Editing MDMA (section)

==Pharmacology==
===Pharmacodynamics===
{{See also|Empathogen#Mechanism of action|Serotonin releasing agent#Effects and comparisons|Monoamine releasing agent#Mechanism of action}}

{| class="wikitable floatright" style="font-size:small;"
|+ {{Nowrap|Activities of MDMA<ref name="DunlapAndrewsOlson2018" />}}
|-
! [[Biological target|Target]] !! [[Affinity (pharmacology)|Affinity]] (K<sub>i</sub>, nM)
|-
| {{Abbrlink|SERT|Serotonin transporter}} || 0.73–13,300 (K<sub>i</sub>)<br />380–2,500 ({{Abbrlink|IC<sub>50</sub>|half-maximal inhibitory concentration}})<br />50–72 ({{Abbrlink|EC<sub>50</sub>|Half-maximal effective concentration}}) (rat)
|-
| {{Abbrlink|NET|Norepinephrine transporter}} || 27,000–30,500 (K<sub>i</sub>)<br />360–405 ({{Abbr|IC<sub>50</sub>|half-maximal inhibitory concentration}})<br />54–110 ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}}) (rat)
|-
| {{Abbrlink|DAT|Dopamine transporter}} || 6,500–>10,000 (K<sub>i</sub>)<br />1,440–21,000 ({{Abbr|IC<sub>50</sub>|half-maximal inhibitory concentration}})<br />51–278 ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}}) (rat)
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 6,300–12,200 (K<sub>i</sub>)<br />36,000{{nbsp}}nM ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}})<br />64% ({{Abbrlink|E<sub>max</sub>|maximal efficacy}})
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || >10,000
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || >10,000
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]] || >10,000
|-
| [[5-HT1F receptor|5-HT<sub>1F</sub>]] || {{Abbr|ND|No data}}
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 4,600–>10,000 (K<sub>i</sub>)<br />6,100–12,484 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />40–55% ({{Abbr|E<sub>max</sub>|maximal efficacy}})
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]] || 500–2,000 (K<sub>i</sub>)<br />2,000–>20,000 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />32% ({{Abbr|E<sub>max</sub>|maximal efficacy}})
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 4,400–>13,000 (K<sub>i</sub>)<br />831–9,100 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />92% ({{Abbr|E<sub>max</sub>|maximal efficacy}})
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || >10,000
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]] || {{Abbr|ND|No data}}
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] || >10,000
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || >10,000
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || >10,000
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]] || 6,900–>10,000
|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || >10,000
|-
| [[Alpha-1D adrenergic receptor|α<sub>1D</sub>]] || {{Abbr|ND|No data}}
|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || 2,532–15,000
|-
| [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]] || 1,785
|-
| [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] || 1,123–1,346
|-
| [[Beta-1 adrenergic receptor|β<sub>1</sub>]], [[Beta-2 adrenergic receptor|β<sub>2</sub>]] || >10,000
|-
| [[D1 receptor|D<sub>1</sub>]] || >13,600
|-
| [[D2 receptor|D<sub>2</sub>]] || 25,200
|-
| [[D3 receptor|D<sub>3</sub>]] || >17,700
|-
| [[D4 receptor|D<sub>4</sub>]] || >10,000
|-
| [[D5 receptor|D<sub>5</sub>]] || >10,000
|-
| [[H1 receptor|H<sub>1</sub>]] || 2,138–>14,400
|-
| [[H2 receptor|H<sub>2</sub>]] || >10,000
|-
| [[H3 receptor|H<sub>3</sub>]], [[H4 receptor|H<sub>4</sub>]] || {{Abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine M1 receptor|M<sub>1</sub>]] || >10,000
|-
| [[Muscarinic acetylcholine M2 receptor|M<sub>2</sub>]] || >10,000
|-
| [[Muscarinic acetylcholine M3 receptor|M<sub>3</sub>]] || 1,850–>10,000
|-
| [[Muscarinic acetylcholine M4 receptor|M<sub>4</sub>]] || 8,250–>10,000
|-
| [[Muscarinic acetylcholine M5 receptor|M<sub>5</sub>]] || 6,340–>10,000
|-
| [[Nicotinic acetylcholine receptor|nACh]] || >10,000
|-
| [[Trace amine-associated receptor 1|TAAR1]] || 250–370 (K<sub>i</sub>) (rat)<br />1,000–1,700 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) (rat)<br />56% ({{Abbr|E<sub>max</sub>|maximal efficacy}}) (rat)<br />2,400–3,100 (K<sub>i</sub>) (mouse)<br />4,000 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) (mouse)<br />71% ({{Abbr|E<sub>max</sub>|maximal efficacy}}) (mouse)<br />35,000 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) (human)<br />26% ({{Abbr|E<sub>max</sub>|maximal efficacy}}) (human)
|-
| [[I1 receptor|I<sub>1</sub>]] || 220
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]], [[Sigma-2 receptor|σ<sub>2</sub>]] || {{Abbr|ND|No data}}
|- class="sortbottom"
| colspan="2" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. Proteins are human unless otherwise specified. '''Refs:''' <ref name="PDSPKiDatabase">{{cite web | title=PDSP Database | website=UNC | url=https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=MDMA&kiAllRadio=all&doQuery=Submit+Query | language=zu | access-date=11 December 2024}}</ref><ref name="BindingDB">{{cite web | vauthors = Liu T | title=BindingDB BDBM50010588 (RS)-3,4-(methylenedioxy)methamphetamine::1-(1,3-Benzodioxol-5-yl)-N-methyl-2-propanamine::1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine::3,4-methylenedioxymethamphetamine::CHEMBL43048::DL-(3,4-Methylenedioxy)methamphetamine::MDMA::N,alpha-dimethyl-1,3-benzodioxole-5-ethanamine::N-Methyl-3,4-methylenedioxyamphetamine::US11767305, Compound MDMA | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50010588 | access-date=11 December 2024}}</ref><ref name="DunlapAndrewsOlson2018" /><ref name="Ray2010">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 | pages = e9019 | date = February 2010 | pmid = 20126400 | pmc = 2814854 | doi = 10.1371/journal.pone.0009019 | doi-access = free | bibcode = 2010PLoSO...5.9019R | url = }}</ref><ref name="SimmlerBuserDonzelli2013" /><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><br /><ref name="RickliKopfHoener2015">{{cite journal | vauthors = Rickli A, Kopf S, Hoener MC, Liechti ME | title = Pharmacological profile of novel psychoactive benzofurans | journal = Br J Pharmacol | volume = 172 | issue = 13 | pages = 3412–3425 | date = July 2015 | pmid = 25765500 | pmc = 4500375 | doi = 10.1111/bph.13128 | url = }}</ref><ref name="LuethiKolaczynskaWalter2019">{{cite journal | vauthors = Luethi D, Kolaczynska KE, Walter M, Suzuki M, Rice KC, Blough BE, Hoener MC, Baumann MH, Liechti ME | title = Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems | journal = J Psychopharmacol | volume = 33 | issue = 7 | pages = 831–841 | date = July 2019 | pmid = 31038382 | pmc = 8269116 | doi = 10.1177/0269881119844185 | url = }}</ref><ref name="EshlemanForsterWolfrum2014">{{cite journal | vauthors = Eshleman AJ, Forster MJ, Wolfrum KM, Johnson RA, Janowsky A, Gatch MB | title = Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function | journal = Psychopharmacology (Berl) | volume = 231 | issue = 5 | pages = 875–888 | date = March 2014 | pmid = 24142203 | pmc = 3945162 | doi = 10.1007/s00213-013-3303-6 | url = https://www.researchgate.net/publication/258061356}}</ref><ref name="GainetdinovHoenerBerry2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = https://www.researchgate.net/publication/325975689 | doi-access = free }}</ref><ref name="SimmlerBuchyChaboz2016">{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | url-status = dead | archive-date = 2025-05-09 }}</ref><ref name="SotnikovaCaronGainetdinov2009">{{cite journal | vauthors = Sotnikova TD, Caron MG, Gainetdinov RR | title = Trace amine-associated receptors as emerging therapeutic targets | journal = Mol Pharmacol | volume = 76 | issue = 2 | pages = 229–235 | date = August 2009 | pmid = 19389919 | pmc = 2713119 | doi = 10.1124/mol.109.055970 | url = }}</ref>
