MDMA

MDMA

Systematic (IUPAC) name
(RS)-1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine
Clinical data
Pronunciation	methylenedioxy­methamphetamine: /ˈmɛ.θɪ.liːn.daɪ.ˈɒk.si./ /ˌmɛθæmˈfɛtəmiːn/
AHFS/Drugs.com	entry
Dependence liability	Physical: none[1] Psychological: moderate
Addiction liability	Moderate[2]
Routes of administration	Common: by mouth[3] Uncommon: snorting,[3] inhalation (vaporization),[3] injection,[3][4] rectal
Legal status
Legal status	AU: S9 (Prohibited) CA: Schedule I DE: Anlage I (Controlled) NZ: Class B UK: Class A US: Schedule I UN: Psychotropic Schedule I
Pharmacokinetic data
Metabolism	Liver, CYP450 extensively involved, including CYP2D6
Metabolites	MDA, HMMA, HMA, DHA, MDP2P, MDOH[5]
Onset of action	30–45 minutes (by mouth)[6]
Biological half-life	(R)-MDMA: 5.8 ± 2.2 hours[7] (S)-MDMA: 3.6 ± 0.9 hours[7]
Duration of action	4–6 hours[6]
Excretion	Kidney
Identifiers
CAS Number	42542-10-9^[TOXNET]
ATC code	none
PubChem	CID 1615
IUPHAR/BPS	4574
DrugBank	DB01454
ChemSpider	1556
UNII	KE1SEN21RM
KEGG	C07577
ChEBI	CHEBI:1391
ChEMBL	CHEMBL43048
Synonyms	3,4-MDMA, Ecstasy (E, X, XTC), Molly, Mandy[8][9]
PDB ligand ID	B41 (PDBe, RCSB PDB)
Chemical data
Formula	C11H15NO2
Molar mass	193.25 g·mol^−1
Chirality	Racemic mixture
SMILES CC(NC)CC1=CC=C(OCO2)C2=C1
InChI InChI=1S/C11H15NO2/c1-8(12-2)5-9-3-4-10-11(6-9)14-7-13-10/h3-4,6,8,12H,5,7H2,1-2H3 Key:SHXWCVYOXRDMCX-UHFFFAOYSA-N
Physical data
Boiling point	105 °C (221 °F) at 0.4 mmHg (experimental)
(verify)

3,4-Methylenedioxymethamphetamine (MDMA),^{[note 1]} commonly known as ecstasy (E), is a psychoactive drug used primarily as a recreational drug. Desired effects of MDMA include increased empathy, pleasure; heightened sensations; and sexuality.^[10][11][12] When taken by mouth, effects begin after 30–45 minutes and resolve after 3–6 hours.^[6][13] It is also sometimes snorted or smoked.^[12] As of 2016, MDMA has no accepted medical uses.^[3]

Adverse effects of MDMA use include addiction, memory problems, paranoia, difficulty sleeping, teeth grinding, blurred vision, sweating, and a rapid heartbeat. Use may also lead to depression and fatigue. Deaths have been reported due to increased body temperature and dehydration.^[12] MDMA increases the release and slows the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine in parts of the brain — and has stimulant and psychedelic effects.^[1][14] The initial increase is followed by a short-term decrease in the neurotransmitters.^[13][12] MDMA belongs to the substituted methylenedioxyphenethylamine and substituted amphetamine classes of drugs.

MDMA was first made in 1912.^[12] It was used to improve psychotherapy beginning in the 1970s and became popular as a street drug in the 1980s.^[13][12][15] MDMA is commonly associated with dance parties, raves, and electronic dance music.^[16] It is often sold mixed with other substances such as ephedrine or ketamine.^[12] In 2013, between 9 and 28 million people between the ages of 15 and 65 used ecstasy (0.2% to 0.6% of the world population). This was broadly similar to the percentage of people who use cocaine, amphetamines, and opioids, but fewer than for cannabis.^[17] In the United States, it was used by about 0.9 million people in 2010.^[12]

Having or using MDMA is generally illegal in most countries. Limited exceptions are sometimes made for research. Research is investigating whether a few low doses of MDMA may assist in treating severe, treatment-resistant mental disorders.^[10][18] More research is needed to determine if its usefulness outweighs the risk of harm.^[10][18]

Uses

Medical

As of 2016, MDMA has no accepted medical indications.^[3][19] Previously, it saw limited use in therapy.^[3][20]

Alternative medicine

A small number of therapists continue to use MDMA in therapy despite its illegal status.^[21][22]

