MDMA (3,4-methylenedioxymethamphetamine), most commonly known today by the street name ecstasy, is a synthetic entactogen of the phenethylamine family whose primary effect is to stimulate the secretion of and inhibit the re-uptake of large amounts of serotonin as well as dopamine and noradrenaline in the brain, causing a general sense of openness, empathy, energy, euphoria, and well-being. Tactile sensations are enhanced for some users, making general physical contact with others more pleasurable; but, contrary to popular mythology it generally does not have aphrodisiac effects. Its ability to facilitate self-examination with reduced fear has proven useful in some therapeutic settings, leading to its 2001 approval by the United States FDA for testing in patients with post-traumatic stress disorder.

Acute dehydration is a risk among users who are highly physically active and forget to drink water, as the drug may mask one's normal sense of exhaustion and thirst. Also the opposite, "water intoxication" resulting in acute hyponatremia has been reported. By far the biggest danger comes from the fact that other, more dangerous chemicals (such as PMA, or methamphetamine) are either added to ecstasy tablets, or more often simply sold as ecstasy. Long-term effects in humans are largely unknown and the subject of much controversy —particularly with regard to the risks of severe long-term depression as a result of a reduction in the natural production of serotonin.

MDMA is also known by many other street names, including Adam, Beans, Biscuits, Candy, E, Eccies, Googs, Jack and Jills, MaDMAn, Mollies, Pills, Rolls, Scoobies, Smarties, Tabs, Thizz, Vitamin E, Vitamin X, X, XTC, Yaotou (in East Asia), and Yokes.

History

A patent for MDMA was originally filed on Christmas eve 1912 by the German pharmaceutical company Merck, and granted two years later (to the day). At the time, MDMA was not known to be a drug in its own right; rather, it was patented as an intermediate chemical used in the synthesis of a styptic (a drug intended to control bleeding from wounds.) Over half a century would pass before the first known ingestion of MDMA by humans.

Contrary to many rumours, the drug was never used as an appetite suppressant or as a stimulant for armed forces during wartime. (This was in fact methamphetamine.) The U.S. Army did, however, do lethal dose studies of it and several other compounds in the mid-1950's. It was given the name EA-1475, with the EA standing for Edgewood Arsenal. The results of these studies were not declassified until 1969. MDMA was first brought to public attention through Dr. Alexander Shulgin in the 1960s who recommended it for use in certain therapy sessions, naming the drug 'window' (he discovered it while searching for compounds that might have a similar psychoactive effect as other compounds contained in nutmeg). It was widely used therapeutically by US psychotherapists because of its empathogenic effects until its criminalization in the late 1980s. The drug was hailed as a miracle by therapists and counselors who claimed couples could have six months worth of progress in one use of the drug, and soldiers returning from the Vietnam war could overcome their PTSD sometimes more effectively than talk or group therapy. A small number of therapists continue to use it in their practices today. (See below for 2001 FDA approval and DEA licensing for use in patients with post-traumatic stress disorder.)

Until 1985, MDMA was legal in the United States. Recreationally, it first came into prominence in certain trendy yuppie bars in the Dallas area, then in gay dance clubs. From there, use spread to rave clubs, and then to mainstream society. During the 1990s, along with the growing popularity of the rave subculture, MDMA use became increasingly popular among young adults in universities and later in high schools. It rapidly became one of the four most widely used illegal drugs in the US, along with cocaine, heroin and marijuana. In the late 80's and early 90's ecstasy was widely used in the U.K., such as The Haçienda night club in Manchester, where bands like The Stone Roses and The Happy Mondays mixed classic 60's psychedelic pop with dance bass groove to create a unique indie-dance crossover sound. It would be these gigs (and "sound") at The Haçienda that would give birth to rave culture in which ecstasy is so widely associated.

Chemistry

The chemical structure of MDMA is similar to those of Mescaline and methamphetamine, but the phenyl ring is substituted with a methylenedioxy group in position 3,4. It is a member of the phenethylamine family, a group of substances typically having pronounced biological activity. MDMA is synthesized from MDP2P through a chemical reaction known as reductive amination. MDMA has a chiral center at the alpha carbon (next to the methylamino group).

Pharmacokinetics

MDMA has complex nonlinear pharmacokinetics, due MDMA's ability to inhibit CYP2D6 and CYP2d8. It is metabolised via N-demethylation to several active metabolites including MDA, although the conversion rate in humans is low. The metabolism is primarily by the cytochrome P450 enzymes CYP2D6 (in humans, but CYP2D1 in mice), and CYP3A4 . Large increases in blood and brain concentrations are mostly due to autoinhibition of CYP2D6 metabolism--if the user takes consecutive doses of the drug, disproportionately high plasma concentrations can result. A significant quantity is excreted unchanged in the urine, especially when the drug is taken at higher doses.

