MDMA

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Psychological: Moderate<ref>Template:Cite book</ref> Common: By mouth<ref name=EU2015 />
Uncommon: Insufflation,<ref name=EU2015 /> inhalation,<ref name=EU2015 /> injection,<ref name=EU2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> rectalEntactogen; Stimulant; Psychedelic; Serotonin–norepinephrine–dopamine releasing agent; Serotonin 5-HT₂ receptor agonistNone | _legal_data=Template:Unbulleted list<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>F2Schedule IAnlage IClass BClass APsychotropic Schedule ISchedule I

| _other_data=(RS)-1-(1,3-Benzodioxol-5-yl)-N-methylpropan-2-amine

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3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form),<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> is an empathogen–entactogenic drug with stimulant and minor psychedelic properties.<ref name="DunlapAndrewsOlson2018">Template:Cite journal</ref><ref name="GreenMechanElliott2003">Template:Cite journal</ref><ref name="Current2013">Template:Cite journal</ref> In studies, it has been used alongside psychotherapy in the treatment of post-traumatic stress disorder (PTSD) and social anxiety in autism spectrum disorder.<ref>Template:Cite journal</ref><ref name=":1">Template:Cite journal</ref><ref name=":2">Template:Cite journal</ref> The purported pharmacological effects that may be prosocial include altered sensations, increased energy, empathy, and pleasure.<ref name=Current2013/><ref name=Drugs2014>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> When taken by mouth, effects begin in 30 to 45 minutes and last three to six hours.<ref name=Freye2009>Template:Cite book</ref><ref name=NIH2016/>

MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch.<ref name="FreudenmannÖxlerBernschneider-Reif2006">Template:Cite journal</ref> It was used to enhance psychotherapy beginning in the 1970s and became popular as a street drug in the 1980s.<ref name=Drugs2014/><ref name=NIH2016/> MDMA is commonly associated with dance parties, raves, and electronic dance music.<ref name=WHO2004>Template:Cite book</ref> Tablets sold as ecstasy may be mixed with other substances such as ephedrine, amphetamine, and methamphetamine.<ref name=Drugs2014/> In 2016, about 21 million people between the ages of 15 and 64 used ecstasy (0.3% of the world population).<ref name=UN2018>Template:Cite book</ref> This was broadly similar to the percentage of people who use cocaine or amphetamines, but lower than for cannabis or opioids.<ref name=UN2018/> In the United States, as of 2017, about 7% of people have used MDMA at some point in their lives and 0.9% have used it in the last year.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The lethal risk from one dose of MDMA is estimated to be from 1 death in 20,000 instances to 1 death in 50,000 instances.<ref>Template:Cite journal</ref>

Short-term adverse effects include grinding of the teeth, blurred vision, sweating, and a rapid heartbeat,<ref name="Drugs2014" /> and extended use can also lead to addiction, memory problems, paranoia, and difficulty sleeping. Deaths have been reported due to increased body temperature and dehydration. Following use, people often feel depressed and tired, although this effect does not appear in clinical use, suggesting that it is not a direct result of MDMA administration.<ref name=Drugs2014/><ref>Template:Cite journal</ref> MDMA acts primarily by increasing the release of the neurotransmitters serotonin, dopamine, and norepinephrine in parts of the brain.<ref name=Drugs2014/><ref name=NIH2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It belongs to the substituted amphetamine classes of drugs.<ref name=EU2015/><ref>Template:Cite book</ref> MDMA is structurally similar to mescaline (a psychedelic), methamphetamine (a stimulant), as well as endogenous monoamine neurotransmitters such as serotonin, norepinephrine, and dopamine.<ref>Template:Cite journal</ref>

MDMA has limited approved medical uses in a small number of countries,<ref>Template:Cite newsTemplate:Cbignore</ref> but is illegal in most jurisdictions.<ref>Template:Cite book</ref> In the United States, the Food and Drug Administration (FDA) is evaluating the drug for clinical use Template:As of.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Canada has allowed limited distribution of MDMA upon application to and approval by Health Canada.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In Australia, it may be prescribed in the treatment of PTSD by specifically authorised psychiatrists.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Uses

Recreational

MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals, and house parties.<ref name="pmid22392347" /> 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.<ref>Template:Cite book</ref> MDMA is used less often than other stimulants, typically less than once per week.<ref name=Epstein2013/>

MDMA is sometimes taken in conjunction with other psychoactive drugs such as LSD,<ref name=":0">Template:Cite journal</ref> psilocybin mushrooms, 2C-B, and ketamine. The combination with LSD is called "candy-flipping".<ref name=":0" /> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

MDMA is often co-administered with alcohol, methamphetamine, and prescription drugs such as SSRIs with which MDMA has several drug-drug interactions.<ref name="HysekSimmlerNicola2012">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Three life-threatening reports of MDMA co-administration with ritonavir have been reported;<ref>Template:Cite journal</ref> with ritonavir having severe and dangerous drug-drug interactions with a wide range of both psychoactive, anti-psychotic, and non-psychoactive drugs.<ref name="pmid31038898">Template:Cite journal</ref>

Medical

As of 2023, MDMA therapies have only been approved for research purposes, with no widely accepted medical indications,<ref name=EU2015 /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> although this varies by jurisdiction. Before it was widely banned, it saw limited use in psychotherapy.<ref name=Betzler2017/><ref name=EU2015/><ref>Template:Cite journal</ref> In 2017 the United States Food and Drug Administration (FDA) granted breakthrough therapy designation for MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD),<ref>Template:Cite news</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> with some preliminary evidence that MDMA may facilitate psychotherapy efficacy for PTSD.<ref name="Zarembo">Template:Cite news</ref><ref>Template:Cite journal</ref> Pilot studies indicate that MDMA-assisted psychotherapy may be beneficial in treating social anxiety in autistic adults.<ref name=":1" /><ref name=":2" /> In these pilot studies, the vast majority of participants reported increased feelings of empathy that persisted after the therapy sessions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Some have proposed that psychedelics in general may act as active "super placebos" used for therapeutic purposes.<ref name="DupuisVeissière2022">Template:Cite journal</ref><ref name="vanElkYaden2022">Template:Cite journal</ref>

Others

Small doses of MDMA are used by some religious practitioners as an entheogen to enhance prayer or meditation.<ref name="MDMA and Religion">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> MDMA has been used as an adjunct to New Age spiritual practices.<ref name="Watson & Beck">Template:Cite journal</ref>

Forms

File:1g MDMA-HCl.jpg

1 gram of pure MDMA hydrochloride crystals

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.<ref name="nature.com"/><ref name=DrugFacts/><ref name="DEA 2015 assessment" /> MDMA is also sold in the form of the hydrochloride salt, either as loose crystals or in gelcaps.<ref name="Molly S05E07" /><ref name="Molly S06E05" /> 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".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name=DrugFacts /><ref name="DEA 2015 assessment" /><ref name="Molly S05E07">Template:Cite AV media</ref><ref name="Molly S06E05">Template:Cite AV media</ref> Powdered MDMA ranges from pure MDMA to crushed tablets with 30–40% purity.<ref name=EU2015 /> 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.<ref name=EU2015 /> Tablets sold as ecstasy sometimes contain 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), other amphetamine derivatives, caffeine, opiates, or painkillers.<ref name=Betzler2017/> Some tablets contain little or no MDMA.<ref name=Betzler2017/><ref name=EU2015 /><ref name="Toxnet MDMA after-effects">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.<ref name=EU2015 /> The average content of MDMA in a preparation is 70 to 120Template:Nbspmg with the purity having increased since the 1990s.<ref name=Betzler2017/>

