Para-Methoxymethamphetamine Explained

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). It is the 4-methoxy analogue of methamphetamine. 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.[1] In the early 2010s, a number of deaths in users of the drug MDMA were linked to misrepresented tablets and capsules of PMMA.[2]

PMMA is a serotonin–norepinephrine releasing agent (SNRA) as well as potent monoamine oxidase inhibitor (MAOI). Its effects in humans are reputedly similar to those of PMA, but slightly more empathogenic in nature. It has a reduced tendency to produce severe hyperthermia at low dosages,[3] [4] but at higher dosages side effects and risk of death become similar to those of PMA.[5]

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). Shulgin reported that PMMA produces an increase in blood pressure and in heart rate, at doses above 100 mg, but causes no psychoactive effects at these levels.

Pharmacology

Pharmacodynamics

PMMA is a monoamine releasing agent (MRA).[6] The drug's values for induction of monoamine release in rat brain synaptosomes have been reported for the individual enantiomers of PMMA.[7] [8] [9] In the case of (S)-PMMA, they are 41nM for serotonin, 147nM for norepinephrine, and 1,000nM for dopamine, whereas for (R)-PMMA, they are 134nM for serotonin, >14,000nM for norepinephrine, and 1,600nM for dopamine. Hence, PMMA appears to be a serotonin–norepinephrine releasing agent (SNRA) with weak effects on dopamine. The drug has been found to strongly release serotonin and to weakly release dopamine in the brain in rodents in vivo.

In addition to its MRA activity, PMMA is a potent monoamine oxidase A (MAO-A) inhibitor.[10] Its for MAO-A inhibition has been reported to be 1,700nM. This is several-fold less potent than the related agents para-methoxyamphetamine (PMA) and 4-methylthioamphetamine (4-MTA).

Compound Ref
698–1,765 6.6–7.2 5.8–24.8 [11] [12]
736–1,292 12.3–13.8 8.5–24.5 [13]
473 1,478 [14]
58.0 103
para-Methoxyamphetamine (PMA) 166 867 [15]
(S)-PMMA 41 147 1,000 [16] [17]
(R)-PMMA 134 >14,000 1,600
4-Methylamphetamine (4-MA) 53.4 22.2 44.1 [18] [19]
4-Methylmethamphetamine (4-MMA) 67.4 66.9 41.3 [20] [21]
para-Chloroamphetamine (PCA) 28.3 23.5–26.2 42.2–68.5 [22] [23]
para-Chloromethamphetamine (PCMA) 29.9 36.5 54.7
Methedrone (4-MeO-MC) 120–195 111 506–881 [24] [25] [26] [27] [28]
Mephedrone (4-MMC) 118.3–122 58–62.7 49.1–51
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: [29] [30]

Recreational use

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.[31] [32] 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.[33]

PMMA can be detected with reagent testing kits.

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.[34] In April 2011, Icelandic media reported the death of a young woman that may have been connected to PMMA.

In 2011, four deaths were recorded in Scotland as a result of ecstasy tablets which also contained PMMA.[35]

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.[36] [37] [38] [39] [40] [41]

In September 2012, the deaths of two men in County Cork, Ireland, have been linked to PMMA overdoses.[42] In the same month, the death of a man in Queensland, Australia was attributed to PMMA.[43]

In June 2013 a PMMA-related death occurred in the Dutch city of 's-Hertogenbosch.[44] Two months later, In August 2013, another possibly PMMA-related death occurred in the nearby town of Sliedrecht.[45] [46] [47]

In January 2015 in the UK four people died, suspected of taking ecstasy containing PMMA.[48] In the same month, in Sweden, another man died from ecstasy laced with PMMA.[49]

In May 2015 a young woman died in Dublin, Ireland, after taking what is suspected to be PMMA.[50]

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.[51]

Legal status

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.[52]

United Kingdom

PMMA is controlled as a Schedule 1, Class A drug in the UK.