Recreational

MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and house parties.^[5] In the rave environment, the sensory effects from the music and lighting are often highly synergistic with the drug. The psychedelic amphetamine quality of MDMA offers multiple reasons for its appeals 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.^[23]

MDMA is sometimes taken in conjunction with other psychoactive drugs, such as LSD, psilocybin mushrooms, and ketamine. Users sometimes use mentholated products while taking MDMA for its cooling sensation.^[24]

MDMA has been used as an adjunct to New Age spiritual practices.^[25]

Forms

Ecstasy tablets which allegedly contain MDMA, but may contain adulterants

A salt of MDMA (typically white) with impurities, resulting in a tan discoloration

High purity MDMA in capsules

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. 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.^[8][9][26] However, due to the global supply shortage of sassafras oil, substances that are sold as "Molly" frequently contain no MDMA and instead contain methylone, ethylone, MDPV, mephedrone, or any other of the group of compounds commonly known as bath salts.^{[9][26][27][28]}

Powdered MDMA is typically 30–40% pure, due to bulking agents (e.g., lactose) and binding agents.^[3] Tablets sold as ecstasy sometimes only contain 3,4-methylenedioxyamphetamine (MDA) instead of MDMA;^[7][3] the proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.^[3]

MDMA is also sold in the form of the hydrochloride salt, either as loose crystals or in gelcaps.^[27][28]

Corporate logos on pills

A number of ecstasy manufacturers brand their pills with a logo, often being a corporate logo,^[29] to help distinguish between suppliers; one of the most notable logos which appeared on pills is the Mitsubishi logo which was very popular during one time.^[30] There have also been sightings of pills with logos of products or shows popular with children, such as Shaun the Sheep.^[31]

Effects

In general, MDMA users begin reporting subjective effects within 30 to 60 minutes of consumption, hitting a peak at about 75 to 120 minutes which plateaus for about 3.5 hours.^[32]

The desired short-term psychoactive effects of MDMA have been reported to include:

• Euphoria – a sense of general well-being and happiness^[10][11]
• Increased sociability and feelings of communication being easy or simple^[10][11]
• Entactogenic effects – increased empathy or feelings of closeness with others^[10][11]
• A sense of inner peace^[11]
• Mild hallucination^[11]
• Enhanced sensation, perception, or sexuality^[10][11]
• Altered sense of time^[13]

Adverse effects

Short-term

The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.^[11][33] 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.^[11][33][34]

The immediate adverse effects of MDMA use can include:

Dehydration[5][11][33] Hyperthermia[5][11][33] Bruxism (grinding and clenching of the teeth)[5][10][11] Increased wakefulness or insomnia[11] Increased perspiration and sweating[11][33] Increased heart rate and blood pressure[5][11][33]

Loss of appetite[7] Nausea and vomiting[10] Diarrhea[11] Erectile dysfunction[35] Mydriasis[36]

Intermediate-term

The adverse effects that last up to a week^[10][37] following cessation of moderate MDMA use include:

Physical Trismus[10] Loss of appetite[37] Insomnia[37]

Psychological Anxiety or paranoia[37] Depression[10][37] Irritability[37] Impulsiveness[37] Restlessness[37] Memory impairment[10] Anhedonia[37]

Long-term

As of 2015, the long-term effects of MDMA on human brain structure and function have not been fully determined.^[38] However, there is evidence of structural and functional deficits in MDMA users with a high lifetime exposure.^[38][39] In contrast, there is no evidence of structural or functional changes in MDMA users with only a moderate (<50 doses used and <100 tablets consumed) lifetime exposure.^[39] MDMA use at high doses has been shown to produce brain lesions, a form of brain damage, in the serotonergic neural pathways of humans and animals.^[2][7] It is unclear if typical MDMA users may develop neurotoxic brain lesions.^[40] In addition, long-term exposure to MDMA in humans has been shown to produce marked neurotoxicity in striatal, hippocampal, prefrontal, and occipital serotonergic axon terminals.^[38][41] Neurotoxic damage to axon terminals has been shown to persist for more than two years.^[41] Brain temperature during MDMA use is positively correlated with MDMA-induced neurotoxicity.^[5][38] Adverse neuroplastic changes to brain microvasculature and white matter also occur in humans using low doses of MDMA.^[5][38] Reduced gray matter density in certain brain structures has also been noted in human MDMA users.^[5][38] The effects established so far for recreational use of ecstasy lie in the range of moderate to large effects for SERT reduction.^[42]

