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MDMA

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MDMA
Clinical data
Other names(±)-1,3-benzodioxolyl-N-methyl-2-propanamine;
(±)-3,4-methylenedioxy-N-methyl-α-methyl-2-phenethylamine;
3,4-methylenedioxy-N-methylamphetamine;
methylenedioxymethamphetamine
Pregnancy
category
Routes of
administration		Oral, sublingual, insufflation, inhalation (smoking), injection[2]
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic, CYP450 extensively involved, especially CYP2D6
Elimination half-life6–10 (though duration of effects is typically actually 3-5 hours)
ExcretionRenal
Identifiers
  • (RS)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC11H15NO2
Molar mass193.25 g/mol g·mol−1
3D model (JSmol)
  • CC(NC)CC1=CC=C(OCO2)C2=C1

MDMA (3,4-Methylenedioxymethamphetamine, Ecstasy) is an awesomepsychoactive amphetamine drug with entactogenic, psychedelic, and stimulant effects.

MDMA is considered unusual for its tendency to induce a sense of intimacy with others and diminished feelings of fear and anxiety. These effects have led some to suggest it might have therapeutic benefits in certain individuals. Before it was made a controlled substance, MDMA was used as an augmentation to psychotherapy, often couples therapy, and to help treat clinical depression as well as anxiety disorders, the results of which are poorly documented. Clinical trials have now testing the therapeutic potential of MDMA for post-traumatic stress disorder (PTSD) and anxiety associated with terminal cancer.

MDMA is criminalized in most countries in the world under a United Nations (U.N.) agreement,[3] and its possession, manufacture, or sale may result in criminal prosecution, although some limited exceptions exist for scientific and medical research. MDMA is one of the most widely used recreational illicit drugs in the world and is taken in a variety of contexts far removed from its roots in psychotherapeutic settings. It is commonly associated with the rave or electronica subculture and related genres of music.

There have been debates within scientific, health care, and drug policy circles about the risks of MDMA, specifically the possibility of neurotoxic damage to the central nervous system (CNS). Regulatory authorities in several locations around the world have approved scientific studies administering MDMA to humans to examine either its therapeutic potential, or, more commonly, simply its basic effects.[4]

Terminology

MDMA was first introduced clinically under the names "Adam" and "Empathy" when it was used in psychotherapy in the late 1970s and early to mid 1980s.[5] Later on, upon making it into the recreational drug use scene, it came to be widely known as "Ecstasy", often abbreviated as "E", "X", or "XTC".[5] MDMA in its pure, powder, crystalline, or capsule form, is commonly referred to as "Molly".[5] Various other nicknames have been used to describe MDMA as well, including "Clarity", "Essence", "Euphoria", "Magic", "Thizz","Smackers", "Transcendence", and "Hug Drug", as well as "Love Drug", "Lover's Speed", or merely "Love", among many more.[5] A widespread term used in the United States to describe coming under the influence of MDMA is to "Roll" or to be "Rolling",[5] in reference to the involuntary eye movements experienced by those under the influence. Another term used to describe someone under its influence who is acting strange or out-of-hand under the influence of MDMA is to be an "E-Tard".[5]

History

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 evade an existing patent, held by Bayer, for one such compound - hydrastinine . At the behest of his superiors Walther Beckh and Otto Wolfes, Köllisch developed a preparation of a hydrastinine analogue, methylhydrastinine. MDMA was an intermediate compound in the synthesis of methylhydrastinine, and Merck was not interested in its properties at the time.[6] On December 24, 1912 Merck filed two patent applications that described the synthesis of MDMA[7] and its subsequent conversion to methylhydrastinine.[8]

Over the following 65 years, MDMA was largely forgotten. Merck records indicate that its researchers returned to the compound sporadically. In 1927, Max Oberlin studied the pharmacology of MDMA and observed that its effects on blood sugar and smooth muscles were similar to ephedrine's, but that, in contrast, MDMA did not appear to produce pupil dilation. Researchers at Merck conducted experiments with MDMA in 1952 and 1959.[6] In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals of injected mescaline and several analogues, including MDMA. These originally classified investigations were declassified and published in 1973.[9] The first scientific paper on MDMA appeared in 1958 in Yakugaku Zasshi, the Journal of the Pharmaceutical Society of Japan. In this paper, Yutaka Kasuya described the synthesis of MDMA, a part of his research on antispasmodics.[10]

