Methylenedioxymethamphetamine

MDMA (3,4-methylenedioxy-N-methamphetamine), most commonly known today by the street name ecstasy (often abbreviated E, X, or XTC), is a semisynthetic member of the amphetamine class of psychoactive drugs, a subclass of the phenethylamines.

MDMA's experiential effects are more consistent than those produced by most psychedelics, and its euphoria appears to be distinct from most stimulants. It is also considered unusual for its tendency to produce 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 to some individuals. Before it was made a controlled substance, MDMA was used to aid psychotherapy, often couples therapy, the results of which are poorly documented. Studies have also recently been initiated to examine the therapeutic potential of MDMA for post-traumatic stress disorder and anxiety associated with cancer.

MDMA is criminalized in all countries in the world under a UN agreement,  and its possession, manufacture, or sale may result in criminal prosecution. Use of MDMA is limited to licensed scientific and medical research. MDMA is one of the most widely 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.

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

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 was not 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 described how MDMA killed 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 is not 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 remains almost unknown. In 1978 Alexander Shulgin and David Nichols published the first report 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 first appeared sporadically as a street drug in the early 1970s after its counterculture analogue, MDA, became criminalized in the United States in 1970.  MDMA use, however, remained very limited until the end of the decade. MDMA began to be used therapeutically in the late-1970s after noted 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.

Although some therapists continued to conduct therapy illegally, MDMA was not 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 the U.S

Due to the wording of the United Kingdom'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 United States, MDMA rose to prominence as "Adam" 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 MDMA as "ecstasy" began to be 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. MDMA became one of the four most widely used illicit drugs in the United States, along with cocaine, heroin and cannabis. Today in the US, according to some estimates, only cannabis will attract more first-time users.

Therapeutic uses

There have long been suggestions that MDMA might be useful in psychotherapy, facilitating self-examination with reduced fear.   Indeed, a small number of therapists, including Leo Zeff, George Greer, Peter Mandelson, 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,  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 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. Studies in the US and other countries are evaluating the efficacy of MDMA-assisted psychotherapy for treating those diagnosed with posttraumatic stress disorder (PTSD) or anxiety related to cancer. In a newspaper interview, the researchers from the South Carolina PTSD study report tendencies for some participants to have reduced disease severity after MDMA psychotherapy.  However, these reports focus on individual participants. Statistical results from the entire study will need to be published and, ultimately, results will need to be confirmed in studies by other scientists to demonstrate the efficacy of MDMA as a psychotherapeutic agent.

Mechanism of action

The mechanism 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 SERTs. 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 the release of norepinephrine and 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-HT_1A 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 is not known conclusively if MDMA has oxytocinergic action in humans. The question of why other serotonergic drugs do not produce a similarly profound emotional state like MDMA also remains unanswered.

Effects

Acute effects

The primary effects attributable to MDMA consumption are predictable and fairly consistent amongst users.  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 proprioception, hearing and touch
• Decreased appetite
• Urinary retention (also see hyponatremia)
• Mydriasis (abnormal pupil dilation)
• Increased physical energy
• Increased heart rate and blood pressure
• Increased mean body temperature

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, sometimes accompanied by residual euphoria
• 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 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

The long-term health effects of ecstasy use are generally not well-known, and the research that has been devoted to addressing the relevant issues thus far has been largely inconclusive. The primary concern is generally that there may be negative long-term consequences that result from the drug's alleged neurotoxic effects on serotonergic neurons.  Some further studies have also shown that this damage causes increased rates of depression and anxiety, even after quitting the drug.  In addition to this, some studies have indicated that MDMA may cause long-term memory  and cognition impairment.  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,  excessive wear of teeth, and (very rarely) Hallucinogen persisting perception disorder.

Recreational use

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. The United Nations Office on Drugs and Crime claimed in its 2008 World Drug Report that typical US retail prices are higher, at 15 to 20 dollars per tablet, or can be from 5 to 10 dollars per tablet if bought in stacks of 10 or more.

MDMA, which has been made criminally illegal worldwide, is taken most commonly in pill form.

MDMA hydrochloride is used to manufacture ecstasy pills. Some users take this powdered form for recreation.

Legal issues

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.

In the United States, 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. Nonetheless, the DEA chose to ignore the ruling of its own Administrative Law Judge and unilaterally classified MDMA as Schedule I.  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%,  despite scientific protest calling for a decrease in the penalties for MDMA possession and distribution.  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.  

That same year, 1985, the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the Convention on Psychotropic Substances. 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.

Health concerns

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

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   have demonstrated lasting serotonergic changes occurring due to MDMA exposure. Other studies  have suggested that that the brain may recover from serotonergic damage; however, damage caused by heavy, prolonged use of MDMA may be long lasting.

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

One now infamous 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.  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.  

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, etc.

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.  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 MAO-A inhibitor. When combined with an ecstasy-like substance, serotonin syndrome can result.

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 normalized 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 minimal.^[

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 do not seem to carry these risks when taken at selective doses, and have been used to completely block neurotoxicity in rats.

Poly substance 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,  and "hippie flipping" when combined with psilocybin mushrooms. Such combinations have 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. Many users use mentholated products while taking MDMA, believing it heightens the drug's effects. Examples include menthol cigarettes, Vicks  and lozenges. This sometimes has deleterious results on the upper respiratory tract. Some also drink orange juice with the pill, which they believe heightens the effects.