MDMA

MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals, and house parties. In the rave environment, the sensory effects of music and lighting are often highly synergistic with the drug. The psychedelic amphetamine quality of MDMA offers multiple appealing aspects to users in the rave setting. Some users enjoy the feeling of mass communion from the inhibition-reducing effects of the drug, while others use it as party fuel because of the drug's stimulatory effects.{{cite book|vauthors=Reynolds S|title=Generation Ecstasy: Into the World of Techno and Rave Culture|year=1999|publisher=Routledge|isbn=978-0-415-92373-6|page=81|url=https://books.google.com/books?id=tGaRJiXe74UC&q=Generation+Ecstasy+MDMA&pg=PA81|access-date=13 October 2020|archive-date=8 November 2023|archive-url=https://web.archive.org/web/20231108064150/https://books.google.com/books?id=tGaRJiXe74UC&q=Generation+Ecstasy+MDMA&pg=PA81#v=snippet&q=Generation%20Ecstasy%20MDMA&f=false|url-status=live}} MDMA is used less often than other stimulants, typically less than once per week.

MDMA is sometimes taken in conjunction with other psychoactive drugs such as LSD,{{cite journal | vauthors = Zeifman RJ, Kettner H, Pagni BA, Mallard A, Roberts DE, Erritzoe D, Ross S, Carhart-Harris RL | title = Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences | journal = Scientific Reports | volume = 13 | issue = 1 | pages = 13645 | date = August 2023 | pmid = 37608057 | doi = 10.1038/s41598-023-40856-5 | pmc = 10444769 | bibcode = 2023NatSR..1313645Z }} psilocybin mushrooms, 2C-B, and ketamine. The combination with LSD is called "candy-flipping". The combination with 2C-B is called "nexus flipping". For this combination, most people take the MDMA first, wait until the peak is over, and then take the 2C-B.{{Cite web | vauthors = Weiss S |date=2024-02-16 |title=Nexus Flipping: What Happens When You Combine MDMA and 2C-B |url=https://doubleblindmag.com/nexus-flipping/ |access-date=2024-07-10 |website=DoubleBlind Mag |language=en-US}}

MDMA is often co-administered with alcohol, methamphetamine, and prescription drugs such as SSRIs with which MDMA has several drug-drug interactions.{{cite journal | vauthors = Hysek CM, Simmler LD, Nicola VG, Vischer N, Donzelli M, Krähenbühl S, Grouzmann E, Huwyler J, Hoener MC, Liechti ME | title = Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study | journal = PLOS ONE | volume = 7 | issue = 5 | pages = e36476 | date = 2012-05-04 | pmid = 22574166 | doi = 10.1371/journal.pone.0036476 | pmc = 3344887 | bibcode = 2012PLoSO...736476H | veditors = Laks J | doi-access = free | quote = Fig. 7 shows the mean PD effects of MDMA plotted against simultaneous plasma concentrations at the different time points (hysteresis loops). The increases in “any drug effect" (Fig. 7a) and MAP (Fig. 7b) returned to baseline within 6 h when MDMA concentrations were still high. This clockwise hysteresis indicates that a smaller MDMA effect was seen at a given plasma concentration later in time, indicating rapid acute pharmacodynamic tolerance, which was similarly described for cocaine [33]. [...] Figure 7. Pharmacokinetic-pharmacodynamic (PK-PD) relationship. MDMA effects are plotted against simultaneous MDMA plasma concentrations (a, b). The time of sampling is noted next to each point in minutes or hours after MDMA administration. The clockwise hysteresis indicates acute tolerance to the effects of MDMA. }}{{cite journal | vauthors = Yuki F, Rie I, Miki K, Mitsuhiro W, Naotaka K, Kenichiro N | title = Warning against co-administration of 3,4-methylenedioxymethamphetamine (MDMA) with methamphetamine from the perspective of pharmacokinetic and pharmacodynamic evaluations in rat brain | journal = European Journal of Pharmaceutical Sciences | volume = 49 | issue = 1 | pages = 57–64 | date = April 2013 | pmid = 23395913 | doi = 10.1016/j.ejps.2013.01.014 }}{{cite journal | vauthors = Hamida SB, Tracqui A, de Vasconcelos AP, Szwarc E, Lazarus C, Kelche C, Jones BC, Cassel JC | title = Ethanol increases the distribution of MDMA to the rat brain: possible implications in the ethanol-induced potentiation of the psychostimulant effects of MDMA | journal = The International Journal of Neuropsychopharmacology | volume = 12 | issue = 6 | pages = 749–759 | date = July 2009 | pmid = 19046482 | doi = 10.1017/s1461145708009693 | s2cid = 24230367 | doi-access = free }} Three life-threatening reports of MDMA co-administration with ritonavir have been reported;{{cite journal | vauthors = Oesterheld JR, Armstrong SC, Cozza KL | title = Ecstasy: pharmacodynamic and pharmacokinetic interactions | journal = Psychosomatics | volume = 45 | issue = 1 | pages = 84–87 | date = 2004-03-01 | pmid = 14709765 | doi = 10.1176/appi.psy.45.1.84 | doi-access = free }} with ritonavir having severe and dangerous drug-drug interactions with a wide range of both psychoactive, anti-psychotic, and non-psychoactive drugs.{{cite journal | vauthors = Carpenter M, Berry H, Pelletier AL | title = Clinically Relevant Drug-Drug Interactions in Primary Care | journal = American Family Physician | volume = 99 | issue = 9 | pages = 558–564 | date = May 2019 | pmid = 31038898 | doi = }}

{{See also|MDMA#Research directions|MDMA-assisted psychotherapy}}

As of 2023, MDMA therapies have only been approved for research purposes, with no widely accepted medical indications,{{cite journal | vauthors = Sessa B, Nutt D | title = Making a medicine out of MDMA | journal = The British Journal of Psychiatry | volume = 206 | issue = 1 | pages = 4–6 | date = January 2015 | pmid = 25561485 | doi = 10.1192/bjp.bp.114.152751 | doi-access = free }}{{cite journal | vauthors = Ebrahimian Z, Karimi Z, Khoshnoud MJ, Namavar MR, Daraei B, Haidari MR | title = Behavioral and Stereological Analysis of the Effects of Intermittent Feeding Diet on the Orally Administrated MDMA ("ecstasy") in Mice | journal = Innovations in Clinical Neuroscience | volume = 14 | issue = 1–2 | pages = 40–52 | date = 1 February 2017 | pmid = 28386520 | pmc = 5373794 | quote = MDMA is listed as a Schedule 1 drug by the United States Drug Enforcement Agency, meaning that currently there are no accepted medical uses for MDMA in the United States, there is a lack of accepted safety for use under medical supervision, and there is a high potential for abuse. }} although this varies by jurisdiction. Before it was widely banned, it saw limited use in psychotherapy.{{cite journal | vauthors = Climko RP, Roehrich H, Sweeney DR, Al-Razi J | title = Ecstacy: a review of MDMA and MDA | journal = International Journal of Psychiatry in Medicine | volume = 16 | issue = 4 | pages = 359–72 | year = 1986 | pmid = 2881902 | doi = 10.2190/dcrp-u22m-aumd-d84h | s2cid = 31902958 }} In 2017 the United States Food and Drug Administration (FDA) granted breakthrough therapy designation for MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD),{{Cite news|vauthors=Wan W|date=6 August 2017|title=Ecstasy could be 'breakthrough' therapy for soldiers, others suffering from PTSD|language=en-US|newspaper=The Washington Post|url=https://www.washingtonpost.com/national/health-science/ecstasy-could-be-breakthrough-therapy-for-soldiers-others-suffering-from-ptsd/2017/08/26/009314ca-842f-11e7-b359-15a3617c767b_story.html|access-date=3 April 2021|archive-date=28 August 2017|archive-url=https://web.archive.org/web/20170828230759/https://www.washingtonpost.com/national/health-science/ecstasy-could-be-breakthrough-therapy-for-soldiers-others-suffering-from-ptsd/2017/08/26/009314ca-842f-11e7-b359-15a3617c767b_story.html|url-status=live}}{{Cite web|vauthors=Kupferschmidt K|date=26 August 2017|title=All clear for the decisive trial of ecstasy in PTSD patients|url=https://www.science.org/content/article/all-clear-decisive-trial-ecstasy-ptsd-patients|access-date=3 April 2021|website=Science (magazine)|language=en|archive-date=28 December 2021|archive-url=https://web.archive.org/web/20211228220713/https://www.science.org/content/article/all-clear-decisive-trial-ecstasy-ptsd-patients|url-status=live}} with some preliminary evidence that MDMA may facilitate psychotherapy efficacy for PTSD.{{cite news |vauthors=Zarembo A |date=15 March 2014 |title=Exploring therapeutic effects of MDMA on post-traumatic stress |work=Los Angeles Times |url=https://www.latimes.com/local/la-me-mdma-20140316-story.html |access-date=2023-04-07 |archive-date=7 April 2023 |archive-url=https://web.archive.org/web/20230407052723/https://www.latimes.com/local/la-me-mdma-20140316-story.html |url-status=live }}{{Cite journal | vauthors = Singleton SP, Wang J, Mithoefer M, Hanlon CA, George MS, Mithoefer A, Mithoefer O, Coker AR, Klosinski B, Emerson AL, Doblin R |date=2023 |title=Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder |journal=Frontiers in Psychiatry |volume=13 | page = 947622 |doi=10.3389/fpsyt.2022.947622 | pmid = 36713926 | pmc = 9879604 |issn=1664-0640| doi-access = free }} Pilot studies indicate that MDMA-assisted psychotherapy may be beneficial in treating social anxiety in autistic adults. In these pilot studies, the vast majority of participants reported increased feelings of empathy that persisted after the therapy sessions.{{Cite web |title=Psychedelic Support: First Clinical Trial: Social Anxiety in Autistic Adults Successfully Treated with MDMA Therapy – Multidisciplinary Association for Psychedelic Studies – MAPS |url=https://maps.org/news/media/psychedelic-support-first-clinical-trial-social-anxiety-in-autistic-adults-successfully-treated-with-mdma-therapy/ |access-date=2024-09-17 |website=maps.org}} Some have proposed that psychedelics in general may act as active "super placebos" used for therapeutic purposes.{{cite journal | vauthors = Dupuis D, Veissière S | title = Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos? | journal = Transcult Psychiatry | volume = 59 | issue = 5 | pages = 571–578 | date = October 2022 | pmid = 36263513 | doi = 10.1177/13634615221131465 | url = }}{{cite journal | vauthors = van Elk M, Yaden DB | title = Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review | journal = Neurosci Biobehav Rev | volume = 140 | issue = | pages = 104793 | date = September 2022 | pmid = 35878791 | doi = 10.1016/j.neubiorev.2022.104793 | url = | quote = In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a ‘super-placebo’ (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility. | hdl = 1887/3515020 | hdl-access = free }}

Small doses of MDMA are used by some religious practitioners as an entheogen to enhance prayer or meditation.{{cite web | url = http://csp.org/practices/entheogens/docs/saunders-ecstasy_rel.html | vauthors = Saunders N | date = 29 July 1995 | title = The Agony and Ecstasy of God's path | archive-url = https://web.archive.org/web/20130424024232/http://csp.org/practices/entheogens/docs/saunders-ecstasy_rel.html | archive-date=24 April 2013 | work = Council on Spiritual Practices (CSP) | access-date = 11 June 2011 }} MDMA has been used as an adjunct to New Age spiritual practices.{{cite journal |vauthors=Watson L, Beck J |year=1991 |title=New age seekers: MDMA use as an adjunct to spiritual pursuit |url=http://research.lycaeum.org/researchpdfs/1991_watson_1.pdf |journal=Journal of Psychoactive Drugs |volume=23 |issue=3 |pages=261–70 |doi=10.1080/02791072.1991.10471587 |pmid=1685513 |archive-url=https://web.archive.org/web/20041122213135/http://research.lycaeum.org/researchpdfs/1991_watson_1.pdf |archive-date=22 November 2004 |access-date=28 April 2024 |url-status=bot: unknown }}

File:1g_MDMA-HCl.jpg

MDMA has become widely known as ecstasy (shortened "E", "X", or "XTC"), usually referring to its tablet form, although this term may also include the presence of possible adulterants or diluents. The UK term "mandy" and the US term "molly" colloquially refer to MDMA in a crystalline powder form that is thought to be free of adulterants. MDMA is also sold in the form of the hydrochloride salt, either as loose crystals or in gelcaps. MDMA tablets can sometimes be found in a shaped form that may depict characters from popular culture. These are sometimes collectively referred to as "fun tablets".{{cite web | vauthors = Kelly M | date = 20 June 2019 | work = Nintendo Enthusiast | title = Man arrested for possession of ecstasy tablets shaped like Wario | url = https://www.nintendoenthusiast.com/man-arrested-for-possession-of-ecstasy-tablets-shaped-like-wario/ | access-date = 17 June 2021 | archive-date = 24 June 2021 | archive-url = https://web.archive.org/web/20210624195901/https://www.nintendoenthusiast.com/man-arrested-for-possession-of-ecstasy-tablets-shaped-like-wario/ | url-status = dead }}{{cite web | author = | title = Groesbeck: Students caught with deceptively shaped Ecstasy pills | date = 31 October 2019 | work = KWTX | url = https://www.kwtx.com/content/news/Students-caught-with-deceptively-shaped-Ecstasy-pills-at-local-school-564188221.html | access-date = 17 June 2021 | archive-date = 24 June 2021 | archive-url = https://web.archive.org/web/20210624195735/https://www.kwtx.com/content/news/Students-caught-with-deceptively-shaped-Ecstasy-pills-at-local-school-564188221.html | url-status = live }}

Partly due to the global supply shortage of sassafras oil—a problem largely assuaged by use of improved or alternative modern methods of synthesis—the purity of substances sold as molly have been found to vary widely. Some of these substances contain methylone, ethylone, MDPV, mephedrone, or any other of the group of compounds commonly known as bath salts, in addition to, or in place of, MDMA.{{cite AV media |date=13 August 2014 |title=Molly Madness |medium=TV documentary |url= |publisher=National Geographic Channel | work = Drugs, Inc. |asin=B00LIC368M }}{{cite AV media |date=10 December 2014 |title=Manic Molly |medium=TV documentary |url= |publisher=National Geographic Channel | work = Drugs, Inc. |asin=B00LIC368M }} Powdered MDMA ranges from pure MDMA to crushed tablets with 30–40% purity. MDMA tablets typically have low purity due to bulking agents that are added to dilute the drug and increase profits (notably lactose) and binding agents. Tablets sold as ecstasy sometimes contain 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), other amphetamine derivatives, caffeine, opiates, or painkillers. Some tablets contain little or no MDMA.{{cite web|title=3,4-Methylenedioxymethamphetamine|url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+42542-10-9|website=Hazardous Substances Data Bank|publisher=National Library of Medicine|access-date=22 August 2014|date=28 August 2008|archive-date=4 April 2019|archive-url=https://web.archive.org/web/20190404201340/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs%20hsdb%3A%40term%20%40rn%20%40rel%2042542-10-9|url-status=live}} The proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country. The average content of MDMA in a preparation is 70 to 120{{nbsp}}mg with the purity having increased since the 1990s.

MDMA is usually consumed by mouth. It is also sometimes snorted.