Recreational use

The primary effects of MDMA include feelings of openness, euphoria, empathy, love, and heightened self-awareness. Its initial adoption by the dance club sub-culture is probably due to the enhancement of the overall social and musical experience. Taking MDMA or Ecstasy is commonly referred to as pinging, rolling, popping, peaking, rushing, buzzing, dropping, pilling, flipping, getting off-tap, eating skittles, or dosing.

Some users employ practices to enhance the effects of MDMA, often called "Blowin' up". Because of the euphoric sensitivity to touch it is common, while on ecstasy, to have someone around the individual rub his or her fingers sensually and/or massage through the hair and scalp. Often times someone around the individual will flash lights on and off, use glow sticks--moving them in front of the individual vigorously--or spin the individual around, asking him/her to concentrate on one source of light. Because of the extreme intensity to colors, lights and touch this causes a 'sensory overload' to the individual, inducing an extreme sensation of euphoria.

MDMA use has increased markedly since the late 1980s and spread beyond its original sub-cultures to mainstream use. Prices have also fallen since the 1980s, with the street price in the US varying between $5 and $40 per tablet, depending on the quantity purchased, and with higher prices paid when the drug is purchased in a club or at a rave. In countries in which distribution is more extensive, such as in the Netherlands, prices can sometimes be as low as $1 per tablet. In Britain, a usual price is around £2.50 for a pill (although media reports in September 2005 show the price dropping as low as 50p in many parts of the country), the standard price in a nightclub is three pills for £10, and £20 for a half gram of pure MDMA powder, although like any illegal substance the price varies wildly depending on how many hands it has passed through. In the U.S. the price varies anywhere from $10 a pill to $30. In countries where distribution is more difficult prices are accordingly higher; for example in New Zealand prices start at around $60 NZD ($40 US) and can get as high as NZ $80.

Supply and administration

MDMA is usually ingested in pill form. Pills come in a variety of "brands", usually identified by the icons stamped on the pills. The brands never consistently designate the actual active compound within the pill, as anyone can make their own pills which copy the features of a well-known brand.

Pills sold illegally on the street don't always have MDMA as the only active ingredient. Black market pills most likely contain methamphetamine, but have been found to contain analogues such as MDEA, MDA and MBDB, and occasionally other unrelated psychoactive additives such as amphetamines (speed), DXM, ephedrine, PMA, caffeine, ketamine (Special K), and others. Other contaminants include: ketamine, ephedrine, DXM, Pseudophedrine, and other unidentified chemicals. There are anecdotal stories of pills containing cocaine, heroin, or mescaline; however, there have been no documented cases where these contaminants have been found. Mescaline is an especially unlikely contaminant, as a large amount is required for an effective dose. There have been a few cases where an extremely potent synthetic opiate, Fenantyl, has been identified in pills.

Many legal pills such as aspirin, paracetamol (acetaminophen), or even canine heartworm tablets have had the letter E scratched into them and been sold as ecstasy, for enormous profit. (This is a minor plot device in the movie Go.) Such false labeling can have deadly results, as a significant number of people are allergic to aspirin. Paracetamol is fairly hepatotoxic and can cause significant liver damage or death if taken in large doses, as might happen to a person taking four or five tablets in quick succession, thinking the tablets to be ecstasy. While overdose from MDMA itself is rare, many more toxic substances are often sold as ecstasy, and overdose or other adverse reaction to adulterants is not uncommon.

Although full and proper characterization of ecstasy pills requires advanced lab techniques such as Gas chromatography-mass spectrometry, it is also possible to use a less accurate presumptive alkaloid test known as the Marquis reagent. DanceSafe sells testing kits, and includes an extensive database of photographs of different pills, along with the results of a laboratory analysis of their contents. EcstasyData.org [1] is a non-profit site that tests the purity of street pills and compiles results. Most blackmarket pills are made in basement labs with household chemicals (often containing other products) and are thus dangerous because of their impurity content.

Effects

Pharmacodynamics

Serotonin is a neurotransmitter believed to play a role in the regulation of mood and pleasure. MDMA's main action is believed to cause serotonin vescicles in the brain to release quantities of serotonin into the synapses. MDMA also has slight agonist effects on dopamine and norepinephrine levels and promotes the release of the hormone prolactin. These effects are primarily due to MDMA's action on the monoamine transporters, SERT (serotonin transporter), DAT (dopamine transporter) and NET (norepinephrine transporter).

