MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch.[27] It was used to enhance psychotherapy beginning in the 1970s and became popular as a street drug in the 1980s.[25][26] MDMA is commonly associated with dance parties, raves, and electronic dance music.[28] Tablets sold as ecstasy may be mixed with other substances such as ephedrine, amphetamine, and methamphetamine.[25] In 2016, about 21 million people between the ages of 15 and 64 used ecstasy (0.3% of the world population).[29] This was broadly similar to the percentage of people who use cocaine or amphetamines, but lower than for cannabis or opioids.[29] 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.[30] 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.[31]
MDMA has limited approved medical uses in a small number of countries,[35] but is illegal in most jurisdictions.[36] In the United States, the Food and Drug Administration (FDA) is evaluating the drug for clinical use as of 2021[update].[37] Canada has allowed limited distribution of MDMA upon application to and approval by Health Canada.[38][39] In Australia, it may be prescribed in the treatment of PTSD by specifically authorised psychiatrists.[40]
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.[41] The desired short-term psychoactive effects of MDMA have been reported to include:
The experience elicited by MDMA depends on the dose, setting, and user.[8] 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.[15][43] In psychotherapeutic settings, MDMA effects have been characterized by infantile ideas, mood lability, and memories and moods connected with childhood experiences.[43][44]
MDMA has been described as an "empathogenic" drug because of its empathy-producing effects.[45][46] Results of several studies show the effects of increased empathy with others.[45] When testing MDMA for medium and high doses, it showed increased hedonic and arousal continuum.[47][48] The effect of MDMA increasing sociability is consistent, while its effects on empathy have been more mixed.[49]
Use
Recreational
MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals, and house parties.[15] 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.[50] MDMA is used less often than other stimulants, typically less than once per week.[51]
MDMA is sometimes taken in conjunction with other psychoactive drugs such as LSD,[52]psilocybin mushrooms, 2C-B, and ketamine. The combination with LSD is called "candy-flipping".[52] 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.[53]
MDMA is often co-administered with alcohol, methamphetamine, and prescription drugs such as SSRIs with which MDMA has several drug-drug interactions.[54][55][56] Three life-threatening reports of MDMA co-administration with ritonavir have been reported;[57] with ritonavir having severe and dangerous drug-drug interactions with a wide range of both psychoactive, anti-psychotic, and non-psychoactive drugs.[58]
As of 2023, MDMA therapies have only been approved for research purposes, with no widely accepted medical indications,[10][59][60] although this varies by jurisdiction. Before it was widely banned, it saw limited use in psychotherapy.[8][10][61] In 2017 the United States Food and Drug Administration (FDA) granted breakthrough therapy designation for MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD),[62][63] with some preliminary evidence that MDMA may facilitate psychotherapy efficacy for PTSD.[64][65] Pilot studies indicate that MDMA-assisted psychotherapy may be beneficial in treating social anxiety in autistic adults.[23][24] In these pilot studies, the vast majority of participants reported increased feelings of empathy that persisted after the therapy sessions.[66]
Other
Small doses of MDMA are used by some religious practitioners as an entheogen to enhance prayer or meditation.[67] MDMA has been used as an adjunct to New Age spiritual practices.[68]
Forms
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.[2][3][69] MDMA is also sold in the form of the hydrochloride salt, either as loose crystals or in gelcaps.[70][71] MDMA tablets can sometimes be found in a shaped form that may depict characters from popular culture, likely for deceptive reasons.[clarification needed] These are sometimes collectively referred to as "fun tablets".[72][73]
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.[3][69][70][71] Powdered MDMA ranges from pure MDMA to crushed tablets with 30–40% purity.[10] 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.[10] Tablets sold as ecstasy sometimes contain 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), other amphetamine derivatives, caffeine, opiates, or painkillers.[8] Some tablets contain little or no MDMA.[8][10][74] The proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.[10] The average content of MDMA in a preparation is 70 to 120mg with the purity having increased since the 1990s.[8]
MDMA is usually consumed by mouth. It is also sometimes snorted.[25]
Ecstasy tablets which may contain MDMA
A salt of MDMA (typically white) with impurities, resulting in a tan discoloration
Crushed MDMA (1 gram) crystals
Adverse effects
Short-term
Acute adverse effects are usually the result of high or multiple doses, although single dose toxicity can occur in susceptible individuals.[21] The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.[42][75] 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.[42][75][76]
The immediate adverse effects of MDMA use can include:
As of 2015[update], the long-term effects of MDMA on human brain structure and function have not been fully determined.[83] However, there is consistent evidence of structural and functional deficits in MDMA users with high lifetime exposure.[83] 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.[84]