|}

MDMA is an [[entactogen]] or [[empathogen]], as well as a [[stimulant]], [[euphoriant]], and weak [[psychedelic drug|psychedelic]].<ref name="DunlapAndrewsOlson2018" /><ref name="Nichols2022" /> It is a [[substrate (biochemistry)|substrate]] of the [[monoamine transporter]]s (MATs) and acts as a [[monoamine releasing agent]] (MRA).<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021">{{cite journal | vauthors = Docherty JR, Alsufyani HA | title = Pharmacology of Drugs Used as Stimulants | journal = J Clin Pharmacol | volume = 61 | issue = Suppl 2 | pages = S53–S69 | date = August 2021 | pmid = 34396557 | doi = 10.1002/jcph.1918 | url = | quote = Receptor-mediated actions of amphetamine and other amphetamine derivatives [...] may involve trace amine-associated receptors (TAARs) at which amphetamine and MDMA also have significant potency.85–87 Many stimulants have potency at the rat TAAR1 in the micromolar range but tend to be about 5 to 10 times less potent at the human TAAR1, [...] Activation of the TAAR1 receptor causes inhibition of dopaminergic transmission in the mesocorticolimbic system, and TAAR1 agonists attenuated psychostimulant abuse-related behaviors.89 It is likely that TAARs contribute to the actions of specific stimulants to modulate dopaminergic, serotonergic, and glutamate signaling,90 and drugs acting on the TAAR1 may have therapeutic potential.91 In the periphery, stimulants such as MDMA and cathinone produce vasoconstriction, part of which may involve TAARs, although only relatively high concentrations produced vascular contractions resistant to a cocktail of monoamine antagonist drugs.86 | doi-access = free }}</ref><ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = European Journal of Pharmacology | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 }}</ref><ref name="RothmanBaumann2006" /> The drug is specifically a well-balanced [[serotonin–norepinephrine–dopamine releasing agent]] (SNDRA).<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" /><ref name="RothmanBaumann2003" /><ref name="RothmanBaumann2006" /> To a lesser extent, MDMA also acts as a [[serotonin–norepinephrine–dopamine reuptake inhibitor]] (SNDRI).<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" /><ref name="RothmanBaumann2003" /> MDMA enters [[monoaminergic]] [[neuron]]s via the MATs and then, via poorly understood [[mechanism of action|mechanism]]s, reverses the direction of these transporters to produce [[efflux pump|efflux]] of the [[monoamine neurotransmitter]]s rather than the usual [[reuptake]].<ref name="DunlapAndrewsOlson2018" /><ref name="SulzerSondersPoulsen2005">{{cite journal | vauthors = Sulzer D, Sonders MS, Poulsen NW, Galli A | title = Mechanisms of neurotransmitter release by amphetamines: a review | journal = Prog Neurobiol | volume = 75 | issue = 6 | pages = 406–433 | date = April 2005 | pmid = 15955613 | doi = 10.1016/j.pneurobio.2005.04.003 | url = }}</ref><ref name="ReithGnegy2020">{{cite journal | vauthors = Reith ME, Gnegy ME | title = Molecular Mechanisms of Amphetamines | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 258 | issue = | pages = 265–297 | date = 2020 | pmid = 31286212 | doi = 10.1007/164_2019_251 | isbn = 978-3-030-33678-3 | url = }}</ref><ref name="VaughanHenryFoster2024">{{cite book | vauthors = Vaughan RA, Henry LK, Foster JD, Brown CR | title = Pharmacological Advances in Central Nervous System Stimulants | chapter = Post-translational mechanisms in psychostimulant-induced neurotransmitter efflux | series = Adv Pharmacol | volume = 99 | pages = 1–33 | date = 2024 | pmid = 38467478 | doi = 10.1016/bs.apha.2023.10.003 | isbn = 978-0-443-21933-7 | chapter-url = https://books.google.com/books?id=2Sr6EAAAQBAJ&pg=PA1 }}</ref> Induction of monoamine efflux by [[amphetamine-type stimulant|amphetamine]]s in general may involve [[intracellular]] [[sodium ion|Na<sup>+</sup>]] and [[calcium ion|Ca<sup>2+</sup>]] elevation and [[protein kinase C|PKC]] and [[CaMKIIα]] activation.<ref name="SulzerSondersPoulsen2005" /><ref name="ReithGnegy2020" /><ref name="VaughanHenryFoster2024" /> MDMA also acts on the [[vesicular monoamine transporter 2]] (VMAT2) on [[synaptic vesicle]]s to increase the [[cytosol]]ic concentrations of the monoamine neurotransmitters available for efflux.<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" /> By inducing release and reuptake inhibition of [[serotonin]], [[norepinephrine]], and [[dopamine]], MDMA increases levels of these neurotransmitters in the [[brain]] and [[peripheral nervous system|periphery]].<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" />

In addition to its actions as an SNDRA, MDMA directly but more modestly interacts with a number of [[monoamine receptor|monoamine]] and other [[receptor (biochemistry)|receptor]]s.<ref name="DunlapAndrewsOlson2018" /><ref name="PDSPKiDatabase" /><ref name="BindingDB" /><ref name="Ray2010" /> It is a low-[[potency (pharmacology)|potency]] [[partial agonist]] of the serotonin [[5-HT2 receptor|5-HT<sub>2</sub> receptor]]s, including of the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2B receptor|5-HT<sub>2B</sub>]], and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]]s.<ref name="DunlapAndrewsOlson2018" /><ref name="PittsCurryHampshire2018" /><ref name="SetolaHufeisenGrande-Allen2003" /><ref name="NashRothBrodkin1994">{{cite journal | vauthors = Nash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA | title = Effect of the R(-) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors | journal = Neurosci Lett | volume = 177 | issue = 1–2 | pages = 111–115 | date = August 1994 | pmid = 7824160 | doi = 10.1016/0304-3940(94)90057-4 | url = }}</ref> The drug also interacts with [[alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]]s, with the [[sigma receptor|sigma]] [[sigma-1 receptor|σ<sub>1</sub>]] and [[sigma-2 receptor|σ<sub>2</sub> receptor]]s, and with the [[imidazoline receptor|imidazoline]] [[I1 receptor|I<sub>1</sub> receptor]].<ref name="DunlapAndrewsOlson2018" /><ref name="PDSPKiDatabase" /><ref name="BindingDB" /><ref name="Ray2010" /> It is thought that agonism of the serotonin 5-HT<sub>2A</sub> receptor by MDMA may mediate the weak psychedelic effects of the drug in humans.<ref name="SimmlerLiechti2018" /><ref name="Meyer2013">{{cite journal | vauthors = Meyer JS | title = 3,4-methylenedioxymethamphetamine (MDMA): current perspectives | journal = Subst Abuse Rehabil | volume = 4 | issue = | pages = 83–99 | date = 2013 | pmid = 24648791 | pmc = 3931692 | doi = 10.2147/SAR.S37258 | doi-access = free | url = }}</ref><ref name="StraumannAvedisianKlaiber2024" /> However, findings in this area appear to be conflicting.<ref name="Meyer2013" /><ref name="HalberstadtNichols2020" /><ref name="Bedi2024">{{cite journal | vauthors = Bedi G | title = Is the stereoisomer R-MDMA a safer version of MDMA? | journal = Neuropsychopharmacology | volume = 50| issue = 2| date = October 2024 | pages = 360–361 | pmid = 39448866 | doi = 10.1038/s41386-024-02009-8 | doi-access = free | pmc = 11631934 }}</ref><ref name="StraumannAvedisianKlaiber2024" /> Likewise, findings on MDMA and induction of the [[head-twitch response]] (HTR), a behavioral proxy of psychedelic-like effects, are contradictory in animals, and MDMA does not substitute for or generalize with psychedelics like [[LSD]] or [[DOM (drug)|DOM]] in animal [[drug discrimination]] tests.<ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences | volume = 36 | issue = | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | chapter-url = | quote = [MDxx] have been assessed in head twitch studies. Racemic [MDA] and S-(+)-MDA reportedly induce WDS in monkeys and rats, respectively (Schlemmer and Davis 1986; Hiramatsu et al. 1989). Although [MDMA] does not induce the HTR in mice, both of the stereoisomers of MDMA have been shown to elicit the response (Fantegrossi et al. 2004, 2005b). 5-HT depletion inhibits the response to S-(+)-MDMA but does not alter the response to R-(−)-MDMA, suggesting the isomers act through different mechanisms (Fantegrossi et al. 2005b). This suggestion is consistent with the fact that S-(+)- and R-(−)-MDMA exhibit qualitatively distinct pharmacological profiles, with the S-(+)isomer working primarily as a monoamine releaser (Johnson et al. 1986; Baumann et al. 2008; Murnane et al. 2010) and the R-(−)-enantiomer acting directly through 5-HT2A receptors (Lyon et al. 1986; Nash et al. 1994). In contrast to their effects in mice, Hiramatsu reported that S-(+)- and R-(−)-MDMA fail to produce WDS in rats (Hiramatsu et al. 1989). The discrepant findings with MDMA in mice and rats may reflect species differences in sensitivity to the HTR (see below for further discussion). }}</ref><ref name="Dunlap2022">{{cite thesis | vauthors = Dunlap LE | title=Development of Non-Hallucinogenic Psychoplastogens | publisher=University of California, Davis | date=2022 | url=https://escholarship.org/uc/item/5qr3w0gm | access-date=18 November 2024 | quote=Finally, since R-MDMA is known to partially substitute for LSD in animal models we decided to test both compounds in the head twitch response assay (HTR) (FIG 3.3C).3 The HTR is a well-validated mouse model for predicting the hallucinogenic potential of test drugs. Serotonergic psychedelics will cause a rapid back and forth head movement in mice. The potency measured in the HTR assay has been shown to correlate very well with the human potencies of psychedelics.18 Neither R-MDMA or LED produced any head twitches at all doses tested, suggesting that neither has high hallucinogenic potential.}}</ref><ref name="HalberstadtNichols2020" /> Along with the preceding receptor interactions, MDMA is a potent partial agonist of the rodent [[trace amine-associated receptor 1]] (TAAR1).<ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016" /> Conversely however, it is far weaker in terms of potency as an agonist of the human TAAR1.<ref name="DunlapAndrewsOlson2018" /><ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016" /><ref name="LewinMillerGilmour2011">{{cite journal | vauthors = Lewin AH, Miller GM, Gilmour B | title = Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journal = Bioorganic & Medicinal Chemistry | volume = 19 | issue = 23 | pages = 7044–7048 | date = December 2011 | pmid = 22037049 | pmc = 3236098 | doi = 10.1016/j.bmc.2011.10.007 }}</ref> Moreover, MDMA acts as a weak partial agonist or [[receptor antagonist|antagonist]] of the human TAAR1 rather than as an [[intrinsic activity|efficacious]] agonist.<ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016" /> In relation to the preceding, MDMA has been said to be inactive as a human TAAR1 agonist.<ref name="DunlapAndrewsOlson2018" /> TAAR1 activation is thought to auto-inhibit and constrain the effects of amphetamines that possess TAAR1 agonism, for instance MDMA in rodents.<ref name="DochertyAlsufyani2021" /><ref name="EspinozaGainetdinov2014">{{cite book | vauthors = Espinoza S, Gainetdinov RR | title=Taste and Smell | chapter=Neuronal Functions and Emerging Pharmacology of TAAR1 | series=Topics in Medicinal Chemistry | publisher=Springer International Publishing | publication-place=Cham | volume=23 | date=2014 | isbn=978-3-319-48925-4 | doi=10.1007/7355_2014_78 | pages=175–194 | quote = Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission. }}</ref><ref name="KuropkaZawadzkiSzpot2023">{{cite journal | vauthors = Kuropka P, Zawadzki M, Szpot P | title = A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse | journal = Hum Psychopharmacol | volume = 38 | issue = 3 | pages = e2866 | date = May 2023 | pmid = 36866677 | doi = 10.1002/hup.2866 | url = | quote = Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 2016). The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013). }}</ref><ref name="SimmlerBuserDonzelli2013">{{cite journal | vauthors = Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME | title = Pharmacological characterization of designer cathinones in vitro | journal = Br J Pharmacol | volume = 168 | issue = 2 | pages = 458–470 | date = January 2013 | pmid = 22897747 | pmc = 3572571 | doi = 10.1111/j.1476-5381.2012.02145.x | url = | quote = β-Keto-analogue cathinones also exhibited approximately 10-fold lower affinity for the TA1 receptor compared with their respective non-β-keto amphetamines. [...] Activation of TA1 receptors negatively modulates dopaminergic neurotransmission. Importantly, methamphetamine decreased DAT surface expression via a TA1 receptor-mediated mechanism and thereby reduced the presence of its own pharmacological target (Xie and Miller, 2009). MDMA and amphetamine have been shown to produce enhanced DA and 5-HT release and locomotor activity in TA1 receptor knockout mice compared with wild-type mice (Lindemann et al., 2008; Di Cara et al., 2011). Because methamphetamine and MDMA auto-inhibit their neurochemical and functional effects via TA1 receptors, low affinity for these receptors may result in stronger effects on monoamine systems by cathinones compared with the classic amphetamines. }}</ref><ref name="DiCaraMaggioAloisi2011">{{cite journal | vauthors = Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L, Cistarelli L, Veiga S, De Montrion C, Rodriguez M, Galizzi JP, Lockhart BP, Cogé F, Boutin JA, Vayer P, Verdouw PM, Groenink L, Millan MJ | title = Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA) | journal = J Neurosci | volume = 31 | issue = 47 | pages = 16928–16940 | date = November 2011 | pmid = 22114263 | pmc = 6623861 | doi = 10.1523/JNEUROSCI.2502-11.2011 | url = }}</ref>

Elevation of serotonin, norepinephrine, and dopamine levels by MDMA is believed to mediate most of the drug's effects, including its entactogenic, stimulant, euphoriant, [[hyperthermia|hyperthermic]], and [[sympathomimetic]] effects.<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" /><ref name="ReinRaymondBoustani2024">{{cite journal | vauthors = Rein B, Raymond K, Boustani C, Tuy S, Zhang J, St Laurent R, Pomrenze MB, Boroon P, Heifets B, Smith M, Malenka RC | title = MDMA enhances empathy-like behaviors in mice via 5-HT release in the nucleus accumbens | journal = Sci Adv | volume = 10 | issue = 17 | pages = eadl6554 | date = April 2024 | pmid = 38657057 | pmc = 11042730 | doi = 10.1126/sciadv.adl6554 | bibcode = 2024SciA...10L6554R | url = }}</ref><ref name="Kamilar-BrittBedi2015">{{cite journal | vauthors = Kamilar-Britt P, Bedi G | title = The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals | journal = Neurosci Biobehav Rev | volume = 57 | issue = | pages = 433–446 | date = October 2015 | pmid = 26408071 | pmc = 4678620 | doi = 10.1016/j.neubiorev.2015.08.016 | url = }}</ref> The entactogenic effects of MDMA, including increased [[sociability]], [[empathy]], [[emotional intimacy|feelings of closeness]], and [[antiaggressive|reduced aggression]], are thought to be mainly due to induction of serotonin release.