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In general, MDMA users report feeling the onset of subjective effects within 30 to 60 minutes of oral consumption and reaching peak effect at 75 to 120 minutes, which then plateaus for about 3.5 hours.{{cite journal | vauthors = Liechti ME, Gamma A, Vollenweider FX | title = Gender differences in the subjective effects of MDMA | journal = Psychopharmacology | volume = 154 | issue = 2 | pages = 161–8 | date = March 2001 | pmid = 11314678 | doi = 10.1007/s002130000648 | s2cid = 20251888}} The desired short-term psychoactive effects of MDMA have been reported to include:

• Euphoria – a sense of general well-being and happiness
• Increased self-confidence, sociability, and perception of facilitated communication
• Entactogenic effects—increased empathy or feelings of closeness with others and oneself
• Dilated pupils
• Relaxation and reduced anxiety
• Increased emotionality
• A sense of inner peace
• Mild hallucination
• Enhanced sensation, perception, or sexuality
• Altered sense of time

The experience elicited by MDMA depends on the dose, setting, and user. The variability of the induced altered state is lower compared to other psychedelics. For example, MDMA used at parties is associated with high motor activity, reduced sense of identity, and poor awareness of surroundings. Use of MDMA individually or in small groups in a quiet environment and when concentrating, is associated with increased lucidity, concentration, sensitivity to aesthetic aspects of the environment, enhanced awareness of emotions, and improved capability of communication.{{cite journal | vauthors = Landriscina F |title=MDMA and the states of Consciousness|journal=Eleusis|date=1995|volume=2|pages=3–9}} In psychotherapeutic settings, MDMA effects have been characterized by infantile ideas, mood lability, and memories and moods connected with childhood experiences.{{cite journal | vauthors = Baggott MJ, Kirkpatrick MG, Bedi G, de Wit H | title = Intimate insight: MDMA changes how people talk about significant others | journal = Journal of Psychopharmacology | volume = 29 | issue = 6 | pages = 669–77 | date = June 2015 | pmid = 25922420 | pmc = 4698152 | doi = 10.1177/0269881115581962 }}

MDMA has been described as an "empathogenic" drug because of its empathy-producing effects.{{cite journal | vauthors = Schmid Y, Hysek CM, Simmler LD, Crockett MJ, Quednow BB, Liechti ME | title = Differential effects of MDMA and methylphenidate on social cognition | journal = Journal of Psychopharmacology | volume = 28 | issue = 9 | pages = 847–56 | date = September 2014 | pmid = 25052243 | doi = 10.1177/0269881114542454 | s2cid = 25713943 | url = http://edoc.unibas.ch/42235/1/20160316152928_56e96dc8bdaad.pdf | access-date = 29 June 2019 | archive-date = 17 September 2020 | archive-url = https://web.archive.org/web/20200917151735/https://edoc.unibas.ch/42235/1/20160316152928_56e96dc8bdaad.pdf | url-status = live }}{{cite journal | vauthors = Wardle MC, de Wit H | title = MDMA alters emotional processing and facilitates positive social interaction | journal = Psychopharmacology | volume = 231 | issue = 21 | pages = 4219–29 | date = October 2014 | pmid = 24728603 | pmc = 4194242 | doi = 10.1007/s00213-014-3570-x }} Results of several studies show the effects of increased empathy with others. When testing MDMA for medium and high doses, it showed increased hedonic and arousal continuum.{{cite book | vauthors = Bravo GL | veditors =Holland J |title=Ecstasy: The complete guide. A comprehensive look at the risks and benefits of MDMA.|date=2001|publisher=Park Street Press|location=Rochester|chapter=What does MDMA feel like?}}{{cite book | vauthors = Metzner R |chapter=Psychedelic, Psychoactive, and Addictive Drugs and States of Consciousness | veditors = Earleywine M |title=Mind-Altering Drugs: The Science of Subjective Experience |date=2005|publisher=Oxford University|location=New York | chapter-url= http://www.greenearthfound.org/write/psychedelic.html|access-date=8 October 2017|archive-date=9 October 2017 |archive-url= https://web.archive.org/web/20171009092337/http://www.greenearthfound.org/write/psychedelic.html |url-status=dead}} The effect of MDMA increasing sociability is consistent, while its effects on empathy have been more mixed.{{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 = Neuroscience and Biobehavioral Reviews | volume = 57 | pages = 433–46 | date = October 2015 | pmid = 26408071 | pmc = 4678620 | doi = 10.1016/j.neubiorev.2015.08.016 }}

Acute adverse effects are usually the result of high or multiple doses, although single dose toxicity can occur in susceptible individuals. The most serious short-term physical health risks of MDMA are hyperthermia and dehydration. Cases of life-threatening or fatal hyponatremia (excessively low sodium concentration in the blood) have developed in MDMA users attempting to prevent dehydration by consuming excessive amounts of water without replenishing electrolytes.{{cite journal | vauthors = White CM | title = How MDMA's pharmacology and pharmacokinetics drive desired effects and harms | journal = Journal of Clinical Pharmacology | volume = 54 | issue = 3 | pages = 245–52 | date = March 2014 | pmid = 24431106 | doi = 10.1002/jcph.266 | s2cid = 6223741 }}

The immediate adverse effects of MDMA use can include:

{{div col|colwidth=27em}}

• Bruxism (grinding and clenching of the teeth)
• Dehydration
• Diarrhea
• Erectile dysfunction{{cite journal | vauthors = Spauwen LW, Niekamp AM, Hoebe CJ, Dukers-Muijrers NH | title = Drug use, sexual risk behaviour and sexually transmitted infections among swingers: a cross-sectional study in The Netherlands | journal = Sexually Transmitted Infections | volume = 91 | issue = 1 | pages = 31–6 | date = February 2015 | pmid = 25342812 | doi = 10.1136/sextrans-2014-051626 | quote = It is known that some recreational drugs (eg, MDMA or GHB) may hamper the potential to ejaculate or maintain an erection. | doi-access = free }}
• Hyperthermia
• Increased wakefulness or insomnia
• Increased perspiration and sweating
• Increased heart rate and blood pressure
• Increased psychomotor activity
• Loss of appetite
• Nausea and vomiting
• Visual and auditory hallucinations (rarely)

{{div col end}}

Other adverse effects that may occur or persist for up to a week following cessation of moderate MDMA use include:

; Physiological

{{div col|colwidth=18em}}

• Insomnia
• Loss of appetite
• Tiredness or lethargy{{Cite web|url=http://emedicine.medscape.com/article/821572-overview#showall|title=MDMA Toxicity: Background, Pathophysiology, Epidemiology|vauthors=Hahn IH|date=25 March 2015|website=Medscape|access-date=14 May 2016|archive-date=11 May 2016|archive-url=https://web.archive.org/web/20160511222711/http://emedicine.medscape.com/article/821572-overview#showall|url-status=live}}{{Cite book|chapter-url=https://books.google.com/books?id=yGeBj9U6Za8C|title=Drug Abuse and Addiction in Medical Illness: Causes, Consequences and Treatment| vauthors = Parrott AC |date=2012|publisher=Springer Science & Business Media|isbn=978-1-4614-3375-0| veditors = Verster J, Brady K, Galanter M, Conrod P |page=179|chapter=13. MDMA and LSD }}
• Trismus (lockjaw)

{{div col end}}

;Psychological

{{div col|colwidth=18em}}

• Anhedonia
• Anxiety or paranoia
• Depression
• Impulsiveness
• Irritability
• Memory impairment
• Restlessness

{{div col end}}

{{As of|2015}}, the long-term effects of MDMA on human brain structure and function have not been fully determined.{{cite journal | vauthors = Garg A, Kapoor S, Goel M, Chopra S, Chopra M, Kapoor A, McCann UD, Behera C | title = Functional Magnetic Resonance Imaging in Abstinent MDMA Users: A Review | journal = Current Drug Abuse Reviews | volume = 8 | issue = 1 | pages = 15–25 | date = 2015 | pmid = 25731754 | doi = 10.2174/1874473708666150303115833 }} However, there is consistent evidence of structural and functional deficits in MDMA users with high lifetime exposure. These structural or functional changes appear to be dose dependent and may be less prominent in MDMA users with only a moderate (typically <50 doses used and <100 tablets consumed) lifetime exposure. Nonetheless, moderate MDMA use may still be neurotoxic and what constitutes moderate use is not clearly established.{{cite journal | vauthors = Mueller F, Lenz C, Steiner M, Dolder PC, Walter M, Lang UE, Liechti ME, Borgwardt S | title = Neuroimaging in moderate MDMA use: A systematic review | journal = Neuroscience and Biobehavioral Reviews | volume = 62 | pages = 21–34 | date = March 2016 | pmid = 26746590 | doi = 10.1016/j.neubiorev.2015.12.010 | doi-access = free }}

Furthermore, it is not clear yet whether "typical" recreational users of MDMA (1 to 2 pills of 75 to 125{{nbsp}}mg MDMA or analogue every 1 to 4 weeks) will develop neurotoxic brain lesions.{{cite journal | vauthors = Gouzoulis-Mayfrank E, Daumann J | title = Neurotoxicity of drugs of abuse--the case of methylenedioxyamphetamines (MDMA, ecstasy), and amphetamines | journal = Dialogues in Clinical Neuroscience | volume = 11 | issue = 3 | pages = 305–17 | date = 2009 | doi = 10.31887/DCNS.2009.11.3/egmayfrank | pmid = 19877498 | pmc = 3181923 }} Long-term exposure to MDMA in humans has been shown to produce marked neurodegeneration in striatal, hippocampal, prefrontal, and occipital serotonergic axon terminals.{{cite journal | vauthors = Halpin LE, Collins SA, Yamamoto BK | title = Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine | journal = Life Sciences | volume = 97 | issue = 1 | pages = 37–44 | date = February 2014 | pmid = 23892199 | pmc = 3870191 | doi = 10.1016/j.lfs.2013.07.014 | quote = In contrast, MDMA produces damage to serotonergic, but not dopaminergic axon terminals in the striatum, hippocampus, and prefrontal cortex (Battaglia et al., 1987, O'Hearn et al., 1988). The damage associated with Meth and MDMA has been shown to persist for at least 2 years in rodents, non-human primates and humans (Seiden et al., 1988, Woolverton et al., 1989, McCann et al., 1998, Volkow et al., 2001a, McCann et al., 2005) }} Neurotoxic damage to serotonergic axon terminals has been shown to persist for more than two years. Elevations in brain temperature from MDMA use are positively correlated with MDMA-induced neurotoxicity. However, most studies on MDMA and serotonergic neurotoxicity in humans focus more on heavy users who consume as much as seven times or more the amount that most users report taking. The evidence for the presence of serotonergic neurotoxicity in casual users who take lower doses less frequently is not conclusive.{{cite journal | vauthors = Szigeti B, Winstock AR, Erritzoe D, Maier LJ | title = Are ecstasy induced serotonergic alterations overestimated for the majority of users? | journal = Journal of Psychopharmacology | volume = 32 | issue = 7 | pages = 741–748 | date = July 2018 | pmid = 29733742 | doi = 10.1177/0269881118767646 | s2cid = 13660975 | quote = Given the dose-response relationship between MDMA exposure and SERT reductions and the statistically non-significant SERT binding differences for users with use levels similar to the majority of real-life users, it can be speculated that SERT levels may not be significantly affected for most recreational ecstasy users. }}

However, adverse neuroplastic changes to brain microvasculature and white matter have been observed to occur in humans using low doses of MDMA. Reduced gray matter density in certain brain structures has also been noted in human MDMA users. Global reductions in gray matter volume, thinning of the parietal and orbitofrontal cortices, and decreased hippocampal activity have been observed in long term users. The effects established so far for recreational use of ecstasy lie in the range of moderate to severe effects for serotonin transporter reduction.{{cite journal | vauthors = Roberts CA, Jones A, Montgomery C | title = Meta-analysis of molecular imaging of serotonin transporters in ecstasy/polydrug users | journal = Neuroscience and Biobehavioral Reviews | volume = 63 | pages = 158–67 | date = April 2016 | pmid = 26855234 | doi = 10.1016/j.neubiorev.2016.02.003 | doi-access = free }}

Impairments in multiple aspects of cognition, including attention, learning, memory, visual processing, and sleep, have been found in regular MDMA users.{{cite journal | vauthors = Parrott AC | title = The potential dangers of using MDMA for psychotherapy | journal = Journal of Psychoactive Drugs | volume = 46 | issue = 1 | pages = 37–43 | year = 2014 | pmid = 24830184 | doi = 10.1080/02791072.2014.873690 | s2cid = 23485480 | url = https://www.researchgate.net/publication/262381558 }} The magnitude of these impairments is correlated with lifetime MDMA usage and are partially reversible with abstinence. Several forms of memory are impaired by chronic ecstasy use; however, the effects for memory impairments in ecstasy users are generally small overall.{{cite journal|vauthors=Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, Zawada A, Somerville M|date=January 2009|title=The harmful health effects of recreational ecstasy: a systematic review of observational evidence|journal=Health Technology Assessment|volume=13|issue=6|pages=iii–iv, ix–xii, 1–315|doi=10.3310/hta13050|pmid=19195429|doi-access=free|hdl=10871/11534|hdl-access=free}}{{cite journal | vauthors = Kuypers KP, Theunissen EL, van Wel JH, de Sousa Fernandes Perna EB, Linssen A, Sambeth A, Schultz BG, Ramaekers JG | title = Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective | journal = PLOS ONE | volume = 11 | issue = 2 | pages = e0149438 | year = 2016 | pmid = 26907605 | pmc = 4764468 | doi = 10.1371/journal.pone.0149438 | bibcode = 2016PLoSO..1149438K | doi-access = free }} MDMA use is also associated with increased impulsivity and depression.

Serotonin depletion following MDMA use can cause depression in subsequent days. In some cases, depressive symptoms persist for longer periods. Some studies indicate repeated recreational use of ecstasy is associated with depression and anxiety, even after quitting the drug.{{cite journal | vauthors = Laws KR, Kokkalis J | title = Ecstasy (MDMA) and memory function: a meta-analytic update | journal = Human Psychopharmacology | volume = 22 | issue = 6 | pages = 381–8 | date = August 2007 | pmid = 17621368 | doi = 10.1002/hup.857 | s2cid = 25353240 }} Depression is one of the main reasons for cessation of use.