MDMA is usually consumed by mouth. It is also sometimes snorted.<ref name=Drugs2014/>

Effects

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.<ref name="mcn">Template:Cite journal</ref> The desired short-term psychoactive effects of MDMA have been reported to include:

• Euphoria – a sense of general well-being and happiness<ref name=Current2013/><ref name="Acute amph toxicity" />
• Increased self-confidence, sociability, and perception of facilitated communication<ref name=Betzler2017/><ref name=Current2013 /><ref name="Acute amph toxicity" />
• Entactogenic effects—increased empathy or feelings of closeness with others<ref name=Current2013 /><ref name="Acute amph toxicity" /> and oneself<ref name=Betzler2017/>
• Dilated pupils<ref name=Betzler2017/>
• Relaxation and reduced anxiety<ref name=Betzler2017/>
• Increased emotionality<ref name=Betzler2017/>
• A sense of inner peace<ref name="Acute amph toxicity" />
• Mild hallucination<ref name="Acute amph toxicity" />
• Enhanced sensation, perception, or sexuality<ref name=Betzler2017/><ref name=Current2013 /><ref name="Acute amph toxicity" />
• Altered sense of time<ref name=NIH2016/>

The experience elicited by MDMA depends on the dose, setting, and user.<ref name=Betzler2017/> 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.<ref name="pmid22392347" /><ref name="Landriscina">Template:Cite journal</ref> In psychotherapeutic settings, MDMA effects have been characterized by infantile ideas, mood lability, and memories and moods connected with childhood experiences.<ref name="Landriscina" /><ref name="Baggott">Template:Cite journal</ref>

MDMA has been described as an "empathogenic" drug because of its empathy-producing effects.<ref name="Schmid">Template:Cite journal</ref><ref name="Wardle">Template:Cite journal</ref> Results of several studies show the effects of increased empathy with others.<ref name="Schmid" /> When testing MDMA for medium and high doses, it showed increased hedonic and arousal continuum.<ref name="Bravo">Template:Cite book</ref><ref name="Metzner">Template:Cite book</ref> The effect of MDMA increasing sociability is consistent, while its effects on empathy have been more mixed.<ref>Template:Cite journal</ref>

Side effects

Short-term

Acute adverse effects are usually the result of high or multiple doses, although single dose toxicity can occur in susceptible individuals.<ref name="Current2013" /> The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.<ref name="Acute amph toxicity" /><ref name="Hyponatremia" /> 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.<ref name="Acute amph toxicity" /><ref name="Hyponatremia" /><ref name="hyperpyrexia">Template:Cite journal</ref>

The immediate adverse effects of MDMA use can include:

• Bruxism (grinding and clenching of the teeth)<ref name=Betzler2017/><ref name="pmid22392347" /><ref name=Current2013 />
• Dehydration<ref name="pmid22392347"/><ref name="Acute amph toxicity" /><ref name="Hyponatremia" />
• Diarrhea<ref name="Acute amph toxicity" />
• Erectile dysfunction<ref name=Betzler2017/><ref>Template:Cite journal</ref>
• Hyperthermia<ref name=Betzler2017/><ref name="pmid22392347" /><ref name="Hyponatremia" />
• Increased wakefulness or insomnia<ref name=Betzler2017/><ref name="Acute amph toxicity" />
• Increased perspiration and sweating<ref name="Acute amph toxicity" /><ref name="Hyponatremia" />
• Increased heart rate and blood pressure<ref name=Betzler2017/><ref name="pmid22392347" /><ref name="Hyponatremia" />
• Increased psychomotor activity<ref name=Betzler2017/>
• Loss of appetite<ref name=Betzler2017/><ref name="Toxnet MDMA after-effects"/>
• Nausea and vomiting<ref name=Current2013 />
• Visual and auditory hallucinations (rarely)<ref name=Betzler2017/>

Other adverse effects that may occur or persist for up to a week following cessation of moderate MDMA use include:<ref name="Toxnet MDMA after-effects" /><ref name=Current2013 />

Physiological

• Insomnia<ref name="Toxnet MDMA after-effects" />
• Loss of appetite<ref name="Toxnet MDMA after-effects" />
• Tiredness or lethargy<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref>Template:Cite book</ref>

• Trismus (lockjaw)<ref name="Current2013" />

Psychological

• Anhedonia<ref name="Toxnet MDMA after-effects" />
• Anxiety or paranoia<ref name="Toxnet MDMA after-effects"/>
• Depression<ref name="Toxnet MDMA after-effects" /><ref name="Current2013" />
• Impulsiveness<ref name="Toxnet MDMA after-effects" />
• Irritability<ref name="Toxnet MDMA after-effects" />
• Memory impairment<ref name="Current2013" />
• Restlessness<ref name="Toxnet MDMA after-effects" />

Long-term

Template:As of, the long-term effects of MDMA on human brain structure and function have not been fully determined.<ref name="Abstinent MDMA fMRI review">Template:Cite journal</ref> However, there is consistent evidence of structural and functional deficits in MDMA users with high lifetime exposure.<ref name="Abstinent MDMA fMRI review" /> 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.<ref name="mueller2015">Template:Cite journal</ref>

Furthermore, it is not clear yet whether "typical" recreational users of MDMA (1 to 2 pills of 75 to 125Template:Nbspmg MDMA or analogue every 1 to 4 weeks) will develop neurotoxic brain lesions.<ref>Template:Cite journal</ref> Long-term exposure to MDMA in humans has been shown to produce marked neurodegeneration in striatal, hippocampal, prefrontal, and occipital serotonergic axon terminals.<ref name="Abstinent MDMA fMRI review" /><ref name="Meth MDMA NTox">Template:Cite journal</ref> Neurotoxic damage to serotonergic axon terminals has been shown to persist for more than two years.<ref name="Meth MDMA NTox" /> Elevations in brain temperature from MDMA use are positively correlated with MDMA-induced neurotoxicity.<ref name="pmid22392347" /><ref name="Abstinent MDMA fMRI review" /><ref name="mueller2015" /> 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.<ref>Template:Cite journal</ref>

However, adverse neuroplastic changes to brain microvasculature and white matter have been observed to occur in humans using low doses of MDMA.<ref name="pmid22392347" /><ref name="Abstinent MDMA fMRI review" /> Reduced gray matter density in certain brain structures has also been noted in human MDMA users.<ref name="pmid22392347" /><ref name="Abstinent MDMA fMRI review" /> Global reductions in gray matter volume, thinning of the parietal and orbitofrontal cortices, and decreased hippocampal activity have been observed in long term users.<ref name="Betzler2017" /> The effects established so far for recreational use of ecstasy lie in the range of moderate to severe effects for serotonin transporter reduction.<ref>Template:Cite journal</ref>

Impairments in multiple aspects of cognition, including attention, learning, memory, visual processing, and sleep, have been found in regular MDMA users.<ref name=Betzler2017/><ref name=Current2013 /><ref name=Pharm2014>Template:Cite journal</ref><ref name="Abstinent MDMA fMRI review" /> The magnitude of these impairments is correlated with lifetime MDMA usage<ref name=Current2013 /><ref name=Pharm2014 /><ref name="Abstinent MDMA fMRI review" /> and are partially reversible with abstinence.<ref name=Betzler2017/> Several forms of memory are impaired by chronic ecstasy use;<ref name=Current2013 /><ref name=Pharm2014 /> however, the effects for memory impairments in ecstasy users are generally small overall.<ref>Template:Cite journal</ref><ref name="Meta analysis - MDMA memory impairment">Template:Cite journal</ref> MDMA use is also associated with increased impulsivity and depression.<ref name=Betzler2017/>