<ref name="Kamilar-BrittBedi2015" /><ref name="HalberstadtNichols2020" /><ref name="Oeri2021">{{cite journal | vauthors = Oeri HE | title = Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy | journal = J Psychopharmacol | volume = 35 | issue = 5 | pages = 512–536 | date = May 2021 | pmid = 32909493 | pmc = 8155739 | doi = 10.1177/0269881120920420 | url = }}</ref> The exact [[serotonin receptor]]s responsible for these effects are unclear, but may include the serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]],<ref name="EsakiSasakiNishitani2023">{{cite journal | vauthors = Esaki H, Sasaki Y, Nishitani N, Kamada H, Mukai S, Ohshima Y, Nakada S, Ni X, Deyama S, Kaneda K | title = Role of 5-HT1A receptors in the basolateral amygdala on 3,4-methylenedioxymethamphetamine-induced prosocial effects in mice | journal = Eur J Pharmacol | volume = 946 | issue = | pages = 175653 | date = May 2023 | pmid = 36907260 | doi = 10.1016/j.ejphar.2023.175653 | url = }}</ref> [[5-HT1B receptor|5-HT<sub>1B</sub> receptor]],<ref name="HeifetsSalgadoTaylor2019">{{cite journal | vauthors = Heifets BD, Salgado JS, Taylor MD, Hoerbelt P, Cardozo Pinto DF, Steinberg EE, Walsh JJ, Sze JY, Malenka RC | title = Distinct neural mechanisms for the prosocial and rewarding properties of MDMA | journal = Sci Transl Med | volume = 11 | issue = 522 | pages = | date = December 2019 | pmid = 31826983 | pmc = 7123941 | doi = 10.1126/scitranslmed.aaw6435 | url = }}</ref> and 5-HT<sub>2A</sub> receptor,<ref name="PittsMinervaChandler2017">{{cite journal | vauthors = Pitts EG, Minerva AR, Chandler EB, Kohn JN, Logun MT, Sulima A, Rice KC, Howell LL | title = 3,4-Methylenedioxymethamphetamine Increases Affiliative Behaviors in Squirrel Monkeys in a Serotonin 2A Receptor-Dependent Manner | journal = Neuropsychopharmacology | volume = 42 | issue = 10 | pages = 1962–1971 | date = September 2017 | pmid = 28425496 | pmc = 5561347 | doi = 10.1038/npp.2017.80 | url = }}</ref> as well as 5-HT<sub>1A</sub> receptor-mediated [[oxytocin]] release and consequent activation of the [[oxytocin receptor]].<ref name="DunlapAndrewsOlson2018" /><ref name="Kamilar-BrittBedi2015" /><ref name="Blanco-GandíaMateos-GarcíaGarcía-Pardo2015">{{cite journal | vauthors = Blanco-Gandía MC, Mateos-García A, García-Pardo MP, Montagud-Romero S, Rodríguez-Arias M, Miñarro J, Aguilar MA | title = Effect of drugs of abuse on social behaviour: a review of animal models | journal = Behav Pharmacol | volume = 26 | issue = 6 | pages = 541–570 | date = September 2015 | pmid = 26221831 | doi = 10.1097/FBP.0000000000000162 | url = }}</ref><ref name="HeifetsOlson2024">{{cite journal | vauthors = Heifets BD, Olson DE | title = Therapeutic mechanisms of psychedelics and entactogens | journal = Neuropsychopharmacology | volume = 49 | issue = 1 | pages = 104–118 | date = January 2024 | pmid = 37488282 | doi = 10.1038/s41386-023-01666-5 | pmc = 10700553 | url = }}</ref><ref name="Nichols2022">{{cite journal | vauthors = Nichols DE | title = Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated | journal = Front Psychiatry | volume = 13 | issue = | pages = 863088 | date = 2022 | pmid = 35401275 | pmc = 8990025 | doi = 10.3389/fpsyt.2022.863088 | doi-access = free | url = }}</ref> Induction of dopamine release is thought to be importantly involved in the stimulant and euphoriant effects of MDMA,<ref name="DunlapAndrewsOlson2018" /><ref name="PittsCurryHampshire2018" /><ref name="KaurKarabulutGauld2023" /> while induction of norepinephrine release and serotonin 5-HT<sub>2A</sub> receptor stimulation are believed to mediate its sympathomimetic effects.<ref name="FonsecaFibeiroTapadas2021" /><ref name="DochertyAlsufyani2021" /> MDMA has been associated with a unique subjective "magic" or [[euphoria]] that few or no other known entactogens are said to fully reproduce.<ref name="Baggott2023">{{cite conference | vauthors = Baggott M | title = Beyond Ecstasy: Progress in Developing and Understanding a Novel Class of Therapeutic Medicine | conference = PS2023 [Psychedelic Science 2023, June 19–23, 2023, Denver, Colorado] | date = 23 June 2023 | publisher = [[Multidisciplinary Association for Psychedelic Studies]] | location = Denver, CO | url = https://2023.psychedelicscience.org/sessions/beyond-ecstasy-progress-in-developing-and-understanding-a-novel-class-of-therapeutic-medicine/}}</ref><ref name="Baggott2024" /> The mechanisms underlying this property of MDMA are unknown, but it has been theorized to be due to a very specific mixture and balance of pharmacological activities, including combined serotonin, norepinephrine, and dopamine release and direct serotonin receptor agonism.<ref name="RothmanBaumann2002">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic and adverse actions of serotonin transporter substrates | journal = Pharmacol Ther | volume = 95 | issue = 1 | pages = 73–88 | date = July 2002 | pmid = 12163129 | doi = 10.1016/s0163-7258(02)00234-6 | url = }}</ref><ref name="Baggott2023" /><ref name="Baggott2024">{{cite web | title=Better Than Ecstasy: Progress in Developing a Novel Class of Therapeutic with Matthew Baggott, PhD. | website=YouTube | date=6 March 2024 | url=https://www.youtube.com/watch?v=OnhJvKxwfZI&t=1048 | access-date=20 November 2024}}</ref><ref name="LuethiLiechti2020">{{cite journal | vauthors = Luethi D, Liechti ME | title = Designer drugs: mechanism of action and adverse effects | journal = Arch Toxicol | volume = 94 | issue = 4 | pages = 1085–1133 | date = April 2020 | pmid = 32249347 | pmc = 7225206 | doi = 10.1007/s00204-020-02693-7 | url = https://repositorium.meduniwien.ac.at/obvumwoa/content/titleinfo/5270457/full.pdf}}</ref> Repeated activation of serotonin 5-HT<sub>2B</sub> receptors by MDMA is thought to result in risk of [[valvular heart disease]] (VHD) and [[primary pulmonary hypertension]] (PPH).<ref name="McIntyre2023">{{cite journal | vauthors = McIntyre RS | title = Serotonin 5-HT2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents | journal = Expert Opin Drug Saf | volume = 22 | issue = 10 | pages = 881–883 | date = 2023 | pmid = 37581427 | doi = 10.1080/14740338.2023.2248883 | url = }}</ref><ref name="TagenMantuanivanHeerden2023">{{cite journal | vauthors = Tagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R | title = The risk of chronic psychedelic and MDMA microdosing for valvular heart disease | journal = J Psychopharmacol | volume = 37 | issue = 9 | pages = 876–890 | date = September 2023 | pmid = 37572027 | doi = 10.1177/02698811231190865 | url = https://unlimitedsciences.org/wp-content/uploads/2024/01/tagen-et-al-2023-the-risk-of-chronic-psychedelic-and-mdma-microdosing-for-valvular-heart-disease.pdf | quote = [...] Both [MDMA and MDA] bind to the human 5-HT2B receptor, although with a 5-fold lower Ki value for MDA compared to MDMA (Ray, 2010; Setola et al., 2003). Both compounds were agonists in an assay of PI hydrolysis, with MDA (EC50=190nM) 10-fold more potent than MDMA (EC50=2000 nM) in addition to greater intrinsic efficacy (90% vs 32%) (Setola et al., 2003). [...] A 50mg dose of MDMA resulted in a mean plasma Cmax 266nM for MDMA and 28.5nM for MDA (de la Torre et al., 2000). }}</ref><ref name="Wsół2023"/><ref name="RothmanBaumann2009">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Serotonergic drugs and valvular heart disease | journal = Expert Opin Drug Saf | volume = 8 | issue = 3 | pages = 317–329 | date = May 2009 | pmid = 19505264 | pmc = 2695569 | doi = 10.1517/14740330902931524 | url = }}</ref><ref name="RothmanBaumann2002" /><ref name="RothmanBaumann2002b">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Serotonin releasing agents. Neurochemical, therapeutic and adverse effects | journal = Pharmacol Biochem Behav | volume = 71 | issue = 4 | pages = 825–836 | date = April 2002 | pmid = 11888573 | doi = 10.1016/s0091-3057(01)00669-4 | url = }}</ref> MDMA has been associated with [[serotonergic neurotoxicity]].