At high doses, MDMA induces a neuroimmune response that, through several mechanisms, increases the permeability of the blood–brain barrier, thereby making the brain more susceptible to environmental toxins and pathogens.{{cite journal | vauthors = Kousik SM, Napier TC, Carvey PM | title = The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation | journal = Frontiers in Pharmacology | volume = 3 | pages = 121 | year = 2012 | pmid = 22754527 | pmc = 3386512 | doi = 10.3389/fphar.2012.00121 | doi-access = free }}{{cite book| vauthors = McMillan B, Starr C |title=Human biology |date=2014 |publisher=Brooks/Cole Cengage Learning |location=Belmont, CA |isbn=978-1-133-59916-6 |edition=10th }}{{Page needed|date=September 2015}} In addition, MDMA has immunosuppressive effects in the peripheral nervous system and pro-inflammatory effects in the central nervous system.{{cite journal | vauthors = Boyle NT, Connor TJ | title = Methylenedioxymethamphetamine ('Ecstasy')-induced immunosuppression: a cause for concern? | journal = British Journal of Pharmacology | volume = 161 | issue = 1 | pages = 17–32 | date = September 2010 | pmid = 20718737 | pmc = 2962814 | doi = 10.1111/J.1476-5381.2010.00899.X }}

MDMA may increase the risk of cardiac valvulopathy in heavy or long-term users due to activation of serotonin 5-HT_2B receptors.{{cite journal | vauthors = Cavero I, Guillon JM | title = Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy | journal = Journal of Pharmacological and Toxicological Methods | volume = 69 | issue = 2 | pages = 150–161 | date = 2014 | pmid = 24361689 | doi = 10.1016/j.vascn.2013.12.004 }}{{cite journal | vauthors = Padhariya K, Bhandare R, Canney D, Velingkar V | title = Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists | journal = Cardiovascular & Hematological Disorders Drug Targets | volume = 17 | issue = 2 | pages = 86–104 | date = 2017 | pmid = 28676029 | doi = 10.2174/1871529X17666170703115111 }} MDMA induces cardiac epigenetic changes in DNA methylation, particularly hypermethylation changes.{{cite journal | vauthors = Koczor CA, Ludlow I, Hight RS, Jiao Z, Fields E, Ludaway T, Russ R, Torres RA, Lewis W | title = Ecstasy (MDMA) Alters Cardiac Gene Expression and DNA Methylation: Implications for Circadian Rhythm Dysfunction in the Heart | journal = Toxicological Sciences | volume = 148 | issue = 1 | pages = 183–191 | date = November 2015 | pmid = 26251327 | pmc = 4731408 | doi = 10.1093/toxsci/kfv170 }}

Approximately 60% of MDMA users experience withdrawal symptoms when they stop taking MDMA. Some of these symptoms include fatigue, loss of appetite, depression, and trouble concentrating. Tolerance to some of the desired and adverse effects of MDMA is expected to occur with consistent MDMA use. A 2007 delphic analysis of a panel of experts in pharmacology, psychiatry, law, policing and others estimated MDMA to have a psychological dependence and physical dependence potential roughly three-fourths to four-fifths that of cannabis.{{cite journal |vauthors=Nutt D, King LA, Saulsbury W, Blakemore C |title=Development of a rational scale to assess the harm of drugs of potential misuse |journal=Lancet |volume=369 |issue=9566 |pages=1047–1053 |date=March 2007 |pmid=17382831 |doi=10.1016/S0140-6736(07)60464-4 |s2cid=5903121 |author-link1=David Nutt |author-link4=Colin Blakemore}}
Lay summary: {{cite web |date=23 March 2007 |title=Scientists want new drug rankings |website=BBC News |url=http://news.bbc.co.uk/2/hi/health/6474053.stm |access-date=4 April 2008 |archive-date=2 December 2007 |archive-url=https://web.archive.org/web/20071202233524/http://news.bbc.co.uk/2/hi/health/6474053.stm |url-status=live }}

MDMA has been shown to induce ΔFosB in the nucleus accumbens.{{cite journal | vauthors = Olausson P, Jentsch JD, Tronson N, Neve RL, Nestler EJ, Taylor JR | title = DeltaFosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation | journal = The Journal of Neuroscience | volume = 26 | issue = 36 | pages = 9196–204 | date = September 2006 | pmid = 16957076 | pmc = 6674495 | doi = 10.1523/JNEUROSCI.1124-06.2006 }} Because MDMA releases dopamine in the striatum, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other dopaminergic psychostimulants.{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–37 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }} Therefore, chronic use of MDMA at high doses can result in altered brain structure and drug addiction that occur as a consequence of ΔFosB overexpression in the nucleus accumbens. MDMA is less addictive than other stimulants such as methamphetamine and cocaine.{{cite book| vauthors = Mack AH, Brady KT, Miller SI, Frances RJ |title=Clinical Textbook of Addictive Disorders|publisher=Guilford Publications |isbn=978-1-4625-2169-2 |page=169 |url=https://books.google.com/books?id=88W_CwAAQBAJ&pg=PA171 |quote=MDMA's addictive liability appears to be lower than that of other drugs of abuse....|date=2016-05-12}}{{cite journal | vauthors = Favrod-Coune T, Broers B | title = The Health Effect of Psychostimulants: A Literature Review | journal = Pharmaceuticals | volume = 3 | issue = 7 | pages = 2333–2361 | date = July 2010 | pmid = 27713356 | pmc = 4036656 | doi = 10.3390/ph3072333 | quote = It seems to present a smaller addiction potential than cocaine or methamphetamine. | doi-access = free }} Compared with amphetamine, MDMA and its metabolite MDA are less reinforcing.{{cite book |vauthors=Ries R, Miller SC, Fiellin DA |title=Principles of addiction medicine. |date=2009 |publisher=Wolters Kluwer/Lippincott Williams & Wilkins |location=Philadelphia |isbn=978-0-7817-7477-2 |page=226 |edition=4th |url=https://books.google.com/books?id=j6GGBud8DXcC&pg=PA226 |quote=MDA and MDMA are less reinforcing than amphetamine... |access-date=11 January 2017 |archive-date=13 January 2023 |archive-url=https://web.archive.org/web/20230113000536/https://books.google.com/books?id=j6GGBud8DXcC&pg=PA226 |url-status=live }}

One study found approximately 15% of chronic MDMA users met the DSM-IV diagnostic criteria for substance dependence.{{cite journal | vauthors = Steinkellner T, Freissmuth M, Sitte HH, Montgomery T | title = The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), methamphetamine and D-amphetamine | journal = Biological Chemistry | volume = 392 | issue = 1–2 | pages = 103–15 | date = January 2011 | pmid = 21194370 | pmc = 4497800 | doi = 10.1515/BC.2011.016 | quote = ...approximately 15% of routine MDMA users recently fit the diagnostic criteria for MDMA dependence according to the Diagnostic and Statistical Manual, fourth edition/DSMIV. }} However, there is little evidence for a specific diagnosable MDMA dependence syndrome because MDMA is typically used relatively infrequently.{{cite book|veditors=McCrady BS, Epstein EE|title=Addictions: a comprehensive guidebook|date=2013|publisher=Oxford University Press|location=Oxford|isbn=978-0-19-975366-6|page=299|edition=Second|url=https://books.google.com/books?id=MUYfAQAAQBAJ&pg=PA299|access-date=11 January 2017|archive-date=13 January 2023|archive-url=https://web.archive.org/web/20230113000537/https://books.google.com/books?id=MUYfAQAAQBAJ&pg=PA299|url-status=live}}

There are currently no medications to treat MDMA addiction.{{cite book|vauthors=Mack AH, Brady KT, Miller SI, Frances RJ|title=Clinical Textbook of Addictive Disorders|publisher=Guilford Publications|isbn=978-1-4625-2169-2|page=171|url=https://books.google.com/books?id=88W_CwAAQBAJ&q=mdma+addiction&pg=PA171|quote=There are no known pharmacological treatments for MDMA addiction.|date=2016-05-12|access-date=13 October 2020|archive-date=19 January 2023|archive-url=https://web.archive.org/web/20230119130056/https://books.google.com/books?id=88W_CwAAQBAJ&q=mdma+addiction&pg=PA171|url-status=live}}

MDMA is a moderately teratogenic drug (i.e., it is toxic to the fetus).{{cite journal | vauthors = Vorhees CV | title = Methods for detecting long-term CNS dysfunction after prenatal exposure to neurotoxins | journal = Drug and Chemical Toxicology | volume = 20 | issue = 4 | pages = 387–99 | date = November 1997 | pmid = 9433666 | doi = 10.3109/01480549709003895 }}{{cite journal | vauthors = Meamar R, Karamali F, Sadeghi HM, Etebari M, Nasr-Esfahani MH, Baharvand H | title = Toxicity of ecstasy (MDMA) towards embryonic stem cell-derived cardiac and neural cells | journal = Toxicology in Vitro | volume = 24 | issue = 4 | pages = 1133–8 | date = June 2010 | pmid = 20230888 | doi = 10.1016/j.tiv.2010.03.005 | bibcode = 2010ToxVi..24.1133M | quote = In summary, MDMA is a moderate teratogen that could influence cardiac and neuronal differentiation in the ESC model and these results are in concordance with previous in vivo and in vitro models. }} In utero exposure to MDMA is associated with a neuro- and cardiotoxicity and impaired motor functioning. Motor delays may be temporary during infancy or long-term. The severity of these developmental delays increases with heavier MDMA use.{{cite journal | vauthors = Singer LT, Moore DG, Fulton S, Goodwin J, Turner JJ, Min MO, Parrott AC | title = Neurobehavioral outcomes of infants exposed to MDMA (Ecstasy) and other recreational drugs during pregnancy | journal = Neurotoxicology and Teratology | volume = 34 | issue = 3 | pages = 303–10 | year = 2012 | pmid = 22387807 | pmc = 3367027 | doi = 10.1016/j.ntt.2012.02.001 | bibcode = 2012NTxT...34..303S }} MDMA has been shown to promote the survival of fetal dopaminergic neurons in culture.{{cite journal | vauthors = Lipton JW, Tolod EG, Thompson VB, Pei L, Paumier KL, Terpstra BT, Lynch KA, Collier TJ, Sortwell CE | title = 3,4-Methylenedioxy-N-methamphetamine (ecstasy) promotes the survival of fetal dopamine neurons in culture | journal = Neuropharmacology | volume = 55 | issue = 5 | pages = 851–859 | date = October 2008 | pmid = 18655796 | doi = 10.1016/j.neuropharm.2008.06.062 | pmc = 2572681 }}

MDMA overdose symptoms vary widely due to the involvement of multiple organ systems. Some of the more overt overdose symptoms are listed in the table below. The number of instances of fatal MDMA intoxication is low relative to its usage rates. In most fatalities, MDMA was not the only drug involved. Acute toxicity is mainly caused by serotonin syndrome and sympathomimetic effects. Sympathomimetic side effects can be managed with carvedilol. MDMA's toxicity in overdose may be exacerbated by caffeine, with which it is frequently cut in order to increase volume.{{cite journal | vauthors = Vanattou-Saïfoudine N, McNamara R, Harkin A | title = Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and related psychostimulants: mechanisms and mediators | journal = British Journal of Pharmacology | volume = 167 | issue = 5 | pages = 946–59 | date = November 2012 | pmid = 22671762 | pmc = 3492978 | doi = 10.1111/j.1476-5381.2012.02065.x }} A scheme for management of acute MDMA toxicity has been published focusing on treatment of hyperthermia, hyponatraemia, serotonin syndrome, and multiple organ failure.{{cite journal | vauthors = Hall AP, Henry JA | title = Acute toxic effects of 'Ecstasy' (MDMA) and related compounds: overview of pathophysiology and clinical management | journal = British Journal of Anaesthesia | volume = 96 | issue = 6 | pages = 678–85 | date = June 2006 | pmid = 16595612 | doi = 10.1093/bja/ael078 | doi-access = free }}

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

A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.{{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 }} MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors. Life-threatening reactions and death have occurred in people who took MDMA while on ritonavir.{{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 = }} Bupropion, a strong CYP2D6 inhibitor, has been found to increase MDMA exposure with administration of MDMA. Concurrent use of MDMA high dosages with another serotonergic drug can result in a life-threatening condition called serotonin syndrome. Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors (MAOIs), such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).{{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 }} Serotonin reuptake inhibitors (SRIs) such as citalopram (Celexa), duloxetine (Cymbalta), fluoxetine (Prozac), and paroxetine (Paxil) have been shown to block most of the subjective effects of MDMA.{{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}} Norepinephrine reuptake inhibitors (NRIs) such as reboxetine (Edronax) have been found to reduce emotional excitation and feelings of stimulation with MDMA but do not appear to influence its entactogenic or mood-elevating effects.

MDMA induces the release of monoamine neurotransmitters and thereby acts as an indirectly acting sympathomimetic and produces a variety of cardiostimulant effects.{{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 = }} It dose-dependently increases heart rate, blood pressure, and cardiac output. SRIs like citalopram and paroxetine, as well as the serotonin 5-HT_2A receptor antagonist ketanserin, have been found to partially block the increases in heart rate and blood pressure with MDMA.{{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 = }} It is notable in this regard that serotonergic psychedelics such as psilocybin, which act as serotonin 5-HT_2A receptor agonists, likewise have sympathomimetic effects.{{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 = }}{{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 = }}{{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 = }} The NRI reboxetine and the serotonin–norepinephrine reuptake inhibitor (SNRI) duloxetine block MDMA-induced increases in heart rate and blood pressure. Conversely, bupropion, a norepinephrine–dopamine reuptake inhibitor (NDRI) with only weak dopaminergic activity,{{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 = }}{{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 }} reduced MDMA-induced heart rate and circulating norepinephrine increases but did not affect MDMA-induced blood pressure increases.{{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 = }} 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.{{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}}

The non-selective beta blocker pindolol blocked MDMA-induced increases in heart rate but not blood pressure.{{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}} The α₂-adrenergic receptor agonist clonidine did not affect the cardiovascular effects of MDMA, though it reduced blood pressure.{{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 = }} The α₁-adrenergic receptor antagonists doxazosin and prazosin blocked or reduced MDMA-induced blood pressure increases but augmented MDMA-induced heart rate and cardiac output increases.{{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 = }}{{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.}} The dual α₁- and β-adrenergic receptor blocker carvedilol reduced MDMA-induced heart rate and blood pressure increases.{{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 = }}{{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 = }} In contrast to the cases of serotonergic and noradrenergic agents, the dopamine D₂ receptor antagonist haloperidol did not affect the cardiovascular responses to MDMA.{{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 = }} Due to the theoretical risk of "unopposed α-stimulation" and possible consequences like coronary vasospasm, it has been suggested that dual α₁- 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.{{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 = }}

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

MDMA is an entactogen or empathogen, as well as a stimulant, euphoriant, and weak psychedelic. It is a substrate of the monoamine transporters (MATs) and acts as a monoamine releasing agent (MRA).{{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 }}{{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 }} The drug is specifically a well-balanced serotonin–norepinephrine–dopamine releasing agent (SNDRA). To a lesser extent, MDMA also acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI). MDMA enters monoaminergic neurons via the MATs and then, via poorly understood mechanisms, reverses the direction of these transporters to produce efflux of the monoamine neurotransmitters rather than the usual reuptake.{{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 = }}{{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 = }}{{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 }} Induction of monoamine efflux by amphetamines in general may involve intracellular Na⁺ and Ca²⁺ elevation and PKC and CaMKIIα activation. MDMA also acts on the vesicular monoamine transporter 2 (VMAT2) on synaptic vesicles to increase the cytosolic concentrations of the monoamine neurotransmitters available for efflux. By inducing release and reuptake inhibition of serotonin, norepinephrine, and dopamine, MDMA increases levels of these neurotransmitters in the brain and periphery.