MDMA also produces persistent cognitive impairments in humans.^[10][18][38] Impairments in multiple aspects of cognition, including memory, visual processing, and sleep have been noted in humans;^[10][18][38] the magnitude of these impairments is correlated with lifetime MDMA usage.^[10][18][38] Memory is impacted by ecstasy use, which is associated with impairments in several forms of memory.^[10][18] Some studies indicate repeated recreational users of ecstasy have increased rates of depression and anxiety, even after quitting the drug.^[43][44][45] However, these effects are typically considered small.^[46][47]

At high doses, MDMA induces a neuroimmune response which, through several mechanisms, increases the permeability of the blood-brain barrier, thereby making the brain more susceptible to environmental toxins and pathogens.^[48][49] In addition, MDMA has immunosuppressive effects in the peripheral nervous system, but pro-inflammatory effects in the central nervous system.^[50]

During pregnancy

MDMA is a toxic to the fetus and considered to have a moderate toxic effect.^[51][52] In utero exposure to MDMA is associated with a neuro- and cardiotoxicity^[52] 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.^[18][53]

Reinforcement disorders

Approximately 60% of MDMA users experience withdrawal symptoms, including, but not limited to: fatigue, loss of appetite, depression, and trouble concentrating.^[7] Tolerance is expected to occur with consistent MDMA use.^[7]

MDMA has been shown to induce ΔFosB in the nucleus accumbens.^[54] Since MDMA releases dopamine in the striatum, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other dopaminergic psychostimulants.^[54][55] Therefore, chronic use of MDMA at high doses can result in altered brain structure and drug addiction, which occur as a consequence of ΔFosB overexpression in the nucleus accumbens.^[55]

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.

Symptoms of overdose

System	Minor or moderate overdose[36]	Severe overdose[36]
Cardiovascular		Disseminated intravascular coagulation[11] Intracranial hemorrhage[11] Severe hypertension[11][56] or hypotension[11]
Central nervous system	Abnormally fast reflexes[57] Agitation[11][56] Mental confusion[11] Paranoia[11][56] Stimulant psychosis[5]	Cognitive and memory impairment[11] potentially to the point of retrograde or anterograde amnesia[58] Coma[5][56] Convulsions[11][56] Hallucinations[11][56] Loss of consciousness[5] Serotonin syndrome[5][11][34]
Musculoskeletal		Muscle rigidity[11] Rhabdomyolysis (i.e., rapid muscle breakdown)[11][34]
Respiratory		Acute respiratory distress syndrome[11]
Urinary		Renal failure[11]
Other		Cerebral edema[5] Hepatitis[11][34] Hyperpyrexia (a life-threatening elevation of body temperature)[11][34] Hyponatremia (Syndrome of inappropriate antidiuretic hormone)[11][33][34]

Interactions

A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.^[7][59] MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors.^[7] Concurrent use of MDMA with another serotonergic drug can result in a life-threatening condition called serotonin syndrome.^[7] Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors,^[7] such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).^[60]

Pharmacology

Pharmacodynamics

MDMA binds to serotonin transporters.

MDMA acts primarily as a presynaptic releasing agent of serotonin, norepinephrine, and dopamine, which arises from its activity at trace amine-associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (VMAT2).^[7][61][62] MDMA is a monoamine transporter substrate (i.e., a substrate for DAT, NET, and SERT), so it enters monoamine neurons via these neuronal membrane transport proteins;^[61] by acting as a monoamine transporter substrate, MDMA produces competitive reuptake inhibition at the neuronal membrane transporters (i.e., it competes with endogenous monoamines for reuptake).^[61][63] MDMA inhibits both vesicular monoamine transporters (VMATs), the second of which (VMAT2) is highly expressed within monoamine neurons at vesicular membranes.^[62] Once inside a monoamine neuron, MDMA acts as a VMAT2 inhibitor and a TAAR1 agonist.^[61][62]

Inhibition of VMAT2 by MDMA results in increased concentrations of the associated neurotransmitter (serotonin, norepinephrine, or dopamine) in the cytosol of a monoamine neuron.^[62][64] Activation of TAAR1 by MDMA triggers protein kinase A and protein kinase C signaling events which then phosphorylates the associated monoamine transporters – DAT, NET, or SERT – of the neuron.^[61] In turn, these phosphorylated monoamine transporters either reverse transport direction – i.e., move neurotransmitters from the cytosol to the synaptic cleft – or withdraw into the neuron, respectively producing neurotransmitter efflux and noncompetitive reuptake inhibition at the neuronal membrane transporters.^[61] MDMA has ten times more affinity for uptake at serotonin transporters compared to dopamine and norepinephrine transporters and consequently has mainly serotonergic effects.^[65]:1080