<ref name="CostaGołembiowska2022" /><ref name="Oeri2021" /><ref name="SpragueEvermanNichols1998" /> This may be due to formation of toxic MDMA [[metabolite]]s and/or induction of [[serotonin–norepinephrine–dopamine releasing agent|simultaneous serotonin and dopamine release]], with consequent uptake of dopamine into serotonergic neurons and breakdown into [[reactive oxygen species|toxic species]].<ref name="CostaGołembiowska2022">{{cite journal | vauthors = Costa G, Gołembiowska K | title = Neurotoxicity of MDMA: Main effects and mechanisms | journal = Exp Neurol | volume = 347 | issue = | pages = 113894 | date = January 2022 | pmid = 34655576 | doi = 10.1016/j.expneurol.2021.113894 | hdl = 11584/325355 | url = https://www.didyouno.fr/wp-content/uploads/2023/03/1-s2.0-S0014488621003022-main.pdf }}</ref><ref name="Oeri2021" /><ref name="SpragueEvermanNichols1998">{{cite journal | vauthors = Sprague JE, Everman SL, Nichols DE | title = An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine | journal = Neurotoxicology | volume = 19 | issue = 3 | pages = 427–441 | date = June 1998 | pmid = 9621349 | doi = | url = https://www.researchgate.net/publication/13663847}}</ref>

MDMA is a [[racemic mixture]] of two [[enantiomers]], (''S'')-MDMA and [[(R)-MDMA|(''R'')-MDMA]].<ref name="PittsCurryHampshire2018">{{cite journal | vauthors = Pitts EG, Curry DW, Hampshire KN, Young MB, Howell LL | title = (±)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA | journal = Psychopharmacology | volume = 235 | issue = 2 | pages = 377–392 | date = February 2018 | pmid = 29248945 | doi = 10.1007/s00213-017-4812-5 }}</ref><ref name="StraumannAvedisianKlaiber2024" /> (''S'')-MDMA is much more potent as an SNDRA ''[[in vitro]]'' and in producing MDMA-like subjective effects in humans than (''R'')-MDMA.<ref name="PittsCurryHampshire2018" /><ref name="RothmanBaumann2006" /><ref name="StraumannAvedisianKlaiber2024" /><ref name="AndersonBraunBraun1978">{{cite journal | vauthors = Anderson GM, Braun G, Braun U, Nichols DE, Shulgin AT | title = Absolute configuration and psychotomimetic activity | journal = NIDA Research Monograph | volume = | issue = 22 | pages = 8–15 | date = 1978 | pmid = 101890 | doi = | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=2ab674b010611df18c029a78f6d17e52dba5f82f }}</ref> By contrast, (''R'')-MDMA acts as a lower-potency [[serotonin–norepinephrine releasing agent]] (SNRA) with weak or negligible effects on dopamine.<ref name="PittsCurryHampshire2018" /><ref name="RothmanBaumann2006" /><ref name="AcquasPisanuSpiga2007">{{cite journal | vauthors = Acquas E, Pisanu A, Spiga S, Plumitallo A, Zernig G, Di Chiara G | title = Differential effects of intravenous R,S-(+/-)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)- and R(-)-enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core | journal = Journal of Neurochemistry | volume = 102 | issue = 1 | pages = 121–132 | date = July 2007 | pmid = 17564678 | doi = 10.1111/j.1471-4159.2007.04451.x }}</ref> Relatedly, (''R'')-MDMA shows weak or negligible stimulant-like and [[reward system|rewarding]] effects in animals.<ref name="PittsCurryHampshire2018" /><ref name="CurryYoungTran2018">{{cite journal | vauthors = Curry DW, Young MB, Tran AN, Daoud GE, Howell LL | title = Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice | journal = Neuropharmacology | volume = 128 | issue = | pages = 196–206 | date = January 2018 | pmid = 28993129 | pmc = 5714650 | doi = 10.1016/j.neuropharm.2017.10.003 }}</ref> Both (''S'')-MDMA and (''R'')-MDMA produce entactogen-type effects in animals and humans.<ref name="PittsCurryHampshire2018" /><ref name="StraumannAvedisianKlaiber2024" /> In addition, both (''S'')-MDMA and (''R'')-MDMA are weak agonists of the serotonin 5-HT<sub>2</sub> receptors.<ref name="PittsCurryHampshire2018" /><ref name="KaurKarabulutGauld2023">{{cite journal | vauthors = Kaur H, Karabulut S, Gauld JW, Fagot SA, Holloway KN, Shaw HE, Fantegrossi WE | title = Balancing Therapeutic Efficacy and Safety of MDMA and Novel MDXX Analogues as Novel Treatments for Autism Spectrum Disorder | date = 2023 | journal = Psychedelic Medicine | volume = 1 | issue = 3 | pages = 166–185 | doi = 10.1089/psymed.2023.0023 | url = | quote = It is postulated that MDMA-induced neuronal apoptosis arises from directly stimulating the 5HT2A receptor. However, it is unclear whether MDMA binds here directly or whether one of its active metabolites (for example, MDA exhibits a 5-HT2A affinity almost 10-fold better than MDMA) is responsible.70,80,81 In addition, R-MDMA more potently activates 5-HT2A second messenger signaling, with S-MDMA having a minimal effect and racemic MDMA acting as a weak partial agonist. | pmc = 11661495 }}</ref><ref name="StraumannAvedisianKlaiber2024" /><ref name="SetolaHufeisenGrande-Allen2003" /><ref name="NashRothBrodkin1994" /> (''R'')-MDMA is more potent and efficacious as a serotonin 5-HT<sub>2A</sub> and 5-HT<sub>2B</sub> receptor agonist than (''S'')-MDMA, whereas (''S'')-MDMA is somewhat more potent as an agonist of the serotonin 5-HT<sub>2C</sub> receptor.<ref name="PittsCurryHampshire2018" /><ref name="KaurKarabulutGauld2023" /><ref name="StraumannAvedisianKlaiber2024" /> Despite its greater serotonin 5-HT<sub>2A</sub> receptor agonism however, (''R'')-MDMA did not produce more psychedelic-like effects than (''S'')-MDMA in humans.<ref name="Bedi2024" /><ref name="StraumannAvedisianKlaiber2024" />

MDMA produces [[3,4-methylenedioxyamphetamine]] (MDA) as a minor [[active metabolite]].<ref name="delaTorreFarréRoset2004" /> [[Cmax (pharmacology)|Peak levels]] of MDA are about 5 to 10% of those of MDMA and [[area-under-the-curve (pharmacokinetics)|total exposure]] to MDA is almost 10% of that of MDMA with [[oral administration|oral]] MDMA administration.<ref name="delaTorreFarréRoset2004" /><ref name="TagenMantuanivanHeerden2023" /> As a result, MDA may contribute to some extent to the effects of MDMA.<ref name="delaTorreFarréRoset2004">{{cite journal | vauthors = de la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J | title = Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition | journal = Ther Drug Monit | volume = 26 | issue = 2 | pages = 137–144 | date = April 2004 | pmid = 15228154 | doi = 10.1097/00007691-200404000-00009 | url = http://www.maps.org/w3pb/new/2004/2004_de_20593_2.pdf | archive-url = https://web.archive.org/web/20140305194315id_/http://www.maps.org/w3pb/new/2004/2004_de_20593_2.pdf | url-status = dead | archive-date = 2014-03-05 }}</ref><ref name="SimmlerLiechti2018" /> MDA is an entactogen, stimulant, and weak psychedelic similarly to MDMA.<ref name="Oeri2021" /> Like MDMA, it acts as a potent and well-balanced SNDRA and as a weak serotonin 5-HT<sub>2</sub> receptor agonist.<ref name="RothmanBaumann2006" /><ref name="SetolaHufeisenGrande-Allen2003" /><ref name="NashRothBrodkin1994" /> However, MDA shows much more potent and efficacious serotonin 5-HT<sub>2A</sub>, 5-HT<sub>2B</sub>, and 5-HT<sub>2C</sub> receptor agonism than MDMA.