In addition to its actions as an SNDRA, MDMA directly but more modestly interacts with a number of monoamine and other receptors. It is a low-potency partial agonist of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors.{{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 = }} The drug also interacts with α₂-adrenergic receptors, with the sigma σ₁ and σ₂ receptors, and with the imidazoline I₁ receptor. It is thought that agonism of the serotonin 5-HT_2A receptor by MDMA may mediate the weak psychedelic effects of the drug in humans.{{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 = }} However, findings in this area appear to be conflicting.{{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 }} 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 in animal drug discrimination tests.{{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). }}{{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.}} Along with the preceding receptor interactions, MDMA is a potent partial agonist of the rodent trace amine-associated receptor 1 (TAAR1). Conversely however, it is far weaker in terms of potency as an agonist of the human TAAR1.{{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 }} Moreover, MDMA acts as a weak partial agonist or antagonist of the human TAAR1 rather than as an efficacious agonist. In relation to the preceding, MDMA has been said to be inactive as a human TAAR1 agonist. TAAR1 activation is thought to auto-inhibit and constrain the effects of amphetamines that possess TAAR1 agonism, for instance MDMA in rodents.{{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. }}{{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). }}{{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. }}{{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 = }}

Elevation of serotonin, norepinephrine, and dopamine levels by MDMA is believed to mediate most of the drug's effects, including its entactogenic, stimulant, euphoriant, hyperthermic, and sympathomimetic effects.{{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 = }}{{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 = }} The entactogenic effects of MDMA, including increased sociability, empathy, feelings of closeness, and reduced aggression, are thought to be mainly due to induction of serotonin release.{{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 = }} The exact serotonin receptors responsible for these effects are unclear, but may include the serotonin 5-HT_1A receptor,{{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 = }} 5-HT_1B receptor,{{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 = }} and 5-HT_2A receptor,{{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 = }} as well as 5-HT_1A receptor-mediated oxytocin release and consequent activation of the oxytocin receptor.{{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 = }}{{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 = }}{{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 = }} Induction of dopamine release is thought to be importantly involved in the stimulant and euphoriant effects of MDMA, while induction of norepinephrine release and serotonin 5-HT_2A receptor stimulation are believed to mediate its sympathomimetic effects. MDMA has been associated with a unique subjective "magic" or euphoria that few or no other known entactogens are said to fully reproduce.{{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/}} 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.{{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 = }}{{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}}{{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}} Repeated activation of serotonin 5-HT_2B receptors by MDMA is thought to result in risk of valvular heart disease (VHD) and primary pulmonary hypertension (PPH).{{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 = }}{{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). }}{{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 = }}{{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 = }} MDMA has been associated with serotonergic neurotoxicity. This may be due to formation of toxic MDMA metabolites and/or induction of simultaneous serotonin and dopamine release, with consequent uptake of dopamine into serotonergic neurons and breakdown into toxic species.{{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 }}{{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}}

MDMA is a racemic mixture of two enantiomers, (S)-MDMA and (R)-MDMA.{{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 }} (S)-MDMA is much more potent as an SNDRA in vitro and in producing MDMA-like subjective effects in humans than (R)-MDMA.{{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 }} By contrast, (R)-MDMA acts as a lower-potency serotonin–norepinephrine releasing agent (SNRA) with weak or negligible effects on dopamine.{{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 }} Relatedly, (R)-MDMA shows weak or negligible stimulant-like and rewarding effects in animals.{{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 }} Both (S)-MDMA and (R)-MDMA produce entactogen-type effects in animals and humans. In addition, both (S)-MDMA and (R)-MDMA are weak agonists of the serotonin 5-HT₂ receptors.{{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 }} (R)-MDMA is more potent and efficacious as a serotonin 5-HT_2A and 5-HT_2B receptor agonist than (S)-MDMA, whereas (S)-MDMA is somewhat more potent as an agonist of the serotonin 5-HT_2C receptor. Despite its greater serotonin 5-HT_2A receptor agonism however, (R)-MDMA did not produce more psychedelic-like effects than (S)-MDMA in humans.

MDMA produces 3,4-methylenedioxyamphetamine (MDA) as a minor active metabolite. Peak levels of MDA are about 5 to 10% of those of MDMA and total exposure to MDA is almost 10% of that of MDMA with oral MDMA administration. As a result, MDA may contribute to some extent to the effects of MDMA.{{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 }} MDA is an entactogen, stimulant, and weak psychedelic similarly to MDMA. Like MDMA, it acts as a potent and well-balanced SNDRA and as a weak serotonin 5-HT₂ receptor agonist. However, MDA shows much more potent and efficacious serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor agonism than MDMA.{{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. }} Accordingly, MDA produces greater psychedelic effects than MDMA in humans and might particularly contribute to the mild psychedelic-like effects of MDMA. On the other hand, MDA may also be importantly involved in toxicity of MDMA, such as cardiac valvulopathy.{{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. }}

The duration of action of MDMA (3–6{{nbsp}}hours) is much shorter than its elimination half-life (8–9{{nbsp}}hours) would imply.{{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. }} In relation to this, MDMA's duration and the offset of its effects appear to be determined more by rapid acute tolerance rather than by circulating drug concentrations. Similar findings have been made for amphetamine and methamphetamine.{{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 }}{{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]. }}{{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 }}{{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)). }} One mechanism by which tolerance to MDMA may occur is internalization of the serotonin transporter (SERT).{{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). }}{{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 = }}{{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 }}{{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}}{{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 }} Although MDMA and serotonin are not significant TAAR1 agonists in humans, TAAR1 activation by MDMA may result in SERT internalization.{{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. }}

File:Main metabolic pathways of MDMA in humans.svg

The MDMA concentration in the blood stream starts to rise after about 30 minutes,{{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 }} and reaches its maximal concentration in the blood stream between 1.5 and 3 hours after ingestion.{{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 }} It is then slowly metabolized and excreted, with levels of MDMA and its metabolites decreasing to half their peak concentration over the next several hours.{{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 }} The duration of action of MDMA is about 3 to 6{{nbsp}}hours. Brain serotonin levels are depleted after MDMA administration but serotonin levels typically return to normal within 24 to 48{{nbsp}}hours.

Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-dihydroxyamphetamine (DHA) (also called alpha-methyldopamine (α-Me-DA)), 3,4-methylenedioxyphenylacetone (MDP2P), and 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.

MDMA is known to be metabolized by two main metabolic pathways: (1) O-demethylenation followed by 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. The metabolism may be primarily by cytochrome P450 (CYP450) enzymes CYP2D6 and CYP3A4 and COMT. Complex, nonlinear pharmacokinetics arise via autoinhibition of CYP2D6 and CYP2D8, resulting in zeroth order kinetics at higher doses. It is thought that this can result in sustained and higher concentrations of MDMA if the user takes consecutive doses of the drug.{{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 }}{{primary source inline|date=October 2014}}

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.{{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 }} MDMA is a chiral compound and has been almost exclusively administered as a 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{{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 }} 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 was significantly longer than that of the (S)-enantiomer (5.8{{nbsp}}±{{nbsp}}2.2 hours vs 3.6{{nbsp}}±{{nbsp}}0.9 hours). However, because MDMA excretion and metabolism have nonlinear kinetics,{{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 }} the half-lives would be higher at more typical doses (100{{nbsp}}mg is sometimes considered a typical dose).

MDMA is in the substituted methylenedioxyphenethylamine and substituted amphetamine classes of chemicals. As a free base, MDMA is a colorless oil insoluble in water. The most common salt of MDMA is the hydrochloride salt; pure MDMA hydrochloride is water-soluble and appears as a white or off-white powder or crystal.

There are numerous methods available to synthesize MDMA via different intermediates.{{cite journal | vauthors = Milhazes N, Martins P, Uriarte E, Garrido J, Calheiros R, Marques MP, Borges F | title = Electrochemical and spectroscopic characterisation of amphetamine-like drugs: application to the screening of 3,4-methylenedioxymethamphetamine (MDMA) and its synthetic precursors | journal = Analytica Chimica Acta | volume = 596 | issue = 2 | pages = 231–41 | date = July 2007 | pmid = 17631101 | doi = 10.1016/j.aca.2007.06.027 | bibcode = 2007AcAC..596..231M | hdl = 10316/45124 | hdl-access = free }}{{cite journal | vauthors = Milhazes N, Cunha-Oliveira T, Martins P, Garrido J, Oliveira C, Rego AC, Borges F | title = Synthesis and cytotoxic profile of 3,4-methylenedioxymethamphetamine ("ecstasy") and its metabolites on undifferentiated PC12 cells: A putative structure-toxicity relationship | journal = Chemical Research in Toxicology | volume = 19 | issue = 10 | pages = 1294–304 | date = October 2006 | pmid = 17040098 | doi = 10.1021/tx060123i | hdl = 10316/12872 | url = https://estudogeral.sib.uc.pt/bitstream/10316/12872/1/Synthesis%20and%20Cytotoxic%20Profile.pdf | hdl-access = free | access-date = 24 September 2019 | archive-date = 28 June 2021 | archive-url = https://web.archive.org/web/20210628070418/https://estudogeral.sib.uc.pt/bitstream/10316/12872/1/Synthesis%20and%20Cytotoxic%20Profile.pdf | url-status = live }}{{cite journal | vauthors = Baxter EW, Reitz AB |title = Reductive aminations of carbonyl compounds with borohydride and borane reducing agents. | journal = Organic Reactions | date = April 2004 | volume = 59 | page = 59 | location = Hoboken, New Jersey, United States | doi = 10.1002/0471264180.or059.01 |isbn = 0471264180 }}{{cite journal | vauthors = Gimeno P, Besacier F, Bottex M, Dujourdy L, Chaudron-Thozet H | title = A study of impurities in intermediates and 3,4-methylenedioxymethamphetamine (MDMA) samples produced via reductive amination routes | journal = Forensic Science International | volume = 155 | issue = 2–3 | pages = 141–57 | date = December 2005 | pmid = 16226151 | doi = 10.1016/j.forsciint.2004.11.013 }} The original MDMA synthesis described in Merck's patent involves brominating safrole to 1-(3,4-methylenedioxyphenyl)-2-bromopropane and then reacting this adduct with methylamine.{{cite journal | vauthors = Palhol F, Boyer S, Naulet N, Chabrillat M | title = Impurity profiling of seized MDMA tablets by capillary gas chromatography | journal = Analytical and Bioanalytical Chemistry | volume = 374 | issue = 2 | pages = 274–81 | date = September 2002 | pmid = 12324849 | doi = 10.1007/s00216-002-1477-6 | s2cid = 42666306 }}{{cite journal | vauthors = Renton RJ, Cowie JS, Oon MC | title = A study of the precursors, intermediates and reaction by-products in the synthesis of 3,4-methylenedioxymethylamphetamine and its application to forensic drug analysis | journal = Forensic Science International | volume = 60 | issue = 3 | pages = 189–202 | date = August 1993 | pmid = 7901132 | doi = 10.1016/0379-0738(93)90238-6 }} Most illicit MDMA is synthesized using MDP2P (3,4-methylenedioxyphenyl-2-propanone) as a precursor. MDP2P in turn is generally synthesized from piperonal, safrole or isosafrole.{{cite book|title=World Drug Report 2014|date=June 2014|publisher=United Nations Office on Drugs and Crime|location=Vienna, Austria|isbn=978-92-1-056752-7|url=http://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf|access-date=1 December 2014|pages=2, 3, 123–152|veditors=Mohan J|archive-date=13 November 2014|archive-url=https://web.archive.org/web/20141113173315/http://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf|url-status=live}} One method is to isomerize safrole to isosafrole in the presence of a strong base, and then oxidize isosafrole to MDP2P. Another method uses the Wacker process to oxidize safrole directly to the MDP2P intermediate with a palladium catalyst. Once the MDP2P intermediate has been prepared, a reductive amination leads to racemic MDMA (an equal parts mixture of (R)-MDMA and (S)-MDMA).{{citation needed|date=January 2015}} Relatively small quantities of essential oil are required to make large amounts of MDMA. The essential oil of Ocotea cymbarum, for example, typically contains between 80 and 94% safrole. This allows 500{{nbsp}}mL of the oil to produce between 150 and 340 grams of MDMA.{{cite journal | url = https://www.justice.gov/dea/pr/micrograms/2005/mg1105.pdf | date = 11 November 2005 | title = Early Warning - MDMA and MDA Producers Using Ocotea Cymbarum as a Precursor | journal = DEA Microgram Newsletter | volume = 38 | issue = 11 | page = 166 | archive-url = https://web.archive.org/web/20121018052300/http://www.justice.gov/dea/pr/micrograms/2005/mg1105.pdf | archive-date=18 October 2012 | publisher = Drug Enforcement Agency, U.S. Department of Justice }}

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MDMA and MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDMA or its major metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10% those of the parent drug.{{cite journal | vauthors = Barnes AJ, De Martinis BS, Gorelick DA, Goodwin RS, Kolbrich EA, Huestis MA | title = Disposition of MDMA and metabolites in human sweat following controlled MDMA administration | journal = Clinical Chemistry | volume = 55 | issue = 3 | pages = 454–62 | date = March 2009 | pmid = 19168553 | pmc = 2669283 | doi = 10.1373/clinchem.2008.117093 }}{{cite book | vauthors = Baselt RC |title=Disposition of toxic drugs and chemicals in man |date=2011 |publisher=Biomedical Publications |location=Seal Beach, Ca. |isbn=978-0-9626523-8-7 |edition=9th | pages = 1078–1080 }}

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| image2 = Merck patent for synthesizing methylhydrastinine from MDMA.pdf

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| footer = German patents for MDMA synthesis and the subsequent methylhydrastinine synthesis filed by Merck on 24 December 1912 and issued in 1914

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MDMA was first synthesized and patented in 1912 by Merck chemist Anton Köllisch.{{cite book | last=Passie | first=Torsten | title=The History of MDMA | publisher=Oxford University Press | date=29 June 2023 | isbn=978-0-19-886736-4 | doi=10.1093/oso/9780198867364.001.0001 | url=https://books.google.com/books?id=KSvCEAAAQBAJ&pg=PA6 | pages=6–16, 18, 27, 29, 32, 40}}{{cite journal | vauthors = Bernschneider-Reif S, Oxler F, Freudenmann RW | title = The origin of MDMA ("ecstasy")--separating the facts from the myth | journal = Pharmazie | volume = 61 | issue = 11 | pages = 966–972 | date = November 2006 | pmid = 17152992 | doi = | url = }} At the time, Merck was interested in developing substances that stopped abnormal bleeding. Merck wanted to avoid an existing patent held by Bayer for one such compound: hydrastinine. Köllisch developed a preparation of a hydrastinine analogue, methylhydrastinine, at the request of fellow lab members, Walther Beckh and Otto Wolfes. MDMA (called methylsafrylamin, safrylmethylamin or N-Methyl-a-Methylhomopiperonylamin in Merck laboratory reports) was an intermediate compound in the synthesis of methylhydrastinine. Merck was not interested in MDMA itself at the time. On 24 December 1912, Merck filed two patent applications that described the synthesis and some chemical properties of MDMA{{cite web|url = http://v3.espacenet.com/publicationDetails/originalDocument?CC=DE&NR=274350C&FT=D|title = German Patent 274350: Verfahren zur Darstellung von Alkyloxyaryl-, Dialkyloxyaryl- und Alkylendioxyarylaminopropanen bzw. deren am Stickstoff monoalkylierten Derivaten.|author = Firma E. Merck in Darmstadt|date = 16 May 1914|publisher = Kaiserliches Patentamt|access-date = 12 April 2009|archive-date = 28 August 2021|archive-url = https://web.archive.org/web/20210828153545/https://worldwide.espacenet.com/publicationDetails/originalDocument?locale=en_EP&FT=D&CC=DE&NR=274350C|url-status = live}} and its subsequent conversion to methylhydrastinine.{{cite web|url = http://v3.espacenet.com/publicationDetails/originalDocument?CC=DE&NR=279194C&FT=D|title = German Patent 279194: Verfahren zur Darstellung von Hydrastinin Derivaten.|author = Firma E. Merck in Darmstadt|date = 15 October 1914|publisher = Kaiserliches Patentamt|access-date = 20 July 2009|archive-date = 28 August 2021|archive-url = https://web.archive.org/web/20210828153659/https://worldwide.espacenet.com/publicationDetails/originalDocument?locale=en_EP&FT=D&CC=DE&NR=279194C|url-status = live}} Merck records indicate its researchers returned to the compound sporadically. A 1920 Merck patent describes a chemical modification to MDMA.{{cite book | last=Shulgin | first=Alexander T. | veditors = Peroutka SJ | title=Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA | chapter=History of MDMA | publisher=Springer US | publication-place=Boston, MA | volume=9 | date=1990 | isbn=978-1-4612-8799-5 | doi=10.1007/978-1-4613-1485-1_1 | url=http://link.springer.com/10.1007/978-1-4613-1485-1_1 | access-date=15 May 2025 | pages=1–20 (2, 14)}}