In summary, MDMA enters monoamine neurons by acting as a monoamine transporter substrate.^[61] MDMA activity at VMAT2 moves neurotransmitters out from synaptic vesicles and into the cytosol;^[62] MDMA activity at TAAR1 moves neurotransmitters out of the cytosol and into the synaptic cleft.^[61]

MDMA also has weak agonist activity at postsynaptic serotonin receptors 5-HT₁ and 5-HT₂ receptors, and its more efficacious metabolite MDA likely augments this action.^{[66][67][68][69]} A placebo-controlled study in 15 human volunteers found 100 mg MDMA increased blood levels of oxytocin, and the amount of oxytocin increase was correlated with the subjective prosocial effects of MDMA.^[70](S)-MDMA is more effective in eliciting 5-HT, NE, and DA release, while (D)-MDMA is overall less effective, and more selective for 5-HT and NE release (having only a very faint efficacy on DA release).^[71]

MDMA is a ligand at both sigma receptor subtypes, though its efficacies at the receptors have not yet been elucidated.^[72]

Pharmacokinetics

Diagram showing the sequence of MDMA metabolization.

MDMA reaches maximal concentrations in the blood stream between 1.5 and 3 hr after ingestion.^[73] 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.^[74]

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.^[5]

MDMA is known to be metabolized by two main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine.^[36] 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.^[75]

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.^[76] 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^[77] 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 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 ± 2.2 hours vs 3.6 ± 0.9 hours).^[7] However, because MDMA excretion and metabolism have nonlinear kinetics,^[78] the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose^[73]).

Physical and chemical properties

(R)-MDMA

(S)-MDMA

MDMA is chiral and exists as two enantiomers: (R)- and (S)-MDMA.

A powdered salt of MDMA

Reactors used to synthesize MDMA on an industrial scale in a chemical factory in Cikande, Indonesia

MDMA is in the substituted methylenedioxyphenethylamine and substituted amphetamine classes of chemicals. As a free base, MDMA is a colorless oil insoluble in water.^[3] The most common salt of MDMA is the hydrochloride salt;^[3] pure MDMA hydrochloride is water-soluble and appears as a white or off-white powder or crystal.^[3]

Synthesis

There are numerous methods available in the literature to synthesize MDMA via different intermediates.^{[79][80][81][82]} 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.^[83][84] 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.^[85] 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). 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 ml of the oil to produce between 150 and 340 grams of MDMA.^[86]

Synthesis of MDMA from piperonal

Synthesis of MDMA and related analogs from safrole

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.^[87][88][89]

History

Early research and use

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

MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch. 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.^[90] On 24 December 1912, Merck filed two patent applications that described the synthesis and some chemical properties of MDMA^[91] and its subsequent conversion to methylhydrastinine.^[92]

Merck records indicate its researchers returned to the compound sporadically. A 1920 Merck patent describes a chemical modification to MDMA.^[93] 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.^[90]

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.^[94][95] 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.^[90][95][96]

MDMA may have been in non-medical use in the western United States in 1968.^[97] An August 1970 report at a meeting of crime laboratory chemists indicates MDMA was being used recreationally in the Chicago area by 1970.^[95][98] MDMA likely emerged as a substitute for its analog methylenedioxyamphetamine (MDA),^[99] a drug at the time popular among users of psychedelics^[100] which was made a Schedule 1 substance in the United States in 1970.^[101][102]

Shulgin's research and therapeutic use

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.^[95]

Shulgin first heard of the psychoactive effects of N-methylated MDA around 1975 from a young student who reported "amphetamine-like content".^[95] Around 30 May 1976, Shulgin again heard about the effects of N-methylated MDA,^[95] this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University^[100][103] who directed him to the University of Michigan study.^[104] She and two close friends had consumed 100 mg of MDMA and reported positive emotional experiences.^[95] 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.^[95][100] Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.^[95] 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".^[105] Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug "window".^[104][106]

While not finding his own experiences with MDMA particularly powerful,^[104][107] Shulgin was impressed with the drug's disinhibiting effects and believed it could be useful in therapy.^[107] Shulgin took to occasionally using MDMA for relaxation, referring to it as "my low-calorie martini", and giving the drug to his friends, researchers, and others whom he thought could benefit from it.^[104] 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 so impressed with the effects of MDMA that he came out of his semi-retirement to promote its use in therapy. Over the following years, Zeff traveled around the US and occasionally to Europe, eventually training an estimated four thousand psychotherapists in the therapeutic use of MDMA.^[107][108] Zeff named the drug "Adam", believing it put users in a state of primordial innocence.^[100]

