|Systematic (IUPAC) name|
Uncommon: sublingual, insufflation, inhalation (vaporization), injection, rectal
|Metabolism||Hepatic, CYP450 extensively involved, including CYP2D6|
|Metabolites||MDA, HMMA, HMA, DHA, MDP2P, MDOH|
|Onset of action||30–45 minutes (oral)|
|Biological half-life||(R)-MDMA: 5.8 ± 2.2 hours
(S)-MDMA: 3.6 ± 0.9 hours
|Duration of action||4–6 hours|
|CAS Registry Number||TOXNET][|
|Synonyms||3,4-MDMA, Ecstasy, Molly|
|PDB ligand ID||B41 (, )|
|Molecular mass||193.25 g·mol−1|
|Boiling point||105 °C (221 °F) at 0.4 mmHg (experimental)|
|(what is this?)|
MDMA (contracted from 3,4-methylenedioxy-methamphetamine) is a psychoactive drug of the substituted methylenedioxyphenethylamine and substituted amphetamine classes of drugs that is consumed primarily for its euphoric and empathogenic effects. Pharmacologically, MDMA acts as a serotonin-norepinephrine-dopamine releasing agent and reuptake inhibitor.
MDMA has become widely known as "ecstasy" (shortened to "E", "X", or "XTC"), usually referring to its tablet street 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 relatively free of adulterants. "Molly" can sometimes also refer to the related drugs methylone, MDPV, mephedrone or any other of the pharmacological group of compounds commonly known as bath salts.
Possession of MDMA is illegal in most countries. Some limited exceptions exist for scientific and medical research. In 2013 between 9 and 28 million people used ecstasy recreationally (0.2% to 0.6% of the global population between the ages of 15 and 65). This was broadly similar to the number for cocaine, substituted amphetamines, and opioids, but far fewer than the number of cannabis users. It is taken in a variety of contexts and is commonly associated with dance parties (or "raves") and electronic dance music.
MDMA may have health benefits in certain mental disorders, but has potential adverse effects, such as neurotoxicity and cognitive impairment. More research is needed in order to determine if its potential usefulness in posttraumatic stress disorder (PTSD) treatment outweighs the risk of persistent neuropsychological harm to a patient.
- 1 Uses
- 2 Adverse effects
- 3 Interactions
- 4 Pharmacology
- 5 Physical and chemical properties
- 6 History
- 7 Society and culture
- 8 Research
- 9 References
- 10 External links
MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and house parties. In the rave environment, the sensory effects 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.
MDMA is occasionally known for being taken in conjunction with psychedelic drugs the more common combinations include MDMA combined with LSD, MDMA with psilocybin mushrooms, and MDMA with ketamine. Many users use mentholated products while taking MDMA for its cooling sensation while experiencing the drug's effects. Examples include menthol cigarettes, Vicks VapoRub, NyQuil, and lozenges.
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.
The desired short-term psychoactive effects of MDMA include:
- Euphoria – a sense of general well-being and happiness
- Increased sociability and feelings of communication being easy or simple
- Entactogenic effects – increased empathy or feelings of closeness with others
- A sense of inner peace
- Mild hallucination (e.g., colors and sounds are enhanced and mild closed-eye visuals)
- Enhanced sensation, perception, or sexuality
The average ecstasy tablet contains 60–70 mg (base equivalent) of MDMA, usually as the hydrochloride salt. Powdered MDMA is typically 30–40% pure, due to bulking agents (e.g., lactose) and binding agents. Tablets sold as ecstasy sometimes only contain 3,4-methylenedioxyamphetamine (MDA) instead of MDMA; the proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.
