Para-Methoxymethamphetamine

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para-Methoxymethamphetamine
4-Methoxymethamphetamine.svg
Clinical data
Other namesPMMA; p-Methoxymethamphetamine; para-Methoxy-N-methylamphetamine; 4-Methoxy-N-methylamphetamine; 4-MMA; Methyl-MA; 4-PMDA
Drug class Serotonin–norepinephrine releasing agent; Monoamine oxidase inhibitor
Legal status
Legal status
Identifiers
  • 1-(4-Methoxyphenyl)-N-methylpropan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.040.818 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H17NO
Molar mass 179.263 g·mol−1
3D model (JSmol)
  • CC(CC1=CC=C(C=C1)OC)NC

  • C1=CC(=CC=C1CC(C)NC)OC
  • InChI=1S/C11H17NO/c1-9(12-2)8-10-4-6-11(13-3)7-5-10/h4-7,9,12H,8H2,1-3H3
  • Key:UGFMBZYKVQSQFX-UHFFFAOYSA-N
   (verify)

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. [2] In the early 2010s, a number of deaths in users of the drug MDMA were linked to misrepresented tablets and capsules of PMMA. [3]

Contents

PMMA is a serotonin–norepinephrine releasing agent (SNRA) [4] [5] [6] [7] as well as potent monoamine oxidase inhibitor (MAOI). [8] Its effects in humans are reputedly similar to those of PMA, but slightly more empathogenic in nature.[ medical citation needed ] It has a reduced tendency to produce severe hyperthermia at low dosages, [9] [10] but at higher dosages side effects and risk of death become similar to those of PMA. [11]

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). [4] [5] [6] [7] The drug's EC50 Tooltip half-maximal effective concentration values for induction of monoamine release in rat brain synaptosomes have been reported for the individual enantiomers of PMMA. [4] [5] [6] In the case of (S)-PMMA, they are 41 nM for serotonin, 147 nM for norepinephrine, and 1,000 nM for dopamine, whereas for (R)-PMMA, they are 134 nM for serotonin, >14,000 nM for norepinephrine, and 1,600 nM for dopamine. [4] [5] [6] Hence, PMMA appears to be a serotonin–norepinephrine releasing agent (SNRA) with weak effects on dopamine. [4] [5] [6] [7] The drug has been found to strongly release serotonin and to weakly release dopamine in the brain in rodents in vivo . [7]

In addition to its MRA activity, PMMA is a potent monoamine oxidase A (MAO-A) inhibitor. [8] Its IC50 Tooltip half-maximal inhibitory concentration for MAO-A inhibition has been reported to be 1,700 nM. [8] This is several-fold less potent than the related agents para-methoxyamphetamine (PMA) and 4-methylthioamphetamine (4-MTA). [8]

Monoamine release of PMMA Tooltip para-methoxymethamphetamine and related agents (EC50 Tooltip Half maximal effective concentration, nM)
Compound 5-HT Tooltip Serotonin NE Tooltip Norepinephrine DA Tooltip DopamineRef
d-Amphetamine 698–1,7656.6–7.25.8–24.8 [12] [13]
d-Methamphetamine 736–1,29212.3–13.88.5–24.5 [12] [14]
2-Methoxyamphetamine ND4731,478 [15]
3-Methoxyamphetamine ND58.0103 [15]
para-Methoxyamphetamine (PMA)ND166867 [15] [6]
PMMA Tooltip para-MethoxymethamphetamineNDNDNDND
  (S)-PMMA411471,000 [4] [5] [6]
  (R)-PMMA134>14,0001,600 [4] [5] [6]
4-Methylamphetamine (4-MA)53.422.244.1 [16] [17] [15]
4-Methylmethamphetamine (4-MMA)67.466.941.3 [18] [19]
para-Chloroamphetamine (PCA)28.323.5–26.242.2–68.5 [17] [15] [20] [21]
para-Chloromethamphetamine (PCMA)29.936.554.7 [20] [21]
Methedrone (4-MeO-MC)120–195111506–881 [22] [23] [24] [25] [26]
Mephedrone (4-MMC)118.3–12258–62.749.1–51 [14] [13] [23] [25] [26]
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: [27] [28]

Recreational use

Tablets of PMMA recovered by the U.S. Drug Enforcement Administration PMMA tablets.jpg
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. [29] [30] 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. [31]

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

In 2011, four deaths were recorded in Scotland as a result of ecstasy tablets which also contained PMMA. [33]

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. [34] [35] [36] [37] [38] [39]

In September 2012, the deaths of two men in County Cork, Ireland, have been linked to PMMA overdoses. [40] In the same month, the death of a man in Queensland, Australia was attributed to PMMA. [41]

