MDMA

MDMA

Clinical data
Pregnancy category	C [2]
Routes of administration	Sublingual salla
Legal status
Legal status	AU: S9 (Prohibited substance) CA: Schedule III UK: Class A US: Schedule I
Pharmacokinetic data
Metabolism	Hepatic, CYP extensively involved
Elimination half-life	The half-life of MDMA is dose dependent, increasing with higher doses, but is around 6–10 hours at doses of 40–125 mg
Excretion	Renal
Identifiers
IUPAC name 1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine
CAS Number	42542-10-9 66142-89-0 69610-10-2 81262-70-6
PubChem CID	1615
CompTox Dashboard (EPA)	DTXSID90860791
Chemical and physical data
Formula	C11H15NO2
Molar mass	193.25 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(NC)CC1=CC=C(OCO2)C2=C1

MDMA (3,4-methylenedioxy-N-methylamphetamine), most commonly known today by the street name ecstasy, (often abbreviated to E, X, or XTC) is a semisynthetic entactogen of the phenethylamine family. It is considered a recreational drug, and has long had a strong association with the rave culture. MDMA is illegal in most countries, and its possession, manufacture or sale may result in criminal prosecution.

The primary physiological effect of MDMA is believed to be the stimulation of secretion, as well as inhibition of re-uptake, of large amounts of serotonin, as well as dopamine and norepinephrine in the brain. Many users report subjective feelings of openness, empathy, energy, euphoria, and well-being. Tactile sensations are enhanced for some users, making physical contact with others more pleasurable. Other side effects, such as jaw clenching and elevated pulse, are common. Some users report effects similar to those of softer stimulants such as caffeine, and a few report effects comparable to harder stimulants such as cocaine.

The short-term health risks of taking MDMA include hypertension, dehydration and hyperthermia, with the last two particularly notable in the rave context of dancing for long periods of time, as the drug's stimulatory effects can mask the body's normal sense of exhaustion and thirst. The risk of hyperthermia may be increased by a high fat diet, and the mechanism the activation of uncoupling protein (UCP) in mitochondria. [3] Because the lethal dose is many times higher than the typical recreational dose of 100-150 mg, overdoses are rare, but between 10 to 100 people die each year in the US with MDMA in the blood samples.

The effects of long-term use in humans are debatable 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. Studies are difficult to undertake due to the illegality of the drug, and at least one study purported to show brain damage but was later retracted by its authors. The chief executive of the UK Medical Research Council stated MDMA was "on the bottom of the scale of harm", and the Science & Technology Committee rated it of lower concern than for alcohol, tobacco, and cannabis, believing it should be changed to less harmful category B, while at the same time found methamphetamine should be scheduled up to the most harmful category A.

History

The MDMA molecule

A patent for MDMA—referred to as methylsafrylamin—was originally filed on December 24 1912 by the German pharmaceutical company Merck, after being first synthesised for them by German chemist Anton Köllisch at Darmstadt earlier that year. The patent was granted in 1914; Köllisch died in 1916 unaware of the impact his synthesis would have. 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 hydrastinine (a drug intended to control bleeding from wounds). During 1927, Max Oberlin used MDMA as a mimic for adrenaline as the compound has a similar chemical structure. At this time the first animal studies were performed to demonstrate the effects of MDMA on blood glucose levels and vascular tissue. This study was discontinued due to the high costs of the chemical synthesis. Interest was revived in the compound as a possible human stimulant by Wolfgang Fruhstorfer in 1959, although it is unclear if tests were actually performed on humans. The synthesis of the compound first appeared in 1960.

The U.S. Army did, however, carry out lethal dose studies on animals of MDMA and several other compounds 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.

Due to the wording of the existing Misuse of Drugs Act 1971, MDMA was automatically classified as a Class A drug in 1977 in UK and was classified as a Schedule I controlled substance in the United States from May 31, 1985. However this link contradicts the US Department of Justice classification table. Before then, it was used both as an adjunct to psychotherapy and as a recreational drug. MDMA began to be used therapeutically in the mid-1970s after the chemist Alexander Shulgin introduced it to psychotherapist Leo Zeff. As Zeff and others spread word about MDMA, it developed a reputation for enhancing communication, reducing psychological defenses, and increasing capacity for introspection. There have even been accounts that the military also used this for interrogating enemy spiesdue to these effects. 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.

MDMA appeared sporadically as a street drug in the late 1960s (when it was known as the "love drug"), but it came into prominence in the early 1980s 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. The street name of "ecstasy" was coined in California in 1984. The drug was first proposed for scheduling by the DEA in July 1984. During the 1990s, along with the growing popularity of the rave subculture, MDMA use became increasingly widespread among young adults in universities and later in high schools. It rapidly became one of the four most widely used illegal drugs in the U.S., along with cocaine, heroin and cannabis.