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 therapist was minimized in favor of patient self-discovery accompanied by MDMA induced feelings of empathy. Depression, substance abuse, relationship problems, premenstrual syndrome, and autism were among several psychiatric disorders MDMA assisted therapy was reported to treat.^[102] 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.^[107]

Rising recreational use

In the late seventies and early eighties, "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.^[102][109] Early MDMA distributors were deterred from large scale operations by the threat of possible legislation.^[110] Between the 1970s and the mid-1980s, this network of MDMA users consumed an estimated 500,000 doses.^[10][111]

A small recreational market for MDMA developed by the late 1970s,^[112] consuming perhaps 10,000 doses in 1976.^[101] By the early 1980s MDMA was being used in Boston and New York City nightclubs such as Studio 54 and Paradise Garage.^[113][114] 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.^[110]

Perceiving a business opportunity, Michael Clegg, the Southwest distributor for the Boston Group, started his own "Texas Group" backed financially by Texas friends.^[110][115] In 1981,^[110] Clegg had coined "Ecstasy" as a slang term for MDMA to increase its marketability.^[106][109] Starting in 1983,^[110] the Texas Group mass-produced MDMA in a Texas lab^[109] or imported it from California^[106] and marketed tablets using pyramid sales structures and toll-free numbers.^[111] MDMA could be purchased via credit card and taxes were paid on sales.^[110] Under the brand name "Sassyfras", MDMA tablets were sold in brown bottles.^[109] The Texas Group advertised "Ecstasy parties" at bars and discos, describing MDMA as a "fun drug" and "good to dance to".^[110] MDMA was openly distributed in Austin and Dallas-Fort Worth area bars and nightclubs, becoming popular with yuppies, college students, and gays.^{[99][110][111]}

Recreational use also increased after several cocaine dealers switched to distributing MDMA following experiences with the drug.^[111] 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.^[116][117] By the mid-1980s, MDMA use had spread to colleges around the United States.^[110]:33

Media attention and scheduling

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.^[118][119]

United States

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.^[110] 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.^[109]

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.^[109][120] The DEA was surprised when a number of psychiatrists, psychotherapists, and researchers objected to the proposed scheduling and requested a hearing.^[102] In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.^[121] 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.^[109] 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.^[102][109]

Sensational media attention was given to the proposed criminalization and the reaction of MDMA proponents, effectively advertising the drug.^[102] 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.^[122] By some estimates the Texas Group distributed 500,000 tablets per month in Dallas alone.^[106] 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.^[110] By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States.^[97][123] According to the DEA there was evidence of use in twenty-eight states^[124] and Canada.^[97] 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.^{[123][125][126]} The ban took effect one month later on 1 July 1985^[122] in the midst of Nancy Reagan's "Just Say No" campaign.^[127][128]

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.^[102][129] Later Harvard psychiatrist Lester Grinspoon 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. 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 weren't published in medical journals.^[102] No double blind studies had yet been conducted as to the efficacy of MDMA for therapy.

United Nations

While engaged in scheduling debates in the United States, the DEA also pushed for international scheduling.^[122] 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.^[130] The Commission on Narcotic Drugs added MDMA to Schedule I of the convention on 11 February 1986.^[131]

Post-scheduling

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

A 2000 United States Air Force video dramatizing the dangers of MDMA abuse.

The use of MDMA in Texas clubs declined rapidly after criminalization, although by 1991 the drug remained popular among young middle-class whites and in nightclubs.^[110]:46 In 1985, MDMA use became associated with Acid House on the Spanish island of Ibiza.^{[110]:50[132]} Thereafter in the late 1980s, the drug spread alongside rave culture to the UK and then to other European and American cities.^[110]: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.^[65]:1080 MDMA became one of the four most widely used illicit drugs in the US, along with cocaine, heroin, and cannabis.^[106] According to some estimates as of 2004, only marijuana attracts more first time users in the US.^[106]

After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later, Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent legally-approved MDMA studies in humans have taken place in the US. 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, as well as in Switzerland (University Hospital of Psychiatry, Zürich), the Netherlands (Maastricht University), and Spain (Universitat Autònoma de Barcelona).^[133]

"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.^[134][135]