The most serious short-term physical health risks of MDMA are hyperthermia and dehydration. Cases of life-threatening or fatal hyponatremia (excessively low sodium concentration in the blood) have developed in MDMA users attempting to prevent dehydration by consuming excessive amounts of water without replenishing electrolytes. Even without excessive water intake, MDMA can increase water retention through syndrome of inappropriate antidiuretic hormone secretion, so that water intake must be restricted (unless heavy sweating occurs).[non-primary source needed] The resultant hypervolumia can simultaneously cause both dilutional hyponatremia (which can cause brain swelling and seizures) and hypertension (which can cause stroke). In the case of excessive water intake, salt can be administered to increase osmotic pressure, but while this improves hyponatremia it can also further worsen hypertension. Both are associated with a sensation of intracranial pressure, either in the brain's arteries as in hypertension, or in the brain's tissues as in hyponatremia.[medical citation needed]
The immediate adverse effects of MDMA use can include:
MDMA use has been shown to produce brain lesions, a form of brain damage, in the serotonergic neural pathways of humans and other animals. In addition, long-term exposure to MDMA in humans has been shown to produce marked neurotoxicity in serotonergic axon terminals. Neurotoxic damage to axon terminals has been shown to persist for more than two years. Brain temperature during MDMA use is positively correlated with MDMA-induced neurotoxicity in animals. Adverse neuroplastic changes to brain microvasculature and white matter also seem to occur in humans using low doses of MDMA. Reduced gray matter density in certain brain structures has also been noted in human MDMA users. In addition, MDMA has immunosuppressive effects in the peripheral nervous system, but pro-inflammatory effects in the central nervous system. Babies of mothers who used MDMA during pregnancy exhibit impaired motor function at 4 months of age, which may reflect either a delay in development or a persistent neurological deficit.
MDMA also produces persistent cognitive impairments in human users. Impairments in multiple aspects of cognition, including memory, visual processing, and sleep have been noted in humans; the magnitude of these impairments is correlated with lifetime ecstasy or MDMA usage. Memory is significantly impacted by ecstasy use, which is associated with marked impairments in all forms of memory (e.g., long-term, short-term, working). Some studies indicate repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug. Other meta analyses have reported possibility of impairment of executive functioning.
Approximately 60% of MDMA users experience withdrawal symptoms, including, but not limited to: fatigue, loss of appetite, depression, and trouble concentrating. Tolerance is expected to occur with consistent MDMA use.
MDMA has been shown to induce ΔFosB in the nucleus accumbens. Since MDMA releases dopamine in the mesocorticolimbic projection, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other psychostimulants. 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.
Overdose symptoms vary widely with MDMA; they can include:
|System||Minor or moderate overdose||Severe overdose|
A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs. MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors. Concurrent use of MDMA with another serotonergic drug can result in a life-threatening condition called serotonin syndrome. Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors, such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).
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). 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; 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). MDMA inhibits both vesicular monoamine transporters (VMATs), the second of which (VMAT2) is highly expressed within monoamine neurons at vesicular membranes. Once inside a monoamine neuron, MDMA acts as a VMAT2 inhibitor and a TAAR1 agonist. Inhibition of VMAT2 by MDMA results in increased concentrations of the associated neurotransmitter (serotonin, norepinephrine, or dopamine) in the cytosol of a monoamine neuron. 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. 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.
In summary, MDMA enters monoamine neurons by acting as a monoamine transporter substrate. MDMA activity at VMAT2 moves neurotransmitters out from synaptic vesicles and into the cytosol; MDMA activity at TAAR1 moves neurotransmitters out of the cytosol and into the synaptic cleft.
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. 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.(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).
MDMA reaches maximal concentrations in the blood stream between 1.5 and 3 hr after ingestion. 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.
Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (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. Sixty-five percent of MDMA is excreted unchanged in the urine (in addition, 7% is metabolized into MDA) during the 24 hours after ingestion.
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. 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.[non-primary source needed]
MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides. 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 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). However, because MDMA excretion and metabolism have nonlinear kinetics, the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose).
Physical and chemical properties
The free base of MDMA is a colorless oil that is insoluble in water. The most common salt of MDMA is the hydrochloride salt; pure MDMA hydrochloride is water-soluble and appears as a white or off-white powder or crystal.