Serotonin depletion following MDMA use can cause depression in subsequent days. In some cases, depressive symptoms persist for longer periods.<ref name=Betzler2017/> Some studies indicate repeated recreational use of ecstasy is associated with depression and anxiety, even after quitting the drug.<ref>Template:Cite journal</ref> Depression is one of the main reasons for cessation of use.<ref name=Betzler2017/>

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.<ref name="MDMA BBB">Template:Cite journal</ref><ref>Template:Cite book</ref>Template:Page needed In addition, MDMA has immunosuppressive effects in the peripheral nervous system and pro-inflammatory effects in the central nervous system.<ref>Template:Cite journal</ref>

MDMA may increase the risk of cardiac valvulopathy in heavy or long-term users due to activation of serotonin 5-HT_2B receptors.<ref name="pmid24361689">Template:Cite journal</ref><ref name="pmid28676029">Template:Cite journal</ref> MDMA induces cardiac epigenetic changes in DNA methylation, particularly hypermethylation changes.<ref>Template:Cite journal</ref>

Reinforcement disorders

Approximately 60% of MDMA users experience withdrawal symptoms when they stop taking MDMA.<ref name="Toxnet MDMA after-effects"/> Some of these symptoms include fatigue, loss of appetite, depression, and trouble concentrating.<ref name="Toxnet MDMA after-effects"/> Tolerance to some of the desired and adverse effects of MDMA is expected to occur with consistent MDMA use.<ref name="Toxnet MDMA after-effects"/> 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.<ref name="pmid17382831">Template:Cite journal
Lay summary: {{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

MDMA has been shown to induce ΔFosB in the nucleus accumbens.<ref name="MDMA ΔFosB">Template:Cite journal</ref> Because MDMA releases dopamine in the striatum, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other dopaminergic psychostimulants.<ref name="MDMA ΔFosB" /><ref name="Nestler">Template:Cite journal</ref> 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.<ref name="Nestler" /> MDMA is less addictive than other stimulants such as methamphetamine and cocaine.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref> Compared with amphetamine, MDMA and its metabolite MDA are less reinforcing.<ref>Template:Cite book</ref>

One study found approximately 15% of chronic MDMA users met the DSM-IV diagnostic criteria for substance dependence.<ref name=Steinkellner2011>Template:Cite journal</ref> However, there is little evidence for a specific diagnosable MDMA dependence syndrome because MDMA is typically used relatively infrequently.<ref name=Epstein2013>Template:Cite book</ref>

There are currently no medications to treat MDMA addiction.<ref>Template:Cite book</ref>

During pregnancy

MDMA is a moderately teratogenic drug (i.e., it is toxic to the fetus).<ref name=vorhees>Template:Cite journal</ref><ref name=meamar>Template:Cite journal</ref> In utero exposure to MDMA is associated with a neuro- and cardiotoxicity<ref name=meamar/> 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.<ref name=Pharm2014 /><ref name=singer>Template:Cite journal</ref> MDMA has been shown to promote the survival of fetal dopaminergic neurons in culture.<ref>Template:Cite journal</ref>

Overdose

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.<ref name=Steinkellner2011/> Sympathomimetic side effects can be managed with carvedilol.<ref name="RichardsAlbertsonDerlet2015" /><ref name="HysekSchmidRickli2012" /> MDMA's toxicity in overdose may be exacerbated by caffeine, with which it is frequently cut in order to increase volume.<ref>Template:Cite journal</ref> A scheme for management of acute MDMA toxicity has been published focusing on treatment of hyperthermia, hyponatraemia, serotonin syndrome, and multiple organ failure.<ref>Template:Cite journal</ref>

Symptoms of overdose

System	Minor or moderate overdose<ref name="delaTorreFarréRoset2004" />	Severe overdose<ref name="delaTorreFarréRoset2004" />
Cardiovascular		Disseminated intravascular coagulation<ref name="Acute amph toxicity" /> Intracranial hemorrhage<ref name="Acute amph toxicity" /> Severe hypertension<ref name="Acute amph toxicity" /><ref name=oxford/> or hypotension<ref name="Acute amph toxicity" /> Hypotensive bleeding<ref name=Betzler2017/>
Central nervous system	Hyperreflexia<ref name="delaTorreFarréRoset2004" /> Agitation<ref name="Acute amph toxicity" /><ref name=oxford/> Mental confusion<ref name="Acute amph toxicity" /> Paranoia<ref name="Acute amph toxicity" /><ref name=oxford/> Stimulant psychosis<ref name=Betzler2017/><ref name="pmid22392347" />	Cognitive and memory impairment<ref name="Acute amph toxicity" /> potentially to the point of retrograde or anterograde amnesia<ref>Template:Cite journal</ref> Coma<ref name="pmid22392347" /><ref name=oxford>Template:Cite book</ref> Convulsions<ref name="Acute amph toxicity" /><ref name=oxford/> Hallucinations<ref name="Acute amph toxicity" /><ref name=oxford/> Loss of consciousness<ref name="pmid22392347" /> Serotonin syndrome<ref name="pmid22392347" /><ref name="Acute amph toxicity" /><ref name="hyperpyrexia" />
Musculoskeletal		Muscle rigidity<ref name="Acute amph toxicity" /> Rhabdomyolysis (i.e., rapid muscle breakdown)<ref name="Acute amph toxicity" /><ref name="hyperpyrexia" />
Respiratory		Acute respiratory distress syndrome<ref name="Acute amph toxicity" />
Urinary		Acute kidney injury<ref name="Acute amph toxicity" /><ref>Template:Cite journal</ref>
Other		Cerebral edema<ref name="pmid22392347" /> Hepatitis<ref name="Acute amph toxicity" /><ref name="hyperpyrexia" /> Hyperpyrexia (a life-threatening elevation of body temperature greater than or equal to Template:Convert)<ref name="Acute amph toxicity" /><ref name="hyperpyrexia" /> Hyponatremia (syndrome of inappropriate antidiuretic hormone)<ref name="Acute amph toxicity">Template:Cite journal</ref><ref name="Hyponatremia">Template:Cite journal</ref><ref name="hyperpyrexia" />

Interactions

A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.<ref name="Toxnet MDMA after-effects"/><ref>Template:Cite journal</ref> MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors.<ref name="Toxnet MDMA after-effects"/> Life-threatening reactions and death have occurred in people who took MDMA while on ritonavir.<ref name="pmid32228243">Template:Cite journal</ref> Bupropion, a strong CYP2D6 inhibitor, has been found to increase MDMA exposure with administration of MDMA.<ref name="FonsecaFibeiroTapadas2021" /><ref name="SchmidRickliSchaffner2015" /> Concurrent use of MDMA high dosages with another serotonergic drug can result in a life-threatening condition called serotonin syndrome.<ref name=Betzler2017/><ref name="Toxnet MDMA after-effects"/> Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors (MAOIs),<ref name=Betzler2017/><ref name="Toxnet MDMA after-effects"/> such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).<ref>Template:Cite journal</ref> 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.<ref name="HalberstadtNichols2020">Template:Cite book</ref> 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.<ref name="HalberstadtNichols2020" />