In June 2013 a PMMA-related death occurred in the Dutch city of 's-Hertogenbosch. [42] Two months later, In August 2013, another possibly PMMA-related death occurred in the nearby town of Sliedrecht. [43] [44] [45]

In January 2015 in the UK four people died, suspected of taking ecstasy containing PMMA. [46] In the same month, in Sweden, another man died from ecstasy laced with PMMA. [47]

In May 2015 a young woman died in Dublin, Ireland, after taking what is suspected to be PMMA. [48]

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. [49]

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. [50]

United Kingdom

PMMA is controlled as a Schedule 1, Class A drug in the UK.[ citation needed ]

See also

References

  1. ↑ Anvisa (24 July 2023). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 25 July 2023). Archived from the original on 27 August 2023. Retrieved 27 August 2023.
  2. ↑ Becker J, Neis P, Röhrich J, Zörntlein S (March 2003). "A fatal paramethoxymethamphetamine intoxication". Legal Medicine. 5. 5 (Suppl 1): S138-41. doi:10.1016/s1344-6223(02)00096-2. PMID   12935573.
  3. ↑ "Five B.C. deaths linked to lethal chemical PMMA". Vancouver Sun. 10 January 2012.
  4. 1 2 3 4 5 6 7 Glennon RA (April 2017). "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. doi:10.1021/acs.jmedchem.7b00085. PMC   5824997 . PMID   28244748. 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.
  5. 1 2 3 4 5 6 7 Glennon RA, Young R (5 August 2011). "Drug Discrimination and Mechanisms of Drug Action". Drug Discrimination. Wiley. pp. 183–216. doi:10.1002/9781118023150.ch6. ISBN   978-0-470-43352-2. 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).
  6. 1 2 3 4 5 6 7 8 Vekariya, Rakesh (2012). "Towards Understanding the Mechanism of Action of Abused Cathinones". VCU Theses and Dissertations. doi:10.25772/AR93-7024.
  7. 1 2 3 4 Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, Nagao M, Aoki Y (August 2014). "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. doi:10.1016/j.euroneuro.2014.04.009. PMID   24862256.
  8. 1 2 3 4 Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol. 10: 1590. doi: 10.3389/fphar.2019.01590 . PMC   6989591 . PMID   32038257.
  9. ↑ Glennon RA, Young R, Dukat M, Cheng Y (1997). "Initial characterization of PMMA as a discriminative stimulus". Pharmacology, Biochemistry, and Behavior. 57 (1–2): 151–8. doi:10.1016/S0091-3057(96)00306-1. PMID   9164566. S2CID   28758326.
  10. ↑ Rangisetty JB, Bondarev ML, Chang-Fong J, Young R, Glennon RA (2001). "PMMA-stimulus generalization to the optical isomers of MBDB and 3,4-DMA". Pharmacology, Biochemistry, and Behavior. 69 (1–2): 261–7. doi:10.1016/S0091-3057(01)00530-5. PMID   11420094. S2CID   41953749.
  11. ↑ Johansen SS, Hansen AC, Müller IB, Lundemose JB, Franzmann MB (2003). "Three fatal cases of PMA and PMMA poisoning in Denmark". Journal of Analytical Toxicology. 27 (4): 253–6. doi: 10.1093/jat/27.4.253 . PMID   12820749. S2CID   42519181.
  12. 1 2 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707.
  13. 1 2 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 (2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC   3572453 . PMID   23072836.
  14. 1 2 Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC   3306880 . PMID   22169943.
  15. 1 2 3 4 5 Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. OCLC   181862653. OL   18589888W.
  16. ↑ Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (May 2005). "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. doi:10.1124/jpet.104.080101. PMID   15677348. S2CID   12135483.
  17. 1 2 Forsyth, Andrea N (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  18. ↑ Solis E, Partilla JS, Sakloth F, Ruchala I, Schwienteck KL, De Felice LJ, Eltit JM, Glennon RA, Negus SS, Baumann MH (September 2017). "N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability". Neuropsychopharmacology. 42 (10): 1950–1961. doi:10.1038/npp.2017.98. PMC   5561352 . PMID   28530234.
  19. ↑ Sakloth, Farhana (11 December 2015). Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action. VCU Scholars Compass (Thesis). doi:10.25772/AY8R-PW77 . Retrieved 24 November 2024.
  20. 1 2 Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE (March 2024). "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology. 245: 109827. doi:10.1016/j.neuropharm.2023.109827. PMC  10842458. PMID   38154512.
  21. 1 2 Nicole, Lauren (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". ProQuest. Retrieved 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. [...]