There are numerous methods available in the literature to synthesize MDMA via different intermediates. 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. 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. 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.
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.
Early research and use
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 his coworkers, Walther Beckh and Otto Wolfes. MDMA (called methylsafrylamin, safrylmethylamin or N-Methyl-a-Methylhomopiperonylamin in Merck laboratory reports) was an intermediate compound in the synthesis of methylhydrastinine. Merck was not interested in MDMA itself at the time. On 24 December 1912, Merck filed two patent applications that described the synthesis and some chemical properties of MDMA and its subsequent conversion to methylhydrastinine.
Merck records indicate its researchers returned to the compound sporadically. A 1920 Merck patent describes a chemical modification to MDMA. In 1927, Max Oberlin studied the pharmacology of MDMA while searching for substances with effects similar to adrenaline or ephedrine, the latter being structurally similar to MDMA. Compared to ephedrine, Oberlin observed that it had similar effects on vascular smooth muscle tissue, stronger effects at the uterus, and no "local effect at the eye". MDMA was also found to have effects on blood sugar levels comparable to high doses of ephedrine. Oberlin concluded that the effects of MDMA were not limited to the sympathetic nervous system. Research was stopped "particularly due to a strong price increase of safrylmethylamine", which was still used as an intermediate in methylhydrastinine synthesis. Albert van Schoor performed simple toxicological tests with the drug in 1952, most likely while researching new stimulants or circulatory medications. After pharmacological studies, research on MDMA was not continued. In 1959, Wolfgang Fruhstorfer synthesized MDMA for pharmacological testing while researching stimulants. It is unclear if Fruhstorfer investigated the effects of MDMA in humans.
Outside of Merck, other researchers began to investigate MDMA. In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals injected with mescaline and several analogues, including MDMA. Conducted at the University of Michigan in Ann Arbor, these investigations were declassified in October 1969 and published in 1973. 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.
MDMA may have been in non-medical use in the western United States in 1968. An August 1970 report at a meeting of crime laboratory chemists indicates MDMA was being used recreationally in the Chicago area by 1970. MDMA likely emerged as a substitute for its analog methylenedioxyamphetamine (MDA), a drug at the time popular among users of psychedelics which was made a Schedule 1 substance in the United States in 1970.
Shulgin's research and therapeutic use
American chemist and psychopharmacologist Alexander Shulgin reported that 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 first heard of the psychoactive effects of N-methylated MDA around 1975 from a young student who reported "amphetamine-like content". Around 30 May 1976, Shulgin again heard about the effects of N-methylated MDA, this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University who directed him to the University of Michigan study. She and two close friends consumed 100 mg of MDMA and reported positive emotional experiences. Following the self-trials of a colleague at the University of San Francisco, Shulgin synthesized MDMA and tried it himself in September and October 1976. Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976. In 1978, he and David E. Nichols published a report on the drug's psychoactive effect in humans. They described MDMA as inducing "an easily controlled altered state of consciousness with emotional and sensual overtones" comparable "to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA". Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug "window".
While not finding his own experiences with MDMA particularly powerful, Shulgin was impressed with the drug's disinhibiting effects and believed it could be useful in psychotherapy. 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. One such person was Leo Zeff, a psychotherapist who had been known to use psychedelics 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 psychotherapy. Over the following years, Zeff traveled around the U.S. and occasionally to Europe, eventually training an estimated four thousand psychotherapists in the therapeutic use of MDMA. Zeff named the drug "Adam", believing it put users in a state of primordial innocence.
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. 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.
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. Early MDMA distributors were deterred from large scale operations by the threat of possible legislation. Between the 1970s and the mid-1980s, this network of MDMA users consumed an estimated 500,000 doses.
A small recreational market for MDMA developed by the late 1970s, consuming perhaps 10,000 doses in 1976. By the early 1980s MDMA was being used in Boston and New York City nightclubs such as Studio 54 and Paradise Garage. Into the early 1980s, as the recreational market slowly expanded, production of MDMA was dominated by a small group of therapeutically minded Boston chemists. Having commenced production in 1976, this "Boston Group" did not keep up with growing demand and shortages frequently occurred.