Other short-term effects

Apart from the dangers from impurities, the primary acute risks of taking MDMA are allergic reaction, which is extremely rare, and dehydration. Like amphetamine, MDMA can mask the body's normal thirst and exhaustion responses, particularly if a user is dancing or is otherwise physically active for long periods of time without hydration. MDMA can temporarily reduce the body's ability to regulate its core temperature, and in high-temperature surroundings (e.g. clubs) combined with physical exertion this may lead to hyperpyrexia if precautions are not taken to remain cool. While dehydration is undesirable, there also have been a very small number of users overly concerned about hydration drinking excessive water and suffering from water intoxication and associated hyponatremia (dilution of the blood that can cause swelling of the brain). This is what caused the death of British teen Leah Betts, which may be the world's most widely publicised MDMA-related fatality. Some users also report decreased libido or impotence; however, studies have had conflicting results [2].

Long-term effects

Long-term effects are still unknown and heavily debated among scientists. There are several reports of Hallucinogen Persisting Perception Disorder being induced by MDMA. In some cases, the disorder appears to be permanent. The disorder seems to occur in only a small percentage of users, and its mechanism of causation is unknown.

Some experiments indicate that prolonged or excessive use at very high doses may lead to the synaptic terminals of serotonin neurons being damaged. The precise mechanism of this action is unknown, but recent evidence (Jones 2004; Miller 1997; Monks et al. 2004) suggests that the metabolic breakdown of MDMA includes the formation of reactive oxygen species (ROS), chemicals known to cause oxidative cell damage when taken up into the releasing synapse.

This effect has been experimentally verified in the brains of rats, where the serotonin terminals of animals who are given extremely high doses of MDMA over a prolonged period of time (usually one to two orders of magnitude greater than a typical human dose) become withered and useless. This hypothesis is supported by the fact that the administration of selective serotonin reuptake inhibitors ("SSRIs", which bind to the serotonin cell's reuptake transporters and thus block ROS from entering the serotonin cells) along with or immediately following MDMA seems to block neuron damage in rats given MDMA. Vitamin C in large doses has also been shown to prevent oxidative stress in vivo, and Vitamin C should be considered as a harm prevention adjunct to MDMA use.

Some MDMA users administer an SSRI while, or shortly after taking MDMA, in an attempt to prevent possible neurotoxicity. These SSRIs are typically antidepressants such as Prozac or Zoloft. It should be noted, however, that MDMA use in conjunction with a different class of antidepressants, namely Monoamine oxidase inhibitors, is strongly contra-indicated due to danger of serotonin syndrome and the possibility of life-threatening hypertension.

Many users also attempt to replenish the deficit of serotonin which follows the use of MDMA by administering 5-HTP. The serotonin precursor 5-HTP, which is commercially available as a dietary supplement, reportedly supplies the user with more of the raw materials to synthesize the neurotransmitter. Pre-loading with 5-HTP has not been shown to increase the subjective effects of MDMA.

Because MDMA's neurotoxicity is known to be highly dependent on its metabolic disposition (Jones 2004; de la Torre & Farré 2004), it is not known whether experiments in rats and monkeys have any direct bearing on human users.

Considerable research has been done into possible cognitive-behavioral deficits among ecstasy users but data have been largely inconclusive. At least two meta-analyses of these studies have been completed (Morgan 2000; Sumnall & Cole 2005). Morgan's analysis of 17 studies showed that ecstasy users had a slight tendency to be more impulsive and depressed than controls. Sumnall and Cole's analysis showed a slight increase in the prevalence of depressive symptoms in ecstasy users over controls. Of course, in retrospective studies like these we are always faced with a chicken-or-egg question: did these impulsive and depressed people use ecstasy to self-medicate or did otherwise normal people become depressed and impulsive after using ecstasy? This question has not been answered. Moreover, such research is problematic as ecstasy users are much more likely than control subjects to have taken other drugs in addition to ecstasy. This makes it difficult for researchers to establish a direct causal relationship.

Although some experimental evidence exists indicating that long-term ecstasy users experience memory difficulties, a large study in 2002 (Strote et al.) showed that ecstasy users in 4-year colleges have GPAs which do not differ significantly from those of non-users.

