Methylenedioxymethamphetamine Totally Explained

Everything about Mdma totally explained

MDMA (3,4-methylenedioxy-N-methylamphetamine), most commonly known today by the street name Ecstasy (often abbreviated E, X, or XTC), is a semisynthetic member of the phenethylamine class of psychoactive drugs. MDMA also falls under many other broad categories of substances, including amphetamines/stimulants, psychedelics, and the empathogenic-entactogens.
   The drug is considered unusual for its tendency to produce feelings of euphoria, a sense of intimacy with others, and diminished feelings of fear and anxiety. MDMA has more consistent emotional effects than most psychedelics and has a euphoria that appears to be different from most stimulants. Before it was made a controlled substance, MDMA was used to aid psychotherapy, often couples therapy, although results of this therapy are poorly documented.
   MDMA is criminalized in most countries, and its possession, manufacture, or sale may result in criminal prosecution. Despite widespread illegality, MDMA is today one of the most commonly-used 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 culture and its related genres of music.
   Many within science, health care, and drug policy are concerned that MDMA may lead to neurotoxic damage of the central nervous system, the reversibility, extent and significance of which is yet to be fully determined. Based on these and other health concerns, some feel the risks of even single doses of MDMA outweigh its potential benefits. Others feel that these concerns are based on inconclusive evidence and that MDMA deserves further study. Studies have been initiated to examine the therapeutic potential of MDMA for posttraumatic stress disorder and anxiety associated with cancer. In addition, several research groups are using it in humans for basic scientific research.

History

At the end of the 19th century, the Merck company of Germany was interested in developing substances that stopped abnormal bleeding. One of the most important compounds was hydrastinine. The plant from which it was isolated became rarer, and they started looking for alternatives. The scientific reports from the laboratory from 1911 and 1912 show that they wanted to use 3-methyl-hydrastinine as an alternative. They believed that this methylated analog of hydrastinine might be similarly effective. Drs. Walther Beck, Otto Wolfes and Anton Köllisch started on the project. In the newly developed synthetic pathway to 3-methyl-hydrastinine, MDMA was mentioned as one of several key precursors under the name of Methylsafrylamin. In 1912 Dr. Anton Köllisch was requested to develop a patentable synthesis for 3-methyl-hydrastinine. The patent started on December 24, 1912. It is a procedural patent for compounds which are key precursors for therapeutics. MDMA wasn't the purpose of the patent. It was Dr. Max Oberlin (also at Merck) who in 1927 was the first person interested in the pharmacological properties of MDMA. Research on the substance was stopped for economic reasons, and the substance was buried in oblivion for some decades. In the 1950s the American and German armies were interested in psychotropic agents; MDMA was among the tested substances. Most probably for this reason, MDMA was re-synthesized at Merck. In his laboratory journal of 1952 Dr. Albert van Schoor describes how MDMA kills 6 flies in 30 minutes. In 1959 Dr. Fruhstorfer works on MDMA and similar psychotropics, his substance H671 was identified to be MDMA. The research on these substances led to the marketing of Reaktivin in 1960. Its chemical structure isn't related to MDMA. The first scientific paper on MDMA appeared in 1960 and described a synthesis for MDMA. It is written in Polish by Biniecki and Krajewski and almost unknown. In 1978 Shulgin published the first scientific article on the drug’s psychotropic effect in humans.
   The U.S. Army did, however, carry out lethal dose studies of MDMA and several other compounds on animals in the mid-1950s. It was given the name EA-1475, with the EA standing for either (accounts vary) "Experimental Agent" or "Edgewood Arsenal." The results of these studies were not declassified until 1969.
   MDMA appeared sporadically as a street drug in the late 1960s (when it was known as the "love drug").
MDMA began to be used therapeutically in the late-1970s after the chemist Alexander Shulgin tried it himself, in 1977, and subsequently introduced it to psychotherapist Leo Zeff. As Zeff and others spread word about MDMA, it developed a reputation for enhancing communication during clinical sessions, reducing patients' psychological defenses, and increasing capacity for therapeutic introspection. However, no formal measures of these putative effects were made and blinded or placebo-controlled trials were not conducted. A small number of therapists, including George Greer, Joseph Downing, and Philip Wolfson, used it in their practices until it was made illegal. Other therapists continued to conduct therapy illegally and MDMA wasn't legally given to humans until Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent legally-approved MDMA studies in humans have taken place in Detroit, Chicago, San Francisco, and South Carolina, as well as in Switzerland, the Netherlands, and Spain.
   Due to the wording of the U.K's existing Misuse of Drugs Act of 1971, MDMA was automatically classified as a Class A drug in 1977.
   In the early 1980s in the U.S, MDMA rose to prominence in trendy nightclubs in the Dallas area, then in gay dance clubs. From there use spread to rave clubs in major cities around the country, and then to mainstream society. The drug was first proposed for scheduling by the DEA in July 1984, and was classified as a Schedule I controlled substance in the United States from May 31, 1985.
   In the late 1980s and early 1990s, ecstasy was widely used in the United Kingdom and other parts of Europe, becoming an integral element of rave culture and other psychedelic/dancefloor-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, and it rapidly became one of the four most widely used illicit drugs in the U.S along with cocaine, heroin and cannabis. Today in the U.S, according to some estimates, only cannabis will attract more first-time users.