Furthermore, it is not clear yet whether "typical" recreational users of MDMA (1 to 2 pills of 75 to 125mg MDMA or analogue every 1 to 4 weeks) will develop neurotoxic brain lesions.[85] Long-term exposure to MDMA in humans has been shown to produce marked neurodegeneration in striatal, hippocampal, prefrontal, and occipital serotonergic axon terminals.[83][86] Neurotoxic damage to serotonergic axon terminals has been shown to persist for more than two years.[86] Elevations in brain temperature from MDMA use are positively correlated with MDMA-induced neurotoxicity.[15][83][84] 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.[87]
However, adverse neuroplastic changes to brain microvasculature and white matter have been observed to occur in humans using low doses of MDMA.[15][83] Reduced gray matter density in certain brain structures has also been noted in human MDMA users.[15][83] Global reductions in gray matter volume, thinning of the parietal and orbitofrontal cortices, and decreased hippocampal activity have been observed in long term users.[8] The effects established so far for recreational use of ecstasy lie in the range of moderate to severe effects for serotonin transporter reduction.[88]
Impairments in multiple aspects of cognition, including attention, learning, memory, visual processing, and sleep, have been found in regular MDMA users.[8][21][89][83] The magnitude of these impairments is correlated with lifetime MDMA usage[21][89][83] and are partially reversible with abstinence.[8] Several forms of memory are impaired by chronic ecstasy use;[21][89] however, the effects for memory impairments in ecstasy users are generally small overall.[90][91] MDMA use is also associated with increased impulsivity and depression.[8]
Serotonin depletion following MDMA use can cause depression in subsequent days. In some cases, depressive symptoms persist for longer periods.[8] Some studies indicate repeated recreational use of ecstasy is associated with depression and anxiety, even after quitting the drug.[92] Depression is one of the main reasons for cessation of use.[8]
Approximately 60% of MDMA users experience withdrawal symptoms when they stop taking MDMA.[74] Some of these symptoms include fatigue, loss of appetite, depression, and trouble concentrating.[74]Tolerance to some of the desired and adverse effects of MDMA is expected to occur with consistent MDMA use.[74] 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.[99]
MDMA has been shown to induce ΔFosB in the nucleus accumbens.[100] Because MDMA releases dopamine in the striatum, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other dopaminergic psychostimulants.[100][101] 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.[101] MDMA is less addictive than other stimulants such as methamphetamine and cocaine.[102][103] Compared with amphetamine, MDMA and its metabolite MDA are less reinforcing.[104]
One study found approximately 15% of chronic MDMA users met the DSM-IV diagnostic criteria for substance dependence.[105] However, there is little evidence for a specific diagnosable MDMA dependence syndrome because MDMA is typically used relatively infrequently.[51]
There are currently no medications to treat MDMA addiction.[106]
During pregnancy
MDMA is a moderately teratogenic drug (i.e., it is toxic to the fetus).[107][108]In utero exposure to MDMA is associated with a neuro- and cardiotoxicity[108] 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.[89][109] MDMA has been shown to promote the survival of fetal dopaminergic neurons in culture.[110]
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.[105] Sympathomimetic side effects can be managed with carvedilol.[111][112] MDMA's toxicity in overdose may be exacerbated by caffeine, with which it is frequently cut in order to increase volume.[113] A scheme for management of acute MDMA toxicity has been published focusing on treatment of hyperthermia, hyponatraemia, serotonin syndrome, and multiple organ failure.[114]
A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.[74][120] MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors.[74] Life-threatening reactions and death have occurred in people who took MDMA while on ritonavir.[121]Bupropion, a strong CYP2D6 inhibitor, has been found to increase MDMA exposure with administration of MDMA.[122][123] Concurrent use of MDMA high dosages with another serotonergic drug can result in a life-threatening condition called serotonin syndrome.[8][74] Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors (MAOIs),[8][74] such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).[124]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.[125]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.[125]
MDMA is a substituted amphetamine structurally, and a monoamine-releasing agent mechanistically. Like other monoamine-releasing agents, MDMA enters monoaminergic neurons through monoamine transporters. MDMA has high affinity for dopamine, norepinephrine and serotonin transporters, with some preference for the latter. The methylenedioxy- substitution provides the serotonergic activity, as most other substituted amphetamines show negligible affinity for the serotonin transporter.[citation needed]
Neurotransmitter release induced by monoamine-releasing agents differs significantly from the regular, action potential-evoked neurotransmitter release. Inside the neuron, MDMA inhibits VMAT2 and activates TAAR1. TAAR1 agonism results in the phosphorylation of monoamine transporters by PKA and PKC, which either internalizes the transporter, or reverses its flux direction.[147][148] VMAT2 inhibition prevents the packaging of the cytosolic monoamines into the synaptic vesicles, which allows them to instead be pumped out of the neuron by the phosphorylated transporters. The result is that the neuron constantly "leaks" neurotransmitters into the synapse, regardless of any signal received.[149]