See also

External links

Notes and References

  1. Becker J, Neis P, Röhrich J, Zörntlein S . A fatal paramethoxymethamphetamine intoxication . Legal Medicine . 5 . S138-41 . March 2003 . 12935573 . 10.1016/s1344-6223(02)00096-2 . 5 . Suppl 1 .
  2. Web site: Five B.C. deaths linked to lethal chemical PMMA . 10 January 2012 . Vancouver Sun.
  3. Glennon RA, Young R, Dukat M, Cheng Y . Initial characterization of PMMA as a discriminative stimulus . Pharmacology, Biochemistry, and Behavior . 57 . 1–2 . 151–8 . 1997 . 9164566 . 10.1016/S0091-3057(96)00306-1 . 28758326 .
  4. Rangisetty JB, Bondarev ML, Chang-Fong J, Young R, Glennon RA . PMMA-stimulus generalization to the optical isomers of MBDB and 3,4-DMA . Pharmacology, Biochemistry, and Behavior . 69 . 1–2 . 261–7 . 2001 . 11420094 . 10.1016/S0091-3057(01)00530-5 . 41953749 .
  5. Johansen SS, Hansen AC, Müller IB, Lundemose JB, Franzmann MB . Three fatal cases of PMA and PMMA poisoning in Denmark . Journal of Analytical Toxicology . 27 . 4 . 253–6 . 2003 . 12820749 . 10.1093/jat/27.4.253 . 42519181 . free .
  6. Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, Nagao M, Aoki Y . 5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis . Eur Neuropsychopharmacol . 24 . 8 . 1362–1370 . August 2014 . 24862256 . 10.1016/j.euroneuro.2014.04.009 .
  7. Glennon RA . The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse . J Med Chem . 60 . 7 . 2605–2628 . April 2017 . 28244748 . 5824997 . 10.1021/acs.jmedchem.7b00085 . 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..
  8. Book: Glennon RA, Young R . Drug Discrimination . Drug Discrimination and Mechanisms of Drug Action . Wiley . 5 August 2011 . 978-0-470-43352-2 . 10.1002/9781118023150.ch6 . 183–216 . 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)..
  9. Vekariya . Rakesh . Towards Understanding the Mechanism of Action of Abused Cathinones . VCU Theses and Dissertations . 2012 . 10.25772/AR93-7024 .
  10. Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK . Amphetamine Derivatives as Monoamine Oxidase Inhibitors . Front Pharmacol . 10 . 1590 . 2019 . 32038257 . 6989591 . 10.3389/fphar.2019.01590 . free .
  11. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS . Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin . Synapse . 39 . 1 . 32–41 . January 2001 . 11071707 . 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 .
  12. 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 . Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products . Neuropsychopharmacology . 38 . 4 . 552–562 . 2013 . 23072836 . 3572453 . 10.1038/npp.2012.204 .
  13. Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV . The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue . Neuropsychopharmacology . 37 . 5 . 1192–1203 . 2012 . 22169943 . 3306880 . 10.1038/npp.2011.304 .
  14. Book: Blough B . Dopamine-releasing agents . Trudell ML, Izenwasser S . Dopamine Transporters: Chemistry, Biology and Pharmacology . 305–320 . July 2008 . 978-0-470-11790-3 . 181862653 . OL18589888W . Wiley . Hoboken [NJ] . https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf .
  15. Vekariya . Rakesh . Towards Understanding the Mechanism of Action of Abused Cathinones . VCU Theses and Dissertations . 2012 . 10.25772/AR93-7024 .
  16. Glennon RA . The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse . J Med Chem . 60 . 7 . 2605–2628 . April 2017 . 28244748 . 5824997 . 10.1021/acs.jmedchem.7b00085 . 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..
  17. Book: Glennon RA, Young R . Drug Discrimination . Drug Discrimination and Mechanisms of Drug Action . Wiley . 5 August 2011 . 978-0-470-43352-2 . 10.1002/9781118023150.ch6 . 183–216 . 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)..