Effects

Mode of action

The mechanism of MDMA's unusual effects has yet to be fully understood. One of the primary characteristics leading to production of effects is the drug's higher affinity for SERTs than serotonin itself. SERTs are the part of the serotonergic neuron which remove serotonin from the synapse to be recycled or stored for later use. Not only does MDMA inhibit the reuptake of serotonin into this pump, but it reverses the action of the transporter so that it begins pumping serotonin into the synapse from inside the cell. In addition, MDMA induces release of norepinephrine through an analogous mechanism. as well as an affinity for blocking that of dopamine.
MDMA's unusual empathic/entactogenic effects have been hypothesized to be at least partly the result of the release of oxytocin, a hormone usually released following such events as orgasm and childbirth, which is thought to facilitate bonding and the establishment of trust. MDMA is thought to cause this release by indirectly stimulating 5-HT1A receptors. However, the evidence that oxytocin is involved in the effects of MDMA is derived from studies conducted on rats where the emotional effects can only be indirectly measured, in this case by the time animals spend in close proximity to one another. Controlled human studies have not yet been carried out, and it isn't known conclusively if MDMA has oxytocinergic action in humans. The question of why other serotonergic drugs don't produce a similarly profound emotional state like MDMA also remains unanswered.

Acute effects

The primary effects attributable to MDMA consumption are predictable and fairly consistent amongst users.(External Link

) (External Link

) The most common effects include:

Euphoria
Decreased hostility and insecurity
Increased feelings of intimacy with others
Feelings of empathy towards others
Ability to discuss anxiety-provoking topics with markedly-increased ease
A strong sense of inner peace and self-acceptance
Feelings of insightfulness and mental clarity
Intensification of sensory experience, particularly auditory and tactile
Decreased appetite
Urinary retention (also see hyponatremia)
Mydriasis (abnormal pupil dilation)
Increased physical energy
Increased heart rate and blood pressure

Other effects may include:

Short-term memory lapses

Trisma (lockjaw)

Bruxia (involuntary teeth grinding)

Nystagmus (rapid, uncontrollable eye movements)

Several hours of restlessness following primary subjective effects, often accompanied by a peaceful, "glowing" feeling

A period of general malaise following primary subjective effects, normally resolving within a few days

Mildly-blurred vision following primary subjective effects, gradually resolving over a period of up to several days, also known as "plurring" Serious complications increasing in likelihood with dose, environmental severity, degree of physical activity, and/or certain drug interactions include:

Hyperthermia (due to an intemperate environment and/or lack of hydration and/or rest from physical activity, usually dancing)

Dehydration (due to an intemperate environment and/or lack of hydration and/or rest from physical activity, usually dancing)

Hyponatremia (due to drug induced antidiuretic hormone release and/or excess compensatory intake of fluids, a rare complication)

Serotonin syndrome (believed to be due to excess release of serotonin, sometimes triggered by coadministration of other serotonergic drugs)

Effects of chronic use

neurotoxic effects on serotonergic neurons. Some animal studies suggest that dancing or being in a warm environment may increase risk of neurotoxic damage due to the consequences of increased bodily temperature. However, this hasn't been established in humans.
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.
Generally-speaking, less-frequent and more moderate use of MDMA isn't associated with decreased long-term psychological wellness. Those who consume the drug excessively/frequently are at greater risk of developing depression and other disorders, although according to one four-year study, the vast majority of those who go on to do so have been diagnosed with some disorder prior to ever trying Ecstasy. (External Link

)
The effects of the drug on memory and cognition are less clear still. Although generally not considered to significantly affect long-term memory, MDMA may contribute to reductions in performance on short-term memory and some cognitive tasks. The degree of manifestation of these types of effects and their reversibility are still in question.
MDMA use has been occasionally associated with liver damage, excessive wear of teeth, and Hallucinogen persisting perception disorder.