MDMA has two enantiomers, (S)-MDMA and (R)-MDMA.[16] Recreationally used MDMA is the equimolar mixture of both. (S)-MDMA causes the entactogenic effects of the racemate, because it releases serotonin, norepinephrine and dopamine much more efficiently via monoamine transporters. It also has higher affinity towards 5-HT2CR. (R)-MDMA has notable agonism towards 5-HT2AR,[150] which supposedly contributes to the mild psychedelic hallucinations induced by high doses of MDMA in humans.[151]
Activities of MDMA, its enantiomers, and related compounds
The MDMA concentration in the blood stream starts to rise after about 30 minutes,[160] and reaches its maximal concentration in the blood stream between 1.5 and 3 hours after ingestion.[161] 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.[162] The duration of action of MDMA is usually four to six hours, after which serotonin levels in the brain are depleted.[8] Serotonin levels typically return to normal within 24–48 hours.[8]
MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[164] 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[165] 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 40mg 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).[74] However, because MDMA excretion and metabolism have nonlinear kinetics,[166] the half-lives would be higher at more typical doses (100mg is sometimes considered a typical dose).[161]
There are numerous methods available to synthesize MDMA via different intermediates.[167][168][169][170] 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.[171][172] 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.[173] One method is to isomerize safrole to isosafrole in the presence of a strong base, and then oxidize isosafrole to MDP2P. Another method uses the Wacker process to oxidize safrole directly to the MDP2P intermediate with a palladium catalyst. Once the MDP2P intermediate has been prepared, a reductive amination leads to racemic MDMA (an equal parts mixture of (R)-MDMA and (S)-MDMA).[citation needed] 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 500mL of the oil to produce between 150 and 340 grams of MDMA.[174]
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.[163][175][176]
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.[177] On 24 December 1912, Merck filed two patent applications that described the synthesis and some chemical properties of MDMA[178] and its subsequent conversion to methylhydrastinine.[179]
Merck records indicate its researchers returned to the compound sporadically. A 1920 Merck patent describes a chemical modification to MDMA.[180] 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.[177]
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.[181][182] 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.[177][182][183]
MDMA may have been in non-medical use in the western United States in 1968.[184] An August 1970 report at a meeting of crime laboratory chemists indicates MDMA was being used recreationally in the Chicago area by 1970.[182][185] MDMA likely emerged as a substitute for its analog 3,4-methylenedioxyamphetamine (MDA),[186] a drug at the time popular among users of psychedelics[187] which was made a Schedule 1 controlled substance in the United States in 1970.[188][189]
Shulgin's research
Alexander and Ann Shulgin in December 2011
American chemist and psychopharmacologistAlexander 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.[182]
Shulgin first heard of the psychoactive effects of N-methylated MDA around 1975 from a young student who reported "amphetamine-like content".[182] Around 30 May 1976, Shulgin again heard about the effects of N-methylated MDA,[182] this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University[187][190] who directed him to the University of Michigan study.[191] She and two close friends had consumed 100mg of MDMA and reported positive emotional experiences.[182] 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.[182][187] Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.[182] 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".[192]
While not finding his own experiences with MDMA particularly powerful,[191][193] Shulgin was impressed with the drug's disinhibiting effects and thought it could be useful in therapy.[193] Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug window.[191][194] 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.[191] 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.[193][195] Zeff named the drug Adam, believing it put users in a state of primordial innocence.[187]
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.[189] 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.[193] 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.[196][197]
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.[189][198] Early MDMA distributors were deterred from large scale operations by the threat of possible legislation.[199] Between the 1970s and the mid-1980s, this network of MDMA users consumed an estimated 500,000 doses.[21][200]
A small recreational market for MDMA developed by the late 1970s,[201] consuming perhaps 10,000 doses in 1976.[188] By the early 1980s MDMA was being used in Boston and New York City nightclubs such as Studio 54 and Paradise Garage.[202][203] 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.[199]