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,^[136] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.^[137]

Society and culture

Global estimates of illegal drug users in 2013
(in millions of users)^[138]

Substance	Best estimate	Low estimate	High estimate
Amphetamine- type stimulants	33.90	13.87	53.81
Cannabis	181.79	128.48	232.07
Cocaine	17.04	13.80	20.73
Ecstasy	18.79	9.34	28.39
Opiates	16.53	12.92	20.46
Opioids	32.42	27.99	37.56

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 declared an illegal substance in 1986 because of its harmful effects and potential for abuse. It is classed as a Schedule 9 Prohibited Substance in the country, meaning it is available for scientific research purposes only. Any other type of 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.^[139]

United Kingdom

In the United Kingdom, MDMA is illegal under a 1977 modification to the Misuse of Drugs Act 1971^[119] thereby making it illegal to sell, buy, or possess the drug without a licence. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking.

United States

In the United States, MDMA is currently placed in Schedule I of the Controlled Substances Act.^[140] 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.^[141] 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."^[142]

Netherlands

In the Netherlands, the Expert Committee on the List (Expertcommissie Lijstensystematiek Opiumwet) issued a report in June 2011 which discussed the evidence for harm and the legal status of MDMA, arguing in favor of maintaining it on List I.^{[142][143][144]}

Canada

In Canada, MDMA is listed as a Schedule 1^[145] as it is an analogue of amphetamine.^[146] The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule III to Schedule I in March 2012.

Economics

UNODC map showing the use of ecstasy by country in 2013 for the global population aged 15–64.

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 25–65 mg of MDMA.^[147] By 2014 the EMCDDA reported that the range was more usually between €5 and €10 per tablet, typically containing 57–102 mg of MDMA, although MDMA in powder form was becoming more common.^[148]

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.^[149] 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.^[150] These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks. Among adolescent users in the United States between 1999 and 2008, girls were more likely to use MDMA than boys.^[151]

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.^[26] The market for MDMA in the United States is relatively small compared to methamphetamine, cocaine, and heroin.^[26]

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 70–85 mg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the US.^[152]

Harm assessment

In a 2011 survey of 292 clinical experts in Scotland, MDMA ranked 13th in personal harm and 16th in social harm out of 19 common recreational drugs.^[153]

Researchers such as David Nutt disagree with the categorization of MDMA with other more harmful drugs,^[154] especially when compared to alcohol which ranked as the most harmful drug using a multicriteria approach.^[155][156] A 2010 UK study which took into account impairment of cognitive functioning placed MDMA at number 17 out of 20 recreational drugs.^[157] In a 2011 survey of 292 clinical experts in Scotland, MDMA ranked 13th in personal harm and 16th in social harm out of 19 common recreational drugs.^[153]

Research

The Multidisciplinary Association for Psychedelic Studies (MAPS) is currently funding pilot studies or clinical trials investigating the use of MDMA in psychotherapy to treat posttraumatic stress disorder (PTSD),^[22] social anxiety in autistic adults,^[158] and anxiety in terminal illness.^[159][160] MDMA has also been proposed as an adjunct to substance abuse treatment.^[161] Contrary to ongoing treatment with approved psychiatric medications, MDMA is taken only a few times.^[162]

A review of the safety and efficacy of MDMA as a treatment for various disorders, particularly PTSD, indicated that MDMA has therapeutic efficacy in some patients;^[18] however, it emphasized that issues regarding the control-ability of MDMA-induced experiences and neurochemical recovery must be addressed.^[18] The author noted that oxytocin and D-cycloserine are potentially safer co-drugs in PTSD treatment, albeit with limited evidence of efficacy.^[18] This review and a second corroborating review by a different author both concluded that, because of MDMA's demonstrated 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 to a patient.^[10][18]

Notes

1. The term MDMA is a contraction of 3,4-methylenedioxy-methamphetamine; it is also known as ecstasy (shortened to "E", "X", or "XTC"), Mandy, and Molly.^[8][9]