Recreational use

MDMA use has increased markedly since the late 1980s, and spread beyond its original subcultures to mainstream use, with prices generally falling, although there's still wide geographical variance, both regionally and between countries.

United Kingdom

In 1995 it was reported that the street price per pill in the U.K. was "about £15 each," although two years later this had shifted to a range of £8 to £15 each. A 2001 Home Office study reported that the cost per pill to end-point consumer, "could be as little as £7.50, or as much as £10 to £15 when purchased in clubs."
In 2007 the Greater London Authority highlighted regional variations, reporting on the average street price per pill in five selected cities. They were:

Bristol £5

London £3.50

Manchester £3

Nottingham £2

Torquay £1.50

Supply

Worldwide, almost all MDMA is supplied via clandestine routes. The synthesis of MDMA is more complex than that of analogues such as methamphetamine, but still well within the grasp of a university-level chemistry student. Arguably the most difficult part of the synthesis is obtaining the necessary chemical precursors, as although all have legitimate uses outside of clandestine drug production, their distribution is now heavily monitored by government agencies like the DEA.

Ecstasy pills

Pills come in a variety of "brands or batches", usually identified by the icons stamped on the pills. The purpose of this is to help identify and providing an indicator as to the strength and quality of a particular tablet. Many popular icons are appropriated for this use; an example would be "Red Mercedes", which derives its name from its red color and imprinted Mercedes-Benz logo. However, the brands don't consistently designate the actual active compound(s) within the pill, as it's possible for copycat manufacturers to make their own pills which replicate the appearance of a well-known brand.

MDMA powder/crystals

MDMA powder, usually the hydrochloride salt, is often simply called 'crystal' or 'molly', and 'mandy', and in the UK 'Muds', 'Mud' or 'madman' (a play on words- MaDMAn), a mutation of 'madman' 'mandy', and 'MD'. This powder is produced in MDMA labs and provided to the pill-manufacturers to press the tablets into their desired form. When pressed into pill tablets, MDMA powder is always mixed with pill binders because pure MDMA can't be pressed.
In many parts of the world the usage of plain MDMA powder instead of pills is popular. One of the reasons for this is likely the superior control over dose and purity that the user is granted. This is because the powder form is less likely to be cut due to the greater ease of detecting impurities, and also because of MDMA's distinctive, intensely bitter taste. Because of this unpleasant taste, many users choose to 'bomb' or 'parachute' pure MDMA, whereby a dose is wrapped in cigarette papers or a small piece of toilet paper and then swallowed.
MDMA powder can also be insufflated, a route which leads to a quicker onset and dissipation of more intense effects, although users claim that this method of administration can be very unpleasant.

Use in psychotherapy

Some scientists have suggested that MDMA may facilitate self-examination with reduced fear, which may prove useful in a therapeutic setting.
A small number of therapists, including George Greer, Joseph Downing, and Philip Wolfson, used it 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, 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. 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 isn't known to what extent similar patients might improve from chance or from psychotherapy.
An ongoing study by the Multidisciplinary Association for Psychedelic Studies is evaluating the efficacy of MDMA-assisted psychotherapy for treating those diagnosed with posttraumatic stress disorder. To participate, patients must have had the disorder for a number of years and tried other treatments without success. In a newspaper interview, the researchers report promising tendencies for some participants to have reduced disease severity after MDMA psychotherapy. However, despite the initially positive nature of the results, they're only the findings of a currently-unpublished Phase II study, and similar research by other scientists will need to be conducted in order to demonstrate the efficacy of MDMA as a psychotherapeutic agent.

Synthesis

Safrole, a colorless or slightly yellow 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. 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 in the presence of a strong base to isosafrole and then oxidize isosafrole to MDP2P. Another, reportedly better 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's then consumed via a reductive amination to form MDMA as the product. �

According to DEA Microgram newsletters very little safrole is actually required to make MDMA. "Ocotea cymbarum is an essential oil... that typically contains between 80 and 94 percent safrole," "a 500-milliliter bottle of Ocotea cymbarum sells for $20 to more than $100," "An MDMA producer with access to the proper chemicals can use a 500-milliliter quantity of Ocotea cymbarum to produce an estimated 1,300 to 2,800 tablets containing 120 milligrams of MDMA."