MDMA first appeared as a street drug in the early 1970s after its counterculture analogue, MDA, became criminalized in the United States in 1970.[11] In the mid-1970s, Alexander Shulgin, then at University of California, heard from his students about unusual effects of MDMA; among others, the drug had helped one of them to overcome his stutter. Intrigued, Shulgin synthesized MDMA and tried it himself in 1976.[12] Two years later, he and David Nichols published the first report on the drug's psychotropic effect in humans. They described "altered state of consciousness with emotional and sensual overtones" that can be compared "to marijuana, to psilocybin devoid of the hallucinatory component".[13]

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 other people whom he thought could benefit from it. One such person was psychotherapist Leo Zeff, who had been known to use psychedelics in his practice. Zeff was so impressed with the action of MDMA that he came out of his semi-retirement to proselytize for it. Over the following years, Zeff traveled around the U.S. and occasionally to Europe training other psychotherapists in the use of MDMA.[12][14][15] Among underground psychotherapists, MDMA developed a reputation for enhancing communication during clinical sessions, reducing patients' psychological defenses, and increasing capacity for therapeutic introspection.[citation needed]

Due to the wording of the United Kingdom's existing Misuse of Drugs Act of 1971, MDMA was automatically classified in the U.K. as a Class A drug in 1977.

In the early 1980s in the U.S., MDMA rose to prominence as "Adam" in trendy nightclubs and gay dance clubs in the Dallas area.[16] From there, use spread to raves in major cities around the country, and then to mainstream society. The drug was first proposed for scheduling by the Drug Enforcement Administration (DEA) in July 1984[17] and was classified as a Schedule I controlled substance in the U.S. on May 31, 1985.[18]

In the late 1980s MDMA, as "ecstasy", began to be widely used in the U.K. and other parts of Europe, becoming an integral element of rave culture and other psychedelic- and dance-floor-influenced music scenes, such as Madchester and Acid House. 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 marijuana.[citation needed] According to some estimates as of 2004, only marijuana attracts more first time users in the U.S..[19]

After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent legally-approved MDMA studies in humans have taken place in the 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).[20]

Therapeutic use

There have long been suggestions that MDMA might be useful in psychotherapy, facilitating self-examination with reduced fear.[21][22][23] Indeed, some therapists, including Leo Zeff, Claudio Naranjo, George Greer, Joseph Downing, and Philip Wolfson, used MDMA in their practices until it was made illegal. George Greer synthesized MDMA in the lab of Alexander Shulgin and administered it to about 80 of his clients over the course of the remaining years preceding MDMA's Schedule I placement in 1985. In a published summary of the effects,[24] the authors reported patients felt improved in various, mild psychiatric disorders and other personal benefits, especially improved intimate communication with their significant others. In a subsequent publication on the treatment method, the authors reported that one patient with severe pain from terminal cancer experienced lasting pain relief and improved quality of life.[25] However, few of the results in this early MDMA psychotherapy were measured using methods considered reliable or convincing in scientific practice. For example, the questionnaires used might not have been sensitive to negative changes and it is not known to what extent similar patients might improve from chance or from psychotherapy.

The therapeutic potential of MDMA is currently being tested in several ongoing studies, some sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS). Studies in the U.S., Switzerland, and Israel are evaluating the efficacy of MDMA-assisted psychotherapy for treating those diagnosed with post-traumatic stress disorder (PTSD) or anxiety related to cancer. In interviews, patients and researchers from the South Carolina PTSD study report tendencies for some participants to have reduced disease severity after MDMA psychotherapy.[26][27] MAPS reported statistically significant results,[28] but the full paper is not yet published (nor confirmed in studies by other scientists).

Recreational use

MDMA, which has been made criminally illegal worldwide, is taken most commonly in tablet form.
File:Ecstasy on tongue.jpg
A girl taking an "Ecstasy" tablet.

