Editing MDMA (section)

===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" />