Legal issues

Use, supply and trafficking of ecstasy are currently illegal in most countries. Ecstasy is illegal in all countries belonging to the United Nations. In the United States, MDMA was legal and unregulated until May 31, 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, the 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: � 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 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. A mandatory seven year sentence is now the penalty for a third conviction for trafficking.

Health concerns

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

U.K. government assessment of overall harm

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, and cannabis, 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. (External Link

)

Physical

hyperthermia, and hyponatremia. These dangers usually manifest themselves within the context of the rave subculture, as dancing often occurs in untempered environments where hundreds or even thousands of people are gathered in close proximity, sometimes indoors. Continuous dancing 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 and caffeine, also a stimulant, may exacerbate these risks further.
Hyponatremia (abnormally low salts in the blood) has been reported in some MDMA users. It isn't clear to what extent this is due to the known ability of MDMA to induce antidiruetic hormone release and/or whether these people inadvertently consumed excess fluids in an attempt to remain hydrated. MDMA on its own doesn't cause dehydration and there's no need to drink extra fluids unless one has extra fluid loss, such as from sweating. Premenopausal females experiencing rapidly developing hyponatremia are at risk of neurological complications including seizures, coma, and death because hyponatremia can cause neurons to swell and stop working. MDMA-releated hyponatremia is relatively uncommon. Hypertension is a risk in some users due to the increase in heart rate and blood pressure, but this is normally well-tolerated in young, healthy individuals who don't have pre-existing cardiovascular vulnerabilities.

Neurological overview

serotonin transporters (SERTs) in the brain. The rate at which the brain recovers from serotonergic changes is unclear. A number of studies including some performed by George Ricaurte at Johns Hopkins University, have demonstrated lasting serotonergic changes occurring due to MDMA exposure. Baboons who were given a neurotoxic dose of MDMA showed partial regrowth of SERTs when scanned a year later. Human users also show some recovery of serotonergic markers and, in some PET studies, have been indistinguishable from non-users. However, the same study also concluded that the reduction in memory performance due to heavy, prolonged MDMA use may be long-lasting.
Although oxidative stress (see neurotoxicity theory below) may cause SERTs to degrade faster than they're able to be replaced, the serotonin axon itself seems to have been spared, which indicates that neurotoxicity may not be the means by which SERT count was reduced. It is possible that excess serotonin in the synapse due to MDMA, especially if uses occur within a short period, causes the serotonin cells to produce fewer SERTs, a phenomenon which has already been demonstrated with other serotonin-depleting drugs. MDMA use may also cause a decrease in the number of serotonin receptors on the dendrite of the neuron. (See down-regulation theory below.)
For a detailed and comprehensive explanation of this topic, see TheDea.org's evaluation of studies.

Receptor down-regulation

One theory of SERT-depletion arising out of long-term MDMA use is receptor down-regulation which is one form of synaptic plasticity. When any neurotransmitter is present in excess for prolonged periods of time, the brain responds in an attempt to reestablish its own natural neuro-electrical balance. Weekly use of MDMA over a prolonged period may actually cause serotonin receptors to retreat into the dendrite of serotonin nerve cells. The change in synaptic serotonin concentration due to recreational MDMA use is at the extreme end of what is even possible in the brain and therefore, down-regulation could occur fairly easily with regular use.
This process causes the brain to become desensitized to the neurotransmitters present in the synapses and therefore also to the effects of MDMA itself. Therefore, in addition to a generally decreased quality of mood between doses, greater amounts of MDMA are required to achieve the same level of desired effects. It is this cycle that's often believed to be the cause of long-term emotional problems among regular ecstasy users.