The European Monitoring Centre for Drugs and Drug Addiction notes that although there are some reports of tablets being sold for as little as €1, most countries in Europe now report typical retail prices in the range of €3 to €9 per tablet.[29] The United Nations Office on Drugs and Crime claimed in its 2008 World Drug Report that typical US retail prices are higher 10 to 20 dollars per tablet, or can be from 2 to 10 dollars per tablet if bought in stacks of 10 or more.[30]

Main article: Designer drug

A substantial number of "ecstasy" tablets sold for recreational use (in the UK especially) are actually piperazine (mCPP or BZP) pills.[citation needed] These substances crudely mimic some of the positive effects of ecstasy, yet feature far greater negative side-effects (insomnia, migraines, nausea etc). mCPP is known to induce headaches in humans,[31][32] and has been used for testing potential anti-migraine medications.[33] These "legal highs" represent a considerable profit for the dealer; they are cheaply acquired online (with custom logos to mimic known "good" pills) and, given mCPP's legal status, there is limited risk of prosecution if caught. BZP possession does entail a greater risk.

Polysubstance use

Main article: Poly drug use

MDMA is occasionally known for being taken in conjunction with psychedelic drugs, such as LSD or psilocybin mushrooms. As this practice has become more prevalent, most of the more common combinations have been given nicknames, such as "candy flipping", for MDMA combined with LSD,[34], "hippie flipping" when combined with psilocybin mushrooms and "kitty flipping" when combined 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[35] and lozenges. This sometimes has deleterious results on the upper respiratory tract.[36]

Chemistry

An industrial scale methamphetamine and MDMA chemical factory in Cikande, Indonesia.

Safrole, a colorless or slightly black oil, extracted from the root-bark or the fruit of sassafras plants is the primary precursor for all manufacture of MDMA. There are numerous synthetic methods available in the literature to convert safrole into MDMA via different intermediates.[37][38][39][40] One common route is via the MDP2P (3,4-methylenedioxyphenyl-2-propanone, also known as piperonyl acetone) intermediate. This intermediate can be produced in at least two different ways. One method is to isomerize safrole to isosafrole in the presence of a strong base and then oxidize isosafrole to MDP2P. Another, reportedly better[citation needed], method is to make use of the Wacker process to oxidize safrole directly to the MDP2P (3,4-methylenedioxy phenyl-2-propanone) intermediate. This can be done with a palladium catalyst. Once the MDP2P intermediate has been produced, it is then consumed via a reductive amination to form MDMA as the product.

Relatively small quantities of essential oil are required to make large numbers of MDMA pills. The essential oil of Ocotea cymbarum typically contains between 80 and 94% safrole. This would allow 500 ml of the oil, which retails at between $20 and $100, to be used to produce an estimated 1,300 to 2,800 tablets containing approximately 120 mg of MDMA each.[41]

Pharmacology

Further information: Effects of MDMA on the human body

The mechanism of action of MDMA's unusual effects has yet to be fully understood, although it is generally thought that the primary relevant pharmacological characteristic of the drug is its affinity for the plasmalemmal membrane transport protein the serotonin transporter (SERT). The SERT is a part of serotonergic neurons and removes the neurotransmitter serotonin (5-hydroxytryptamine (5-HT)) from the synapse via reuptake for termination and recycling purposes after action potentials. Not only does MDMA inhibit the reuptake of serotonin through its action at the SERT, but it also reverses its action through a process known as phosphorylation.[42] This results in the transporter conversely releasing serotonin into the synapse from inside the cell instead.

For the above reasons, MDMA is classified as a combination serotonin reuptake inhibitor (SRI) and serotonin releasing agent (SRA), though it is typically only referred to as the latter definition essentially includes SRI properties. In addition to its actions on serotonin, MDMA causes the same effects on the norepinephrine transporter (NET) and dopamine transporter (DAT), thus inducing release of norepinephrine and dopamine as well, respectively,[43] and hence, it can also be called a norepinephrine-dopamine reuptake inhibitor (NDRI) and norepinephrine-dopamine releasing agent (NDRA), or, in full, as a serotonin-norepinephrine-dopamine releasing agent (SNDRA).

