Editing MDMA (section)

==Interactions==
{{See also|Trip killer#Antidotes of other hallucinogens|MDMA/citalopram}}

A number of [[drug interactions]] can occur between MDMA and other drugs, including [[serotonin|serotonergic]] drugs.<ref name="Toxnet MDMA after-effects"/><ref>{{cite journal | vauthors = Silins E, Copeland J, Dillon P | title = Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk | journal = The Australian and New Zealand Journal of Psychiatry | volume = 41 | issue = 8 | pages = 649–55 | date = August 2007 | pmid = 17620161 | doi = 10.1080/00048670701449237 | s2cid = 25832516 }}</ref> MDMA also interacts with drugs which inhibit [[CYP450]] enzymes, like [[ritonavir]] (Norvir), particularly [[CYP2D6]] inhibitors.<ref name="Toxnet MDMA after-effects"/> Life-threatening reactions and death have occurred in people who took MDMA while on ritonavir.<ref name="pmid32228243">{{cite journal | vauthors = Papaseit E, Pérez-Mañá C, Torrens M, Farré A, Poyatos L, Hladun O, Sanvisens A, Muga R, Farré M | title = MDMA interactions with pharmaceuticals and drugs of abuse | journal = Expert Opin Drug Metab Toxicol | volume = 16 | issue = 5 | pages = 357–369 | date = May 2020 | pmid = 32228243 | doi = 10.1080/17425255.2020.1749262 | s2cid = 214750903 | url = }}</ref> [[Bupropion]], a strong CYP2D6 inhibitor, has been found to increase MDMA exposure with administration of MDMA.<ref name="FonsecaFibeiroTapadas2021" /><ref name="SchmidRickliSchaffner2015" /> Concurrent use of MDMA high dosages with another serotonergic drug can result in a life-threatening condition called [[serotonin syndrome]].<ref name=Betzler2017/><ref name="Toxnet MDMA after-effects"/> Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain [[monoamine oxidase inhibitor]]s (MAOIs),<ref name=Betzler2017/><ref name="Toxnet MDMA after-effects"/> such as [[phenelzine]] (Nardil), [[tranylcypromine]] (Parnate), or [[moclobemide]] (Aurorix, Manerix).<ref>{{cite journal | vauthors = Vuori E, Henry JA, Ojanperä I, Nieminen R, Savolainen T, Wahlsten P, Jäntti M | title = Death following ingestion of MDMA (ecstasy) and moclobemide | journal = Addiction | volume = 98 | issue = 3 | pages = 365–8 | date = March 2003 | pmid = 12603236 | doi = 10.1046/j.1360-0443.2003.00292.x }}</ref> [[Serotonin reuptake inhibitor]]s (SRIs) such as [[citalopram]] (Celexa), [[duloxetine]] (Cymbalta), [[fluoxetine]] (Prozac), and [[paroxetine]] (Paxil) have been shown to block most of the subjective effects of MDMA.<ref name="HalberstadtNichols2020">{{cite book| vauthors = Halberstadt AL, Nichols DE |title=Handbook of the Behavioral Neurobiology of Serotonin|chapter=Serotonin and serotonin receptors in hallucinogen action|series=Handbook of Behavioral Neuroscience|volume=31|year=2020|pages=843–863|issn=1569-7339|doi=10.1016/B978-0-444-64125-0.00043-8|isbn=9780444641250|s2cid=241134396}}</ref> [[Norepinephrine reuptake inhibitor]]s (NRIs) such as [[reboxetine]] (Edronax) have been found to reduce [[emotional excitation]] and feelings of [[psychostimulant|stimulation]] with MDMA but do not appear to influence its [[entactogen]]ic or [[euphoriant|mood-elevating]] effects.<ref name="HalberstadtNichols2020" />