  18. Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL . Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs . The Journal of Pharmacology and Experimental Therapeutics . 313 . 2 . 848–854 . May 2005 . 15677348 . 10.1124/jpet.104.080101 . 12135483 .
  19. Forsyth . Andrea N . Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines . ScholarWorks@UNO . 22 May 2012 . 4 November 2024.
  20. Solis E, Partilla JS, Sakloth F, Ruchala I, Schwienteck KL, De Felice LJ, Eltit JM, Glennon RA, Negus SS, Baumann MH . N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability . Neuropsychopharmacology . 42 . 10 . 1950–1961 . September 2017 . 28530234 . 5561352 . 10.1038/npp.2017.98 .
  21. Sakloth . Farhana . Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action . VCU Scholars Compass . 11 December 2015 . 10.25772/AY8R-PW77 . 24 November 2024.
  22. Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE . Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones . Neuropharmacology . 245 . 109827 . March 2024 . 38154512 . 10.1016/j.neuropharm.2023.109827 . 10842458 . March 1, 2025 .
  23. Web site: Nicole . Lauren . In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones . 2022 . ProQuest . 5 December 2024 . 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. [...].
  24. Baumann MH, Walters HM, Niello M, Sitte HH . Neuropharmacology of Synthetic Cathinones . Handb Exp Pharmacol . Handbook of Experimental Pharmacology . 252 . 113–142 . 2018 . 30406443 . 7257813 . 10.1007/164_2018_178 . 978-3-030-10560-0 .
  25. Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB . The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes . Psychopharmacology . 236 . 3 . 915–924 . March 2019 . 30341459 . 6475490 . 10.1007/s00213-018-5063-9 .
  26. Shalabi . Abdelrahman R. . Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters . VCU Scholars Compass . 14 December 2017 . 10.25772/M4E1-3549 . 24 November 2024.
  27. Walther D, Shalabi AR, Baumann MH, Glennon RA . Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents . ACS Chem Neurosci . 10 . 1 . 740–745 . January 2019 . 30354055 . 8269283 . 10.1021/acschemneuro.8b00524 .
  28. Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, Cozzi NV, Partilla JS, Baumann MH, Negus SS . Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues . Br J Pharmacol . 172 . 10 . 2433–2444 . May 2015 . 25438806 . 4409897 . 10.1111/bph.13030 .
  29. Rothman RB, Baumann MH . Monoamine transporters and psychostimulant drugs . Eur J Pharmacol . 479 . 1–3 . 23–40 . October 2003 . 14612135 . 10.1016/j.ejphar.2003.08.054 .
  30. Rothman RB, Baumann MH . Therapeutic potential of monoamine transporter substrates . Current Topics in Medicinal Chemistry . 6 . 17 . 1845–1859 . 2006 . 17017961 . 10.2174/156802606778249766 .
  31. Refstad S . Paramethoxyamphetamine (PMA) poisoning; a 'party drug' with lethal effects . Acta Anaesthesiologica Scandinavica . 47 . 10 . 1298–9 . November 2003 . 14616331 . 10.1046/j.1399-6576.2003.00245.x . 28006785 . free .
  32. Lamberth PG, Ding GK, Nurmi LA . Fatal paramethoxy-amphetamine (PMA) poisoning in the Australian Capital Territory . The Medical Journal of Australia . 188 . 7 . 426 . April 2008 . 18393753 . 10.5694/j.1326-5377.2008.tb01695.x . 11987961 .
  33. Green AL, El Hait MA . p-Methoxyamphetamine, a potent reversible inhibitor of type-A monoamine oxidase in vitro and in vivo . The Journal of Pharmacy and Pharmacology . 32 . 4 . 262–6 . April 1980 . 6103055 . 10.1111/j.2042-7158.1980.tb12909.x . 42213032 .
  34. Web site: PMMA deaths in Holland. nu.nl. 8 June 2011.
  35. Web site: Warning over ecstasy pills that raise overdose risk . 16 December 2011 . BBC News . live . https://web.archive.org/web/20120425143045/http://www.bbc.co.uk/news/uk-scotland-16224849 . 25 April 2012.