Perceiving a business opportunity, Michael Clegg, the Southwest distributor for the Boston Group, started his own "Texas Group" backed financially by Texas friends. In 1981, Clegg had coined "Ecstasy" as a slang term for MDMA to increase its marketability. Starting in 1983, the Texas Group mass-produced MDMA in a Texas lab or imported it from California and marketed tablets using pyramid sales structures and toll-free numbers. MDMA could be purchased via credit card and taxes were paid on sales. Under the brand name "Sassyfras", MDMA tablets were sold in brown bottles. The Texas Group advertised "Ecstasy parties" at bars and discos, describing MDMA as a "fun drug" and "good to dance to". MDMA was openly distributed in Austin and Dallas area bars and nightclubs, becoming popular with yuppies, college students, and gays. According to one knowledgeable individual, the Texas Group produced more MDMA in eighteen months than all other distribution networks combined across their entire histories.
Recreational use also increased after several cocaine dealers switched to distributing MDMA following experiences with the drug. A California laboratory that analyzed confidentially submitted drug samples first detected MDMA in 1975. Over the following years the number of MDMA samples increased, eventually exceeding the number of MDA samples in the early 1980s.
Media attention and scheduling
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.
In an early media report on MDMA published in 1982, a Drug Enforcement Administration (DEA) spokesman stated the agency would ban the drug if enough evidence for abuse could be found. By mid-1984, MDMA use was becoming more noticed. Bill Mandel reported on "Adam" in a June 10 San Francisco Chronicle article, but misidentified the drug as methyloxymethylenedioxyamphetamine (MMDA). In the next month, the World Health Organization identified MDMA as the only substance out of twenty phenethylamines to be seized a significant number of times. After a year of planning and data collection, MDMA was proposed for scheduling by the DEA on 27 July 1984 with a request for comments and objections. The DEA was surprised when a number of psychiatrists, psychotherapists, and researchers objected to the proposed scheduling and requested a hearing. In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists. An initial hearing was held on 1 February 1985 at the DEA offices in Washington, D.C. with administrative law judge Francis L. Young presiding. It was decided there to hold three more hearings that year in Los Angeles on June 10, Kansas City, Missouri on July 10-11, and Washington, D.C. on October 8-11.
Sensational media attention was given to the proposed criminalization and the reaction of MDMA proponents, effectively advertising the drug. In response to the proposed scheduling, the Texas Group increased production from 1985 estimates of 30,000 tablets a month to as many as 8,000 per day, potentially making two million ecstasy tablets in the months before MDMA was made illegal. By some estimates the Texas Group distributed 500,000 tablets per month in Dallas alone. By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States. According to the DEA there was evidence of use in twenty-eight states and Canada. Urged by Senator Lloyd Bentsen, the DEA announced an emergency Schedule I classification of MDMA on 31 May 1985. The agency cited increased distribution in Texas, escalating street use, and new evidence of MDA (an analog of MDMA) neurotoxicity as reasons for the emergency measure. The ban took effect one month later on 1 July 1985 in the midst of Nancy Reagan's "Just Say No" campaign.
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 was classified as a Schedule III substance. Despite this, DEA administrator John C. Lawn overruled and classified the drug as Schedule I. 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. No double blind studies had yet been conducted as to the efficacy of MDMA for psychotherapy.
While engaged in scheduling debates in the United States, the DEA also pushed for international scheduling. In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 United Nations Convention on Psychotropic Substances. The committee made this recommendation on the basis of the pharmacological similarity of MDMA to previously scheduled drugs, reports of illicit trafficking in Canada, drug seizures in the United States, and lack of well-defined therapeutic use. While intrigued by reports of psychotherapeutic uses for the drug, the committee viewed the studies as lacking appropriate methodological design and encouraged further research. Committee chairman Paul Grof dissented, believing international control was not warranted at the time and a recommendation should await further therapeutic data. The Commission on Narcotic Drugs added MDMA to Schedule I of the convention on 11 February 1986.