MDMA [[monoamine releasing agent|induces the release of monoamine neurotransmitter]]s and thereby acts as an indirectly acting [[sympathomimetic]] and produces a variety of [[cardiostimulant]] effects.<ref name="FonsecaFibeiroTapadas2021">{{cite journal | vauthors = Fonseca DA, Ribeiro DM, Tapadas M, Cotrim MD | title = Ecstasy (3,4-methylenedioxymethamphetamine): Cardiovascular effects and mechanisms | journal = Eur J Pharmacol | volume = 903 | issue = | pages = 174156 | date = July 2021 | pmid = 33971177 | doi = 10.1016/j.ejphar.2021.174156 | url = }}</ref> It [[dose dependence|dose-dependently]] increases [[heart rate]], [[blood pressure]], and [[cardiac output]].<ref name="FonsecaFibeiroTapadas2021" /><ref name="MendelsonBaggottLi2012" /> SRIs like citalopram and [[paroxetine]], as well as the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] [[receptor antagonist|antagonist]] [[ketanserin]], have been found to partially block the increases in heart rate and blood pressure with MDMA.<ref name="FonsecaFibeiroTapadas2021" /><ref name="LiechtiSaurGamma2000">{{cite journal | vauthors = Liechti ME, Saur MR, Gamma A, Hell D, Vollenweider FX | title = Psychological and physiological effects of MDMA ("Ecstasy") after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans | journal = Neuropsychopharmacology | volume = 23 | issue = 4 | pages = 396–404 | date = October 2000 | pmid = 10989266 | doi = 10.1016/S0893-133X(00)00126-3 | url = }}</ref> It is notable in this regard that [[serotonergic psychedelic]]s such as [[psilocybin]], which act as serotonin 5-HT<sub>2A</sub> receptor agonists, likewise have sympathomimetic effects.<ref name="Wsół2023">{{cite journal | vauthors = Wsół A | title = Cardiovascular safety of psychedelic medicine: current status and future directions | journal = Pharmacol Rep | volume = 75 | issue = 6 | pages = 1362–1380 | date = December 2023 | pmid = 37874530 | pmc = 10661823 | doi = 10.1007/s43440-023-00539-4 | url = }}</ref><ref name="NeumannDheinKirchhefer2024">{{cite journal | vauthors = Neumann J, Dhein S, Kirchhefer U, Hofmann B, Gergs U | title = Effects of hallucinogenic drugs on the human heart | journal = Front Pharmacol | volume = 15 | issue = | pages = 1334218 | date = 2024 | pmid = 38370480 | pmc = 10869618 | doi = 10.3389/fphar.2024.1334218 | doi-access = free | url = }}</ref><ref name="LeyHolzeArikci2023">{{cite journal | vauthors = Ley L, Holze F, Arikci D, Becker AM, Straumann I, Klaiber A, Coviello F, Dierbach S, Thomann J, Duthaler U, Luethi D, Varghese N, Eckert A, Liechti ME | title = Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants | journal = Neuropsychopharmacology | volume = 48 | issue = 11 | pages = 1659–1667 | date = October 2023 | pmid = 37231080 | pmc = 10517157 | doi = 10.1038/s41386-023-01607-2 | url = }}</ref> The NRI [[reboxetine]] and the [[serotonin–norepinephrine reuptake inhibitor]] (SNRI) duloxetine block MDMA-induced increases in heart rate and blood pressure.<ref name="FonsecaFibeiroTapadas2021" /> Conversely, bupropion, a [[norepinephrine–dopamine reuptake inhibitor]] (NDRI) with only weak [[dopaminergic]] activity,<ref name="HartSpangemacherDefert2024">{{cite journal | vauthors = Hart XM, Spangemacher M, Defert J, Uchida H, Gründer G | title = Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants | journal = Ther Drug Monit | volume = 46 | issue = 2 | pages = 155–169 | date = April 2024 | pmid = 38287888 | doi = 10.1097/FTD.0000000000001142 | url = }}</ref><ref name="EapGründerBaumann2021">{{cite journal | vauthors = Eap CB, Gründer G, Baumann P, Ansermot N, Conca A, Corruble E, Crettol S, Dahl ML, de Leon J, Greiner C, Howes O, Kim E, Lanzenberger R, Meyer JH, Moessner R, Mulder H, Müller DJ, Reis M, Riederer P, Ruhe HG, Spigset O, Spina E, Stegman B, Steimer W, Stingl J, Suzen S, Uchida H, Unterecker S, Vandenberghe F, Hiemke C | title = Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants | journal = The World Journal of Biological Psychiatry | volume = 22 | issue = 8 | pages = 561–628 | date = October 2021 | pmid = 33977870 | doi = 10.1080/15622975.2021.1878427 | s2cid = 234472488 | url = https://serval.unil.ch/resource/serval:BIB_6FD14CC75A02.P001/REF.pdf | access-date = 10 April 2022 | archive-date = 5 May 2022 | archive-url = https://web.archive.org/web/20220505232003/https://serval.unil.ch/resource/serval:BIB_6FD14CC75A02.P001/REF.pdf | url-status = live }}</ref> reduced MDMA-induced heart rate and circulating [[norepinephrine]] increases but did not affect MDMA-induced blood pressure increases.