para-Methoxymethamphetamine (PMMA), also known as4-methoxy-N-methylamphetamine (4-MMA), is aserotonergicdrug of theamphetamine family related topara-methoxyamphetamine (PMA). It is the 4-methoxyanalogue ofmethamphetamine. Little is known about thepharmacological properties,metabolism, andtoxicity of PMMA; because of its structural similarity to PMA, which has knowntoxicity in humans, it is thought to have considerable potential to cause harmfulside effects or death inoverdose.[2] In the early 2010s, a number of deaths in users of the drugMDMA were linked to misrepresented tablets and capsules of PMMA.[3]
The synthesis and effects of PMMA were described by American experimental chemistAlexander Shulgin in his bookPiHKAL, where it is referred to by the name "methyl-MA", as theN-methylated form of 4-MA (PMA).[12]
PMMA is amonoamine releasing agent (MRA).[4][5][6][7] The drug'sEC50Tooltip half-maximal effective concentration values for induction of monoamine release in rat brainsynaptosomes have been reported for the individualenantiomers of PMMA.[4][5][6] In the case of (S)-PMMA, they are 41nM forserotonin, 147nM fornorepinephrine, and 1,000nM fordopamine, whereas for (R)-PMMA, they are 134nM for serotonin, >14,000nM for norepinephrine, and 1,600nM for dopamine.[4][5][6] Hence, PMMA appears to be aserotonin–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 rodentsin vivo.[7]
PMMA has been found in tablets and capsules of theMDMA 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.[33][34] 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 amonoamine oxidase inhibitor (MAOI); if it is used in combination with MDMA or another MDMA-like substance,serotonin syndrome can result.[35]
In January 2011, theNorwegian 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 ofLimburg since November 2010.[36] 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.[37]
In January 2012, a number of ecstasy-related deaths inCanada 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.[38][39][40][41][42][43]
In September 2012, the deaths of two men inCounty Cork,Ireland, have been linked to PMMA overdoses.[44] In the same month, the death of a man in Queensland, Australia was attributed to PMMA.[45]
In June 2013 a PMMA-related death occurred in the Dutch city of's-Hertogenbosch.[46]Two months later, In August 2013, another possibly PMMA-related death occurred in the nearby town ofSliedrecht.[47][48][49]
In January 2015 in the UK four people died, suspected of taking ecstasy containing PMMA.[50] In the same month, in Sweden, another man died from ecstasy laced with PMMA.[51]
In May 2015 a young woman died inDublin, Ireland, after taking what is suspected to be PMMA.[52]
In April 2016 four youngArgentines and oneUruguayan died during a massive rave called "Time Warp" inBuenos Aires and five more were hospitalized. PMMA was found in their bodies.[53]
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.[54]
^abcdefgGlennon RA, Young R (5 August 2011). "Drug Discrimination and Mechanisms of Drug Action".Drug Discrimination. Wiley. pp. 183–216.doi:10.1002/9781118023150.ch6.ISBN978-0-470-43352-2.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).
^abcdefghVekariya R (2012).Towards Understanding the Mechanism of Action of Abused Cathinones (Master of Science thesis). Virginia Commonwealth University.doi:10.25772/AR93-7024 – via VCU Theses and Dissertations.
^abcdMatsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, et al. (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.PMID24862256.
^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.PMID11420094.S2CID41953749.
^abcdGlennon RA (October 1999). "Arylalkylamine drugs of abuse: an overview of drug discrimination studies".Pharmacol Biochem Behav.64 (2):251–256.doi:10.1016/s0091-3057(99)00045-3.PMID10515299.
^abSimmler LD, Rickli A, Hoener MC, Liechti ME (April 2014). "Monoamine transporter and receptor interaction profiles of a new series of designer cathinones".Neuropharmacology.79:152–160.doi:10.1016/j.neuropharm.2013.11.008.PMID24275046.
^abRothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (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.PMID11071707.
^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.PMID15677348.S2CID12135483.
^abNicole L (2022).In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones (Ph.D. thesis). University of Arkansas for Medical Sciences.ProQuest2711781450. Retrieved5 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. [...]
^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.PMID6103055.S2CID42213032.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages. See also:Receptor/signaling modulators