Perceiving a business opportunity, Michael Clegg, the Southwest distributor for the Boston Group, started his own "Texas Group" backed financially by Texas friends.[199][204] In 1981,[199] Clegg had coined "Ecstasy" as a slang term for MDMA to increase its marketability.[194][198] Starting in 1983,[199] the Texas Group mass-produced MDMA in a Texas lab[198] or imported it from California[194] and marketed tablets using pyramid sales structures and toll-free numbers.[200] MDMA could be purchased via credit card and taxes were paid on sales.[199] Under the brand name "Sassyfras", MDMA tablets were sold in brown bottles.[198] The Texas Group advertised "Ecstasy parties" at bars and discos, describing MDMA as a "fun drug" and "good to dance to".[199] MDMA was openly distributed in Austin and Dallas–Fort Worth area bars and nightclubs, becoming popular with yuppies, college students, and gays.[186][199][200]
Recreational use also increased after several cocaine dealers switched to distributing MDMA following experiences with the drug.[200] 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.[205][206] By the mid-1980s, MDMA use had spread to colleges around the United States.[199]:33
Media attention and scheduling
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.[199] 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.[198]
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.[198][207] The DEA was surprised when a number of psychiatrists, psychotherapists, and researchers objected to the proposed scheduling and requested a hearing.[189] In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.[208] 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.[198] 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.[189][198]
Sensational media attention was given to the proposed criminalization and the reaction of MDMA proponents, effectively advertising the drug.[189] 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.[209] By some estimates the Texas Group distributed 500,000 tablets per month in Dallas alone.[194] 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.[199] By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States.[184][210] According to the DEA there was evidence of use in twenty-eight states[211] and Canada.[184] 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.[210][212][213] The ban took effect one month later on 1 July 1985[209] in the midst of Nancy Reagan's "Just Say No" campaign.[214][215]
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.[189][216] 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.[217] 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.[189] In 2017, the FDA grantedbreakthrough therapy designation for its use with psychotherapy for PTSD. However, this designation has been questioned and problematized.[218]
United Nations
While engaged in scheduling debates in the United States, the DEA also pushed for international scheduling.[209] 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.[219] The Commission on Narcotic Drugs added MDMA to Schedule I of the convention on 11 February 1986.[220]
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 misuse
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.[199]:46 In 1985, MDMA use became associated with acid house on the Spanish island of Ibiza.[199]:50[221] Thereafter in the late 1980s, the drug spread alongside rave culture to the UK and then to other European and American cities.[199]: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.[222]:1080 MDMA became one of the four most widely used illicit drugs in the US, along with cocaine, heroin, and cannabis.[194] According to some estimates as of 2004, only marijuana attracts more first time users in the US.[194]
"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.[224][225]
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,[226] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.[227]
In 2017 it was found that some pills being sold as MDMA contained pentylone, which can cause very unpleasant agitation and paranoia.[228]
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.[196]
Society and culture
Global estimates of drug users in 2016 (in millions of users)[229]
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.[230] In 1986, MDMA was declared an illegal substance because of its allegedly harmful effects and potential for misuse.[231] 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.[232]
The Australian Capital Territory passed legislation to decriminalise the possession of small amounts of MDMA, which took effect in October 2023.[233][234]
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.[235][236] 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.[237][238] 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 as well as the resignation of his colleagues from the ACMD.[239]
United States
In the United States, MDMA is listed in Schedule I of the Controlled Substances Act.[240] 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.[241] 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."[242]
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.[242][243][244]
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.[8] 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.[249] Among young adults, 1.8% had used MDMA in the last year.[249]
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.[8] 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%.[8] Among adolescent users in the United States between 1999 and 2008, girls were more likely to use MDMA than boys.[250]
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 25–65mg of MDMA.[251] By 2014 the EMCDDA reported that the range was more usually between €5 and €10 per tablet, typically containing 57–102mg of MDMA, although MDMA in powder form was becoming more common.[252]
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.[253] 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.[254] These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks.