Neurotoxicity

Under another theory, MDMA is considered neurotoxic in humans. While the method of this toxicity hasn't been definitively established, the current leading theory is that the metabolism of MDMA-induced dopamine release leads to the lipid peroxidation of the axons of serotonergic neurons. This occurs when MAO-B metabolizes dopamine into free radicals capable of damaging cells, leading to a reduction in SERT count and damaging or destroying the axon, thus interfering with the integrity of the brain's serotonin network. Neurotoxicity of serotonergic neurons would occur in selective areas of the human brain as serotonin cells are highly concentrated in certain areas such as the neocortex and hippocampus.
   Normally, the brain is able to protect itself from oxidative stress, but it's believed that the aforementioned damage can be partially attributed to MDMA's unique interaction with serotonin transporters. Not only does MDMA reverse the normal functioning of the transporter in which case serotonin is pumped out of the cell, but once the stored serotonin has been depleted, the transporter begins to take up dopamine which has been shown to be toxic to serotonin cells by itself. Once MAO oxidizes dopamine inside the serotonin cell, the damage is greatly magnified. Several studies have demonstrated that such damage in the brain is reversible after prolonged abstinence from the drug.
   One now infamous study on the MDMA toxicity, 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. 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 are normal. Antioxidants have been shown to prevent the neurotoxicity of MDMA in rats. In one study, intravenous administration of alpha lipoic acid completely blocked the neurotoxic effects of MDMA. No scientific experiment has been performed to date with human subjects, although some users report that taking various combinations of antioxidants before, during, and after using MDMA serves to moderate the subsequent mood-dip and improve recovery time.
   The administration of an SSRI in rats prior to the administration of MDMA has been shown to completely block neurotoxicity. This is due to the binding of such medications with SERTs. However, administering an SSRI prior to administration of MDMA also completely or partially blocks the desired effects of the latter, something a large number of users prescribed an SSRI have reported. As a compromise it has been shown that administration of an SSRI 3-4 hours after MDMA, at which time the primary effects will have tapered off significantly, markedly limits neurotoxicity overall despite some axonal damage having already occurred. Several studies have administered MDMA and SSRIs to humans, including paroxetine and citalopram, and these combinations have not cause obvious increases in risk or toxicity. However, the SSRI was always given before the MDMA and potential complications may still exist.

Psychological

MDMA use commonly results in a rebound period of poor mood commonly known as a "comedown", the length and severity of which depends on the user, the dose, time since previous usage, any polydrug use/abuse, and a host of other factors. It is sometimes claimed that heavy or frequent use may precipitate lasting depression and anxiety in vulnerable users, particularly those prone to depression or other mental disorders as well as anyone in a state of life crisis, although there's little published data on this.
"Redosing" in an attempt to extend MDMA's desired effects has been shown to substantially increase neurotoxicity in animals. Users also report increases in undesired physical side effects associated with MDMA use such as trisma and bruxia . The longer MDMA is active and being metabolized in the brain, the greater the neurotoxic damage and the greater the risk of exacerbating pre-existing emotional problems. The more occasions MDMA is used, the greater the chances of long-term problems. Deficits in memory have been shown in long term MDMA users.
A recent University of Louisiana study found no significant relationship between depression and recreational ecstasy use. The preliminary results from an ongoing Dutch study also indicates that the very moderate use of Ecstasy wasn't associated with depression or decreased mental state. These users also appear to be free of neurological injury of any kind.

Drug interactions

Individuals who have stopped taking any type of SSRI after prolonged medication may not be able to experience the desired effects of MDMA for as long as several months following discontinuation of the medication. This is due to the fact that SSRIs decrease the brain's sensitivity to the presence of serotonin as the brain seeks to reestablish a normal neuro-electrical balance.
Most people who die while under the influence of MDMA have also consumed significant quantities of at least one other drug. The risk of MDMA-induced death overall is very low.
The use of MDMA can be dangerous when combined with other drugs (particularly monoamine oxidase inhibitors (MAOIs) and antiretroviral drugs, in particular ritonavir). Combining MDMA with MAOIs can precipitate hypertensive crisis, as well as serotonin syndrome which can be fatal. MAO-B inhibitors such as deprenyl don't seem to carry these risks when taken at selective doses, and have been used to completely block neurotoxicity in rats.