MDMA's analogue 3,4-methylenedioxyamphetamine (MDA) was first synthesized in 1910 as a derivative of adrenaline. Gordon A. Alles, the discoverer of the psychoactive effects of amphetamine, also discovered the psychoactive effects of MDA in 1930 in a self-experiment in which he administered a high dose (126{{nbsp}}mg) to himself.{{cite book | author=Gordon A. Alles | chapter = Some Relations Between Chemical Structure and Physiological Action of Mescaline and Related Compounds / Structure and Action of Phenethylamines | veditors = Abramson HA | title = Neuropharmacology: Transactions of the Fourth Conference, September 25, 26, and 27, 1957, Princeton, N. J. | location = New York | publisher = Josiah Macy Foundation | date = 1959 | pages = 181–268 | oclc = 9802642 | url = https://books.google.com/books?id=sDQLAQAAMAAJ&q=%22Some+relations+between+chemical+structure+and+physiological+action+of+mescaline+and+related+compounds%22 | chapter-url = https://web.archive.org/web/20250321230359/https://bitnest.netfirms.com/external/Books/NeuropharmacologyTrans.4.181#page=5 }}{{cite book | author = Gordon A. Alles | chapter = Subjective Reactions to Phenethylamine Hallucinogens | title = A Pharmacologic Approach to the Study of the Mind | date = 1959 | publisher = CC Thomas | location = Springfield | pages = 238–250 (241–246) | isbn = 978-0-398-04254-7 | url = https://books.google.com/books?id=x45rAAAAMAAJ | chapter-url = https://archive.org/details/pharmacologicapp0000univ/page/238/mode/1up}} However, he did not subsequently describe these effects until 1959.{{cite journal | vauthors = Benzenhöfer U, Passie T | title = Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin | journal = Addiction | volume = 105 | issue = 8 | pages = 1355–61 | date = August 2010 | pmid = 20653618 | doi = 10.1111/j.1360-0443.2010.02948.x | url = }} MDA was later tested as an appetite suppressant by Smith, Kline & French and for other uses by other groups in the 1950s. In relation to the preceding, the psychoactive effects of MDA were discovered well before those of MDMA.

In 1927, Max Oberlin studied the pharmacology of MDMA while searching for substances with effects similar to adrenaline or ephedrine, the latter being structurally similar to MDMA. Compared to ephedrine, Oberlin observed that it had similar effects on vascular smooth muscle tissue, stronger effects at the uterus, and no "local effect at the eye". MDMA was also found to have effects on blood sugar levels comparable to high doses of ephedrine. Oberlin concluded that the effects of MDMA were not limited to the sympathetic nervous system. Research was stopped "particularly due to a strong price increase of safrylmethylamine", which was still used as an intermediate in methylhydrastinine synthesis. Albert van Schoor performed simple toxicological tests with the drug in 1952, most likely while researching new stimulants or circulatory medications. After pharmacological studies, research on MDMA was not continued. In 1959, Wolfgang Fruhstorfer synthesized MDMA for pharmacological testing while researching stimulants. It is unclear if Fruhstorfer investigated the effects of MDMA in humans.

Outside of Merck, other researchers began to investigate MDMA. In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals injected with mescaline and several analogues, including MDMA. Conducted at the University of Michigan in Ann Arbor, these investigations were declassified in October 1969 and published in 1973.{{cite journal | vauthors = Hardman HF, Haavik CO, Seevers MH | title = Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals | journal = Toxicology and Applied Pharmacology | volume = 25 | issue = 2 | pages = 299–309 | date = June 1973 | pmid = 4197635 | doi = 10.1016/S0041-008X(73)80016-X | bibcode = 1973ToxAP..25..299H | url = http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=639 | hdl = 2027.42/33868 | hdl-access = free | access-date = 19 April 2009 | archive-date = 21 October 2008 | archive-url = https://web.archive.org/web/20081021151006/http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=639 | url-status = live }} A 1960 Polish paper by Biniecki and Krajewski describing the synthesis of MDMA as an intermediate was the first published scientific paper on the substance.{{cite journal | vauthors = Biniecki S, Krajewski E |title=Production of d,1-N-methyl-beta-(3,4-methylenedioxyphenyl)-isopropylamine and d,1-N-methyl-beta-(3,4-dimthoxyphenyl)-isopropylamine.|journal=Acta Polon Pharm|date=1960|volume=17|pages=421–5|language=pl}}

MDA appeared as a recreational drug in the mid-1960s. MDMA may have been in non-medical use in the western United States in 1968.{{cite journal | vauthors = Siegel RK | title = MDMA. Nonmedical use and intoxication | journal = Journal of Psychoactive Drugs | volume = 18 | issue = 4 | pages = 349–54 | date = October 1986 | pmid = 2880950 | doi = 10.1080/02791072.1986.10472368 | url = http://www.maps.org/images/pdf/1986_siegel_1.pdf | access-date = 11 August 2015 | archive-date = 4 March 2016 | archive-url = https://web.archive.org/web/20160304090940/http://www.maps.org/images/pdf/1986_siegel_1.pdf | url-status = live }} An August 1970 report at a meeting of crime laboratory chemists indicates MDMA was being used recreationally in the Chicago area by 1970.The first confirmed sample was seized and identified by Chicago Police in 1970, see {{cite journal|vauthors = Sreenivasan VR|title = Problems in Identification of Methylenedioxy and Methoxy Amphetamines|journal = Journal of Criminal Law, Criminology, and Police Science|volume = 63|issue = 2|pages = 304–312|year = 1972|url = http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=1149|doi = 10.2307/1142315|jstor = 1142315|access-date = 19 April 2009|archive-date = 21 October 2008|archive-url = https://web.archive.org/web/20081021200016/http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=1149|url-status = live|url-access = subscription}} MDMA likely emerged as a substitute for MDA,{{cite news|vauthors=Foderaro LW|title=Psychedelic Drug Called Ecstasy Gains Popularity in Manhattan Nightclubs|url=https://www.nytimes.com/1988/12/11/nyregion/psychedelic-drug-called-ecstasy-gains-popularity-in-manhattan-nightclubs.html?pagewanted=2|access-date=27 August 2015|work=The New York Times|date=11 December 1988|archive-date=17 November 2015|archive-url=https://web.archive.org/web/20151117042408/http://www.nytimes.com/1988/12/11/nyregion/psychedelic-drug-called-ecstasy-gains-popularity-in-manhattan-nightclubs.html?pagewanted=2|url-status=live}} a drug at the time popular among users of psychedelics which was made a Schedule 1 controlled substance in the United States in 1970.{{cite web|vauthors=Beck JE|title=Drug Abuse Series: MDMA|url=https://erowid.org/chemicals/mdma/mdma_info6.shtml|website=Erowid|publisher=Drug Abuse Information and Monitoring Project|access-date=6 August 2015|date=April 1987|archive-date=4 August 2015|archive-url=https://web.archive.org/web/20150804125927/https://www.erowid.org/chemicals/mdma/mdma_info6.shtml|url-status=live}}

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American chemist and psychopharmacologist Alexander Shulgin reported he synthesized MDMA in 1965 while researching methylenedioxy compounds at Dow Chemical Company, but did not test the psychoactivity of the compound at this time. Around 1970, Shulgin sent instructions for N-methylated MDA (MDMA) synthesis to the founder of a Los Angeles chemical company who had requested them. This individual later provided these instructions to a client in the Midwest. Shulgin may have suspected he played a role in the emergence of MDMA in Chicago.{{cite journal | vauthors = Benzenhöfer U, Passie T | title = Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin | journal = Addiction | volume = 105 | issue = 8 | pages = 1355–61 | date = August 2010 | pmid = 20653618 | doi = 10.1111/j.1360-0443.2010.02948.x }}

Shulgin first heard of the psychoactive effects of N-methylated MDA around 1975 from a young student who reported "amphetamine-like content". Around 30 May 1976, Shulgin again heard about the effects of N-methylated MDA, this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University{{cite web |title=Alexander 'Sasha' Shulgin |url=http://www.shulginresearch.org/home/about/alexander-sasha-shulgin/ |publisher=Alexander Shulgin Research Institute|access-date=8 January 2015|archive-date=20 December 2014 |archive-url=https://web.archive.org/web/20141220131529/http://www.shulginresearch.org/home/about/alexander-sasha-shulgin/|url-status=dead}} who directed him to the University of Michigan study. She and two close friends had consumed 100{{nbsp}}mg of MDMA and reported positive emotional experiences. Following the self-trials of a colleague at the University of San Francisco, Shulgin synthesized MDMA and tried it himself in September and October 1976. Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976. In 1978, he and David E. Nichols published a report on the drug's psychoactive effect in humans. They described MDMA as inducing "an easily controlled altered state of consciousness with emotional and sensual overtones" comparable "to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA".{{cite book |vauthors=Shulgin AT, Nichols DE | veditors = Willette RE, Stillman RJ |title=The Psychopharmacology of Hallucinogens |publisher=Pergamon Press |location=New York |year=1978 |pages=74–83 |chapter=Characterization of Three New Psychotomimetics |isbn=978-0-08-021938-7 |chapter-url=http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&ID=961&DocPartID=832 |access-date=4 January 2015 |archive-date=15 May 2013 |archive-url=https://web.archive.org/web/20130515124653/http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&ID=961&DocPartID=832 |url-status=live }}

While not finding his own experiences with MDMA particularly powerful, Shulgin was impressed with the drug's disinhibiting effects and thought it could be useful in therapy. Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug window. Shulgin occasionally used MDMA for relaxation, referring to it as "my low-calorie martini", and gave the drug to friends, researchers, and others who he thought could benefit from it.{{cite book| vauthors=Shulgin AT, Shulgin A |author-link1=Alexander Shulgin|author-link2=Ann Shulgin|title=PiHKAL: A Chemical Love Story |date=1991|publisher=Transform Press|location=Berkeley, CA|isbn=978-0-9630096-0-9|edition=7th printing, 1st|chapter= Chapters 12, 22|title-link=PiHKAL}} One such person was Leo Zeff, a psychotherapist who had been known to use psychedelic substances in his practice. When he tried the drug in 1977, Zeff was impressed with the effects of MDMA and came out of his semi-retirement to promote its use in therapy. Over the following years, Zeff traveled around the United States and occasionally to Europe, eventually training an estimated four thousand psychotherapists in the therapeutic use of MDMA.{{cite news|vauthors=Bennett D|url=https://www.nytimes.com/2005/01/30/magazine/30ECSTASY.html|title=Dr. Ecstasy|work=The New York Times Magazine|date=30 January 2005|access-date=10 February 2017|archive-date=17 November 2011|archive-url=https://web.archive.org/web/20111117063356/http://www.nytimes.com/2005/01/30/magazine/30ECSTASY.html|url-status=live}}{{cite book| vauthors=Shulgin A |author1-link=Ann Shulgin |veditors=Doblin R |editor1-link=Rick Doblin |title=The Secret Chief Revealed |date=2004|publisher=Multidisciplinary Association for Psychedelic Studies|location=Sarasota, Fl|isbn=978-0-9660019-6-9|pages=17–18 |edition=2nd|chapter-url=http://maps.org/images/pdf/books/scr/scr.pdf|access-date=7 January 2015|chapter=Tribute to Jacob|url-status=dead|archive-date=16 September 2018|archive-url=https://web.archive.org/web/20180916024833/http://www.maps.org/images/pdf/books/scr/scr.pdf}} Zeff named the drug Adam, believing it put users in a state of primordial innocence.{{cite magazine|vauthors=Brown E|title=Professor X|magazine=Wired|date=September 2002|url=http://archive.wired.com/wired/archive/10.09/professorx.html?pg=3&topic=&topic_set=|access-date=4 January 2015|archive-date=25 June 2015|archive-url=https://web.archive.org/web/20150625015832/http://archive.wired.com/wired/archive/10.09/professorx.html?pg=3&topic=&topic_set=|url-status=live}}

Psychotherapists who used MDMA believed the drug eliminated the typical fear response and increased communication. Sessions were usually held in the home of the patient or the therapist. The role of the therapist was minimized in favor of patient self-discovery accompanied by MDMA induced feelings of empathy. Depression, substance use disorders, relationship problems, premenstrual syndrome, and autism were among several psychiatric disorders MDMA assisted therapy was reported to treat. According to psychiatrist George Greer, therapists who used MDMA in their practice were impressed by the results. Anecdotally, MDMA was said to greatly accelerate therapy. According to David Nutt, MDMA was widely used in the western US in couples counseling, and was called empathy. Only later was the term ecstasy used for it, coinciding with rising opposition to its use.{{cite journal |vauthors=Milroy CM |title=Ten years of 'ecstasy' |journal=Journal of the Royal Society of Medicine |volume=92 |issue=2 |pages=68–72 |date=February 1999 |pmid=10450215 |pmc=1297063 |doi=10.1177/014107689909200206}}

In the late 1970s and early 1980s, "Adam" spread through personal networks of psychotherapists, psychiatrists, users of psychedelics, and yuppies. Hoping MDMA could avoid criminalization like LSD and mescaline, psychotherapists and experimenters attempted to limit the spread of MDMA and information about it while conducting informal research.{{cite journal | vauthors = Pentney AR | title = An exploration of the history and controversies surrounding MDMA and MDA | journal = Journal of Psychoactive Drugs | volume = 33 | issue = 3 | pages = 213–21 | date = 2001 | pmid = 11718314 | doi = 10.1080/02791072.2001.10400568 | s2cid = 31142434 }} Early MDMA distributors were deterred from large scale operations by the threat of possible legislation.{{cite book| vauthors = Beck J, Rosenbaum M |title=Pursuit of Ecstasy : The MDMA Experience|date=1994|publisher=State Univ. of New York Press|location=Albany|isbn=978-0-7914-1817-8|chapter-url=https://books.google.com/books?id=SwdedK36bVMC|chapter=The Distribution of Ecstasy|url-access=registration|url=https://archive.org/details/pursuitofecstasy0000beck}} Between the 1970s and the mid-1980s, this network of MDMA users consumed an estimated 500,000 doses.{{cite book| vauthors = Doblin R, Rosenbaum M | veditors = Inciardi JA |author-link1=Rick Doblin|title=The Drug Legalization Debate|date=1991|publisher=SAGE Publications, Inc.|location=London|isbn=978-0-8039-3678-2|edition=2nd|chapter-url=http://www.drugtext.org/pdf/Dance/party-drugs-clubbing/why-mdma-should-not-have-been-made-illegal.pdf|access-date=10 August 2015|chapter=Chapter 6: Why MDMA Should Not Have Been Made Illegal|url=https://archive.org/details/druglegalization00inci}}

A small recreational market for MDMA developed by the late 1970s,{{cite book| vauthors = Collin M, Godfrey J |title=Altered State: The Story of Ecstasy Culture and Acid House.|date=2010|publisher=Profile Books|location=London|isbn=978-1-84765-641-4|edition=Updated new|chapter-url=https://books.google.com/books?id=fc8x9qeCekQC|chapter=The Technologies of Pleasure}} consuming perhaps 10,000 doses in 1976. By the early 1980s MDMA was being used in Boston and New York City nightclubs such as Studio 54 and Paradise Garage.{{cite news|vauthors=Savlov M|title=Countdown to Ecstasy: A New Drug for a New Millennium|url=http://www.weeklywire.com/ww/06-12-00/austin_music_feature.html|access-date=6 August 2015|work=The Austin Chronicle|publisher=Weekly Wire|date=12 June 2000|archive-date=21 January 2016|archive-url=https://web.archive.org/web/20160121022839/http://weeklywire.com/ww/06-12-00/austin_music_feature.html|url-status=dead}}{{cite magazine| vauthors = Owen F, Gavin L |title=Molly Isn't Who You Think She Is: A Deeper Look at MDMA|url=http://www.playboy.com/articles/molly-party-drug-ecstasy|access-date=6 August 2015|magazine=Playboy|date=20 October 2013|archive-date=27 July 2015|archive-url= https://web.archive.org/web/20150727080003/http://www.playboy.com/articles/molly-party-drug-ecstasy |url-status=dead}} Into the early 1980s, as the recreational market slowly expanded, production of MDMA was dominated by a small group of therapeutically minded Boston chemists. Having commenced production in 1976, this "Boston Group" did not keep up with growing demand and shortages frequently occurred.