MDMA induces the release of monoamine neurotransmitters and thereby acts as an indirectly acting sympathomimetic and produces a variety of cardiostimulant effects.<ref name="FonsecaFibeiroTapadas2021">Template:Cite journal</ref> It dose-dependently increases heart rate, blood pressure, and cardiac output.<ref name="FonsecaFibeiroTapadas2021" /><ref name="MendelsonBaggottLi2012" /> SRIs like citalopram and paroxetine, as well as the serotonin 5-HT_2A receptor antagonist ketanserin, have been found to partially block the increases in heart rate and blood pressure with MDMA.<ref name="FonsecaFibeiroTapadas2021" /><ref name="LiechtiSaurGamma2000">Template:Cite journal</ref> 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.<ref name="Wsół2023">Template:Cite journal</ref><ref name="NeumannDheinKirchhefer2024">Template:Cite journal</ref><ref name="LeyHolzeArikci2023">Template:Cite journal</ref> The NRI reboxetine and the serotonin–norepinephrine reuptake inhibitor (SNRI) duloxetine block MDMA-induced increases in heart rate and blood pressure.<ref name="FonsecaFibeiroTapadas2021" /> Conversely, bupropion, a norepinephrine–dopamine reuptake inhibitor (NDRI) with only weak dopaminergic activity,<ref name="HartSpangemacherDefert2024">Template:Cite journal</ref><ref name="EapGründerBaumann2021">Template:Cite journal</ref> reduced MDMA-induced heart rate and circulating norepinephrine increases but did not affect MDMA-induced blood pressure increases.<ref name="FonsecaFibeiroTapadas2021" /><ref name="SchmidRickliSchaffner2015">Template:Cite journal</ref> On the other hand, the robust NDRI methylphenidate, which has sympathomimetic effects of its own, has been found to augment the cardiovascular effects and increases in circulating norepinephrine and epinephrine levels induced by MDMA.<ref name="FonsecaFibeiroTapadas2021" /><ref name="HysekSimmlerSchillinger2014">Template:Cite journal</ref>

The non-selective beta blocker pindolol blocked MDMA-induced increases in heart rate but not blood pressure.<ref name="FonsecaFibeiroTapadas2021" /><ref name="RichardsAlbertsonDerlet2015" /><ref name="HysekVollenweiderLiechti2010">Template:Cite journal</ref> The α₂-adrenergic receptor agonist clonidine did not affect the cardiovascular effects of MDMA, though it reduced blood pressure.<ref name="FonsecaFibeiroTapadas2021" /><ref name="RichardsAlbertsonDerlet2015" /><ref name="HysekBruggerSimmler2012">Template:Cite journal</ref> 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.<ref name="FonsecaFibeiroTapadas2021" /><ref name="RichardsAlbertsonDerlet2015" /><ref name="HysekFinkSimmler2013">Template:Cite journal</ref><ref name="MendelsonBaggottLi2012">Template:Cite journal</ref> The dual α₁- and β-adrenergic receptor blocker carvedilol reduced MDMA-induced heart rate and blood pressure increases.<ref name="FonsecaFibeiroTapadas2021" /><ref name="RichardsAlbertsonDerlet2015">Template:Cite journal</ref><ref name="HysekSchmidRickli2012">Template:Cite journal</ref> In contrast to the cases of serotonergic and noradrenergic agents, the dopamine D₂ receptor antagonist haloperidol did not affect the cardiovascular responses to MDMA.<ref name="FonsecaFibeiroTapadas2021" /><ref name="LiechtiVollenweider2000">Template:Cite journal</ref> 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.<ref name="RichardsAlbertsonDerlet2015" /><ref name="RichardsHollanderRamoska2017">Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

Template:Nowrap

Target	Affinity (Ki, nM)
Template:Abbrlink	0.73–13,300 (Ki) 380–2,500 (Template:Abbrlink) 50–72 (Template:Abbrlink) (rat)
Template:Abbrlink	27,000–30,500 (Ki) 360–405 (Template:Abbr) 54–110 (Template:Abbr) (rat)
Template:Abbrlink	6,500–>10,000 (Ki) 1,440–21,000 (Template:Abbr) 51–278 (Template:Abbr) (rat)
5-HT1A	6,300–12,200 (Ki) 36,000Template:NbspnM (Template:Abbr) 64% (Template:Abbrlink)
5-HT1B	>10,000
5-HT1D	>10,000
5-HT1E	>10,000
5-HT1F	Template:Abbr
5-HT2A	4,600–>10,000 (Ki) 6,100–12,484 (Template:Abbr) 40–55% (Template:Abbr)
5-HT2B	500–2,000 (Ki) 2,000–>20,000 (Template:Abbr) 32% (Template:Abbr)
5-HT2C	4,400–>13,000 (Ki) 831–9,100 (Template:Abbr) 92% (Template:Abbr)
5-HT3	>10,000
5-HT4	Template:Abbr
5-HT5A	>10,000
5-HT6	>10,000
5-HT7	>10,000
α1A	6,900–>10,000
α1B	>10,000
α1D	Template:Abbr
α2A	2,532–15,000
α2B	1,785
α2C	1,123–1,346
β1, β2	>10,000
D1	>13,600
D2	25,200
D3	>17,700
D4	>10,000
D5	>10,000
H1	2,138–>14,400
H2	>10,000
H3, H4	Template:Abbr
M1	>10,000
M2	>10,000
M3	1,850–>10,000
M4	8,250–>10,000
M5	6,340–>10,000
nACh	>10,000
TAAR1	250–370 (Ki) (rat) 1,000–1,700 (Template:Abbr) (rat) 56% (Template:Abbr) (rat) 2,400–3,100 (Ki) (mouse) 4,000 (Template:Abbr) (mouse) 71% (Template:Abbr) (mouse) 35,000 (Template:Abbr) (human) 26% (Template:Abbr) (human)
I1	220
σ1, σ2	Template:Abbr
Notes: The smaller the value, the more avidly the drug binds to the site. Proteins are human unless otherwise specified. Refs: <ref name="PDSPKiDatabase">{{#invoke:citation/CS1|citation		CitationClass=web }}</ref><ref name="BindingDB">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref><ref name="DunlapAndrewsOlson2018" /><ref name="Ray2010">Template:Cite journal</ref><ref name="SimmlerBuserDonzelli2013" /><ref name="SimmlerRickliHoener2014">Template:Cite journal</ref> <ref name="RickliKopfHoener2015">Template:Cite journal</ref><ref name="LuethiKolaczynskaWalter2019">Template:Cite journal</ref><ref name="EshlemanForsterWolfrum2014">Template:Cite journal</ref><ref name="GainetdinovHoenerBerry2018">Template:Cite journal</ref><ref name="SimmlerBuchyChaboz2016">Template:Cite journal</ref><ref name="SotnikovaCaronGainetdinov2009">Template:Cite journal</ref>

MDMA is an entactogen or empathogen, as well as a stimulant, euphoriant, and weak psychedelic.<ref name="DunlapAndrewsOlson2018" /><ref name="Nichols2022" /> It is a substrate of the monoamine transporters (MATs) and acts as a monoamine releasing agent (MRA).<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021">Template:Cite journal</ref><ref name="RothmanBaumann2003">Template:Cite journal</ref><ref name="RothmanBaumann2006" /> The drug is specifically a well-balanced serotonin–norepinephrine–dopamine releasing agent (SNDRA).<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" /><ref name="RothmanBaumann2003" /><ref name="RothmanBaumann2006" /> To a lesser extent, MDMA also acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI).<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" /><ref name="RothmanBaumann2003" /> MDMA enters monoaminergic 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.<ref name="DunlapAndrewsOlson2018" /><ref name="SulzerSondersPoulsen2005">Template:Cite journal</ref><ref name="ReithGnegy2020">Template:Cite journal</ref><ref name="VaughanHenryFoster2024">Template:Cite book</ref> Induction of monoamine efflux by amphetamines in general may involve intracellular Na⁺ and Ca²⁺ elevation and PKC and CaMKIIα activation.<ref name="SulzerSondersPoulsen2005" /><ref name="ReithGnegy2020" /><ref name="VaughanHenryFoster2024" /> MDMA also acts on the vesicular monoamine transporter 2 (VMAT2) on synaptic vesicles to increase the cytosolic concentrations of the monoamine neurotransmitters available for efflux.<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" /> By inducing release and reuptake inhibition of serotonin, norepinephrine, and dopamine, MDMA increases levels of these neurotransmitters in the brain and periphery.<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" />