<ref name="KaurKarabulutGauld2023" /><ref name="SimmlerLiechti2018">{{cite journal | vauthors = Simmler LD, Liechti ME | title = Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 252 | issue = | pages = 143–164 | date = 2018 | pmid = 29633178 | doi = 10.1007/164_2018_113 | isbn = 978-3-030-10560-0 | url = | quote = MDMA is also a low-potency partial agonist of the 5-HT2A receptor. Although not frequent, mild hallucinogen-like effects of MDMA have been reported, which may be attributable to 5-HT2A agonism (Nichols 2004; Liechti et al. 2000). MDA, the active metabolite of MDMA (Hysek et al. 2011), shows a tenfold higher potency for 5-HT2A agonism than MDMA (Rickli et al. 2015c). MDA likely contributes to the mode of action of MDMA and might contribute to the mild hallucinogenic effects of MDMA. }}</ref><ref name="NashRothBrodkin1994" /><ref name="SetolaHufeisenGrande-Allen2003" /> Accordingly, MDA produces greater psychedelic effects than MDMA in humans<ref name="Oeri2021" /> and might particularly contribute to the mild psychedelic-like effects of MDMA.<ref name="SimmlerLiechti2018" /> On the other hand, MDA may also be importantly involved in [[toxicity]] of MDMA, such as [[cardiac valvulopathy]].<ref name="LuethiLiechti2021">{{cite book | vauthors = Luethi D, Liechti ME | title=5-HT2B Receptors | chapter=Drugs of Abuse Affecting 5-HT2B Receptors | series=The Receptors | publisher=Springer International Publishing | publication-place=Cham | volume=35 | date=2021 | isbn=978-3-030-55919-9 | doi=10.1007/978-3-030-55920-5_16 | pages=277–289 | quote=Notably, in a study by Rickli and colleagues, MDMA did not activate the 5-HT2B receptor in the functional assay at investigated concentrations (EC50 > 20 μM); however, [MDA], the main psychoactive N-demethylated phase I metabolite of MDMA, potently activated the receptor at submicromolar concentrations [14]. This suggests that the metabolite MDA rather than MDMA itself may lead to valvulopathy and that there could be a signifcant metabolic contribution to MDMA-induced effects and adverse effect. }}</ref><ref name="TagenMantuanivanHeerden2023" /><ref name="SetolaHufeisenGrande-Allen2003" />

The [[duration of action]] of MDMA (3–6{{nbsp}}hours) is much shorter than its [[elimination half-life]] (8–9{{nbsp}}hours) would imply.<ref name="MeadParrott2020">{{cite journal | vauthors = Mead J, Parrott A | title = Mephedrone and MDMA: A comparative review | journal = Brain Res | volume = 1735 | issue = | pages = 146740 | date = May 2020 | pmid = 32087112 | doi = 10.1016/j.brainres.2020.146740 | url = | quote = A controlled study on eight experienced MDMA users reported that 1.5 mg/kg (comparable to what was deemed a typical dosage amount) consumed orally resulted in the subjective effects peaking within 2 h of ingestion (Harris et al., 2002). Other research indicates effects to emerge between 20 and 60 min, with them peaking between 60 and 90 min and lasting up to 5 h (Green et al., 2003). A dose of 100 mg has a half-life of 8–9h(De la Torre et al., 2004), although as mentioned above, users are unaware of the dose they ingest. }}</ref> In relation to this, MDMA's duration and the offset of its effects appear to be determined more by [[tachyphylaxis|rapid acute tolerance]] rather than by circulating drug concentrations.<ref name="HysekSimmlerNicola2012" /> Similar findings have been made for [[amphetamine]] and [[methamphetamine]].<ref name="ErmerPennickFrick2016">{{cite journal | vauthors = Ermer JC, Pennick M, Frick G | title = Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy | journal = Clinical Drug Investigation | volume = 36 | issue = 5 | pages = 341–356 | date = May 2016 | pmid = 27021968 | pmc = 4823324 | doi = 10.1007/s40261-015-0354-y }}</ref><ref name="CruickshankDyer2009">{{cite journal | vauthors = Cruickshank CC, Dyer KR | title = A review of the clinical pharmacology of methamphetamine | journal = Addiction | volume = 104 | issue = 7 | pages = 1085–1099 | date = July 2009 | pmid = 19426289 | doi = 10.1111/j.1360-0443.2009.02564.x | quote = Metabolism does not appear to be altered by chronic exposure, thus dose escalation appears to arise from pharmacodynamic rather than pharmacokinetic tolerance [24]. [...] The terminal plasma half-life of methamphetamine of approximately 10 hours is similar across administration routes, but with substantial inter-individual variability. Acute effects persist for up to 8 hours following a single moderate dose of 30 mg [30]. [...] peak plasma methamphetamine concentration occurs after 4 hours [35]. Nevertheless, peak cardiovascular and subjective effects occur rapidly (within 5–15 minutes). The dissociation between peak plasma concentration and clinical effects indicates acute tolerance, which may reflect rapid molecular processes such as redistribution of vesicular monoamines and internalization of monoamine receptors and transporters [6,36]. Acute subjective effects diminish over 4 hours, while cardiovascular effects tend to remain elevated. This is important, as the marked acute tachyphylaxis to subjective effects may drive repeated use within intervals of 4 hours, while cardiovascular risks may increase [11,35]. }}</ref><ref name="AbbasBarnhardtNash2024">{{cite journal | vauthors = Abbas K, Barnhardt EW, Nash PL, Streng M, Coury DL | title = A review of amphetamine extended release once-daily options for the management of attention-deficit hyperactivity disorder | journal = Expert Review of Neurotherapeutics | volume = 24 | issue = 4 | pages = 421–432 | date = April 2024 | pmid = 38391788 | doi = 10.1080/14737175.2024.2321921 | quote = For several decades, clinical benefits of amphetamines have been limited by the pharmacologic half-life of around 4 hours. Although higher doses can produce higher maximum concentrations, they do not affect the half-life of the dose. Therefore, to achieve longer durations of effect, stimulants had to be dosed at least twice daily. Further, these immediate-release doses were found to have their greatest effect shortly after administration, with a rapid decline in effect after reaching peak blood concentrations. The clinical correlation of this was found in comparing math problems attempted and solved between a mixed amphetamine salts preparation (MAS) 10 mg once at 8 am vs 8 am followed by 12 pm [14]. The study also demonstrated the phenomenon of acute tolerance, where even if blood concentrations were maintained over the course of the day, clinical efficacy in the form of math problems attempted and solved would diminish over the course of the day. These findings eventually led to the development of a once daily preparation (MAS XR) [15], which is a composition of 50% immediate-release beads and 50% delayed release beads intended to mimic this twice-daily dosing with only a single administration. | doi-access = free }}</ref><ref name="vanGaalenSchlumbohmFolgering2019">{{cite journal | vauthors = van Gaalen MM, Schlumbohm C, Folgering JH, Adhikari S, Bhattacharya C, Steinbach D, Stratford RE | title = Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 369 | issue = 1 | pages = 107–120 | date = April 2019 | pmid = 30733244 | doi = 10.1124/jpet.118.254508 | doi-access = free | quote = Acute tolerance has been demonstrated for methamphetamine in rats (Segal and Kuczenski, 2006), and for D-amphetamine in rats (Lewander, 1971), [non-human primates (NHPs)] (Jedema et al., 2014) and humans (Angrist et al., 1987; Brauer et al., 1996; Dolder et al., 2017). In vivo measurement of dopamine by microdialysis was used in rats and NHPs to evaluate these time-dependent effects. In humans, various subjective measures of mood related to the drug’s euphoric effects were observed to decline more rapidly than plasma concentrations following D-amphetamine oral doses ranging from 20 to 40 mg (Angrist et al., 1987; Brauer et al., 1996; Dolder et al., 2017). Whereas peak plasma concentrations and subjective effects occurred between 2 and 4 hours following administration, drug effect measures had largely returned to baseline values by 8 hours despite continued exposure to the drug (mean half-life = 8 hours following a 40 mg dose (Dolder et al., 2017)). }}</ref> One mechanism by which [[drug tolerance|tolerance]] to MDMA may occur is [[endocytosis|internalization]] of the [[serotonin transporter]] (SERT).