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.

Recreational use

Recreational uses: euphoria
Other putative uses: Anxiety PTSD
Contraindications: Not for use in combination with stimulants (amphetamines, large doses of caffeine, soda, energy drinks, etc). Not for use in combination with diuretics (alcohol). Not for use in individuals with high blood pressure, hypertension, or blood clotting disorders. Not for use in individuals who have displayed allergies to amphetamine drugs. Must never be used in combination with MAOI (Monoamine Oxidase Inhibitor) drugs.
Side effects:
Endocrine: hyponatremia
Eye: dilated pupils nystagmus
Psychological: euphoria strong sense of empathy increased serotonin amount
Skin: sweaty palms heavy sweating increased heart rate increased body temperature heightened touch sensations
Miscellaneous: "chattiness" restlessness chattering teeth muscle spasms

The primary effects of MDMA include feelings of openness, euphoria, empathy, love, and heightened self-awareness. Some users also report a tactile effect that many users refer to as the "feels" or "touchies". This is a very pleasurable sensation when touching other objects. Its initial adoption by the dance club sub-culture is possibly due to the enhancement of the overall social and musical experience. Taking MDMA or ecstasy is commonly referred to as rolling and many other slang names.

MDMA use has increased markedly since the late 1980s, and spread beyond its original subcultures to mainstream use. Prices have also fallen since the 1980s. In countries where distribution is more extensive prices can sometimes be as low as €0.50 per tablet, such as in the Netherlands but other places in Europe it is common to pay €3-6 each. In Ireland their general price is €3:50-€4. It's use has grown rapidly in Ireland, and there are reports of children as young as 10 years using the drug on a regular basis. it is easily available in Ireland, and is often given for free as a good "gesture" at raves or social functions. In countries where distribution is more difficult, such as the U.S., New Zealand and Australia, prices are accordingly higher at up to US$10–40, NZ$40-70 and AUD$20–40 respectively per tablet. In the United Kingdom it is common to pay around £2 to £3 for a tablet on average, and in larger quantities around £1 a tablet. Prices have been driven very low in Canada due to large supply, CAD$5 to CAD$10 is the average price per tablet, while prices decrease in quantity such as two for CAD$5 or three for CAD$10 depending on quality. Prices are also usually higher when the drug is purchased in a club or at a rave.

Supply

Because its manufacture is generally illegal, 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 procuring the necessary chemical precursors: some have few legitimate uses outside of clandestine drug production, and purchases of them are often illegal or heavily monitored by government agencies like the DEA.

The clandestine nature of a MDMA supply and demand means that purity is rarely known to the typical recreational user. MDMA is often cut with various substances, including caffeine, methamphetamine and ephedrine. Inexpensive tests such as the Marquis reagent can prove or disprove the presence of MDMA (as well as other substances) but do not indicate the total percentage of MDMA in the sample.

Administration

MDMA is typically ingested, although insufflation, and taking as a suppository is possible as well. The drug is commonly found in pressed pills or powder capsules. The typical recreational dose of 100-150 mg creates a "high", which takes effect within 30-60 minutes and lasts 4-6 hours. Some users take additional doses to prolong the high.

Ecstasy-pills

Ecstasy commonly appears in a tablet form, usually imprinted with a monogram.

An assortment of Ecstasy tablets.

Pills come in a variety of "brands", usually identified by the icons stamped on the pills. An example would be "Red Mercedes", which gets its name because of its red color and Mercedes-Benz logo imprinted on it. Most are named after famous persons or places such as "D&G's" (Dolce & Gabbana). However the brands do not consistently designate the actual active compound within the pill, as it is possible for "copycat" manufacturers to make their own pills which replicate the features of a well-known brand.

Although full and proper characterization of ecstasy pills requires advanced lab techniques such as high performance liquid chromatography-mass spectrometry (usually referred to as LC-MS), gas chromatography-mass spectrometry (usually referred to as GC-MS) and gas chromatography-infrared spectroscopy, it is also possible to use a less accurate presumptive alkaloid test known as the Marquis reagent. Many organizations sell pill testing kits containing this reagent. DanceSafe is one such company, and it includes an extensive database of photographs of different pills, along with the results of a laboratory analysis of their contents. EcstasyData.org is a non-profit site that tests the purity of street pills and compiles results. allows users to post reports of pills they have purchased and share the experience, pictures, and testing results. Other users can then post what they think about the pill in question or even rate the report on the pill. In parts of Canada and the United States, tests of pressed pills and capsules have been found to contain only small proportions of pure MDMA, containing instead caffeine, ketamine and methamphetamine in proportions larger than the MDMA. MDMA is also often combined with many other drugs when pressed into tablets which include amphetamines (speed), cocaine, MDEA, MDA, and rarely mescaline. Doing MDMA in combination with LSD is often known as "candy flipping", also ecstasy pills that include methamphetamines are known as "meth bombs." Contrary to popular belief, the majority of pills do not include ingredients such as methamphetamine, cocaine, PCP, heroin, or LSD.