  36. Web site: Rare chemical found in fatal ecstasy. https://web.archive.org/web/20120117004747/http://www.theprovince.com/life/Rare+chemical+found+fatal+ecstasy/5998482/story.html . dead . 17 January 2012 . The Province . 15 January 2012 . 12 January 2012 .
  37. Web site: Overdose death investigated . Nanton News . 24 January 2012.
  38. Web site: Seized substances sent for testing after suspected overdose . Calgary Herald. 24 January 2012 . dead . https://web.archive.org/web/20120127040640/http://www.calgaryherald.com/news/alberta/Update+Seized+substances+sent+testing+after+suspected+overdose+SAIT/6037966/story.html . 27 January 2012.
  39. Web site: Tainted ecstasy linked to five Calgary deaths could be from B.C. . Vancouver Sun . 12 January 2012 . 12 January 2012 . live . https://web.archive.org/web/20130304085614/http://www.vancouversun.com/touch/story.html?id=5980841 . 4 March 2013.
  40. Web site: Authorities renew warning about street drugs . The City of Calgary Newsroom . 11 January 2012 . dead . https://web.archive.org/web/20120115072845/http://newsroom.calgary.ca/pr/calgary/authorities-renew-warning-about-221684.aspx . 15 January 2012.
  41. Web site: Ecstasy laced with meth in overdose cases. 12 January 2012. live. https://web.archive.org/web/20120112020050/http://www.cbc.ca/news/canada/calgary/story/2012/01/11/calgary-ecstasy-meth-deaths.html. 12 January 2012.
  42. Web site: Dangerous drug linked to Kinsale deaths . Irish Independent. 13 September 2012 . 13 September 2012 . live . https://web.archive.org/web/20120913021332/http://www.irishtimes.com/newspaper/ireland/2012/0913/1224323959421.html . 13 September 2012.
  43. Web site: Queensland Police investigate three deaths linked to 'poison pill' ecstasy overdoses . news.com.au . 9 September 2012 . 30 September 2012.
  44. Web site: Den Bosch issues a warning for dangerous XTC-pills. nu.nl. 12 June 2013.
  45. Web site: Tiener overleden aan drugs . 30 August 2013 . dead . 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 . 29 August 2013 .
  46. Web site: Naomi (16): dood door roze xtc-pil. 26 August 2013. live. https://web.archive.org/web/20130829063908/http://www.misdaadjournalist.nl/2013/08/naomi-16-dood-door-roze-xtc-pil/. 29 August 2013. 26 August 2013.
  47. Web site: Waarschuwing: dodelijke 'XTC' in omloop . 26 August 2013 . dead . https://web.archive.org/web/20130829040737/http://www.camilleri.nl/2013/08/waarschuwing-dodelijke-xtc-in-omloop . 29 August 2013.
  48. News: Man charged after ecstasy deaths. 15 May 2018. live. https://web.archive.org/web/20180513000438/http://www.bbc.co.uk/news/uk-england-30671300. 13 May 2018. BBC News.
  49. Web site: Varning för livsfarlig ecstasy . 2 January 2015 . 4 January 2015 . Swedish . live . https://web.archive.org/web/20150105014657/http://www.aftonbladet.se/nyheter/article20103807.ab . 5 January 2015.
  50. Web site: Dublin student dies after taking PMMA tablets in nightclub. 17 May 2015. irishexaminer.com. live. https://web.archive.org/web/20150518114230/http://www.irishexaminer.com/breakingnews/ireland/dublin-student-dies-after-taking-pmma-tablets-in-nightclub-677531.html. 18 May 2015.
  51. News: Conmoción por la muerte de cinco jóvenes en una fiesta electrónica. La Nación. Spanish. 17 April 2016. live. https://web.archive.org/web/20160419003155/http://www.lanacion.com.ar/1890177-conmocion-por-la-muerte-de-cinco-jovenes-en-una-fiesta-electronica. 19 April 2016. Himitian. Evangelina.
  52. Web site: Schedules of Controlled Substances: Placement of para-Methoxymethamphetamine (PMMA) in Schedule I . federalregister.gov . June 25, 2021.

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