<ref name="BisagnoCadet2021">{{cite book | vauthors = Bisagno V, Cadet JL | title=Handbook of Neurotoxicity | chapter=Methamphetamine and MDMA Neurotoxicity: Biochemical and Molecular Mechanisms | publisher=Springer International Publishing | publication-place=Cham | date=2021 | isbn=978-3-030-71519-9 | doi=10.1007/978-3-030-71519-9_80-1 | pages=1–24 | quote = Injections of large doses of MDMA cause massive release of 5-HT from presynaptic vesicles, followed by a rapid decrease in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels and decreased TPH activity (Górska et al., 2018; Lyles & Cadet, 2003). There do not appear to be losses of 5-HT uptake sites at early time points after MDMA administration (Lyles & Cadet, 2003). [...] MDMA also perturbs the function of SERT (Green et al., 2003), a marker of the integrity of serotonin neurons (Blakely et al., 1994). By virtue of its moderating synaptic 5-HT levels, SERT is crucial for the process of 5-HT neurotransmission (Green et al., 2003). MDMA downregulates SERT function without altering SERT mRNA or protein expression, and this rapid downregulation is sustained for at least 90 min and is dose-dependent (Kivell et al., 2010). }}</ref><ref name="KivellDayBosch2010">{{cite journal | vauthors = Kivell B, Day D, Bosch P, Schenk S, Miller J | title = MDMA causes a redistribution of serotonin transporter from the cell surface to the intracellular compartment by a mechanism independent of phospho-p38-mitogen activated protein kinase activation | journal = Neuroscience | volume = 168 | issue = 1 | pages = 82–95 | date = June 2010 | pmid = 20298763 | doi = 10.1016/j.neuroscience.2010.03.018 | url = }}</ref><ref name="HolleySimonsonKivell2013">{{cite journal | vauthors = Holley A, Simonson B, Kivell BM | title = MDMA regulates serotonin transporter function via a Protein kinase C dependent mechanism | date = April 2013 | journal = Journal of Addiction & Prevention | volume = 1 | issue = 1 | pages = 5 | issn = 2330-2178 | url = https://www.researchgate.net/publication/256328051 }}</ref><ref name="UnderhillAmara2020">{{cite journal | vauthors = Underhill S, Amara S | title=MDMA and TAAR1-mediated RhoA Activation in Serotonin Neurons | journal=The FASEB Journal | volume=34 | issue=S1 | date=2020 | issn=0892-6638 | doi=10.1096/fasebj.2020.34.s1.05856 | doi-access=free | pages=1}}</ref><ref name="UnderhillAmara2022">{{cite journal | vauthors = Underhill S, Amara S | title=3,4-methylenedioxymethamphetamine (MDMA) stimulates activation of TAAR1 and subsequent neurotransmitter transporter internalization in serotonin neurons | journal=The FASEB Journal | volume=36 | issue=S1 | date=2022 | issn=0892-6638 | doi=10.1096/fasebj.2022.36.S1.R5394 | page=| doi-access=free }}</ref> Although MDMA and serotonin are not significant TAAR1 agonists in humans, TAAR1 activation by MDMA may result in SERT internalization.<ref name="UnderhillAmara2020" /><ref name="UnderhillAmara2022" /><ref name="KittlerLauSchloss2010">{{cite journal | vauthors = Kittler K, Lau T, Schloss P | title = Antagonists and substrates differentially regulate serotonin transporter cell surface expression in serotonergic neurons | journal = Eur J Pharmacol | volume = 629 | issue = 1–3 | pages = 63–67 | date = March 2010 | pmid = 20006597 | doi = 10.1016/j.ejphar.2009.12.010 | url = | quote = Our results show that exposure to the SSRIs citalopram, fluoxetine, sertraline and paroxetine all induced SERT internalization, but with different efficacies. The substrates 5-HT and MDMA also induced SERT internalization, while cocaine elevated SERT cell surface expression. }}</ref><ref name="GainetdinovHoenerBerry2018" />

{| class="wikitable" style="font-size:small;"
|+ {{Nowrap|[[Monoamine releasing agent|Monoamine release]] by MDMA and related agents ({{Abbrlink|EC<sub>50</sub>|half-maximal effective concentration}}, nM)}}
|-
! Compound !! [[Serotonin releasing agent|Serotonin]] !! [[Norepinephrine releasing agent|Norepinephrine]] !! [[Dopamine releasing agent|Dopamine]]
|-
| [[Amphetamine]] || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}}
|-
| {{nbsp}}{{nbsp}}[[Dextroamphetamine|(''S'')-Amphetamine]] (''d'') || 698–1,765 || 6.6–7.2 || 5.8–24.8
|-
| {{nbsp}}{{nbsp}}[[Levoamphetamine|(''R'')-Amphetamine]] (''l'') || {{Abbr|ND|No data}} || 9.5 || 27.7
|-
| [[Methamphetamine]] || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}}
|-
| {{nbsp}}{{nbsp}}[[Dextromethamphetamine|(''S'')-Methamphetamine]] (''d'') || 736–1,292 || 12.3–13.8 || 8.5–24.5
|-
| {{nbsp}}{{nbsp}}[[Levomethamphetamine|(''R'')-Methamphetamine]] (''l'') || 4,640 || 28.5 || 416
|-
| [[Methylenedioxyamphetamine|MDA]] || 160 || 108 || 190
|-
| MDMA || 49.6–72 || 54.1–110 || 51.2–278
|-
| {{nbsp}}{{nbsp}}(''S'')-MDMA (''d'') || 74 || 136 || 142
|-
| {{nbsp}}{{nbsp}}[[(R)-MDMA|(''R'')-MDMA]] (''l'') || 340 || 560 || 3,700
|-
| [[Methylenedioxyethylamphetamine|MDEA]] || 47 || 2,608 || 622
|-
| [[Methylbenzodioxolylbutanamine|MBDB]] || 540 || 3,300 || >100,000
|-
| [[5,6-Methylenedioxy-2-aminoindane|MDAI]] || 114 || 117 || 1,334
|- class="sortbottom"
| colspan="4" 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="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 | date = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }}</ref><ref name="SetolaHufeisenGrande-Allen2003">{{cite journal | vauthors = Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL | title = 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro | journal = Molecular Pharmacology | volume = 63 | issue = 6 | pages = 1223–1229 | date = June 2003 | pmid = 12761331 | doi = 10.1124/mol.63.6.1223 | s2cid = 839426 }}</ref><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 | s2cid = 15573624 }}</ref><ref name="RothmanPartillaBaumann2012">{{cite journal | vauthors = Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE | title = Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 341 | issue = 1 | pages = 251–262 | date = April 2012 | pmid = 22271821 | pmc = 3364510 | doi = 10.1124/jpet.111.188946 }}</ref><ref name="MarusichAntonazzoBlough2016">{{cite journal | vauthors = Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, Baumann MH | title = The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue | journal = Neuropharmacology | volume = 101 | pages = 68–75 | date = February 2016 | pmid = 26362361 | pmc = 4681602 | doi = 10.1016/j.neuropharm.2015.09.004 }}</ref><ref name="NagaiNonakaKamimura2007">{{cite journal | vauthors = Nagai F, Nonaka R, Satoh Hisashi Kamimura K | title = The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain | journal = European Journal of Pharmacology | volume = 559 | issue = 2–3 | pages = 132–137 | date = March 2007 | pmid = 17223101 | doi = 10.1016/j.ejphar.2006.11.075 }}</ref><ref name="HalberstadtBrandtWalther2019">{{cite journal | vauthors = Halberstadt AL, Brandt SD, Walther D, Baumann MH | title = 2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors | journal = Psychopharmacology (Berl) | volume = 236 | issue = 3 | pages = 989–999 | date = March 2019 | pmid = 30904940 | pmc = 6848746 | doi = 10.1007/s00213-019-05207-1 | url = }}</ref><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><ref name="DunlapAndrewsOlson2018" />
|}

===Pharmacokinetics===
[[File:Main metabolic pathways of MDMA in humans.svg|class=skin-invert-image|thumb|left|300px|Main metabolic pathways of MDMA in humans.]]