As of October 2015[update], most of the MDMA in the United States is produced in British Columbia, Canada and imported by Canada-based Asian transnational criminal organizations.[69] The market for MDMA in the United States is relatively small compared to methamphetamine, cocaine, and heroin.[69] In the United States, about 0.9 million people used ecstasy in 2010.[25]
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 70–85mg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the US.[255]
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.[89] Four clinical trials provide moderate evidence in support of this treatment.[258] 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.[21][89] Other authors have argued that the neurotoxic effects of MDMA are dose-dependent,[259] with lower doses exhibiting lower neurotoxicity or even neuroprotection,[260] and that MDMA assisted psychotherapy is considerably safer than current treatments.[261]
Animal models suggest that postnatal exposure may ameliorate social impairments in autism.[262]
Recent evidence suggests the safe and potentially effective use of MDMA to treat the negative symptoms of schizophrenia.[263] Unlike other treatments for mental illness, MDMA would be intended to be used infrequently and alongside psychotherapy in treatment.
Related Research Articles
Empathogens or entactogens are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy—as particularly observed and reported for experiences with 3,4-methylenedioxymethamphetamine (MDMA). This class of drug is distinguished from the classes of hallucinogen or psychedelic, and amphetamine or stimulants. Major members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, and αET, MDAI among others. Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines. When referring to MDMA and its counterparts, the term MDxx is often used. Entactogens are sometimes incorrectly referred to as hallucinogens or stimulants, although many entactogens such as ecstasy exhibit psychedelic or stimulant properties as well.
3,4-Methylenedioxyamphetamine (MDA), sometimes referred to as “sass,” is an empathogen-entactogen, stimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.
α-Ethyltryptamine, also known as etryptamine, is an entactogen and stimulant drug of the tryptamine family. It was originally developed and marketed as an antidepressant under the brand name Monase by Upjohn in the 1960s before being withdrawn due to toxicity.
para-Methoxyamphetamine (PMA), also known as 4-methoxyamphetamine (4-MA), is a designer drug of the amphetamine class with serotonergic effects. Unlike other similar drugs of this family, PMA does not produce stimulant, euphoriant, or entactogen effects, and behaves more like an antidepressant in comparison, though it does have some psychedelic properties.
MBDB, also known as N-methyl-1,3-benzodioxolylbutanamine or as 3,4-methylenedioxy-N-methyl-α-ethylphenylethylamine, is an entactogen of the phenethylamine, amphetamine, and phenylisobutylamine families related to MDMA. It is known by the street names "Eden" and "Methyl-J".
Methylone, also known as 3,4-methylenedioxy-N-methylcathinone (MDMC), is an empathogen and stimulant psychoactive drug. It is a member of the amphetamine, cathinone and methylenedioxyphenethylamine classes.
3,4-Methylenedioxyphentermine (MDPH) is a lesser-known drug of the amphetamine family. MDPH was first synthesized by Alexander Shulgin. Very little data exists about the pharmacological properties, metabolism, and toxicity of MDPH.
para-Methoxy-N-methylamphetamine, chemically known as methyl-MA, 4-methoxy-N-methylamphetamine, and 4-MMA is a stimulant and psychedelic drug closely related to the amphetamine-class serotonergic drug para-methoxyamphetamine (PMA). PMMA is the 4-methoxy analog of methamphetamine. Little is known about the pharmacological properties, metabolism, and toxicity of PMMA; because of its structural similarity to PMA, which has known toxicity in humans, it is thought to have considerable potential to cause harmful side effects or death in overdose. In the early 2010s, a number of deaths in users of the drug MDMA were linked to misrepresented tablets and capsules of PMMA.
MDAI, also known as 5,6-methylenedioxy-2-aminoindane, is an entactogen drug of the 2-aminoindane group which is related to MDMA and produces similar subjective effects.
A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.
5-Iodo-2-aminoindane (5-IAI) is an entactogen drug of the 2-aminoindane group. Human anecdotal reports suggest that it is entactogenic but produces little euphoria or stimulation.
A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.
3,4-Methylenedioxy-N-ethylamphetamine is an empathogenic psychoactive drug. MDEA is a substituted amphetamine and a substituted methylenedioxyphenethylamine. MDEA acts as a serotonin, norepinephrine, and dopamine releasing agent and reuptake inhibitor.