MDMA's unusual entactogenic effects have been hypothesized to be, at least partly, the result of indirect oxytocin release via serotonergic neuromodulation.[44] Oxytocin is a hormone released following events like hugging, orgasm, and childbirth, and is thought to facilitate bonding and the establishment of trust. Based on studies in rats, MDMA is believed to cause the release of oxytocin, at least in part, by both directly and indirectly agonizing the serotonin 5-HT1A receptor. A placebo-controlled study in 15 human volunteers found that 100 mg MDMA increased blood levels of oxytocin and the amount of oxytocin increase was correlated with the subjective prosocial effects of MDMA.[45]

Pharmacokinetics

File:MDMA crystals.JPG
Pure MDMA crystals

MDMA reaches maximal concentrations in the blood stream between 1.5 and 3 hours after ingestion. It is then slowly metabolized and excreted, with levels decreasing to half their peak concentration over approximately 8 hours. Thus, there are still high MDMA levels in the body when the experiential effects have mostly ended, indicating that acute tolerance has developed to the actions of MDMA. Taking additional supplements of MDMA at this point therefore produces higher concentrations of MDMA in the blood and brain than might be expected based on the perceived effects.

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 N-hydroxy-3,4-methylenedioxyamphetamine (MDOH). The contributions of these metabolites to the psychoactive and toxic effects of MDMA are an area of active research. 65% of MDMA is excreted unchanged in the urine (additionally 7% is metabolized into MDA) during the 24 hours after ingestion.[46]

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 (in humans, but CYP2D1 in mice), 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.

Because the enzyme CYP2D6 is deficient or totally absent in some people[47], it was once hypothesized that these people might have elevated risk when taking MDMA. However, there is still no evidence for this theory and available evidence argues against it.[48] It is now thought that the contribution of CYP2D6 to MDMA metabolism in humans is less than 30% of the metabolism. Indeed, an individual lacking CYP2D6 was given MDMA in a controlled clinical setting and a larger study gave MDMA to healthy volunteers after inhibiting CYP2D6 with paroxetine. Lack of the enzyme caused a modest increase in drug exposure and decreases in some metabolites, but physical effects did not appear appreciably elevated. While there is little or no evidence that low CYP2D6 activity increases risks from MDMA, it is likely that MDMA-induced CYP2D inhibition will increase risk of those prescription drugs that are metabolized by this enzyme. MDMA-induced CYP2D inhibition appears to last for up to a week after MDMA exposure.

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[49]

MDMA is a chiral compound and has been almost exclusively administered as a racemate. However, an early uncontrolled report suggests that the S-enantiomer is significantly more potent in humans than the R-enantiomer[50][51] indicate that the disposition of MDMA is stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. For example, Fallon et al.[50] reported 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. Similarly, 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 has dose dependent kinetics, it is likely that these half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose). Given as the racemate, MDMA has a half-life of around 8 hours.

Drug interactions

There are a number of reported potentially dangerous possible interactions between MDMA and other drugs. Several cases have been reported of death in individuals who ingested MDMA while taking ritonavir (Norvir), which inhibits multiple CYP450 enzymes. Toxicity or death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).[52] On the other hand, MAOB inhibitors like selegiline (Deprenyl; Eldepryl, Zelapar, Emsam) do not seem to carry these risks when taken at selective doses, and have been used to completely block neurotoxicity in rats.[53]

People taking any type of serotonin reuptake inhibitor (SRI) on a chronic basis commonly find that the psychedelic and entactogenic effects of MDMA are near fully abolished, leaving merely stimulation instead. Many people attempt taking a dose around 3x as high and this appears to work as a remedy for the problem to some degree. Additionally, upon discontinuation of the prolonged administration of the SRI in question, such individuals may still not be able to properly experience the full desired effects of MDMA at normal doses for anywhere from a few weeks to as long as several months.

There is a possible risk of experiencing serotonin syndrome if MDMA is combined with another serotonergic drug.[54]

Most people who die while under the influence of MDMA have also consumed significant quantities of at least one other drug in combination. The risk of solely MDMA-induced death is overall relatively minimal.[19]

Effects

Further information: Effects of MDMA on the human body

The primary effects attributable to MDMA consumption are predictable and fairly consistent amongst users. Generally, users report feeling effects within 30–60 minutes of consumption, hitting a peak at approximately 1-1.5 hours, reaching a plateau that lasts about 2–3 hours, followed by a comedown of a few hours which may be accompanied by fatigue and minor effects.[55][56][57]

Beneficial effects

The most common beneficial effects reported by users include:[58]

As well as:

Side effects

The most common adverse side effects reported by users include:

Rebound / withdrawal

The most common withdrawal or rebound side effects reported by users once the drug has worn off include:

These effects are typically reported to last 3 to 7 days.

