Editing Para-Methoxyamphetamine (section)

==Pharmacology==
===Pharmacodynamics===
{| class="wikitable floatright" style="font-size:small;"
|+ {{Nowrap|[[Monoamine releasing agent|Monoamine release]] of {{Abbrlink|PMA|para-methoxyamphetamine}} and related agents ({{Abbrlink|EC<sub>50</sub>|Half maximal effective concentration}}, nM)}}
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! Compound !! {{abbrlink|5-HT|Serotonin}} !! {{abbrlink|NE|Norepinephrine}} !! {{abbrlink|DA|Dopamine}} !! Ref
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| [[Dextroamphetamine|''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>
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| [[Dextromethamphetamine|''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>
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| [[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>
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| [[3-Methoxyamphetamine]] || {{Abbr|ND|No data}} || 58.0 || 103 || <ref name="Blough2008" />
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| ''para''-Methoxyamphetamine (PMA) || {{Abbr|ND|No data}} || 166 || 867 || <ref name="Blough2008" /><ref name="Vekariya2012">{{cite thesis | vauthors = Vekariya R | degree = Master of Science | title=Towards Understanding the Mechanism of Action of Abused Cathinones | publisher = Virginia Commonwealth University | via =VCU Theses and Dissertations | date=2012 | doi=10.25772/AR93-7024 | page=}}</ref>
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| {{Abbrlink|PMMA|para-Methoxymethamphetamine}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}}
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| {{nbsp}}{{nbsp}}(''S'')-PMMA || 41 || 147 || 1,000 || <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 [...] <sup>a</sup> 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" />
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| {{nbsp}}{{nbsp}}(''R'')-PMMA || 134 || >14,000 || 1,600 || <ref name="Glennon2017" /><ref name="GlennonYoung2011" /><ref name="Vekariya2012" />
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| [[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 journal | vauthors = Forsyth AN | title=Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | website=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 | 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>
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| [[para-Chloroamphetamine|''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 = | pages = 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 = The University of Arkansas for Medical Sciences | title=In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones | date=2022 | via = ProQuest | url=https://www.proquest.com/openview/a207e98868b4a9c5ac9296fb24abbcd8/ | access-date=5 December 2024 | 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>
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| [[para-Chloromethamphetamine|''para''-Chloromethamphetamine]] (PCMA) || 29.9 || 36.5 || 54.7 || <ref name="FitzgeraldGannonWalther2024" /><ref name="Nicole2022" />
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| [[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. | title=Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters | publisher = Virginia Commonwealth University | 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>
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| [[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:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more strongly the drug releases the neurotransmitter. The [[bioassay|assay]]s were done in rat brain [[synaptosome]]s and human [[potency (pharmacology)|potencies]] may be different. See also [[Monoamine releasing agent#Activity profiles|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>
|}

PMA acts as a [[selective serotonin releasing agent]] (SSRA) with weak effects on [[dopamine transporter|dopamine]] and [[norepinephrine transporter]]s.<ref name="pmid946817">{{cite journal | vauthors = Menon MK, Tseng LF, Loh HH | title = Pharmacological evidence for the central serotonergic effects of monomethoxyamphetamines | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 197 | issue = 2 | pages = 272–279 | date = May 1976 | doi = 10.1016/S0022-3565(25)30506-9 | pmid = 946817 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=946817 | author-link3 = Horace Loh | url-access = subscription }}</ref><ref name="pmid5132700">{{cite journal | vauthors = Hitzemann RJ, Loh HH, Domino EF | title = Effect of para-methoxyamphetamine on catecholamine metabolism in the mouse brain | journal = Life Sciences | volume = 10 | issue = 19 Pt. 1| pages = 1087–1095 | date = October 1971 | pmid = 5132700 | doi = 10.1016/0024-3205(71)90227-x }}</ref><ref name="pmid1271280">{{cite journal | vauthors = Tseng LF, Menon MK, Loh HH | title = Comparative actions of monomethoxyamphetamines on the release and uptake of biogenic amines in brain tissue | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 197 | issue = 2 | pages = 263–271 | date = May 1976 | doi = 10.1016/S0022-3565(25)30505-7 | pmid = 1271280 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1271280 | url-access = subscription }}</ref><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> Its {{Abbrlink|EC<sub>50</sub>|half-maximal effective concentration}} values for induction of [[monoamine releasing agent|monoamine release]] are 166{{nbsp}}nM for [[dopamine]] and 867{{nbsp}}nM for [[norepinephrine]] in rat brain [[synaptosome]]s, whereas [[serotonin]] was not reported.<ref name="Blough2008"/><ref name="Vekariya2012" /> The drug has been found to robustly increase brain [[serotonin]] levels and to weakly increase brain [[dopamine]] levels in rodents ''[[in vivo]]''.<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> Relative to [[MDMA]], PMA appears to be considerably less effective as a releaser of serotonin, with properties more akin to a [[serotonin reuptake inhibitor]] in comparison.<ref name="pmid11041537">{{cite journal | vauthors = Daws LC, Irvine RJ, Callaghan PD, Toop NP, White JM, Bochner F | title = Differential behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 24 | issue = 6 | pages = 955–977 | date = August 2000 | pmid = 11041537 | doi = 10.1016/S0278-5846(00)00113-5 | s2cid = 24347904 }}</ref>

