United States==== On June 25, 2021, the DEA finalized a rule placing PMMA on the Controlled Substance Act federal Schedule as a Schedule I substance effective July 26, 2021.<ref name="DEA Schedules PMMA as Schedule I">{{cite web|url=https://www.federalregister.gov/documents/2021/06/25/2021-13460/schedules-of-controlled-substances-placement-of-para-methoxymethamphetamine-pmma-in-schedule-i |title=Schedules of Controlled Substances: Placement of para-Methoxymethamphetamine (PMMA) in Schedule I |website=federalregister.gov |date=June 25, 2021}}</ref>

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/130 PMMA - Isomer Design] * [https://psychonautwiki.org/wiki/PMMA PMMA - PsychonautWiki] * [https://erowid.org/chemicals/pmma/pmma.shtml PMMA - Erowid] * [https://www.erowid.org/library/books_online/pihkal/pihkal130.shtml METHYL-MA (PMMA) - PiHKAL - Erowid] * [https://isomerdesign.com/pihkal/read/pk/130 METHYL-MA (PMMA) - PiHKAL - Isomer Design]

Category:Designer drugs Category:Methamphetamines Category:4-Methoxyphenyl compounds Category:Methoxyphenethylamines Category:Monoamine oxidase inhibitors Category:PiHKAL Category:Serotonin-norepinephrine releasing agents Category:TAAR1 modulators