α-Methyldopamine (α-Me-DA), also known as 3,4-dihydroxyamphetamine or as catecholamphetamine, is a research chemical of the catecholamine and amphetamine families. It is a monoamine releasing agent and a metabolite of MDMA and MDA. The bis-glutathionyl metabolite of α-methyldopamine is slightly neurotoxic when directly injected into the brain's ventricles.
Substituted amphetamines, or simply amphetamines, are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents. The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens, among others. Examples of substituted amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone, phentermine, mephentermine, tranylcypromine, bupropion, methoxyphenamine, selegiline, amfepramone (diethylpropion), pyrovalerone, MDMA (ecstasy), and DOM (STP).
Phenylisobutylamine, also known as α-ethylphenethylamine, Butanphenamine, B or AEPEA, is a stimulant drug of the phenethylamine class. It is a higher homologue of amphetamine, differing from amphetamine's molecular structure only by the substitution of the methyl group at the alpha position of the side chain with an ethyl group.
UWA-101 is a phenethylamine derivative researched as a potential treatment for Parkinson's disease. Its chemical structure is very similar to that of the illegal drug MDMA, the only difference being the replacement of the α-methyl group with an α-cyclopropyl group. MDMA has been found in animal studies and reported in unauthorised human self-experiments to be effective in the short-term relief of side-effects of Parkinson's disease therapy, most notably levodopa-induced dyskinesia. However the illegal status of MDMA and concerns about its potential for recreational use, neurotoxicity and potentially dangerous side effects mean that it is unlikely to be investigated for medical use in this application, and so alternative analogues were investigated.
5-MAPB, also known as 5-(N-methyl-2-aminopropyl)benzofuran, is an entactogen and designer drug of the amphetamine family that is similar to MDMA in its structure and effects.
(R)-3,4-Methylenedioxy-N-methylamphetamine ((R)-MDMA), also known as (R)-midomafetamine or as levo-MDMA, is the (R)- or levorotatory (l-) enantiomer of 3,4-methylenedioxy-N-methylamphetamine (MDMA; midomafetamine; "ecstasy"), a racemic mixture of (R)-MDMA and (S)-MDMA. Like MDMA, (R)-MDMA is an entactogen or empathogen. It is taken by mouth.
The Borax combo, also known by the informal brand names Blue Bliss and Pink Star, is a combination recreational and designer drug described as an MDMA-like entactogen.
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1 2 Mendelson J, Baggott MJ, Li L, Coyle J, Galloway GP (2012). "Poster Session II (PII 1-111): PII-41. MDMA-Induced Increases in Blood Pressure Are Not Mediated by α-Adrenergic Mechanisms and Are Not Due To Elevated Peripheral Vascular Resistance". Clinical Pharmacology & Therapeutics. 91 (S1 [American Society for Clinical Pharmacology and Therapeutics Abstract of papers, 2012 Annual Meeting Gaylord National Hotel and Convention Center National Harbor, Maryland March 14–17, 2012]): S51–S93 (S66–S66). doi:10.1038/clpt.2011.361. ISSN0009-9236. MDMA increased heart rate (HR) by 25 bpm (p<.001), [cardiac output (CO)] by 1.75 L/min (p<0.01) but did not alter [stroke volume (SV)] or [systemic vascular resistance (SVR)]. Compared to MDMA alone the combination of MDMA + prazosin further increased HR by 24 bpm (p<0.001) and CO by 3.3L/min (p<0.02). MDMA increased systolic and diastolic blood pressure (SBP, DBP) by 26 mmHg (p<0.001 each); prazosin attenuated MDMA effects on DBP by 9.3 mmHg (p<001) but did not alter SBP. [...] MDMA increases HR, producing elevations in CO. The hypertensive effects of MDMA are not due to elevated peripheral vascular resistance and the blood pressure effects of MDMA are not attenuated by α-adrenergic blockade, suggesting that MDMA may produce CV effects through non-α-adrenergic mechanisms.
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† References for all endogenous human TAAR1 ligands are provided at List of trace amines
‡ References for synthetic TAAR1 agonists can be found at TAAR1 or in the associated compound articles. For TAAR2 and TAAR5 agonists and inverse agonists, see TAAR for references.
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