Overdose

Upon overdose, the potentially serious serotonin syndrome, stimulant psychosis, and/or hypertensive crisis, among other dangerous adverse reactions, may come to prominence, the symptoms of which can include the following:

Potential incarceration, hospitalization, institutionalization, and/or death, on account of extreme erratic behavior which may include acts of crime, accidental or intentional self-injury, and/or suicide, as well as illicit drug abuse, may ensue under such circumstances.

Chronic use

There is currently strong evidence of MDMA neurotoxicity in studies done on rodents and non-human primates. MDMA is believed to be specifically neurotoxic to the serotonergic terminals in humans.[59] Some studies indicate that repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug.[60][61] In addition to this, some studies have indicated that repeated recreational users of MDMA may have impaired long-term memory[62] and cognitive function.[63] Many factors, including total lifetime MDMA consumption, the duration of abstinence between uses, the environment of use, poly-drug use/abuse, quality of mental health, various lifestyle choices, and predispositions to develop clinical depression and other disorders may contribute to various possible health consequences. MDMA use has been occasionally associated with liver damage,[64] excessive wear of teeth,[65] and (very rarely) Hallucinogen persisting perception disorder.[66]

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. Generally, the unlicensed use, sale or manufacture of MDMA are all criminal offenses.

United Kingdom

In the U.K., MDMA is a Class A drug under the Misuse of Drugs Act 1971, making it illegal to sell, buy, or possess without a license. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking. See list of drugs illegal in the U.K. for more information. In February 2009 an official independent scientific advisory board to the UK government recommended that MDMA be re-classified to Class B, but this recommendation was immediately rejected by the government (see Recommendation to downgrade MDMA). This 2009 report on MDMA stated:

The original classification of MDMA in 1977 under the Misuse of Drugs Act 1971 as a Class A drug was carried out before it had become widely used and with limited knowledge of its pharmacology and toxicology. Since then use has increased enormously, despite it being a Class A drug. As a consequence, there is now much more evidence on which to base future policy decisions.... Recommendation 1: A harm minimisation approach to the widespread use of MDMA should be continued.... Recommendation 6: MDMA should be re-classified as a Class B drug.

— [67]

United States

In the U.S., MDMA was legal and unregulated until May 31, 1985, at which time it was emergency scheduled to DEA Schedule I, for drugs deemed to have no medical uses and a high potential for abuse. During DEA hearings to schedule MDMA, most experts recommended DEA Schedule III prescription status for the drug, due to beneficial usage of MDMA in psychotherapy. The judge overseeing the hearings, Francis Young, also recommended that MDMA be placed in Schedule III. Nevertheless, the DEA classified MDMA as Schedule I.[68][69] In 2001, responding to a mandate from the U.S. Congress, the U.S. Sentencing Commission, resulted in an increase in the penalties for MDMA by nearly 3,000%,[70] despite scientific protest calling for a decrease in the penalties for MDMA possession and distribution.[71] The increase makes 1 gram of MDMA (four pills at 250 mg per pill's total weight regardless of purity, standard for Federal charges) equivalent to 1 gram of heroin (approximately fifty doses) or 2.2 pounds (1 kg) of marijuana for sentencing purposes at the federal level.[72] See also the RAVE Act of 2003.

World Health Organization

In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 Convention on Psychotropic Substances, despite noting that

No data are available concerning its clinical abuse liability, nature and magnitude of associated public health or social problems.

— [73]

The decision to recommend scheduling of MDMA was not unanimous:

One member, Professor Paul Grof (Chairman), felt that the decision on the recommendation should be deferred awaiting, in particular, the data on the substance's potential therapeutic usefulness and that at this time international control is not warranted.