Perceiving a business opportunity, Michael Clegg, the Southwest distributor for the Boston Group, started his own "Texas Group" backed financially by Texas friends.{{cite book| vauthors = Sylvan R |title=Trance Formation: The Spiritual and Religious Dimensions of Global Rave Culture|date=2005|publisher=Routledge|location=New York, NY|isbn=978-0-415-97090-7|pages=21–22|chapter=A Brief History of the Rave Scene}} In 1981, Clegg had coined "Ecstasy" as a slang term for MDMA to increase its marketability.{{cite book|vauthors=Eisner B|author-link1=Bruce Eisner|title=Ecstasy : The MDMA Story|date=1994|publisher=Ronin Publishing|location=Berkeley, CA|isbn=978-0-914171-68-3|edition=Expanded 2nd|url=https://books.google.com/books?id=8aqUu5M6UpwC|access-date=1 February 2016|archive-date=13 January 2023|archive-url=https://web.archive.org/web/20230113000538/https://books.google.com/books?id=8aqUu5M6UpwC|url-status=live}} Starting in 1983, the Texas Group mass-produced MDMA in a Texas lab or imported it from California and marketed tablets using pyramid sales structures and toll-free numbers. MDMA could be purchased via credit card and taxes were paid on sales. Under the brand name "Sassyfras", MDMA tablets were sold in brown bottles. The Texas Group advertised "Ecstasy parties" at bars and discos, describing MDMA as a "fun drug" and "good to dance to". MDMA was openly distributed in Austin and Dallas–Fort Worth area bars and nightclubs, becoming popular with yuppies, college students, and gays.

Recreational use also increased after several cocaine dealers switched to distributing MDMA following experiences with the drug. A California laboratory that analyzed confidentially submitted drug samples first detected MDMA in 1975. Over the following years the number of MDMA samples increased, eventually exceeding the number of MDA samples in the early 1980s.{{cite journal | vauthors = Parrott AC | title = Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity | journal = Psychopharmacology | volume = 173 | issue = 3–4 | pages = 234–41 | date = May 2004 | pmid = 15007594 | doi = 10.1007/s00213-003-1712-7 | s2cid = 3347303 | url = http://psy.swansea.ac.uk/staff/parrott/p-IsEcstasyMDMA-Psychopharm-2004.pdf | access-date = 7 August 2015 | archive-date = 18 September 2015 | archive-url = https://web.archive.org/web/20150918181517/http://psy.swansea.ac.uk/staff/parrott/p-IsEcstasyMDMA-Psychopharm-2004.pdf | url-status = live }}{{cite journal | vauthors = Renfroe CL | title = MDMA on the street: Analysis Anonymous | journal = Journal of Psychoactive Drugs | volume = 18 | issue = 4 | pages = 363–9 | date = October 1986 | pmid = 2880953 | doi = 10.1080/02791072.1986.10472371 }} By the mid-1980s, MDMA use had spread to colleges around the United States.{{rp|33}}

File:Federal Register notice of planned MDMA scheduling.pdf

In an early media report on MDMA published in 1982, a Drug Enforcement Administration (DEA) spokesman stated the agency would ban the drug if enough evidence for abuse could be found. By mid-1984, MDMA use was becoming more noticed. Bill Mandel reported on "Adam" in a 10 June San Francisco Chronicle article, but misidentified the drug as methyloxymethylenedioxyamphetamine (MMDA). In the next month, the World Health Organization identified MDMA as the only substance out of twenty phenethylamines to be seized a significant number of times.

After a year of planning and data collection, MDMA was proposed for scheduling by the DEA on 27 July 1984, with a request for comments and objections.{{cite journal|title=Schedules of Controlled Substances Proposed Placement of 3,4-Methylenedioxymethamphetamine in Schedule I|journal=Federal Register|date=27 July 1984|volume=49|issue=146|page=30210|url=http://maps.org/research-archive/dea-mdma/pdf/0194.PDF|access-date=15 January 2015|archive-date=4 March 2016|archive-url=https://web.archive.org/web/20160304002700/http://www.maps.org/research-archive/dea-mdma/pdf/0194.PDF|url-status=live}} The DEA was surprised when a number of psychiatrists, psychotherapists, and researchers objected to the proposed scheduling and requested a hearing. In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.{{cite news |vauthors=Adler J, Abramson P, Katz S, Hager M |title=Getting High on 'Ecstasy' |url=http://www.maps.org/research-archive/hmma/Newsweek4.85.pdf |access-date=1 February 2015 |work=Newsweek Magazine |date=15 April 1985 |location=Life/Style |page=96 |archive-date=20 April 2016 |archive-url=https://web.archive.org/web/20160420122637/http://www.maps.org/research-archive/hmma/Newsweek4.85.pdf |url-status=live }} An initial hearing was held on 1 February 1985 at the DEA offices in Washington, D.C., with administrative law judge Francis L. Young presiding. It was decided there to hold three more hearings that year: Los Angeles on 10 June, Kansas City, Missouri on 10–11 July, and Washington, D.C., on 8–11 October.

Sensational media attention was given to the proposed criminalization and the reaction of MDMA proponents, effectively advertising the drug. In response to the proposed scheduling, the Texas Group increased production from 1985 estimates of 30,000 tablets a month to as many as 8,000 per day, potentially making two million ecstasy tablets in the months before MDMA was made illegal.{{cite book| vauthors = Holland J | veditors = Holland J |title=Ecstasy: the complete guide; a comprehensive look at the risks and benefits of MDMA|date=2001|publisher=Park Street Press|location=Rochester, VT|isbn=978-0-89281-857-0 |chapter=The History of MDMA}} By some estimates the Texas Group distributed 500,000 tablets per month in Dallas alone. According to one participant in an ethnographic study, the Texas Group produced more MDMA in eighteen months than all other distribution networks combined across their entire histories. By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States. According to the DEA there was evidence of use in twenty-eight states{{cite web|title=MDMA – FDA REPORT, 1985|url=https://www.erowid.org/chemicals/mdma/mdma_law3.shtml|website=Erowid|publisher=Food and Drug Administration|access-date=11 August 2015|date=1985|archive-date=11 August 2015|archive-url=https://web.archive.org/web/20150811142554/https://www.erowid.org/chemicals/mdma/mdma_law3.shtml|url-status=live}} and Canada. Urged by Senator Lloyd Bentsen, the DEA announced an emergency Schedule I classification of MDMA on 31 May 1985. The agency cited increased distribution in Texas, escalating street use, and new evidence of MDA (an analog of MDMA) neurotoxicity as reasons for the emergency measure.{{cite news|title=U.S. will ban 'ecstasy,' a hallucinogenic drug|url=https://www.nytimes.com/1985/06/01/us/us-will-ban-ecstasy-a-hallucinogenic-drug.html|newspaper=The New York Times|access-date=29 April 2015|date=1 June 1985|agency=The Associated Press|archive-date=24 May 2015|archive-url=https://web.archive.org/web/20150524161818/http://www.nytimes.com/1985/06/01/us/us-will-ban-ecstasy-a-hallucinogenic-drug.html|url-status=live}}{{cite news|vauthors=Baker K|title=DEA To Ban "Ecstasy" – The Drug MDMA|url=https://apnews.com/26214cd32a8b4c05e361158df14715b0|access-date=7 August 2015|agency=The Associated Press|date=30 May 1985|archive-date=31 August 2018|archive-url=https://web.archive.org/web/20180831174744/https://apnews.com/26214cd32a8b4c05e361158df14715b0|url-status=live}}{{cite news|vauthors=Corwin M|title=U.S. to Ban Use of Drug MDMA : Street Abuse Cited; Used by Psychiatrists|url=https://www.latimes.com/archives/la-xpm-1985-05-31-mn-14566-story.html|access-date=11 August 2015|newspaper=Los Angeles Times|date=31 May 1985|archive-date=17 November 2015|archive-url=https://web.archive.org/web/20151117032749/http://articles.latimes.com/1985-05-31/news/mn-14566_1_street-drugs|url-status=live}} The ban took effect one month later on 1 July 1985 in the midst of Nancy Reagan's "Just Say No" campaign.{{cite news|vauthors=Weber B|title=Alexander Shulgin, Psychedelia Researcher, Dies at 88|url=https://www.nytimes.com/2014/06/08/us/alexander-shulgin-psychedelia-researcher-dies-at-88.html?_r=0|access-date=28 August 2015|work=The New York Times|date=7 June 2014|archive-date=5 September 2015|archive-url=https://web.archive.org/web/20150905200423/http://www.nytimes.com/2014/06/08/us/alexander-shulgin-psychedelia-researcher-dies-at-88.html?_r=0|url-status=live}}{{cite news|vauthors=Vastag B|title=Chemist Alexander Shulgin, popularizer of the drug Ecstasy, dies at 88|url=https://www.washingtonpost.com/national/health-science/chemist-alexander-shulgin-popularizer-of-the-drug-ecstasy-dies-at-88/2014/06/03/19fd9580-eb34-11e3-b98c-72cef4a00499_story.html|access-date=28 August 2015|newspaper=The Washington Post|publisher=WP Company LLC|date=3 June 2014|archive-date=5 August 2015|archive-url=https://web.archive.org/web/20150805104454/http://www.washingtonpost.com/national/health-science/chemist-alexander-shulgin-popularizer-of-the-drug-ecstasy-dies-at-88/2014/06/03/19fd9580-eb34-11e3-b98c-72cef4a00499_story.html|url-status=live}}

As a result of several expert witnesses testifying that MDMA had an accepted medical usage, the administrative law judge presiding over the hearings recommended that MDMA be classified as a Schedule III substance. Despite this, DEA administrator John C. Lawn overruled and classified the drug as Schedule I.{{cite news|title= Ecstasy has its pros and cons|newspaper= Kokomo Tribune|location= Kokomo, Indiana|date= 23 November 1985|page= 6|url= https://newspaperarchive.com/profile/Robert_Thomas/clipnumber/34618/|agency= Harper's Bazaar|via= newspaperarchive.com|access-date= 9 September 2017|archive-date= 28 August 2021|archive-url= https://web.archive.org/web/20210828153542/https://newspaperarchive.com/profile/robert-thomas-512557/|url-status= live}} {{free access}} Harvard psychiatrist Lester Grinspoon then sued the DEA, claiming that the DEA had ignored the medical uses of MDMA, and the federal court sided with Grinspoon, calling Lawn's argument "strained" and "unpersuasive", and vacated MDMA's Schedule I status.{{cite web |title=Lester Grinspoon, M.d., Petitioner, v. Drug Enforcement Administration, Respondent, 828 F.2d 881 (1st Cir. 1987) |url=https://law.justia.com/cases/federal/appellate-courts/F2/828/881/368975/ |website=Justia Law |publisher=US Court of Appeals for the First Circuit |access-date=9 October 2021 |archive-date=9 October 2021 |archive-url=https://web.archive.org/web/20211009212855/https://law.justia.com/cases/federal/appellate-courts/F2/828/881/368975/ |url-status=live }} Despite this, less than a month later Lawn reviewed the evidence and reclassified MDMA as Schedule I again, claiming that the expert testimony of several psychiatrists claiming over 200 cases where MDMA had been used in a therapeutic context with positive results could be dismissed because they were not published in medical journals. In 2017, the FDA granted breakthrough therapy designation for its use with psychotherapy for PTSD. However, this designation has been questioned and problematized.{{cite journal | vauthors = Halvorsen JØ, Naudet F, Cristea IA | title = Challenges with benchmarking of MDMA-assisted psychotherapy | journal = Nature Medicine | volume = 27 | issue = 10 | pages = 1689–1690 | date = October 2021 | pmid = 34635857 | doi = 10.1038/s41591-021-01525-0 | s2cid = 238636360 | url = https://hal.archives-ouvertes.fr/hal-03414583/file/Halvorsen%20et%20al%20-%202021%20-%20Challenges%20with%20benchmarking%20of%20MDMA-assisted%20psychotherapy.pdf | access-date = 9 May 2022 | archive-date = 22 May 2022 | archive-url = https://web.archive.org/web/20220522022351/https://hal.archives-ouvertes.fr/hal-03414583/file/Halvorsen%20et%20al%20-%202021%20-%20Challenges%20with%20benchmarking%20of%20MDMA-assisted%20psychotherapy.pdf | url-status = live }}

While engaged in scheduling debates in the United States, the DEA also pushed for international scheduling. In 1985, the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 United Nations Convention on Psychotropic Substances. The committee made this recommendation on the basis of the pharmacological similarity of MDMA to previously scheduled drugs, reports of illicit trafficking in Canada, drug seizures in the United States, and lack of well-defined therapeutic use. While intrigued by reports of psychotherapeutic uses for the drug, the committee viewed the studies as lacking appropriate methodological design and encouraged further research. Committee chairman Paul Grof dissented, believing international control was not warranted at the time and a recommendation should await further therapeutic data.{{cite book|title=WHO Expert Committee on Drug Dependence: Twenty-second Report.|date=1985|publisher=World Health Organization|location=Geneva|isbn=978-9241207294|url=http://whqlibdoc.who.int/trs/WHO_TRS_729.pdf|access-date=29 August 2012|archive-url=https://web.archive.org/web/20141019192225/http://whqlibdoc.who.int/trs/WHO_TRS_729.pdf|archive-date= 19 October 2014|pages=24–25}} The Commission on Narcotic Drugs added MDMA to Schedule I of the convention on 11 February 1986.{{cite web |url=http://www.unodc.org/documents/commissions/CND/Drug_Resolutions/1980-1989/1986/CND_Decision-1986-07_S-IX.pdf |title=Decision to place MDMA into Schedule I |publisher=Commission on Narcotic Drugs |date=11 February 1986 |website=UNODC |access-date=9 May 2015 |archive-date=22 September 2015 |archive-url=https://web.archive.org/web/20150922000603/http://www.unodc.org/documents/commissions/CND/Drug_Resolutions/1980-1989/1986/CND_Decision-1986-07_S-IX.pdf |url-status=live }}

File:1995-04-08 Vibe Tribe 09 (10937582).jpg, Australia being broken up by police. MDMA use spread globally along with rave culture.]]