In the late 1980s, MDMA began to be widely used in Ibiza, the UK and other parts of Europe, becoming an integral element of rave culture and other psychedelic-influenced music scenes. Spreading along with rave culture, illicit MDMA use became increasingly widespread among young adults in universities and later, in high schools. MDMA became one of the four most widely used illicit drugs in the U.S., along with cocaine, heroin, and cannabis. According to some estimates as of 2004, only marijuana attracts more first time users in the U.S.
After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later,[when?] Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent legally-approved MDMA studies in humans have taken place in the U.S. 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).
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, as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.
Society and culture
MDMA is legally controlled in most of the world under the UN Convention on Psychotropic Substances and other international agreements, although exceptions exist for research and limited medical use. In general, the unlicensed use, sale or manufacture of MDMA are all criminal offences.
In Australia, MDMA was declared illegal 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 the United Kingdom, MDMA is illegal under a 1977 modification to the Misuse of Drugs Act 1971 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.
In the United States, MDMA is currently placed in Schedule I of the Controlled Substances Act. 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. 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."
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.
In Canada, MDMA is listed as a Schedule 1 as it is an analogue of amphetamine. The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule III to Schedule I in March 2012.
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. 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.
The United Nations Office on Drugs and Crime stated in its 2014 World Drug Report that U.S. ecstasy retail prices range from US$1 to $70 per pill, or from $15,000 to $32,000 per kilogram. 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. These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks.
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 U.S.
Some scientists such as David Nutt have disagreed with the categorization of MDMA with other drugs they view as more harmful. A 2007 UK study ranked MDMA 18th in harmfulness out of 20 recreational drugs. Rankings for each drug were based on the risk for acute physical harm, the propensity for physical and psychological dependency on the drug, and the negative familial and societal impacts of the drug. The authors did not evaluate or rate the negative impact of 'ecstasy' on the cognitive health of ecstasy users, e.g., impaired memory and concentration. A later 2010 UK study which took into account impairment of cognitive functioning placed MDMA at number 17 out of 20 recreational drugs.
MAPS is currently funding pilot studies investigating the use of MDMA in PTSD therapy and social anxiety therapy for autistic adults. MDMA has also been proposed as an adjunct to substance abuse treatment.
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; however, it emphasized that MDMA is not a safe medical treatment due to lasting neurotoxic and cognition impairing effects in humans. The author noted that oxytocin and D-cycloserine are potentially safer co-drugs in PTSD treatment, albeit with limited evidence of efficacy. 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 cause long-term harm to a patient.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 375. ISBN 9780071481274.
MDMA has been proven to produce lesions of serotonin neurons in animals and humans.
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/EPIDEMIOLOGY STUDIES/ /Investigators/ compared the prevalence of Diagnostic and Statistical Manual version IV (DSM-IV) mental disorders in 30 current and 29 former ecstasy users, 29 polydrug and 30 drug-naive controls. Groups were approximately matched by age, gender and level of education. The current ecstasy users reported a life-time dose of an average of 821 and the former ecstasy users of 768 ecstasy tablets. Ecstasy users did not significantly differ from controls in the prevalence of mental disorders, except those related to substance use. Substance-induced affective, anxiety and cognitive disorders occurred more frequently among ecstasy users than polydrug controls. The life-time prevalence of ecstasy dependence amounted to 73% in the ecstasy user groups. More than half of the former ecstasy users and nearly half of the current ecstasy users met the criteria of substance-induced cognitive disorders at the time of testing. Logistic regression analyses showed the estimated life-time doses of ecstasy to be predictive of cognitive disorders, both current and life-time. ... Cognitive disorders still present after over 5 months of ecstasy abstinence may well be functional consequences of serotonergic neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA) [Thomasius R et al; Addiction 100(9):1310-9 (2005)] **PEER REVIEWED** PubMed Abstract
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Human Psychopharmacology recently published my review into the increase in empirical knowledge about the human psychobiology of MDMA over the past 25 years (Parrott, 2013a). 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. Neither of these latter reviews suggested that the empirical literature they were reviewing was of poor quality (Laws and Kokkalis, 2007; Nulsen et al., 2010).