References

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    hypertension, aortic dissection, arrhythmias, vasospasm, acute coronary syndrome, hypotension ... Agitation, paranoia, euphoria, hallucinations, bruxism, hyperreflexia, intracerebral haemorrhage ... pulmonary oedema/[Adult respiratory distress syndrome] ... Hepatitis, nausea, vomiting, diarrhoea, gastrointestinal ischaemia ... Hyponatraemia (dilutional/SIADH), acidosis ... Muscle rigidity, rhabdomyolysis
    Desired effects
    [entactogen] – euphoria, inner peace, social facilitation, 'heightens sexuality and expands consciousness', mild hallucinogenic effects ...
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    Bruxism, hyperthermia, ataxia, confusion, hyponatraemia ([Syndrome of inappropriate anti-diuretic hormone]), hepatitis, muscular rigidity, rhabdomyolysis, [Disseminated intravascular coagulation], renal failure, hypotension, serotonin syndrome, chronic mood/memory disturbances ... human data have shown that long-term exposure to MDMA is toxic to serotonergic neurones.^75,76
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18. Parrott AC (2014). "The potential dangers of using MDMA for psychotherapy". J Psychoactive Drugs 46 (1): 37–43. doi:10.1080/02791072.2014.873690. PMID 24830184. Deficits have been demonstrated in retrospective memory, prospective memory, higher cognition, complex visual processing, sleep architecture, sleep apnoea, pain, neurohormonal activity, and psychiatric status. Neuroimaging studies have shown serotonergic deficits, which are associated with lifetime Ecstasy/MDMA usage, and degree of neurocognitive impairment. Basic psychological skills remain intact. Ecstasy/MDMA use by pregnant mothers leads to psychomotor impairments in the children. Hence, the damaging effects of Ecstasy/MDMA were far more widespread than was realized a few years ago. ... Rogers et al. (2009) concluded that recreational ecstasy/MDMA is associated with memory deficits, and other reviews have come to similar conclusions. Nulsen et al. (2010) concluded that 'ecstasy users performed worse in all memory domains'. Laws and Kokkalis (2007) concluded that abstinent Ecstasy/MDMA users showed deficits in both short-term and long-term memory, with moderate to large effects sizes.
19. Sessa, B.; Nutt, D. (5 January 2015). "Making a medicine out of MDMA". The British Journal of Psychiatry 206 (1): 4–6. doi:10.1192/bjp.bp.114.152751. Retrieved 3 February 2016.
20. Climko, R. P.; Roehrich, H.; Sweeney, D. R.; Al-Razi, J. "Ecstacy: a review of MDMA and MDA". International Journal of Psychiatry in Medicine 16 (4): 359–372. ISSN 0091-2174. PMID 2881902.
21. Levy, Enno Freye ; in collaboration with Joseph V. (2009). Pharmacology and abuse of cocaine, amphetamines, ecstasy and related designer drugs a comprehensive review on their mode of action, treatment of abuse and intoxication (Online-Ausg. ed.). Dordrecht: Springer Netherlands. p. 152. ISBN 9789048124480.
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25. Watson L, Beck J. (1991). "New age seekers: MDMA use as an adjunct to spiritual pursuit.". J Psychoactive Drugs. 23 (3): 261–270. doi:10.1080/02791072.1991.10471587. PMID 1685513.
26. "MDMA (3,4-Methylenedioxymethamphetamine)". 2015 National Drug Threat Assessment Summary (PDF). Drug Enforcement Administration (United States Department of Justice: Drug Enforcement Administration). October 2015. pp. 85–88. Retrieved 10 April 2016. MDMA, a synthetic Schedule I drug commonly referred to as “ecstasy” and “molly”, is available throughout the United States. Compared to marijuana, cocaine, heroin, and other illicit drugs, the MDMA market in the United States is small. Most of the MDMA seized in the United States is manufactured in clandestine laboratories in Canada and smuggled across the Northern Border. Canada-based Asian TCOs are the primary suppliers of MDMA in the United States ... MDMA production takes place predominantly in British Columbia; however, it is also manufactured in smaller quantities in Ontario and Quebec. ... The drug “molly” is purported to be a pure form of MDMA—free of any added substances—but the true chemical make-up of “molly” varies. Drugs marketed or sold as “molly” are often made up of several different substances, including synthetic cathinones such as methylone, and do not always contain MDMA. ... Intelligence indicates that some tablets sold as “ecstasy” or “molly” may not be MDMA at all, but another chemical or a mixture of various chemicals which may or may not contain MDMA. DEA laboratories have analyzed samples that have contained methamphetamine, ketamine, caffeine, dimethylsulfone, N-benzylpiperazine (BZP), and trifluoromethylpiperazine (TFMPP), in addition to MDMA
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35. Spauwen, L. W. L.; Niekamp, A.-M.; Hoebe, C. J. P. A.; Dukers-Muijrers, N. H. T. M. (23 October 2014). "Drug use, sexual risk behaviour and sexually transmitted infections among swingers: a cross-sectional study in The Netherlands". Sexually Transmitted Infections 91 (1): 31–36. doi:10.1136/sextrans-2014-051626. It is known that some recreational drugs (eg, MDMA or GHB) may hamper the potential to ejaculate or maintain an erection.