PMA has also been shown to act as a potent [[monoamine oxidase inhibitor]] (MAOI), specifically as a [[Reversible inhibition|reversible]] [[enzyme inhibitor|inhibitor]] of the [[enzyme]] [[monoamine oxidase A]] (MAO-A) with no significant effects on [[monoamine oxidase B]] (MAO-B).<ref name="pmid6103055">{{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 = 262–266 | date = April 1980 | pmid = 6103055 | doi = 10.1111/j.2042-7158.1980.tb12909.x | s2cid = 42213032 }}</ref><ref name="pmid6646243">{{cite journal | vauthors = Ask AL, Fagervall I, Ross SB | title = Selective inhibition of monoamine oxidase in monoaminergic neurons in the rat brain | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 324 | issue = 2 | pages = 79–87 | date = September 1983 | pmid = 6646243 | doi = 10.1007/BF00497011 | s2cid = 403633 }}</ref> The {{Abbrlink|IC<sub>50</sub>|half-maximal inhibitory concentration}} of PMA for MAO-A inhibition has been reported to be 300 to 600{{nbsp}}nM.<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 = | pages = 1590 | date = 2019 | pmid = 32038257 | pmc = 6989591 | doi = 10.3389/fphar.2019.01590 | doi-access = free | url = }}</ref>

PMA shows very low [[affinity (pharmacology)|affinities]] for the [[serotonin]] [[5-HT1A receptor|5-HT<sub>1A</sub>]], [[5-HT2A receptor|5-HT<sub>2A</sub>]], and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]]s.<ref name="SimmlerRickliHoener2014"/> Its affinities for these receptors have been reported to be >20,000{{nbsp}}nM, 11,200{{nbsp}}nM, and >13,000{{nbsp}}nM, respectively.<ref name="SimmlerRickliHoener2014" /> On the other hand, PMA shows much higher affinities for the mouse and rat [[trace amine-associated receptor 1]] (TAAR1).<ref name="SimmlerRickliHoener2014" />

PMA evokes robust [[hyperthermia]] in rodents while producing only modest [[hyperactivity]] and [[serotonergic neurotoxicity]], substantially lower than that caused by MDMA, and only at very high doses.<ref name="pmid5132700"/><ref name="pmid1271280"/><ref name="pmid11041537"/> Accordingly, it is not [[self-administration|self-administered]] by rodents unlike [[amphetamine]] and MDMA.<ref name="pmid1539067"/> Anecdotal reports by humans suggest it is not particularly [[euphoriant|euphoric]] at all, perhaps even [[dysphoric]] in contrast.{{Citation needed|date=April 2010}}

It appears that PMA elevates body temperatures dramatically; the cause of this property is suspected to be related to its ability to inhibit MAO-A and at the same time releasing large amounts of serotonin, effectively causing [[serotonin syndrome]].<ref name="pmid11041537"/><ref name="pmid6646243"/>  Amphetamines, especially serotonergic analogues such as MDMA, are strongly [[contraindication|contraindicated]] to take with MAOIs.  Many amphetamines and adrenergic compounds raise body temperatures, whereas some tend to produce more euphoric activity or peripheral vasoconstriction, and may tend to favor one effect over another. It appears that PMA activates the [[hypothalamus]] much more strongly than MDMA and other drugs like ephedrine, thereby causing rapid increases in body temperature (which is the major cause of death in PMA mortalities).<ref>{{cite journal | vauthors = Jaehne EJ, Salem A, Irvine RJ | title = Effects of 3,4-methylenedioxymethamphetamine and related amphetamines on autonomic and behavioral thermoregulation | journal = Pharmacology, Biochemistry, and Behavior | volume = 81 | issue = 3 | pages = 485–496 | date = July 2005 | pmid = 15904952 | doi = 10.1016/j.pbb.2005.04.005 | s2cid = 9680452 }}</ref><ref>{{cite journal | vauthors = Callaghan PD, Irvine RJ, Daws LC | title = Differences in the in vivo dynamics of neurotransmitter release and serotonin uptake after acute para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine revealed by chronoamperometry | journal = Neurochemistry International | volume = 47 | issue = 5 | pages = 350–361 | date = October 2005 | pmid = 15979209 | doi = 10.1016/j.neuint.2005.04.026 | s2cid = 23372945 }}</ref><ref>{{cite journal | vauthors = Jaehne EJ, Salem A, Irvine RJ | title = Pharmacological and behavioral determinants of cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, and para-methoxyamphetamine-induced hyperthermia | journal = Psychopharmacology | volume = 194 | issue = 1 | pages = 41–52 | date = September 2007 | pmid = 17530474 | doi = 10.1007/s00213-007-0825-9 | s2cid = 25420902 }}</ref> Many people taking PMA try to get rid of the heat by taking off their clothes, taking cold showers or wrapping themselves in wet towels, and even sometimes by shaving off their hair.<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 = 1298–1299 | date = November 2003 | pmid = 14616331 | doi = 10.1046/j.1399-6576.2003.00245.x | s2cid = 28006785 | doi-access = free }}</ref>