— [73]

The 1971 Convention has a provision in Article 7(a) that allows use of Schedule I drugs for "scientific and very limited medical purposes." The committee's report stated:[73][74]

The Expert Committee held extensive discussions concerning therapeutic usefulness of 3,4 Methylenedioxymethamphetamine. While the Expert Committee found the reports intriguing, it felt that the studies lacked the appropriate methodological design necessary to ascertain the reliability of the observations. There was, however, sufficient interest expressed to recommend that investigations be encouraged to follow up these preliminary findings. To that end, the Expert Committee urged countries to use the provisions of article 7 of the Convention on Psychotropic Substances to facilitate research on this interesting substance.

Health concerns

Main article: Effects of MDMA on the human body

While the short-term adverse effects and contraindications of MDMA are fairly well known, there is significant debate within the scientific and medical communities regarding possible long-term physical and psychological effects of MDMA.

Short-term health concerns

Short-term physical health risks of MDMA consumption include hyperthermia,[75][76] and hyponatremia.[77] Continuous activity without sufficient rest or rehydration may cause body temperature to rise to dangerous levels, and loss of fluid via excessive perspiration puts the body at further risk as the stimulatory and euphoric qualities of the drug may render the user oblivious to their energy expenditure for quite some time. Diuretics such as alcohol may exacerbate these risks further.

Long-term effects on serotonin and dopamine

MDMA causes a reduction in the concentration of serotonin transporters (SERTs) in the brain. The rate at which the brain recovers from serotonergic changes is unclear. A number of studies [78] have demonstrated lasting serotonergic changes occurring due to MDMA exposure. Other studies[79][80] have suggested that the brain may recover from serotonergic damage.

Some studies show that MDMA may be neurotoxic in humans.[81][82] Other studies, however, suggest that any potential brain damage may be at least partially reversible following prolonged abstinence from MDMA.[80][83] However, other studies suggest that SERT-depletion arises from long-term MDMA use due to receptor down-regulation, rather than true neurotoxicity.[84] Depression and deficits in memory have been shown to occur more frequently in long-term MDMA users.[85][86] However, some recent studies have suggested that MDMA use may not be associated with chronic depression.[87][88]

One study on MDMA toxicity, by George A. Ricaurte of Johns Hopkins School of Medicine, which claimed that a single recreational dose of MDMA could cause Parkinson's Disease in later life due to severe dopaminergic stress, was actually retracted by Ricaurte himself after he discovered his lab had administered not MDMA but methamphetamine, which is known to cause dopaminergic changes similar to the serotonergic changes caused by MDMA.[89] Ricaurte blamed this mistake on the chemical supply company that sold the material to his lab. Most studies have found that levels of the dopamine transporter (or other markers of dopamine function) in MDMA users deserve further study or are normal.[90][91][92][93][94][95][96]

Purity and dosage of "ecstasy"

Another concern associated with MDMA use is toxicity from chemicals other than MDMA in ecstasy tablets. Due to its near-universal illegality, the purity of a substance sold as ecstasy is unknown to the typical user. The MDMA content of tablets varies widely between regions and different brands of pills and fluctuates somewhat each year. Pills may contain other active substances meant to stimulate in a way similar to MDMA, such as amphetamine, methamphetamine, ephedrine, or caffeine, all of which may be comparatively cheap to produce and can help to boost profit overall. In some cases, tablets sold as ecstasy do not even contain any MDMA. Instead they may contain an assortment of presumably undesirable drugs such as paracetamol, ibuprofen, piperizines etc.[97]

There have been a number of deaths attributed to PMA, a potent and highly neurotoxic hallucinogenic amphetamine, being sold as Ecstasy. PMA is unique in its ability to quickly elevate body temperature and heart rate at relatively low doses, especially in comparison to MDMA.[98] Hence, a user who believes he is consuming two 120 mg pills of MDMA could actually be consuming a dose of PMA that is potentially lethal, depending on the purity of the pill. Not only does PMA cause the release of serotonin, but also acts as an MAOI. When combined with an MDMA-like substance, serotonin syndrome can result.