<ref name="FonsecaFibeiroTapadas2021" /><ref name="SchmidRickliSchaffner2015">{{cite journal | vauthors = Schmid Y, Rickli A, Schaffner A, Duthaler U, Grouzmann E, Hysek CM, Liechti ME | title = Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects | journal = J Pharmacol Exp Ther | volume = 353 | issue = 1 | pages = 102–111 | date = April 2015 | pmid = 25655950 | doi = 10.1124/jpet.114.222356 | url = }}</ref> On the other hand, the robust NDRI [[methylphenidate]], which has sympathomimetic effects of its own, has been found to augment the cardiovascular effects and increases in circulating norepinephrine and [[epinephrine]] levels induced by MDMA.<ref name="FonsecaFibeiroTapadas2021" /><ref name="HysekSimmlerSchillinger2014">{{cite journal | vauthors = Hysek CM, Simmler LD, Schillinger N, Meyer N, Schmid Y, Donzelli M, Grouzmann E, Liechti ME | title = Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone or in combination | journal = Int J Neuropsychopharmacol | volume = 17 | issue = 3 | pages = 371–381 | date = March 2014 | pmid = 24103254 | doi = 10.1017/S1461145713001132 | url = https://edoc.unibas.ch/35606/2/371.full.pdf}}</ref>

The [[binding selectivity|non-selective]] [[beta blocker]] [[pindolol]] blocked MDMA-induced increases in heart rate but not blood pressure.<ref name="FonsecaFibeiroTapadas2021" /><ref name="RichardsAlbertsonDerlet2015" /><ref name="HysekVollenweiderLiechti2010">{{cite journal | vauthors = Hysek CM, Vollenweider FX, Liechti ME | title = Effects of a beta-blocker on the cardiovascular response to MDMA (Ecstasy) | journal = Emerg Med J | volume = 27 | issue = 8 | pages = 586–589 | date = August 2010 | pmid = 20378736 | doi = 10.1136/emj.2009.079905 | url = https://www.zora.uzh.ch/id/eprint/40820/1/Hysek.pdf}}</ref> The [[α2-adrenergic receptor|α<sub>2</sub>-adrenergic receptor]] [[agonist]] [[clonidine]] did not affect the cardiovascular effects of MDMA, though it reduced blood pressure.<ref name="FonsecaFibeiroTapadas2021" /><ref name="RichardsAlbertsonDerlet2015" /><ref name="HysekBruggerSimmler2012">{{cite journal | vauthors = Hysek CM, Brugger R, Simmler LD, Bruggisser M, Donzelli M, Grouzmann E, Hoener MC, Liechti ME | title = Effects of the α₂-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers | journal = J Pharmacol Exp Ther | volume = 340 | issue = 2 | pages = 286–294 | date = February 2012 | pmid = 22034656 | doi = 10.1124/jpet.111.188425 | url = }}</ref> The [[α1-adrenergic receptor|α<sub>1</sub>-adrenergic receptor]] antagonists [[doxazosin]] and [[prazosin]] blocked or reduced MDMA-induced blood pressure increases but augmented MDMA-induced heart rate and cardiac output increases.<ref name="FonsecaFibeiroTapadas2021" /><ref name="RichardsAlbertsonDerlet2015" /><ref name="HysekFinkSimmler2013">{{cite journal | vauthors = Hysek CM, Fink AE, Simmler LD, Donzelli M, Grouzmann E, Liechti ME | title = α₁-Adrenergic receptors contribute to the acute effects of 3,4-methylenedioxymethamphetamine in humans | journal = J Clin Psychopharmacol | volume = 33 | issue = 5 | pages = 658–666 | date = October 2013 | pmid = 23857311 | doi = 10.1097/JCP.0b013e3182979d32 | url = }}</ref><ref name="MendelsonBaggottLi2012">{{cite journal | vauthors=Mendelson J, Baggott MJ, Li L, Coyle J, Galloway GP | title=Poster Session II (PII 