In addition to its actions as an SNDRA, MDMA directly but more modestly interacts with a number of monoamine and other receptors.<ref name="DunlapAndrewsOlson2018" /><ref name="PDSPKiDatabase" /><ref name="BindingDB" /><ref name="Ray2010" /> 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.<ref name="DunlapAndrewsOlson2018" /><ref name="PittsCurryHampshire2018" /><ref name="SetolaHufeisenGrande-Allen2003" /><ref name="NashRothBrodkin1994">Template:Cite journal</ref> The drug also interacts with α₂-adrenergic receptors, with the sigma σ₁ and σ₂ receptors, and with the imidazoline I₁ receptor.<ref name="DunlapAndrewsOlson2018" /><ref name="PDSPKiDatabase" /><ref name="BindingDB" /><ref name="Ray2010" /> 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.<ref name="SimmlerLiechti2018" /><ref name="Meyer2013">Template:Cite journal</ref><ref name="StraumannAvedisianKlaiber2024" /> However, findings in this area appear to be conflicting.<ref name="Meyer2013" /><ref name="HalberstadtNichols2020" /><ref name="Bedi2024">Template:Cite journal</ref><ref name="StraumannAvedisianKlaiber2024" /> Likewise, findings on MDMA and induction of the head-twitch response (HTR), a behavioral proxy of psychedelic-like effects, are contradictory in animals, and MDMA does not substitute for or generalize with psychedelics like LSD or DOM in animal drug discrimination tests.<ref name="HalberstadtGeyer2018">Template:Cite book</ref><ref name="Dunlap2022">Template:Cite thesis</ref><ref name="HalberstadtNichols2020" /> Along with the preceding receptor interactions, MDMA is a potent partial agonist of the rodent trace amine-associated receptor 1 (TAAR1).<ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016" /> Conversely however, it is far weaker in terms of potency as an agonist of the human TAAR1.<ref name="DunlapAndrewsOlson2018" /><ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016" /><ref name="LewinMillerGilmour2011">Template:Cite journal</ref> Moreover, MDMA acts as a weak partial agonist or antagonist of the human TAAR1 rather than as an efficacious agonist.<ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016" /> In relation to the preceding, MDMA has been said to be inactive as a human TAAR1 agonist.<ref name="DunlapAndrewsOlson2018" /> TAAR1 activation is thought to auto-inhibit and constrain the effects of amphetamines that possess TAAR1 agonism, for instance MDMA in rodents.<ref name="DochertyAlsufyani2021" /><ref name="EspinozaGainetdinov2014">Template:Cite book</ref><ref name="KuropkaZawadzkiSzpot2023">Template:Cite journal</ref><ref name="SimmlerBuserDonzelli2013">Template:Cite journal</ref><ref name="DiCaraMaggioAloisi2011">Template:Cite journal</ref>

Elevation of serotonin, norepinephrine, and dopamine levels by MDMA is believed to mediate most of the drug's effects, including its entactogenic, stimulant, euphoriant, hyperthermic, and sympathomimetic effects.<ref name="DunlapAndrewsOlson2018" /><ref name="DochertyAlsufyani2021" /><ref name="ReinRaymondBoustani2024">Template:Cite journal</ref><ref name="Kamilar-BrittBedi2015">Template:Cite journal</ref> 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.<ref name="Kamilar-BrittBedi2015" /><ref name="HalberstadtNichols2020" /><ref name="Oeri2021">Template:Cite journal</ref> The exact serotonin receptors responsible for these effects are unclear, but may include the serotonin 5-HT_1A receptor,<ref name="EsakiSasakiNishitani2023">Template:Cite journal</ref> 5-HT_1B receptor,<ref name="HeifetsSalgadoTaylor2019">Template:Cite journal</ref> and 5-HT_2A receptor,<ref name="PittsMinervaChandler2017">Template:Cite journal</ref> as well as 5-HT_1A receptor-mediated oxytocin release and consequent activation of the oxytocin receptor.<ref name="DunlapAndrewsOlson2018" /><ref name="Kamilar-BrittBedi2015" /><ref name="Blanco-GandíaMateos-GarcíaGarcía-Pardo2015">Template:Cite journal</ref><ref name="HeifetsOlson2024">Template:Cite journal</ref><ref name="Nichols2022">Template:Cite journal</ref> Induction of dopamine release is thought to be importantly involved in the stimulant and euphoriant effects of MDMA,<ref name="DunlapAndrewsOlson2018" /><ref name="PittsCurryHampshire2018" /><ref name="KaurKarabulutGauld2023" /> while induction of norepinephrine release and serotonin 5-HT_2A receptor stimulation are believed to mediate its sympathomimetic effects.<ref name="FonsecaFibeiroTapadas2021" /><ref name="DochertyAlsufyani2021" /> MDMA has been associated with a unique subjective "magic" or euphoria that few or no other known entactogens are said to fully reproduce.<ref name="Baggott2023">Template:Cite conference</ref><ref name="Baggott2024" /> The mechanisms underlying this property of MDMA are unknown, but it has been theorized to be due to a very specific mixture and balance of pharmacological activities, including combined serotonin, norepinephrine, and dopamine release and direct serotonin receptor agonism.<ref name="RothmanBaumann2002">Template:Cite journal</ref><ref name="Baggott2023" /><ref name="Baggott2024">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="LuethiLiechti2020">Template:Cite journal</ref> 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).<ref name="McIntyre2023">Template:Cite journal</ref><ref name="TagenMantuanivanHeerden2023">Template:Cite journal</ref><ref name="Wsół2023"/><ref name="RothmanBaumann2009">Template:Cite journal</ref><ref name="RothmanBaumann2002" /><ref name="RothmanBaumann2002b">Template:Cite journal</ref> MDMA has been associated with serotonergic neurotoxicity.<ref name="CostaGołembiowska2022" /><ref name="Oeri2021" /><ref name="SpragueEvermanNichols1998" /> This may be due to formation of toxic MDMA metabolites and/or induction of simultaneous serotonin and dopamine release, with consequent uptake of dopamine into serotonergic neurons and breakdown into toxic species.<ref name="CostaGołembiowska2022">Template:Cite journal</ref><ref name="Oeri2021" /><ref name="SpragueEvermanNichols1998">Template:Cite journal</ref>