Purity

Due to its nearly-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. These substances may include amphetamine, methamphetamine, ephedrine, and caffeine, all of which may be comparatively cheap to produce and can help to boost profit overall. In some cases, tablets sold as Ecstasy don't even contain any MDMA, chemicals in the Ecstasy Family, or even any kind of stimulant drug. Instead they may contain an assortment of presumably undesirable drugs such as paracetamol, ibuprofen, etc.
Scientific surveys of seized Ecstasy pills in the United Kingdom and Europe indicate that purity levels are generally high, and that adulterants are rare. Although the US government's Office of National Drug Control Policy reports that over 55% of ecstasy pills seized in the United States in 2007 were laced with methamphetamine, it's unknown what percentage of a tablet on average the drug constitutes.(External Link

) It should also be noted that as a general rule, tablets seized don't necessarily represent the entire market accurately, as it's impossible to know how many of each tablet are being consumed and what each contains.
A full and proper characterization of ecstasy pills requires advanced lab techniques, such as high performance liquid chromatography-mass spectrometry (usually referred to as HPLC-MS), gas chromatography-mass spectrometry (usually referred to as GC-MS) and gas chromatography-infrared spectroscopy (usually referred to as GC-IRD). Ecstasydata.org

, an American non-profit organization, uses such techniques to analyze MDMA pills for a fee.
In the Netherlands, testing of pills has been available free of charge and funded by the government at festivals and parties for almost 2 decades, but government funding has ceased in recent years, and testing of pills at festivals and parties has been banned. Testing of pills as well as other common partydrugs is still possible at several testing facilities spread throughout the country, and free of charge. Both GC/MS and HPLC/MS analysis are used to determine the active constituents of the drugs being tested, and quantative analysis is performed on some drugs including Ecstasy pills and LSD blotter paper to analyse the quantities of active consituent(s) in the pills or blotters tested. Results of the quantative analysis are given in milligrams of (each) active constituent(s) in pills, and in micrograms for the constituents of tested blotter papers. Testing results are passed on to a EU monitoring program on new drugs trends. This way early warning reports can been given when possibly dangerous adulterated substances appear on the market, like cocaine adulterated with atropine, or Ecstasy pills adulterated with or containing solely PMA. The latter has never appeared in Dutch pills but is used as an example to explain the aim of the monitoring program. DanceSafe, among other companies, provides home testing kits to verify the contents of MDMA pills. PillReports.com

and Trancesafe.com

each provide the results of home testing kits in addition to the suspected contents when a test hasn't been performed.

PMA

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. Hence, a user who believes he's consuming 2 120mg pills of MDMA could actually be consuming a dose of PMA that's potentially lethal, depending on the purity of the pill. Not only does PMA cause the release of serotonin, but also acts as an MAO-A inhibitor. When combined with an ecstasy-like substance, serotonin syndrome can result.
While both PMA and MDMA are currently Schedule I in the U.S, PMA was scheduled more than 10 years before MDMA. Additionally, both drugs were rescued from obscurity by the same man, Alexander Shulgin, who at the time was synthesizing new psychoactive chemicals having been granted a license by the DEA to conduct autonomous research.
Between the late 1970s and early 1990s, virtually no PMA-related deaths were reported worldwide. However, there's no clear evidence linking lack of this enzyme to problems in users, and the connection remains theoretical.

Poly substance use

Tobacco isn't known for dangerous interactions with MDMA but carries its own risks, and MDMA users may be prone to overindulgence resulting in short term problems such as sore throat or coughing. Alcoholic and caffeinated beverages, which are both diuretics, can enhance the likelihood of dehydration and should be avoided.
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. Some examples include "candy flipping", MDMA combined with LSD, also known as trolling (tripping and rolling), hippie flipping or flower flipping, which is MDMA combined with mushrooms, or triple flipping, which is MDMA with mushrooms and LSD. Any of these combinations has the ability to produce an extremely powerful experience and may carry an increased risk of neurotoxicity, complications and/or injury when compared to any individual substance.
Clubbers in Europe are increasingly using ketamine during or after MDMA use. Using smaller amounts while on MDMA has little pronounced effect, as the stimulation from the MDMA balances out the depressant qualities of the ketamine. This may however increase the hallucinogenic effects of the MDMA. Clubbers more often use ketamine after the primary effects of MDMA have worn off to make the comedown less dysphoric. Clubbers may also take speed during MDMA use to intensify the effects, or after MDMA use to stay awake and energised once tolerance and serotonin depletion has prevented them from gaining any more effect from MDMA. Using MDMA and amphetamine together makes both substances more neurotoxic than using them separately.
Many users use mentholated products while taking MDMA, as it's believed to heighten the drug's effects. Examples include menthol cigarettes, Vicks lozenges, etc. This sometimes has deleterious results on the upper respiratory tract.

Further Information

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