1-111): PII-41. MDMA-Induced Increases in Blood Pressure Are Not Mediated by α-Adrenergic Mechanisms and Are Not Due To Elevated Peripheral Vascular Resistance | journal=Clinical Pharmacology & Therapeutics | volume=91 | issue=S1 [American Society for Clinical Pharmacology and Therapeutics Abstract of papers, 2012 Annual Meeting Gaylord National Hotel and Convention Center National Harbor, Maryland March 14–17, 2012] | date=2012 | issn=0009-9236 | doi=10.1038/clpt.2011.361 | pages=S51–S93 (S66–S66) | quote = MDMA increased heart rate (HR) by 25 bpm (p<.001), [cardiac output (CO)] by 1.75 L/min (p<0.01) but did not alter [stroke volume (SV)] or [systemic vascular resistance (SVR)]. Compared to MDMA alone the combination of MDMA + prazosin further increased HR by 24 bpm (p<0.001) and CO by 3.3L/min (p<0.02). MDMA increased systolic and diastolic blood pressure (SBP, DBP) by 26 mmHg (p<0.001 each); prazosin attenuated MDMA effects on DBP by 9.3 mmHg (p<001) but did not alter SBP. [...] MDMA increases HR, producing elevations in CO. The hypertensive effects of MDMA are not due to elevated peripheral vascular resistance and the blood pressure effects of MDMA are not attenuated by α-adrenergic blockade, suggesting that MDMA may produce CV effects through non-α-adrenergic mechanisms.}}</ref> The dual α<sub>1</sub>- and [[β-adrenergic receptor]] blocker [[carvedilol]] reduced MDMA-induced heart rate and blood pressure increases.<ref name="FonsecaFibeiroTapadas2021" /><ref name="RichardsAlbertsonDerlet2015">{{cite journal | vauthors = Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ | title = Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review | journal = Drug Alcohol Depend | volume = 150 | issue = | pages = 1–13 | date = May 2015 | pmid = 25724076 | doi = 10.1016/j.drugalcdep.2015.01.040 | url = }}</ref><ref name="HysekSchmidRickli2012">{{cite journal | vauthors = Hysek C, Schmid Y, Rickli A, Simmler LD, Donzelli M, Grouzmann E, Liechti ME | title = Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans | journal = Br J Pharmacol | volume = 166 | issue = 8 | pages = 2277–2288 | date = August 2012 | pmid = 22404145 | pmc = 3448893 | doi = 10.1111/j.1476-5381.2012.01936.x | url = }}</ref> In contrast to the cases of serotonergic and noradrenergic agents, the [[dopamine]] [[D2 receptor|D<sub>2</sub> receptor]] antagonist [[haloperidol]] did not affect the cardiovascular responses to MDMA.<ref name="FonsecaFibeiroTapadas2021" /><ref name="LiechtiVollenweider2000">{{cite journal | vauthors = Liechti ME, Vollenweider FX | title = Acute psychological and physiological effects of MDMA ("Ecstasy") after haloperidol pretreatment in healthy humans | journal = Eur Neuropsychopharmacol | volume = 10 | issue = 4 | pages = 289–295 | date = July 2000 | pmid = 10871712 | doi = 10.1016/s0924-977x(00)00086-9 | url = }}</ref> Due to the theoretical risk of "unopposed α-stimulation" and possible consequences like [[coronary vasospasm]], it has been suggested that dual α<sub>1</sub>- and β-adrenergic receptor antagonists like carvedilol and [[labetalol]], rather than selective beta blockers, should be used in the management of stimulant-induced [[sympathomimetic]] [[toxicity]], for instance in the context of [[overdose]].<ref name="RichardsAlbertsonDerlet2015" /><ref name="RichardsHollanderRamoska2017">{{cite journal | vauthors = Richards JR, Hollander JE, Ramoska EA, Fareed FN, Sand IC, Izquierdo Gómez MM, Lange RA | title = β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon | journal = J Cardiovasc Pharmacol Ther | volume = 22 | issue = 3 | pages = 239–249 | date = May 2017 | pmid = 28399647 | doi = 10.1177/1074248416681644 | url = }}</ref>