  22. ↑ Baumann MH, Walters HM, Niello M, Sitte HH (2018). "Neuropharmacology of Synthetic Cathinones". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 252: 113–142. doi:10.1007/164_2018_178. ISBN   978-3-030-10560-0. PMC   7257813 . PMID   30406443.
  23. 1 2 Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology. 236 (3): 915–924. doi:10.1007/s00213-018-5063-9. PMC   6475490 . PMID   30341459.
  24. ↑ Shalabi, Abdelrahman R. (14 December 2017). Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters. VCU Scholars Compass (Thesis). doi:10.25772/M4E1-3549 . Retrieved 24 November 2024.
  25. 1 2 Walther D, Shalabi AR, Baumann MH, Glennon RA (January 2019). "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. doi:10.1021/acschemneuro.8b00524. PMC   8269283 . PMID   30354055.
  26. 1 2 Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, Cozzi NV, Partilla JS, Baumann MH, Negus SS (May 2015). "Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues". Br J Pharmacol. 172 (10): 2433–2444. doi:10.1111/bph.13030. PMC   4409897 . PMID   25438806.
  27. ↑ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
  28. ↑ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961.
  29. ↑ Refstad S (November 2003). "Paramethoxyamphetamine (PMA) poisoning; a 'party drug' with lethal effects". Acta Anaesthesiologica Scandinavica. 47 (10): 1298–9. doi: 10.1046/j.1399-6576.2003.00245.x . PMID   14616331. S2CID   28006785.
  30. ↑ Lamberth PG, Ding GK, Nurmi LA (April 2008). "Fatal paramethoxy-amphetamine (PMA) poisoning in the Australian Capital Territory". The Medical Journal of Australia. 188 (7): 426. doi:10.5694/j.1326-5377.2008.tb01695.x. PMID   18393753. S2CID   11987961.
  31. ↑ Green AL, El Hait MA (April 1980). "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. doi:10.1111/j.2042-7158.1980.tb12909.x. PMID   6103055. S2CID   42213032.
  32. ↑ "PMMA deaths in Holland". nu.nl. Retrieved 8 June 2011.
  33. ↑ "Warning over ecstasy pills that raise overdose risk". BBC News. 16 December 2011. Archived from the original on 25 April 2012.
  34. ↑ "Rare chemical found in fatal ecstasy". The Province. 15 January 2012. Archived from the original on 17 January 2012. Retrieved 12 January 2012.
  35. ↑ "Overdose death investigated". Nanton News. 24 January 2012.
  36. ↑ "Seized substances sent for testing after suspected overdose". Calgary Herald. Archived from the original on 27 January 2012. Retrieved 24 January 2012.
  37. ↑ "Tainted ecstasy linked to five Calgary deaths could be from B.C." Vancouver Sun. 12 January 2012. Archived from the original on 4 March 2013. Retrieved 12 January 2012.
  38. ↑ "Authorities renew warning about street drugs". The City of Calgary Newsroom. Archived from the original on 15 January 2012. Retrieved 11 January 2012.
  39. ↑ "Ecstasy laced with meth in overdose cases". Archived from the original on 12 January 2012. Retrieved 12 January 2012.
  40. ↑ "Dangerous drug linked to Kinsale deaths". Irish Independent. 13 September 2012. Archived from the original on 13 September 2012. Retrieved 13 September 2012.
  41. ↑ "Queensland Police investigate three deaths linked to 'poison pill' ecstasy overdoses". news.com.au. 9 September 2012. Retrieved 30 September 2012.
  42. ↑ "Den Bosch issues a warning for dangerous XTC-pills". nu.nl. Retrieved 12 June 2013.
  43. ↑ "Tiener overleden aan drugs". Archived from the original on 29 August 2013. Retrieved 30 August 2013.
  44. ↑ "Naomi (16): dood door roze xtc-pil". 26 August 2013. Archived from the original on 29 August 2013. Retrieved 26 August 2013.
  45. ↑ "Waarschuwing: dodelijke 'XTC' in omloop". Archived from the original on 29 August 2013. Retrieved 26 August 2013.
  46. ↑ "Man charged after ecstasy deaths". BBC News. 15 May 2018. Archived from the original on 13 May 2018.
  47. ↑ "Varning för livsfarlig ecstasy" (in Swedish). 2 January 2015. Archived from the original on 5 January 2015. Retrieved 4 January 2015.
  48. ↑ "Dublin student dies after taking PMMA tablets in nightclub". irishexaminer.com. 17 May 2015. Archived from the original on 18 May 2015.
  49. ↑ Himitian, Evangelina (17 April 2016). "Conmoción por la muerte de cinco jóvenes en una fiesta electrónica". La Nación (in Spanish). Archived from the original on 19 April 2016.
  50. ↑ "Schedules of Controlled Substances: Placement of para-Methoxymethamphetamine (PMMA) in Schedule I". federalregister.gov. 25 June 2021.
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