File:Ecstasy - Is it Really the Dream Drug.ogv video dramatizing the dangers of MDMA misuse]]

The use of MDMA in Texas clubs declined rapidly after criminalization, but by 1991, the drug became popular among young middle-class whites and in nightclubs. In 1985, MDMA use became associated with acid house on the Spanish island of Ibiza.{{rp|50}}{{cite news|vauthors=McKinley JC|title=Overdoses of 'Molly' Led to Electric Zoo Deaths|url=http://artsbeat.blogs.nytimes.com/2013/09/12/overdoses-of-molly-led-to-electric-zoo-deaths/?_r=0|access-date=9 December 2013|newspaper=The New York Times|date=12 September 2013|archive-date=4 December 2013|archive-url=https://web.archive.org/web/20131204085710/http://artsbeat.blogs.nytimes.com/2013/09/12/overdoses-of-molly-led-to-electric-zoo-deaths/?_r=0|url-status=live}} Thereafter, in the late 1980s, the drug spread alongside rave culture to the United Kingdom and then to other European and American cities.{{rp|50}} Illicit MDMA use became increasingly widespread among young adults in universities and later, in high schools. Since the mid-1990s, MDMA has become the most widely used amphetamine-type drug by college students and teenagers.{{cite book| vauthors = Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE |title=Goldfrank's toxicologic emergencies|date=2011|publisher=McGraw-Hill Medical|location=New York|isbn=978-0-07-160593-9|edition=9th}}{{rp|1080}} MDMA became one of the four most widely used illicit drugs in the US, along with cocaine, heroin, and cannabis.{{cite news| vauthors = Jennings P |author-link1=Peter Jennings|title=Ecstasy Rising|work=Primetime Thursday|issue=Special edition|publisher=ABC News|date=1 April 2004 |url=http://www.thedocumentarygroup.com/PJP/Transcripts%20Files/Script_Ecstasy.doc |url-status=dead|archive-url=https://web.archive.org/web/20150527163756/http://www.thedocumentarygroup.com/PJP/Transcripts%20Files/Script_Ecstasy.doc|archive-date=27 May 2015|df=dmy-all}} According to some estimates as of 2004, only marijuana attracts more first time users in the United States.

After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later,{{when|date=January 2015}} Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent FDA-approved MDMA studies in humans have taken place in the United States in Detroit (Wayne State University), Chicago (University of Chicago), San Francisco (UCSF and California Pacific Medical Center), Baltimore (NIDA–NIH Intramural Program), and South Carolina. Studies have also been conducted in Switzerland (University Hospital of Psychiatry, Zürich), the Netherlands (Maastricht University), and Spain (Universitat Autònoma de Barcelona).{{cite web | url = http://www.maps.org/research/ | title = Bibliography of Psychedelic Research Studies. | work = Multidisciplinary Association for Psychedelic Studies (MAPS) | location = Santa Cruz, CA | archive-url = https://web.archive.org/web/20131203011733/http://www.maps.org/research/ | archive-date=3 December 2013 }}

"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.{{cite web|title = What Is Molly and Why Is It Dangerous?|url = https://www.nbcnews.com/health/health-news/what-molly-why-it-dangerous-n311291|vauthors = James SD|publisher = NBCNews.com|date = 23 February 2015|access-date = 23 February 2015|quote = Why is it called Molly? That's short for "molecule." "You can put a ribbon and bow on it and call it a cute name like 'Molly' and people are all in," said Paul Doering, professor emeritus of pharmacology at the University of Florida.|archive-date = 24 February 2015|archive-url = https://web.archive.org/web/20150224063219/http://www.nbcnews.com/health/health-news/what-molly-why-it-dangerous-n311291|url-status = live}}{{cite news| vauthors = Aleksander I |title=Molly: Pure, but Not So Simple|url=https://www.nytimes.com/2013/06/23/fashion/molly-pure-but-not-so-simple.html |archive-url=https://ghostarchive.org/archive/20220101/https://www.nytimes.com/2013/06/23/fashion/molly-pure-but-not-so-simple.html |archive-date=2022-01-01 |url-access=limited|access-date=24 February 2015|work=The New York Times|date=21 June 2013}}{{cbignore}}

In 2010, the BBC reported that use of MDMA had decreased in the UK in previous years. This may be due to increased seizures during use and decreased production of the precursor chemicals used to manufacture MDMA. Unwitting substitution with other drugs, such as mephedrone and methamphetamine,{{cite news|url=http://scientopia.org/blogs/drugmonkey/2010/09/19/mephedrone-4-methylmethcathinone-appearing-in-ecstasy-in-the-netherlands/|title=Mephedrone (4-Methylmethcathinone) appearing in "Ecstasy" in the Netherlands|date=19 September 2010|access-date=31 December 2012|archive-date=5 November 2012|archive-url=https://web.archive.org/web/20121105125943/http://scientopia.org/blogs/drugmonkey/2010/09/19/mephedrone-4-methylmethcathinone-appearing-in-ecstasy-in-the-netherlands/|url-status=dead}} as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.{{cite news|url=http://news.bbc.co.uk/1/hi/england/london/8468372.stm|title=Why ecstasy is 'vanishing' from UK nightclubs|date=19 January 2010|work=BBC News|access-date=14 February 2010|archive-date=7 September 2017|archive-url=https://web.archive.org/web/20170907220833/http://news.bbc.co.uk/1/hi/england/london/8468372.stm|url-status=live}}

In 2017, it was found that some pills being sold as MDMA contained pentylone, which can cause very unpleasant agitation and paranoia.{{cite journal |vauthors=Bish J |title=Watch Out for Pentylone, the Horrible New MDMA Additive |journal=Vice |date=Aug 4, 2017 |url=https://www.vice.com/en/article/watch-out-for-pentylone-the-horrible-new-mdma-additive/ |access-date=31 May 2018 |archive-date=1 September 2020 |archive-url=https://web.archive.org/web/20200901064627/https://www.vice.com/en_uk/article/pagjxg/watch-out-for-pentylone-the-horrible-new-mdma-additive |url-status=live }}

According to David Nutt, when safrole was restricted by the United Nations in order to reduce the supply of MDMA, producers in China began using anethole instead, but this gives para-methoxyamphetamine (PMA, also known as "Dr Death"), which is much more toxic than MDMA and can cause overheating, muscle spasms, seizures, unconsciousness, and death. People wanting MDMA are sometimes sold PMA instead.{{cite web | url = https://www.bbc.co.uk/programmes/w3cswgvh | title = Ecstasy on Prescription | work = BBC Business Daily | date = 29 May 2018 | access-date = 10 July 2021 | archive-date = 10 July 2021 | archive-url = https://web.archive.org/web/20210710093100/https://www.bbc.co.uk/programmes/w3cswgvh | url-status = live }}

In 2025, the BBC reported on a study of 650 survivors from the Nova music festival massacre. Two-thirds were under the influence of recreational drugs (MDMA, LSD, marijuana or psilocybin) when Hamas attacked the festival on October 7, 2023. MDMA appeared to have a protective effect against later problems with sleeping and emotional distress.{{cite web |last=Williamson |first=Lucy |date=2025-03-07 |title=MDMA may have protected Nova attack survivors from trauma, study suggests |url=https://www.bbc.com/news/articles/c9wpy14wyd0o |access-date=2025-03-16 |website=BBC Home}}{{cite web |last=Burns |first=Brielle |date=2025-03-08 |title=MDMA and LSD may have helped October 7 survivors |url=https://www.news.com.au/world/middle-east/lsd-mdma-party-drugs-may-have-helped-survivors-of-october-7-attack-study-claims/news-story/361e7726844087d6d023f010bccf1c48 |access-date=2025-03-16 |website=news.com.au}}

{{Global estimates of illicit drug users}}

MDMA is legally controlled in most of the world under the UN Convention on Psychotropic Substances and other international agreements, although exceptions exist for research and limited medical use. In general, the unlicensed use, sale or manufacture of MDMA are all criminal offences.

In Australia, MDMA was rescheduled on 1 July 2023 as a schedule 8 substance (available on prescription) when used in the treatment of PTSD, while remaining a schedule 9 substance (prohibited) for all other uses. For the treatment of PTSD, MDMA can only be prescribed by psychiatrists with specific training and authorisation.{{cite news |title=MDMA and psilocybin: What GPs need to know |url=https://www1.racgp.org.au/newsgp/gp-opinion/mdma-and-psilocybin-what-gps-need-to-know#:~:text=It%20means%20psilocybin%20and%20MDMA,restricts%20supply%20to%20clinical%20trials. |newspaper=Newsgp |access-date=2023-06-13 |archive-date=13 June 2023 |archive-url=https://web.archive.org/web/20230613073443/https://www1.racgp.org.au/newsgp/gp-opinion/mdma-and-psilocybin-what-gps-need-to-know#:~:text=It%20means%20psilocybin%20and%20MDMA,restricts%20supply%20to%20clinical%20trials. |url-status=live }}

In 1986, MDMA was declared an illegal substance because of its allegedly harmful effects and potential for misuse.{{Cite web | vauthors = Bedi G |date=2018-03-29 |title=Is psychiatry ready for medical MDMA? |url=http://theconversation.com/is-psychiatry-ready-for-medical-mdma-94105 |access-date=2024-04-12 |website=The Conversation |language=en-US |archive-date=4 January 2023 |archive-url=https://web.archive.org/web/20230104131905/https://theconversation.com/is-psychiatry-ready-for-medical-mdma-94105 |url-status=live }} Any non-authorised sale, use or manufacture is strictly prohibited by law. Permits for research uses on humans must be approved by a recognized ethics committee on human research.

In Western Australia under the Misuse of Drugs Act 1981 4.0g of MDMA is the amount required determining a court of trial, 2.0g is considered a presumption with intent to sell or supply and 28.0g is considered trafficking under Australian law.{{cite web|title=Misuse of Drugs Act 1981|url=https://www.slp.wa.gov.au/legislation/statutes.nsf/main_mrtitle_4607_homepage.html|publisher=The Government of Western Australia|agency=Department of the Premier and Cabinet|date=23 October 1981|access-date=22 July 2016|archive-date=18 August 2016|archive-url=https://web.archive.org/web/20160818132249/https://www.slp.wa.gov.au/legislation/statutes.nsf/main_mrtitle_4607_homepage.html|url-status=live}}

The Australian Capital Territory passed legislation to decriminalise the possession of small amounts of MDMA, which took effect in October 2023.{{cite news |title=ACT government decriminalises small amounts of illicit drugs including speed, heroin and cocaine |url=https://www.abc.net.au/news/2022-10-20/act-decriminalises-small-amounts-of-illicit-drugs-heroin-cocaine/101552008 |website=ABC News |date=20 October 2022 |publisher=Australian Broadcasting Corporation |access-date=2023-06-13 |archive-date=13 June 2023 |archive-url=https://web.archive.org/web/20230613074529/https://www.abc.net.au/news/2022-10-20/act-decriminalises-small-amounts-of-illicit-drugs-heroin-cocaine/101552008 |url-status=live }}{{cite web | vauthors = Roy T |title=The ACT has today decriminalised small amounts of some illicit drugs. But what does that mean? |website=ABC News |date=27 October 2023 |url=https://www.abc.net.au/news/2023-10-28/canberra-drug-decriminalisation-laws-begin-today/103032128 |access-date=7 June 2024}}

In Canada, MDMA is listed as a Schedule 1{{cite web|title=Schedule I|url=http://isomerdesign.com/Cdsa/schedule.php?schedule=1§ion=18.5&structure=C|work=Controlled Drugs and Substances Act|publisher=Isomer Design|access-date=9 December 2013|archive-date=10 November 2013|archive-url=https://web.archive.org/web/20131110200556/http://isomerdesign.com/Cdsa/schedule.php?schedule=1§ion=18.5&structure=C|url-status=dead}} as it is an analogue of amphetamine.{{cite web|title=Definitions and interpretations|url=http://isomerdesign.com/Cdsa/definitions.php?structure=C|work=Controlled Drugs and Substances Act|publisher=Isomer Design|access-date=9 December 2013|archive-date=10 November 2013|archive-url=https://web.archive.org/web/20131110213450/http://isomerdesign.com/Cdsa/definitions.php?structure=C|url-status=dead}} The Controlled Drugs and Substances Act was updated as a result of the Safe Streets and Communities Act changing amphetamines from Schedule III to Schedule I in March 2012. In 2022, the federal government granted British Columbia a 3-year exemption, legalizing the possession of up to {{Convert|2.5|g|oz}} of MDMA in the province from February 2023 until February 2026.{{Cite web |title=Decriminalizing people who use drugs in B.C. |url=https://www2.gov.bc.ca/gov/content/overdose/decriminalization |access-date=2023-03-08 |website=Government of BC |publisher=Government Communications and Public Engagement |archive-date=9 March 2023 |archive-url=https://web.archive.org/web/20230309091348/https://www2.gov.bc.ca/gov/content/overdose/decriminalization |url-status=live }}{{Cite news |date=March 7, 2023 |title=B.C. recorded 211 toxic drug deaths — almost 7 a day — in January, coroner reports |work=CBC.ca |url=https://www.cbc.ca/news/canada/british-columbia/bc-toxic-drugs-deaths-january-2023-1.6770643 |access-date=March 8, 2023 |archive-date=8 March 2023 |archive-url=https://web.archive.org/web/20230308231034/https://www.cbc.ca/news/canada/british-columbia/bc-toxic-drugs-deaths-january-2023-1.6770643 |url-status=live }}

In 2024, a Dutch state commission issued a report advocating for MDMA to be made available to patients with PTSD.{{Cite web |last=Zaken |first=Ministerie van Algemene |date=2024-05-31 |title=MDMA /// Beyond Ecstasy - Report - Government.nl |url=https://www.government.nl/documents/reports/2024/05/31/mdma-beyond-ecstasy |access-date=2025-04-06 |website=www.government.nl |language=en-GB}}

In June 2011, the Expert Committee on the List (Expertcommissie Lijstensystematiek Opiumwet) issued a report which discussed the evidence for harm and the legal status of MDMA, arguing in favor of maintaining it on List I.{{cite web | url = http://www.rijksoverheid.nl/documenten-en-publicaties/rapporten/2011/06/27/rapport-drugs-in-lijsten.html | title = Rapport Drugs in Lijsten | archive-url = https://web.archive.org/web/20120306112130/http://www.rijksoverheid.nl/documenten-en-publicaties/rapporten/2011/06/27/rapport-drugs-in-lijsten.html | archive-date = 6 March 2012 | work = Rijksoverheid.nl | date = 27 June 2011 | access-date = 29 August 2012 }}{{cite web|title=Committee: the current system of the Opium Act does not have to be changed|url=http://www.government.nl/documents-and-publications/press-releases/2011/06/24/committee-the-current-system-of-the-opium-act-does-not-have-to-be-changed.html|website=government.nl|date=24 June 2011|access-date=29 August 2012|archive-date=29 April 2012|archive-url=https://web.archive.org/web/20120429071421/http://www.government.nl/documents-and-publications/press-releases/2011/06/24/committee-the-current-system-of-the-opium-act-does-not-have-to-be-changed.html|url-status=dead}}

In the United Kingdom, MDMA was made illegal in 1977 by a modification order to the existing Misuse of Drugs Act 1971. Although MDMA was not named explicitly in this legislation, the order extended the definition of Class A drugs to include various ring-substituted phenethylamines.{{cite book| vauthors = Power M |title=Drugs 2.0 : the web revolution that's changing how the world gets high|date=2013|publisher=Portobello|location=London|isbn=978-1-84627-459-6 |url=https://books.google.com/books?id=gj6zMQEACAAJ&q=Drugs+2.0|format=epub file}}{{cite web | url = http://www.statutelaw.gov.uk/content.aspx?LegType=All+Primary&PageNumber=57&NavFrom=2&parentActiveTextDocId=1367412&ActiveTextDocId=1367472&filesize=411 | title = Misuse of Drugs Act 1971 | work = Statutelaw.gov.uk | date = 5 January 1998 | access-date = 11 June 2011 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828153546/https://www.legislation.gov.uk/ukpga/1971/38/schedule/2/part/I/2003-04-01?timeline=true | url-status = live }} The drug is therefore illegal to sell, buy, or possess without a licence in the UK. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking.