MDMA is a racemic mixture of two enantiomers, (S)-MDMA and (R)-MDMA.<ref name="PittsCurryHampshire2018">Template:Cite journal</ref><ref name="StraumannAvedisianKlaiber2024" /> (S)-MDMA is much more potent as an SNDRA in vitro and in producing MDMA-like subjective effects in humans than (R)-MDMA.<ref name="PittsCurryHampshire2018" /><ref name="RothmanBaumann2006" /><ref name="StraumannAvedisianKlaiber2024" /><ref name="AndersonBraunBraun1978">Template:Cite journal</ref> By contrast, (R)-MDMA acts as a lower-potency serotonin–norepinephrine releasing agent (SNRA) with weak or negligible effects on dopamine.<ref name="PittsCurryHampshire2018" /><ref name="RothmanBaumann2006" /><ref name="AcquasPisanuSpiga2007">Template:Cite journal</ref> Relatedly, (R)-MDMA shows weak or negligible stimulant-like and rewarding effects in animals.<ref name="PittsCurryHampshire2018" /><ref name="CurryYoungTran2018">Template:Cite journal</ref> Both (S)-MDMA and (R)-MDMA produce entactogen-type effects in animals and humans.<ref name="PittsCurryHampshire2018" /><ref name="StraumannAvedisianKlaiber2024" /> In addition, both (S)-MDMA and (R)-MDMA are weak agonists of the serotonin 5-HT₂ receptors.<ref name="PittsCurryHampshire2018" /><ref name="KaurKarabulutGauld2023">Template:Cite journal</ref><ref name="StraumannAvedisianKlaiber2024" /><ref name="SetolaHufeisenGrande-Allen2003" /><ref name="NashRothBrodkin1994" /> (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.<ref name="PittsCurryHampshire2018" /><ref name="KaurKarabulutGauld2023" /><ref name="StraumannAvedisianKlaiber2024" /> Despite its greater serotonin 5-HT_2A receptor agonism however, (R)-MDMA did not produce more psychedelic-like effects than (S)-MDMA in humans.<ref name="Bedi2024" /><ref name="StraumannAvedisianKlaiber2024" />

MDMA produces 3,4-methylenedioxyamphetamine (MDA) as a minor active metabolite.<ref name="delaTorreFarréRoset2004" /> 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.<ref name="delaTorreFarréRoset2004" /><ref name="TagenMantuanivanHeerden2023" /> As a result, MDA may contribute to some extent to the effects of MDMA.<ref name="delaTorreFarréRoset2004">Template:Cite journal</ref><ref name="SimmlerLiechti2018" /> MDA is an entactogen, stimulant, and weak psychedelic similarly to MDMA.<ref name="Oeri2021" /> Like MDMA, it acts as a potent and well-balanced SNDRA and as a weak serotonin 5-HT₂ receptor agonist.<ref name="RothmanBaumann2006" /><ref name="SetolaHufeisenGrande-Allen2003" /><ref name="NashRothBrodkin1994" /> However, MDA shows much more potent and efficacious serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor agonism than MDMA.<ref name="KaurKarabulutGauld2023" /><ref name="SimmlerLiechti2018">Template:Cite journal</ref><ref name="NashRothBrodkin1994" /><ref name="SetolaHufeisenGrande-Allen2003" /> Accordingly, MDA produces greater psychedelic effects than MDMA in humans<ref name="Oeri2021" /> and might particularly contribute to the mild psychedelic-like effects of MDMA.<ref name="SimmlerLiechti2018" /> On the other hand, MDA may also be importantly involved in toxicity of MDMA, such as cardiac valvulopathy.<ref name="LuethiLiechti2021">Template:Cite book</ref><ref name="TagenMantuanivanHeerden2023" /><ref name="SetolaHufeisenGrande-Allen2003" />

The duration of action of MDMA (3–6Template:Nbsphours) is much shorter than its elimination half-life (8–9Template:Nbsphours) would imply.<ref name="MeadParrott2020">Template:Cite journal</ref> 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.<ref name="HysekSimmlerNicola2012" /> Similar findings have been made for amphetamine and methamphetamine.<ref name="ErmerPennickFrick2016">Template:Cite journal</ref><ref name="CruickshankDyer2009">Template:Cite journal</ref><ref name="AbbasBarnhardtNash2024">Template:Cite journal</ref><ref name="vanGaalenSchlumbohmFolgering2019">Template:Cite journal</ref> One mechanism by which tolerance to MDMA may occur is internalization of the serotonin transporter (SERT).<ref name="BisagnoCadet2021">Template:Cite book</ref><ref name="KivellDayBosch2010">Template:Cite journal</ref><ref name="HolleySimonsonKivell2013">Template:Cite journal</ref><ref name="UnderhillAmara2020">Template:Cite journal</ref><ref name="UnderhillAmara2022">Template:Cite journal</ref> Although MDMA and serotonin are not significant TAAR1 agonists in humans, TAAR1 activation by MDMA may result in SERT internalization.<ref name="UnderhillAmara2020" /><ref name="UnderhillAmara2022" /><ref name="KittlerLauSchloss2010">Template:Cite journal</ref><ref name="GainetdinovHoenerBerry2018" />

Template:Nowrap

Compound	Serotonin	Norepinephrine	Dopamine
Amphetamine	Template:Abbr	Template:Abbr	Template:Abbr
Template:NbspTemplate:Nbsp(S)-Amphetamine (d)	698–1,765	6.6–7.2	5.8–24.8
Template:NbspTemplate:Nbsp(R)-Amphetamine (l)	Template:Abbr	9.5	27.7
Methamphetamine	Template:Abbr	Template:Abbr	Template:Abbr
Template:NbspTemplate:Nbsp(S)-Methamphetamine (d)	736–1,292	12.3–13.8	8.5–24.5
Template:NbspTemplate:Nbsp(R)-Methamphetamine (l)	4,640	28.5	416
MDA	160	108	190
MDMA	49.6–72	54.1–110	51.2–278
Template:NbspTemplate:Nbsp(S)-MDMA (d)	74	136	142
Template:NbspTemplate:Nbsp(R)-MDMA (l)	340	560	3,700
MDEA	47	2,608	622
MBDB	540	3,300	>100,000
MDAI	114	117	1,334
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: <ref name="RothmanBaumann2006">Template:Cite journal</ref><ref name="SetolaHufeisenGrande-Allen2003">Template:Cite journal</ref><ref name="RothmanBaumannDersch2001">Template:Cite journal</ref><ref name="RothmanPartillaBaumann2012">Template:Cite journal</ref><ref name="MarusichAntonazzoBlough2016">Template:Cite journal</ref><ref name="NagaiNonakaKamimura2007">Template:Cite journal</ref><ref name="HalberstadtBrandtWalther2019">Template:Cite journal</ref><ref name="Blough2008">Template:Cite book</ref><ref name="DunlapAndrewsOlson2018" />

Pharmacokinetics

File:Main metabolic pathways of MDMA in humans.svg

Main metabolic pathways of MDMA in humans.

The MDMA concentration in the blood stream starts to rise after about 30 minutes,<ref>Template:Cite journal</ref> and reaches its maximal concentration in the blood stream between 1.5 and 3 hours after ingestion.<ref name="TORRE1">Template:Cite journal</ref> 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.<ref name="TORRE2">Template:Cite journal</ref> The duration of action of MDMA is about 3 to 6Template:Nbsphours.<ref name="Oeri2021" /> Brain serotonin levels are depleted after MDMA administration but serotonin levels typically return to normal within 24 to 48Template:Nbsphours.<ref name=" Betzler2017" />

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.<ref name="pmid22392347"/>

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.<ref name="delaTorreFarréRoset2004" /> 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.<ref name = "Kolbrich_2008">Template:Cite journal</ref>Template:Primary source inline

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.<ref name="pmid17643356">Template:Cite journal</ref> 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<ref name="fallon">Template:Cite journal</ref> that the area under the blood plasma concentration versus time curve (AUC) was two to four times higher for the (R)-enantiomer than the (S)-enantiomer after a 40Template:Nbspmg oral dose in human volunteers. Likewise, the plasma half-life of (R)-MDMA was significantly longer than that of the (S)-enantiomer (5.8Template:Nbsp±Template:Nbsp2.2 hours vs 3.6Template:Nbsp±Template:Nbsp0.9 hours).<ref name="Toxnet MDMA after-effects"/> However, because MDMA excretion and metabolism have nonlinear kinetics,<ref name="mueller">Template:Cite journal</ref> the half-lives would be higher at more typical doses (100Template:Nbspmg is sometimes considered a typical dose).<ref name="TORRE1" />