The MDMA [[concentration]] in the [[blood stream]] starts to rise after about 30 minutes,<ref>{{cite journal | vauthors = Mas M, Farré M, de la Torre R, Roset PN, Ortuño J, Segura J, Camí J | title = Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 290 | issue = 1 | pages = 136–45 | date = July 1999 | doi = 10.1016/S0022-3565(24)34877-3 | pmid = 10381769 }}</ref> and reaches its maximal [[concentration]] in the blood stream between 1.5 and 3 hours after [[ingestion]].<ref name="TORRE1">{{cite journal | vauthors = de la Torre R, Farré M, Ortuño J, Mas M, Brenneisen R, Roset PN, Segura J, Camí J | title = Non-linear pharmacokinetics of MDMA ('ecstasy') in humans | journal = British Journal of Clinical Pharmacology | volume = 49 | issue = 2 | pages = 104–9 | date = February 2000 | pmid = 10671903 | pmc = 2014905 | doi = 10.1046/j.1365-2125.2000.00121.x }}</ref> It is then slowly [[metabolism|metabolized]] and [[excretion|excreted]], with levels of MDMA and its metabolites decreasing to half their peak concentration over the next several hours.<ref name="TORRE2">{{cite journal | vauthors = Farré M, Roset PN, Lopez CH, Mas M, Ortuño J, Menoyo E, Pizarro N, Segura J, Cami J | title = Pharmacology of MDMA in humans | journal = Annals of the New York Academy of Sciences | volume = 914 | issue = 1 | pages = 225–37 | date = September 2000 | pmid = 11085324 | doi = 10.1111/j.1749-6632.2000.tb05199.x | bibcode = 2000NYASA.914..225D | s2cid = 29247621 | doi-access = free }}</ref> The [[duration of action]] of MDMA is about 3 to 6{{nbsp}}hours.<ref name="Oeri2021" /> Brain serotonin levels are depleted after MDMA administration but serotonin levels typically return to normal within 24 to 48{{nbsp}}hours.<ref name=" Betzler2017" />

[[Metabolite]]s of MDMA that have been identified in humans include [[3,4-Methylenedioxyamphetamine|3,4-methylenedioxyamphetamine]] (MDA), [[4-hydroxy-3-methoxymethamphetamine]] (HMMA), 4-hydroxy-3-methoxyamphetamine<!--File:HMA2.png--> (HMA), [[Alpha-Methyldopamine|3,4-dihydroxyamphetamine]] (DHA) (also called alpha-methyldopamine (α-Me-DA)), [[MDP2P|3,4-methylenedioxyphenylacetone]] (MDP2P), and [[Methylenedioxyhydroxyamphetamine|3,4-methylenedioxy-N-hydroxyamphetamine]] (MDOH). The contributions of these metabolites to the psychoactive and [[toxic]] effects of MDMA are an area of active research. 80% of MDMA is metabolised in the liver, and about 20% is excreted unchanged in the [[urine]].<ref name="pmid22392347"/>

MDMA is known to be metabolized by two main [[metabolic pathway]]s: (1) ''O''-demethylenation followed by [[Catechol-O-methyl transferase|catechol-''O''-methyltransferase]] (COMT)-catalyzed methylation or glucuronide/sulfate conjugation; and (2) ''N''-dealkylation, deamination, and oxidation to the corresponding [[benzoic acid]] derivatives conjugated with [[glycine]].<ref name="delaTorreFarréRoset2004" /> The metabolism may be primarily by [[cytochrome P450 oxidase|cytochrome P450]] (CYP450) [[enzyme]]s [[CYP2D6]] and [[CYP3A4]] and COMT. Complex, nonlinear [[pharmacokinetics]] arise via autoinhibition of [[CYP2D6]] and CYP2D8, resulting in [[rate equation|zeroth order kinetics]] at higher doses. It is thought that this can result in sustained and higher [[concentration]]s of MDMA if the user takes consecutive doses of the drug.<ref name = "Kolbrich_2008">{{cite journal | vauthors = Kolbrich EA, Goodwin RS, Gorelick DA, Hayes RJ, Stein EA, Huestis MA | title = Plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine after controlled oral administration to young adults | journal = Therapeutic Drug Monitoring | volume = 30 | issue = 3 | pages = 320–32 | date = June 2008 | pmid = 18520604 | pmc = 2663855 | doi = 10.1097/FTD.0b013e3181684fa0 }}</ref>{{primary source inline|date=October 2014}}

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.<ref name="pmid17643356">{{cite journal | vauthors = Shima N, Kamata H, Katagi M, Tsuchihashi H, Sakuma T, Nemoto N | title = Direct determination of glucuronide and sulfate of 4-hydroxy-3-methoxymethamphetamine, the main metabolite of MDMA, in human urine | journal = Journal of Chromatography B | volume = 857 | issue = 1 | pages = 123–9 | date = September 2007 | pmid = 17643356 | doi = 10.1016/j.jchromb.2007.07.003 }}</ref> MDMA is a [[chirality (chemistry)|chiral]] compound and has been almost exclusively administered as a [[racemic|racemate]]. However, the two enantiomers have been shown to exhibit different kinetics. The disposition of MDMA may also be stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. Evidence suggests<ref name="fallon">{{cite journal | vauthors = Fallon JK, Kicman AT, Henry JA, Milligan PJ, Cowan DA, Hutt AJ | title = Stereospecific analysis and enantiomeric disposition of 3, 4-methylenedioxymethamphetamine (Ecstasy) in humans | journal = Clinical Chemistry | volume = 45 | issue = 7 | pages = 1058–69 | date = July 1999 | pmid = 10388483 | doi = 10.1093/clinchem/45.7.1058 | doi-access = free }}</ref> that the area under the [[blood plasma]] concentration versus time curve (AUC) was two to four times higher for the (''R'')-enantiomer than the (''S'')-enantiomer after a 40{{nbsp}}mg oral dose in human volunteers. Likewise, the plasma half-life of [[(R)-MDMA|(''R'')-MDMA]] was significantly longer than that of the (''S'')-enantiomer (5.8{{nbsp}}±{{nbsp}}2.2 hours vs 3.6{{nbsp}}±{{nbsp}}0.9 hours).<ref name="Toxnet MDMA after-effects"/> However, because MDMA excretion and metabolism have nonlinear kinetics,<ref name="mueller">{{cite journal | vauthors = Mueller M, Peters FT, Maurer HH, McCann UD, Ricaurte GA | title = Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 1 | pages = 38–44 | date = October 2008 | pmid = 18591215 | doi = 10.1124/jpet.108.141366 | s2cid = 38043715 }}</ref> the half-lives would be higher at more typical doses (100{{nbsp}}mg is sometimes considered a typical dose).<ref name="TORRE1" />