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    • Chronic MDMA use results in serotonergic toxicity, thereby altering the regional cerebral blood flow that can be studied using fMRI.
    • The effects of chronic MDMA use have been analysed in various neurocognitive domains such as working memory, episodic memory, semantic memory, visual stimulation, motor function and impulsivity. ...
    Structural neuroimaging in MDMA users has shown reduction in brain 5-HT transporter (5-HTT) [18-21] and 5-HT2a receptor levels [22-24] using positron emission tomography (PET) or single photon emission computed tomography (SPECT) and reduced grey matter density in various brain regions using voxel based morphometry method (VBM) [25]. Chemical Neuroimaging, assaying the levels of myoinositol (MI) and N-acetylaspartate (NAA) in the brains of MDMA users using proton magnetic resonance spectroscopy (MRS), has not revealed any consistent results [17, 26-29]. Functional magnetic resonance imaging (fMRI) studies have shown task evoked differences in regional brain activation, measured as blood oxygen level dependent (BOLD) signal intensity and/or spatial extent of activation, in MDMA users and controls [30-33]. ... Neurocognitive studies, in MDMA users, have consistently revealed dose related memory and learning problems [35-38] ... Serotonergic innervation is known to regulate the cerebral microvasculature. Chronic MDMA use results in serotonin toxicity, therefore MDMA users are expected to have altered regional blood flow detectable in fMRI [17]. ... Animal data has suggested that MDMA is selectively more toxic to the axons more distal to the brainstem cell bodies, that is, those present mainly in the occipital cortex [54, 55]. Also, human PET and SPECT studies have revealed significant reductions in serotonin transporter binding, most evident in the occipital cortex [18, 20] ... The effects of poly-drug exposure may result in additive neurotoxicity or mutual neuro-protection. MDMA is known to induce hyperthermia which is a prooxidant neurotoxic condition [65]. Hyperthermia is known to accentuate the neurotoxic potential of MDMA as well as methamphetamine [66, 67]. On the other hand, lowering of the core body temperature has been shown to have a neuroprotective effect.
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40. Gouzoulis-Mayfrank, E; Daumann, J (2009). "Neurotoxicity of drugs of abuse—the case of methylenedioxyamphetamines (MDMA, ecstasy), and amphetamines". Dialogues Clin Neurosci 11 (3): 305–17. PMC 3181923. PMID 19877498.
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45. Laws KR, Kokkalis J (2007). "Ecstasy (MDMA) and memory function: a meta-analytic update". Human Psychopharmacology: Clinical and Experimental 22 (6): 381–88. doi:10.1002/hup.857. PMID 17621368.
46. Rogers G., Elston J., Garside R., Roome C., Taylor R., Younger P., Zawada A., Somerville M. (2009). "The harmful health effects of recreational ecstasy: a systematic review of observational evidence". Health technology assessment (Winchester, England) 13 (6): iii—iv, ix–xii, 1–315. doi:10.3310/hta13050. ISSN 2046-4924. PMID 19195429. The evidence we identified for this review provides a fairly consistent picture of deficits in neurocognitive function for ecstasy users compared to ecstasy-naïve controls. Although the effects are consistent and strong for some measures, particularly verbal and working memory, the effect sizes generally appear to be small: where single outcome measures were pooled, the mean scores of all participants tended to fall within normal ranges for the instrument in question and, where multiple measures were pooled, the estimated effect sizes were typically in the range that would be classified as ‘small’. […] We did not find any studies directly investigating the quality of life of participants, and we found no attempts to assess the clinical meaningfulness of any inter-cohort differences. The clinical significance of any exposure effect is thus uncertain; it seems unlikely that these deficits significantly impair the average ecstasy user’s everyday functioning or quality of life. However, our methods are unlikely to have identified subgroups that may be particularly susceptible to ecstasy. In addition, it is difficult to know how representative the studies are of the ecstasy-using population as a whole. Generalising the findings is therefore problematic.
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External links

• MDMA Facts and Statistics National Institute on Drug Abuse
• Methylenedioxymethamphetamine (MDMA or 'Ecstasy') drug profile European Monitoring Centre for Drugs and Drug Addiction
• MDMA-Assisted Psychotherapy Multidisciplinary Association for Psychedelic Studies