Chemistry

Template:Annotated image 4

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MDMA is in the substituted methylenedioxyphenethylamine and substituted amphetamine classes of chemicals. As a free base, MDMA is a colorless oil insoluble in water.<ref name=EU2015 /> The most common salt of MDMA is the hydrochloride salt;<ref name=EU2015 /> pure MDMA hydrochloride is water-soluble and appears as a white or off-white powder or crystal.<ref name=EU2015 />

Synthesis

There are numerous methods available to synthesize MDMA via different intermediates.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name="World Drug Report 2014">Template:Cite book</ref> 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).Template:Citation needed 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 500Template:NbspmL of the oil to produce between 150 and 340 grams of MDMA.<ref>Template:Cite journal</ref>

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Detection in body fluids

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.<ref name = "Kolbrich_2008" /><ref>Template:Cite journal</ref><ref>Template:Cite book</ref>

History

Early research and use

MDMA was first synthesized and patented in 1912 by Merck chemist Anton Köllisch.<ref name="Passie2023">Template:Cite book</ref><ref name="Bernschneider-ReifOxlerFreudenmann2006">Template:Cite journal</ref> 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.<ref name="Bernschneider-ReifOxlerFreudenmann2006" /> On 24 December 1912, Merck filed two patent applications that described the synthesis and some chemical properties of MDMA<ref name="DE274350">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and its subsequent conversion to methylhydrastinine.<ref name="DE279194">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Merck records indicate its researchers returned to the compound sporadically. A 1920 Merck patent describes a chemical modification to MDMA.<ref name="Passie2023" /><ref name="Shulgin1990">Template:Cite book</ref>

MDMA's analogue 3,4-methylenedioxyamphetamine (MDA) was first synthesized in 1910 as a derivative of adrenaline.<ref name="Passie2023" /> 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 (126Template:Nbspmg) to himself.<ref name="Passie2023" /><ref name="Alles1959a">Template:Cite book</ref><ref name="Alles1959b">Template:Cite book</ref> However, he did not subsequently describe these effects until 1959.<ref name="BenzenhöferPassie2010">Template:Cite journal</ref><ref name="Alles1959a" /><ref name="Alles1959b" /> MDA was later tested as an appetite suppressant by Smith, Kline & French and for other uses by other groups in the 1950s.<ref name="Passie2023" /> In relation to the preceding, the psychoactive effects of MDA were discovered well before those of MDMA.<ref name="Passie2023" /><ref name="BenzenhöferPassie2010" />

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.<ref name="Bernschneider-ReifOxlerFreudenmann2006" />

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.<ref name="pmid4197635">Template:Cite journal</ref><ref name=Shulgin/> 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.<ref name="Bernschneider-ReifOxlerFreudenmann2006" /><ref name="Shulgin"/><ref>Template:Cite journal</ref>

MDA appeared as a recreational drug in the mid-1960s.<ref name="Passie2023" /> MDMA may have been in non-medical use in the western United States in 1968.<ref name="Passie2023" /><ref name="Siegel 1986">Template:Cite journal</ref> An August 1970 report at a meeting of crime laboratory chemists indicates MDMA was being used recreationally in the Chicago area by 1970.<ref name="Shulgin"/><ref>The first confirmed sample was seized and identified by Chicago Police in 1970, see Template:Cite journal</ref> MDMA likely emerged as a substitute for MDA,<ref name="Foderaro 1988">Template:Cite news</ref> a drug at the time popular among users of psychedelics<ref name="Professor X"/> which was made a Schedule 1 controlled substance in the United States in 1970.<ref name="Beck 1987">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=exploration/>

Shulgin's research

File:Shulgin sasha 2011 hanna jon.jpg

Alexander and Ann Shulgin in December 2011

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.<ref name="Shulgin">Template:Cite journal</ref>

Shulgin first heard of the psychoactive effects of N-methylated MDA around 1975 from a young student who reported "amphetamine-like content".<ref name="Shulgin"/> Around 30 May 1976, Shulgin again heard about the effects of N-methylated MDA,<ref name="Shulgin"/> this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University<ref name="Professor X"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> who directed him to the University of Michigan study.<ref name=PiHKAL/> She and two close friends had consumed 100Template:Nbspmg of MDMA and reported positive emotional experiences.<ref name=Shulgin/> 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.<ref name="Shulgin"/><ref name="Professor X"/> Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.<ref name="Shulgin"/> In 1978, he and David E. Nichols published a report on the drug's psychoactive effect in humans.<ref name="Passie2023" /> 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".<ref name="isbn0-08-021938-1">Template:Cite book</ref>

While not finding his own experiences with MDMA particularly powerful,<ref name=PiHKAL/><ref name="Dr. Ecstasy"/> Shulgin was impressed with the drug's disinhibiting effects and thought it could be useful in therapy.<ref name="Dr. Ecstasy"/> Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug window.<ref name=PiHKAL/><ref name="rising"/> 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.<ref name=PiHKAL>Template:Cite book</ref> 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.<ref name="Dr. Ecstasy">Template:Cite news</ref><ref>Template:Cite book</ref> Zeff named the drug Adam, believing it put users in a state of primordial innocence.<ref name="Professor X">Template:Cite magazine</ref>

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.<ref name=exploration/> 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.<ref name="Dr. Ecstasy"/> 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.<ref name=Nutt/><ref name="pmid10450215">Template:Cite journal</ref>

Rising recreational use

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.<ref name="exploration">Template:Cite journal</ref><ref name=Eisner/> Early MDMA distributors were deterred from large scale operations by the threat of possible legislation.<ref name="Beck & Rosenbaum">Template:Cite book</ref> Between the 1970s and the mid-1980s, this network of MDMA users consumed an estimated 500,000 doses.<ref name=Current2013/><ref name="isbn0803936788">Template:Cite book</ref>

A small recreational market for MDMA developed by the late 1970s,<ref name="isbn9781847656414">Template:Cite book</ref> consuming perhaps 10,000 doses in 1976.<ref name="Beck 1987"/> By the early 1980s MDMA was being used in Boston and New York City nightclubs such as Studio 54 and Paradise Garage.<ref>Template:Cite news</ref><ref>Template:Cite magazine</ref> 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.<ref name="Beck & Rosenbaum"/>

Perceiving a business opportunity, Michael Clegg, the Southwest distributor for the Boston Group, started his own "Texas Group" backed financially by Texas friends.<ref name="Beck & Rosenbaum"/><ref>Template:Cite book</ref> In 1981,<ref name="Beck & Rosenbaum"/> Clegg had coined "Ecstasy" as a slang term for MDMA to increase its marketability.<ref name=rising/><ref name=Eisner>Template:Cite book</ref> Starting in 1983,<ref name="Beck & Rosenbaum"/> the Texas Group mass-produced MDMA in a Texas lab<ref name=Eisner/> or imported it from California<ref name="rising"/> and marketed tablets using pyramid sales structures and toll-free numbers.<ref name="isbn0803936788"/> MDMA could be purchased via credit card and taxes were paid on sales.<ref name="Beck & Rosenbaum"/> Under the brand name "Sassyfras", MDMA tablets were sold in brown bottles.<ref name=Eisner/> The Texas Group advertised "Ecstasy parties" at bars and discos, describing MDMA as a "fun drug" and "good to dance to".<ref name="Beck & Rosenbaum"/> MDMA was openly distributed in Austin and Dallas–Fort Worth area bars and nightclubs, becoming popular with yuppies, college students, and gays.<ref name="Foderaro 1988" /><ref name="Beck & Rosenbaum"/><ref name="isbn0803936788"/>