According to one study, MDMA use has led to to rhabdomyolysis (muscle breakdown) as a consequence of MDMA-induced hyperpyrexia (abnormally high body temperature). Rhabdomyolysis can cause renal failure and death. The author notes the "degree to which the seriousness of the effects can be dependent on environmental factors other than the drug concentration" in describing the fact that of the fatalities, blood concentrations of the drug spanned a large range. This notwithstanding, the author also notes that "Most of the cases of serious toxicity or fatality have involved blood levels... up to 40 times higher than the usual recreational range." (Kalant H., 2001) [3]

Systemic effects

Other effects include:

• Pupil dilation with attendant photosensitivity and color perception
• Jaw clenching or bruxism ("gurning" or "grinding")
• Shutter vision (nystagmus)
• General restlessness
• Loss of appetite/taste sensation changes
• Lack of focus / concentration
• Tingling
• Sweaty palms
• Increased heart rate

Ecstasy and Parkinson's

Research at the University of Manchester indicates that ecstasy dramatically reduces tremors in patients receiving L-DOPA treatment for Parkinson's Disease.

In a now-retracted study, a research team led by Dr. George A. Ricaurte at Johns Hopkins University implicated MDMA as a cause of Parkinson's-like brain abnormalities in monkeys, suggesting that a single use of MDMA caused permanent and serious brain damage. These claims were hotly disputed by physicians, therapists, and other experts, including a team of scientists at New York University. Criticisms of the study included its use of injection rather than oral administration; that this type and scale of damage (>20% mortality) would translate to hundreds of thousands or millions of deaths which had not materialized in the real world amidst extremely broad global MDMA usage; and, perhaps most important, that other research teams could not duplicate the study's findings.

On September 6, 2003, Dr. George A. Ricaurte and his team announced that they were retracting all results of their commonly cited and controversial study. The researchers said that the labels on the drugs had been somehow switched, and they had inadvertently injected their experimental monkeys and baboons with extremely high doses of methamphetamine instead of MDMA. The chemical supplier, Research Triangle Institute, has publicly claimed that the proper drug was supplied, and Ricaurte has yet to pursue them for their alleged error.

Ricaurte had also come under fire for supplying PET scans to the U.S. Office of National Drug Control Policy that were used in anti-drug literature (Plain Brain/Brain After Ecstasy) that seemed to suggest MDMA created holes in human brains, an implication that critics called misleading. Ricaurte later asked the Agency to change the literature, citing the "poor quality" of the images.

Legal issues

Use, supply and trafficking of ecstasy are currently illegal in most countries. In the United States, MDMA was legal and unregulated until May 31st 1985, at which time it was added to DEA Schedule I, for drugs deemed to have no medical uses and a high potential for abuse. During DEA hearings to criminalize MDMA, most experts recommended DEA Schedule III prescription status for the drug, due to its beneficial usage in psychotherapy. The judge overseeing the hearings, Francis Young, also made this recommendation. Nonetheless, DEA classified it as Schedule I.

That same year, the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the Convention on Psychotropic Substances. Unlike the Controlled Substances Act, the 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[4]:

It should be noted that 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.

In the United Kingdom, MDMA is Schedule I/Class A, 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. A mandatory seven year sentence is now the penalty for a third conviction for trafficking.

Medical use

In 2001, the FDA approved MDMA for research with patients suffering from post-traumatic stress disorder. In March of 2004, the DEA issued its first Schedule I possession licenses for those conducting research under the FDA approval; research is being conducted through the Multidisciplinary Association for Psychedelic Studies (MAPS) on veterans from the U.S. invasion of Afghanistan, rape victims, and cancer patients. For further information on this, see MAPS's MDMA Research Information and the recent article from MSNBC/Newsweek.

Safety

The illegality of this drug in many countries makes exact study of its effects difficult. Some of the effects ascribed to ecstasy, which may or may not be conclusive, are the following:

• Because of its illegality, the dose and purity of a pill advertised as ecstasy may be stronger than is desired or may be unsafe.
• Ecstasy affects the regulation of the body's internal systems. Continuous dancing without sufficient breaks or drinks can lead to dangerous overheating and dehydration. Drinking too much water without consuming a corresponding amount of salt can lead to hyponatremia or Water intoxication.
• The use of ecstasy can exacerbate depression and produces temporary depression as an after-effect of its use.
• The use of ecstasy can be very dangerous when combined with other drugs (particularly monoamine oxidase inhibitors (MAOIs) and antiretroviral drugs).
• Because it substantially affects perception, concentration, and motor skills, it is dangerous to operate heavy machinery or motor vehicles when using ecstasy.
• Long-term after-effects are greatly exacerbated by high doses and frequent use.
• A small percentage of users may be highly sensitive to MDMA; this may make first-time use especially hazardous. This includes but is not limited to people with congenital heart defects, and a small percentage of people who lack the proper enzymes to break down the drug.