Harm assessment

The chief executive of the U.K. Medical Research Council stated that MDMA is "on the bottom of the scale of harm", and was rated to be of lesser concern than alcohol, tobacco, as well as several classes of prescription medications, when examining the harmfulness of twenty popular recreational drugs. The U.K. study placed great weight 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. Based on these factors, the study placed MDMA at number 18 in the list of 20 popular drugs.[99]

David Nutt, chairman of the U.K. Advisory Council on the Misuse of Drugs, stated in the Journal of Psychopharmacology in January 2009 that ecstasy use compared favorably with horse riding in terms of risk, leading to around 50 deaths a year compared to about 100 from horse riding.[100] The ACMD subsequently made clear that Professor Nutt's comments were not made on behalf of the ACMD.[101]

Recommendation to downgrade MDMA to Class B in the UK (Feb 2009)

In 2000, the UK Police Foundation issued the Runciman Report which reviewed the medical and social harms of MDMA and recommended: "Ecstasy and related compounds should be transferred from Class A to Class B."[102] In 2002, the Home Affairs Committee of the UK House of Commons, issued a report, The Government's Drugs Policy: Is it working?, which also recommended that MDMA should be reclassified to a Class B drug.[103] The UK government rejected both recommendations, saying that re-classification of MDMA would not be considered without a recommendation from the Advisory Council on the Misuse of Drugs, the official UK scientific advisory board on drug abuse issues.[104]

In February 2009, the UK Advisory Council on the Misuse of Drugs issued A review of MDMA ('ecstasy'), its harms and classification under the Misuse of Drugs Act 1971, which recommended that MDMA be re-classified in the UK from a class A drug to a class B drug.[67]

From the Discussion section of the ACMD report on MDMA:

Physical harms: (10.2) Use of MDMA is undoubtedly harmful. High doses may lead to death: by direct toxicity, in situations of hyperthermia/dehydration, excessive water intake, or for other reasons. However, fatalities are relatively low given its widespread use, and are substantially lower than those due to some other Class A drugs, particularly heroin and cocaine. Although it is no substitute for abstinence, the risks can be minimised by following advice such as drinking appropriate amounts of water (see Annex E). (10.3) Some people experience acute medical consequences as a result of MDMA use which can lead to hospital admission, sometimes with the requirement for intensive care. MDMA poisonings are not currently increasing in number and are less frequent than episodes due to cocaine. (10.4) MDMA appears not to have a high propensity for dependence or withdrawal reactions although a number of users seek help through treatment services. (10.5) MDMA appears to have little acute or enduring effect on the mental health of the average user, and unlike amphetamines and cocaine, it is seldom implicated in significant episodes of paranoia. (10.6) There is presently little evidence of longer-term harms to the brain in terms of either its structure or function. However, there is evidence for some small decline in a variety of domains, including verbal memory, even at low cumulative dose. The magnitude of such deficits appears to be small and their clinical relevance is unclear. The evidence shows that MDMA has been misused in the UK for 20 years but it should be noted that long-term effects of use cannot be ruled out. (10.7) Overall, the ACMD judges that the physical harms of MDMA more closely equate with those of amphetamine than of heroin or cocaine.

Societal harms: (10.8) MDMA use seems to have few societal effects in terms of intoxication-related harms or social disorder. However, the ACMD notes the very small proportion of cases where ‘ecstasy’ use has been implicated in sexual assault. (10.9) Disinhibition and impulsive, violent or risky behaviours are not commonly seen under the influence of MDMA, unlike with cocaine, amphetamines, heroin and alcohol. (10.10) The major issue for law enforcement is ‘ecstasy’s’ position, alongside other Class A drugs, as a commodity favoured by organised criminal groups. It is therefore generally associated with a range of secondary harms connected with the trafficking of illegal drugs.

The UK Home Office rejected the recommendation of its independent scientific advisory board to downgrade MDMA to Class B, "saying it is not prepared to send a message to young people that it takes ecstasy less seriously".[105][106]

The government's veto was criticized in scientific publications. Colin Blakemore, Professor of Neuroscience, Oxford, stated in the British Medical Journal, "The government’s decisions compromise its commitment to evidence based policy".[107] Also in response, an editorial in the New Scientist noted "A much larger percentage of people suffer a fatal acute reaction to peanuts than to MDMA.... Sadly, perspective is something that is generally lacking in the long and tortuous debate over illegal drugs."[108]

See also

References

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Further reading

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