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MDMA has become a popular recreational drug of abuse at nightclubs and rave or techno parties, where it is combined with intense physical activity (all-night dancing), crowded conditions (aggregation), high ambient temperature, poor hydration, loud noise, and is commonly taken together with other stimulant club drugs and/or alcohol (Parrott 2006; Von Huben et al. 2007; Walubo and Seger 1999). This combination is probably the main reason why it is generally seen an increase in toxicity events at rave parties since all these factors are thought to induce or enhance the toxicity (particularly the hyperthermic response) of MDMA. ... Another report showed that MDMA users displayed multiple regions of grey matter reduction in the neocortical, bilateral cerebellum, and midline brainstem brain regions, potentially accounting for previously reported neuropsychiatric impairments in MDMA users (Cowan et al. 2003). Neuroimaging techniques, like PET, were used in combination with a 5-HTT ligand in human ecstasy users, showing lower density of brain 5-HTT sites (McCann et al. 1998, 2005, 2008). Other authors correlate the 5-HTT reductions with the memory deficits seen in humans with a history of recreational MDMA use (McCann et al. 2008). A recent study prospectively assessed the sustained effects of ecstasy use on the brain in novel MDMA users using repeated measurements with a combination of different neuroimaging parameters of neurotoxicity. The authors concluded that low MDMA dosages can produce sustained effects on brain microvasculature, white matter maturation, and possibly axonal damage (de Win et al. 2008).
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Clinical manifestation ...
hypertension, aortic dissection, arrhythmias, vasospasm, acute coronary syndrome, hypotension ... Agitation, paranoia, euphoria, hallucinations, bruxism, hyperreflexia, intracerebral haemorrhage ... pulmonary oedema/ARDS ... Hepatitis, nausea, vomiting, diarrhoea, gastrointestinal ischaemia ... Hyponatraemia (dilutional/SIADH), acidosis ... Muscle rigidity, rhabdomyolysis
[entactogen] – euphoria, inner peace, social facilitation, 'heightens sexuality and expands consciousness', mild hallucinogenic effects ...
Bruxism, hyperthermia, ataxia, confusion, hyponatraemia (SIADH), hepatitis, muscular rigidity, rhabdomyolysis, DIC, 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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Hyponatremia can occur from free water uptake in the collecting tubules secondary to the ADH effects and from over consumption of water to prevent dehydration and overheating. ... Hyperpyrexia resulting in rhabdomyolysis or heat stroke has occurred due to serotonin syndrome or enhanced physical activity without recognizing clinical clues of overexertion, warm temperatures in the clubs, and dehydration.1,4,9 ... Hepatic injury can also occur secondary to hyperpyrexia with centrilobular necrosis and microvascular steatosis.
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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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It is known that some recreational drugs (e.g., MDMA or GHB) may hamper the potential to ejaculate or maintain an erection.
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Over the course of a week following moderate use of the drug, many MDMA users report feeling a range of emotions, including anxiety, restlessness, irritability, and sadness that in some individuals can be as severe as true clinical depression. Similarly, elevated anxiety, impulsiveness, and aggression, as well as sleep disturbances, lack of appetite, and reduced interest in and pleasure from sex have been observed in regular MDMA users.
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In contrast, MDMA produces damage to serotonergic, but not dopaminergic axon terminals in the striatum, hippocampus, and prefrontal cortex (Battaglia et al., 1987, O'Hearn et al., 1988). The damage associated with Meth and MDMA has been shown to persist for at least 2 years in rodents, non-human primates and humans (Seiden et al., 1988, Woolverton et al., 1989, McCann et al., 1998, Volkow et al., 2001a, McCann et al., 2005)
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ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
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