Some researchers such as David Nutt have criticized the scheduling of MDMA, which he determined to be a relatively harmless drug.{{Cite news|vauthors = Hope C|date = 7 February 2009|title = Ecstasy 'no more dangerous than horse riding'|url = https://www.telegraph.co.uk/news/uknews/law-and-order/4537874/Ecstasy-no-more-dangerous-than-horse-riding.html|website = Telegraph.co.uk|access-date = 4 December 2015|archive-date = 10 December 2015|archive-url = https://web.archive.org/web/20151210201615/http://www.telegraph.co.uk/news/uknews/law-and-order/4537874/Ecstasy-no-more-dangerous-than-horse-riding.html|url-status = live}}{{cite journal | vauthors = Nutt DJ | title = Equasy-- an overlooked addiction with implications for the current debate on drug harms | journal = Journal of Psychopharmacology | volume = 23 | issue = 1 | pages = 3–5 | date = January 2009 | pmid = 19158127 | doi = 10.1177/0269881108099672 | s2cid = 32034780 }} An editorial he wrote in the Journal of Psychopharmacology, where he compared the risk of harm for horse riding (1 adverse event in 350) to that of ecstasy (1 in 10,000) resulted in his dismissal, leading to the resignation of several of his colleagues from the ACMD.{{cite news|url=https://www.theguardian.com/politics/2009/nov/02/drug-policy-alan-johnson-nutt|title=Why Professor David Nutt was shown the door|vauthors=Johnson A|date=2 November 2009|newspaper=The Guardian|access-date=3 November 2009|location=London|archive-date=18 January 2014|archive-url=https://web.archive.org/web/20140118223546/http://www.theguardian.com/politics/2009/nov/02/drug-policy-alan-johnson-nutt|url-status=live}}

In the United States, MDMA is listed in Schedule I of the Controlled Substances Act.Schedules of Controlled Substances; Scheduling of 3,4-Methylenedioxymethamphetamine (MDMA) Into Schedule I of the Controlled Substances Act; Remand, 53 Fed. Reg. 5,156 (DEA 22 February 1988). In a 2011 federal court hearing, the American Civil Liberties Union successfully argued that the sentencing guideline for MDMA/ecstasy is based on outdated science, leading to excessive prison sentences.{{cite web | url = https://www.aclu.org/criminal-law-reform/court-rejects-harsh-federal-drug-sentencing-guideline-scientifically-unjustified | title = Court Rejects Harsh Federal Drug Sentencing Guideline as Scientifically Unjustified | work = American Civil Liberties Union | date = 15 July 2011 | access-date = 29 August 2012 | archive-date = 14 March 2014 | archive-url = https://web.archive.org/web/20140314210920/https://www.aclu.org/criminal-law-reform/court-rejects-harsh-federal-drug-sentencing-guideline-scientifically-unjustified | url-status = live }} Other courts have upheld the sentencing guidelines. The United States District Court for the Eastern District of Tennessee explained its ruling by noting that "an individual federal district court judge simply cannot marshal resources akin to those available to the Commission for tackling the manifold issues involved with determining a proper drug equivalency."{{Cite journal|ssrn=2481227 | vauthors = Hennig AC |title=An Examination of Federal Sentencing Guidelines' Treatment of MDMA ('Ecstasy') |journal=Belmont Law Review |volume=1 |page=267 |year=2014}}

File:UNODC 2016 World Drug Report use of ecstasy in 2014 (page 1 crop).jpg

In 2014, 3.5% of 18 to 25 year-olds had used MDMA in the United States. In the European Union as of 2018, 4.1% of adults (15–64 years old) have used MDMA at least once in their life, and 0.8% had used it in the last year.{{Cite web|url=http://www.emcdda.europa.eu/data/stats2018/gps_en|title=Statistical Bulletin 2018 —{{nbsp}}prevalence of drug use|publisher=European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)|access-date=2019-02-05|archive-date=31 December 2018|archive-url=https://web.archive.org/web/20181231102708/http://www.emcdda.europa.eu/data/stats2018/gps_en|url-status=live}} Among young adults, 1.8% had used MDMA in the last year.

In Europe, an estimated 37% of regular club-goers aged 14 to 35 used MDMA in the past year according to the 2015 European Drug report. The highest one-year prevalence of MDMA use in Germany in 2012 was 1.7% among people aged 25 to 29 compared with a population average of 0.4%. Among adolescent users in the United States between 1999 and 2008, girls were more likely to use MDMA than boys.{{cite journal | vauthors = Wu P, Liu X, Pham TH, Jin J, Fan B, Jin Z | title = Ecstasy use among US adolescents from 1999 to 2008 | journal = Drug and Alcohol Dependence | volume = 112 | issue = 1–2 | pages = 33–8 | date = November 2010 | pmid = 20570447 | pmc = 2967577 | doi = 10.1016/j.drugalcdep.2010.05.006 }}

In 2008 the European Monitoring Centre for Drugs and Drug Addiction noted that although there were some reports of tablets being sold for as little as €1, most countries in Europe then reported typical retail prices in the range of €3 to €9 per tablet, typically containing 25–65{{nbsp}}mg of MDMA.{{cite book |author=European Monitoring Centre for Drugs and Drug Addiction |title=Annual report: the state of the drugs problem in Europe |year=2008 |publisher=Office for Official Publications of the European Communities |location=Luxembourg |isbn=978-92-9168-324-6 |page=49 |url=http://www.emcdda.europa.eu/attachements.cfm/att_64227_EN_EMCDDA_AR08_en.pdf |access-date=1 December 2008 |archive-date=25 April 2013 |archive-url=https://web.archive.org/web/20130425191815/http://www.emcdda.europa.eu/attachements.cfm/att_64227_EN_EMCDDA_AR08_en.pdf |url-status=dead }} By 2014 the EMCDDA reported that the range was more usually between €5 and €10 per tablet, typically containing 57–102{{nbsp}}mg of MDMA, although MDMA in powder form was becoming more common.{{cite book | chapter = Ecstasy: high purity powder available | title = European Drug Report | date = 2014 | page = 26 | publisher = European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) | url = http://www.emcdda.europa.eu/attachements.cfm/att_228272_EN_TDAT14001ENN.pdf | isbn = 978-92-9168-694-0 | doi = 10.2810/32306 | author1 = European Monitoring Centre for Drugs Drug Addiction | access-date = 4 June 2014 | archive-date = 7 September 2014 | archive-url = https://web.archive.org/web/20140907142119/http://www.emcdda.europa.eu/attachements.cfm/att_228272_EN_TDAT14001ENN.pdf | url-status = dead }}

The United Nations Office on Drugs and Crime stated in its 2014 World Drug Report that US ecstasy retail prices range from US$1 to $70 per pill, or from $15,000 to $32,000 per kilogram.{{cite web|title=Ecstasy-type substances Retail and wholesale prices* and purity levels, by drug, region and country or territory|url=http://www.unodc.org/documents/wdr2014/Statistics/Prices_ATS.xls|publisher=United Nations Office on Drugs and Crime|access-date=2 January 2015|archive-date=8 December 2015|archive-url=https://web.archive.org/web/20151208142205/http://www.unodc.org/documents/wdr2014/Statistics/Prices_ATS.xls}} A new research area named Drug Intelligence aims to automatically monitor distribution networks based on image processing and machine learning techniques, in which an Ecstasy pill picture is analyzed to detect correlations among different production batches.{{cite journal | vauthors = Camargo J, Esseiva P, González F, Wist J, Patiny L | title = Monitoring of illicit pill distribution networks using an image collection exploration framework | journal = Forensic Science International | volume = 223 | issue = 1–3 | pages = 298–305 | date = November 2012 | pmid = 23107059 | doi = 10.1016/j.forsciint.2012.10.004 | url = http://www.fsijournal.org/article/S0379-0738(12)00458-6/abstract | access-date = 9 December 2013 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828153543/http://www.allmallorcahotels.com/fsijournalorg/ | url-status = live | url-access = subscription }} These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks.

{{As of|October 2015}}, most of the MDMA in the United States is produced in British Columbia, Canada and imported by Canada-based Asian transnational criminal organizations.{{cite book | title=2015 National Drug Threat Assessment Summary | chapter-url=http://www.dea.gov/docs/2015%20NDTA%20Report.pdf | publisher=United States Department of Justice: Drug Enforcement Administration | access-date=10 April 2016 | chapter=MDMA (3,4-Methylenedioxymethamphetamine) | pages=85–88 | date=October 2015 | archive-date=10 April 2016 | archive-url=https://web.archive.org/web/20160410100038/http://www.dea.gov/docs/2015%20NDTA%20Report.pdf | url-status=dead }} The market for MDMA in the United States is relatively small compared to methamphetamine, cocaine, and heroin. In the United States, about 0.9 million people used ecstasy in 2010.

MDMA is particularly expensive in Australia, costing A$15–A$30 per tablet. In terms of purity data for Australian MDMA, the average is around 34%, ranging from less than 1% to about 85%. The majority of tablets contain 70–85{{nbsp}}mg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the US.{{cite web | vauthors = Dillon P | url = http://www.drugtext.org/library/articles/dillon.htm | title = 10 years of ecstasy and other party drug use in Australia: What have we done and what is there left to do? | work = Drugtext.org | archive-url = https://web.archive.org/web/20120209142314/http://www.drugtext.org/library/articles/dillon.htm | archive-date = 9 February 2012 }}

A number of ecstasy manufacturers brand their pills with a logo, often being the logo of an unrelated corporation.{{cite web|url=https://www.erowid.org/chemicals/mdma/mdma_images.shtml|title=Erowid MDMA Vault : Images|access-date=3 March 2016|archive-date=6 March 2016|archive-url=https://web.archive.org/web/20160306030258/https://www.erowid.org/chemicals/mdma/mdma_images.shtml|url-status=live}} Some pills depict logos of products or media popular with children, such as Shaun the Sheep.{{cite web | vauthors = Cork T | date = 31 July 2015 |url=http://www.westerndailypress.co.uk/sick-dealers-peddle-Shaun-Sheep-Ecstasy-tablets/story-27521142-detail/story.html |title=Now sick dealers peddle Shaun the Sheep Ecstasy tablets |work=Western Daily Press|access-date=3 March 2016 |url-status=dead |archive-url=https://web.archive.org/web/20150812022920/http://www.westerndailypress.co.uk/sick-dealers-peddle-Shaun-Sheep-Ecstasy-tablets/story-27521142-detail/story.html |archive-date=12 August 2015|df=dmy-all}}

{{See also|List of investigational anxiolytics|Psychedelic therapy}}

A 2014 review of the safety and efficacy of MDMA as a treatment for various disorders, particularly post-traumatic stress disorder (PTSD), indicated that MDMA has therapeutic efficacy in some patients. Four clinical trials provide moderate evidence in support of this treatment.{{cite journal |vauthors=Breeksema JJ, Niemeijer AR, Krediet E, Vermetten E, Schoevers RA |date=September 2020 |title=Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies |journal=CNS Drugs |type=Systematic review |volume=34 |issue=9 |pages=925–946 |doi=10.1007/s40263-020-00748-y |pmc=7447679 |pmid=32803732}} Some authors have concluded that because of MDMA's potential to cause lasting harm in humans (e.g., serotonergic neurotoxicity and persistent memory impairment), "considerably more research must be performed" on its efficacy in PTSD treatment to determine if the potential treatment benefits outweigh its potential to harm a patient. Other authors have argued that the neurotoxic effects of MDMA are dose-dependent,{{cite journal | vauthors = Battaglia G, Yeh SY, De Souza EB | title = MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons | journal = Pharmacology, Biochemistry, and Behavior | volume = 29 | issue = 2 | pages = 269–274 | date = February 1988 | pmid = 2452449 | doi = 10.1016/0091-3057(88)90155-4 }} with lower doses exhibiting lower neurotoxicity or even neuroprotection,{{cite journal | vauthors = Bhide NS, Lipton JW, Cunningham JI, Yamamoto BK, Gudelsky GA | title = Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain | journal = Brain Research | volume = 1286 | pages = 32–41 | date = August 2009 | pmid = 19555677 | doi = 10.1016/j.brainres.2009.06.042 | pmc = 2754382 }} and that MDMA assisted psychotherapy is considerably safer than current treatments.{{cite journal | vauthors = Feduccia AA, Jerome L, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R | title = Breakthrough for Trauma Treatment: Safety and Efficacy of MDMA-Assisted Psychotherapy Compared to Paroxetine and Sertraline | language = English | journal = Frontiers in Psychiatry | volume = 10 | pages = 650 | date = 2019-09-12 | pmid = 31572236 | pmc = 6751381 | doi = 10.3389/fpsyt.2019.00650 | doi-access = free }}{{clear}}

Animal models suggest that postnatal exposure may ameliorate social impairments in autism.{{cite journal | vauthors = Chaliha D, Mamo JC, Albrecht M, Lam V, Takechi R, Vaccarezza M | title = A Systematic Review of the MDMA Model to Address Social Impairment in Autism | journal = Current Neuropharmacology | volume = 19 | issue = 7 | pages = 1101–1154 | date = 2021-07-01 | pmid = 33388021 | doi = 10.2174/1570159X19666210101130258 | pmc = 8686313 }}

Recent evidence suggests the safe and potentially effective use of MDMA to treat the negative symptoms of schizophrenia.{{cite journal | vauthors = Arnovitz MD, Spitzberg AJ, Davani AJ, Vadhan NP, Holland J, Kane JM, Michaels TI | title = MDMA for the Treatment of Negative Symptoms in Schizophrenia | journal = Journal of Clinical Medicine | volume = 11 | issue = 12 | pages = 3255 | date = June 2022 | pmid = 35743326 | pmc = 9225098 | doi = 10.3390/jcm11123255 | doi-access = free }} Unlike other treatments for mental illness, MDMA would be intended to be used infrequently and alongside psychotherapy in treatment.

• Multidisciplinary Association for Psychedelic Studies (MAPS)
• Lykos Therapeutics
• I Feel Love: MDMA and the Quest for Connection in a Fractured World

{{Reflist}}

{{Sister project links|b=no|q=Drugs#MDMA|commons=Category:MDMA|wikt=MDMA|voy=no|n=MDMA|s=no|v=no|species=no|mw=no|m=no|d=Q69488}}

• [https://maps.org/mdma/ptsd/mapp2/ A Multi-Site Phase 3 Study of MDMA-Assisted Therapy for PTSD (MAPP2)]
• {{cite web | url = https://www.drugabuse.gov/publications/drugfacts/mdma-ecstasymolly | title = MDMA Facts and Statistics | work = National Institute on Drug Abuse | date = 15 June 2020 }}

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