Recreational use also increased after several cocaine dealers switched to distributing MDMA following experiences with the drug.<ref name="isbn0803936788"/> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> By the mid-1980s, MDMA use had spread to colleges around the United States.<ref name="Beck & Rosenbaum"/>Template:Rp

Media attention and scheduling

United States

File:Federal Register notice of planned MDMA scheduling.pdf

27 July 1984 Federal Register notice of the proposed MDMA scheduling

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.<ref name="Beck & Rosenbaum"/> 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.<ref name="Eisner" />

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.<ref name=Eisner/><ref>Template:Cite journal</ref> The DEA was surprised when a number of psychiatrists, psychotherapists, and researchers objected to the proposed scheduling and requested a hearing.<ref name="exploration"/> In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.<ref>Template:Cite news</ref> 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.<ref name=Eisner/> 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.<ref name=exploration/><ref name=Eisner/>

Sensational media attention was given to the proposed criminalization and the reaction of MDMA proponents, effectively advertising the drug.<ref name=exploration/> 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.<ref name=comprehensive>Template:Cite book</ref> By some estimates the Texas Group distributed 500,000 tablets per month in Dallas alone.<ref name=rising/> 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.<ref name="Beck & Rosenbaum"/> By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States.<ref name="Siegel 1986"/><ref name="New York Times"/> According to the DEA there was evidence of use in twenty-eight states<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and Canada.<ref name="Siegel 1986"/> 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.<ref name="New York Times">Template:Cite news</ref><ref>Template:Cite news</ref><ref>Template:Cite news</ref> The ban took effect one month later on 1 July 1985<ref name=comprehensive/> in the midst of Nancy Reagan's "Just Say No" campaign.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>

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.<ref name=exploration/><ref name=Harpers>Template:Cite news Template:Free access</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=exploration/> In 2017, the FDA granted breakthrough therapy designation for its use with psychotherapy for PTSD. However, this designation has been questioned and problematized.<ref name="Halvorsen 1689–1690">Template:Cite journal</ref>

United Nations

While engaged in scheduling debates in the United States, the DEA also pushed for international scheduling.<ref name=comprehensive/> 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.<ref>Template:Cite book</ref> The Commission on Narcotic Drugs added MDMA to Schedule I of the convention on 11 February 1986.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Post-scheduling

File:1995-04-08 Vibe Tribe 09 (10937582).jpg

A 1995 Vibe Tribe rave in Erskineville, New South Wales, Australia being broken up by police. MDMA use spread globally along with rave culture.

File:Ecstasy - Is it Really the Dream Drug.ogv

A 2000 United States Air Force 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.<ref name="Beck & Rosenbaum"/> In 1985, MDMA use became associated with acid house on the Spanish island of Ibiza.<ref name="Beck & Rosenbaum"/>Template:Rp<ref>Template:Cite news</ref> Thereafter, in the late 1980s, the drug spread alongside rave culture to the United Kingdom and then to other European and American cities.<ref name="Beck & Rosenbaum"/>Template:Rp 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.<ref name="Goldfrank 2011">Template:Cite book</ref>Template:Rp MDMA became one of the four most widely used illicit drugs in the US, along with cocaine, heroin, and cannabis.<ref name=rising>Template:Cite news</ref> According to some estimates as of 2004, only marijuana attracts more first time users in the United States.<ref name="rising"/>

After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later,Template:When 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).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite newsTemplate:Cbignore</ref>

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,<ref>Template:Cite news</ref> as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.<ref>Template:Cite news</ref>

In 2017, it was found that some pills being sold as MDMA contained pentylone, which can cause very unpleasant agitation and paranoia.<ref>Template:Cite journal</ref>

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.<ref name=Nutt>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="a325">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="x587">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Society and culture

Legal status

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.

Australia

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.<ref>Template:Cite news</ref> In 1986, MDMA was declared an illegal substance because of its allegedly harmful effects and potential for misuse.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The Australian Capital Territory passed legislation to decriminalise the possession of small amounts of MDMA, which took effect in October 2023.<ref>Template:Cite news</ref><ref name="Roy 2023">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Canada

In Canada, MDMA is listed as a Schedule 1<ref name="CDSA Schedule I: Amphetamines">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> as it is an analogue of amphetamine.<ref name="Definitions and Interpretations">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 Template:Convert of MDMA in the province from February 2023 until February 2026.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite news</ref>

Netherlands

In 2024, a Dutch state commission issued a report advocating for MDMA to be made available to patients with PTSD.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="papers.ssrn.com" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

United Kingdom

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.<ref name="Drugs 2.0">Template:Cite book</ref><ref name="UK legality">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite news</ref><ref>Template:Cite journal</ref> 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.<ref name="johnson">Template:Cite news</ref>

United States

In the United States, MDMA is listed in Schedule I of the Controlled Substances Act.<ref>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).</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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."<ref name="papers.ssrn.com">Template:Cite journal</ref>

Demographics

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

UNODC map showing the use of ecstasy by country in 2014 for the global population aged 15–64

In 2014, 3.5% of 18 to 25 year-olds had used MDMA in the United States.<ref name=Betzler2017/> 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.<ref name="European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Among young adults, 1.8% had used MDMA in the last year.<ref name="European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)" />

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.<ref name="Betzler2017" /> 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%.<ref name="Betzler2017" /> Among adolescent users in the United States between 1999 and 2008, girls were more likely to use MDMA than boys.<ref>Template:Cite journal</ref>

Economics

Europe

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 25–65Template:Nbspmg of MDMA.<ref>Template:Cite book</ref> By 2014 the EMCDDA reported that the range was more usually between €5 and €10 per tablet, typically containing 57–102Template:Nbspmg of MDMA, although MDMA in powder form was becoming more common.<ref>Template:Cite book</ref>

North America

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref> These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks.

Template:As of, most of the MDMA in the United States is produced in British Columbia, Canada and imported by Canada-based Asian transnational criminal organizations.<ref name="DEA 2015 assessment">Template:Cite book</ref> The market for MDMA in the United States is relatively small compared to methamphetamine, cocaine, and heroin.<ref name="DEA 2015 assessment" /> In the United States, about 0.9 million people used ecstasy in 2010.<ref name=Drugs2014/>

Australia

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 70–85Template:Nbspmg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the US.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Corporate logos on pills

A number of ecstasy manufacturers brand their pills with a logo, often being the logo of an unrelated corporation.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Some pills depict logos of products or media popular with children, such as Shaun the Sheep.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

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.<ref name="Pharm2014" /> Four clinical trials provide moderate evidence in support of this treatment.<ref>Template:Cite journal</ref> 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.<ref name="Current2013" /><ref name="Pharm2014" /> Other authors have argued that the neurotoxic effects of MDMA are dose-dependent,<ref>Template:Cite journal</ref> with lower doses exhibiting lower neurotoxicity or even neuroprotection,<ref>Template:Cite journal</ref> and that MDMA assisted psychotherapy is considerably safer than current treatments.<ref>Template:Cite journal</ref>

Animal models suggest that postnatal exposure may ameliorate social impairments in autism.<ref>Template:Cite journal</ref>

Recent evidence suggests the safe and potentially effective use of MDMA to treat the negative symptoms of schizophrenia.<ref>Template:Cite journal</ref> Unlike other treatments for mental illness, MDMA would be intended to be used infrequently and alongside psychotherapy in treatment.

See also

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

External links

• A Multi-Site Phase 3 Study of MDMA-Assisted Therapy for PTSD (MAPP2)
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