MDMA powder/crystals

File:MDMA crystals.JPG

The pure form of MDMA hydrochloride, used by pill-manufacturers and recreational users.

File:MDMA capsules.JPG

Because of the extremely bitter taste, some users prefer to put the MDMA powder into capsules before consuming.

MDMA powder, usually the hydrochloride, is often simply called 'crystal' or 'moli' (short for molecule). This powder is produced in MDMA labs and provided to the pill-manufacturers to press the tablets at a different place. In many parts of the world the usage of plain MDMA powder instead of pills is popular. One of the reasons for this might be the control over dosage and purity. When pressed into pill tablets, MDMA powder is always mixed with pill binders because pure MDMA cannot be pressed.

Effects

Further information: Effects of MDMA on the human body

Use in psychotherapy

Some scientists have suggested that MDMA may facilitate self-examination with reduced fear, which may prove useful in some therapeutic settings, leading in 2001 to permission from the United States FDA for testing in patients with post-traumatic stress disorder in conjunction with psychotherapy. A parallel similar study is currently underway in Switzerland which should finish in 2008. MDMA has been classed in an entirely new category of drug action as an "empathogen" and/or an "entactogen."

Synthesis

Industrial scale methamphetamine/MDMA factory in Cikande, Indonesia

Safrole, a colorless or slightly yellow oil, extracted from the root-bark or the fruit of sassafras plants is the primary precursor for all clandestine 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 is then consumed via a reductive amination to form MDMA as the product.

There are restrictions on obtaining safrole or sassafras oil because it is a DEA List I chemical. It is unlikely that anyone obtaining safrole in large quantities for the purpose of manufacturing MDMA would be able to do so without arousing the suspicion of law enforcement. It is also important to note that MDMA is a federal DEA Schedule I compound in the United States and any attempt to manufacture MDMA is a federal offense.

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. 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.

Medical use and clinical studies

In 2001, the FDA granted permission for experimental administration of MDMA to patients suffering from post-traumatic stress disorder. This research is being sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS). For further information on this, see MAPS's MDMA Research Information and the recent article from MSNBC/Newsweek. This research in patients builds on studies in which MDMA was given to healthy volunteers. The first of these healthy volunteer studies was conducted by Dr. Charles Grob, with other studies done by Dr. Franz Vollenweider in Switzerland, Drs. John Mendelson and Reese Jones at the University of California San Francisco, and Drs. Magi Faree and Rafael de la Torre in Spain.

Safety and contraindications

The illegality of MDMA in many countries makes study of its effects difficult. Some safety considerations to consider with the use of ecstasy, which may or may not be conclusive, are the following:

• The dose and purity of ecstasy pills vary dramatically. The MDMA dosage may be stronger or weaker than is advertised. The pills may also contain other substances. In some cases, pills marketed as ecstasy do not contain MDMA or the similar MDEA or MDA, but instead are substituted with various substances like ketamine, methamphetamine, and caffeine. Some users purchase pill testing kits to verify that pills are actually MDMA. Organizations such as DanceSafe provide pill testing kits.

• Hypertension is a risk factor given the increased cardiac load.

• The use of ecstasy can be very dangerous when combined with other drugs (particularly monoamine oxidase inhibitors (MAOIs) and antiretroviral drugs, in particular Ritonavir). Combining MDMA with MAOIs can precipitate a hypertensive crisis and can result in a near-fatal repercussion.

• 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.

• Because of the manner in which ecstasy acts on neurotransmitters in the brain, its use may produce temporary depression as an after-effect for some users.

• 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. (Some scientists have suggested that a small percentage of people lack the proper enzymes to break down the drug. One enzyme involved in MDMA's breakdown is CYP2D6, which is deficient or totally absent in 5-10% of the Caucasian population and those of African descent, and in 1-2% of Asians. However, there is no clear evidence linking lack of this enzyme to problems in users, and the connection remains theoretical.)

Poly substance use

Main article: Poly drug use

MDMA is known for being taken in conjunction with other recreational drugs. It is said to complement psychedelics such as LSD and hallucinogenic mushrooms by preventing difficult experiences and bad trips. Use is so prevalent, most of the more common combinations have been given nicknames that are well known throughout the drug culture. Examples include "candy flipping", MDMA combined with LSD, also known as trolling (tripping and rolling) , hippy flipping, which is MDMA combined with mushrooms, or triple flipping, which is MDMA with mushrooms and LSD

Many users use mentholated products while taking MDMA, as it is believed to heighten the drug's effects. Examples include menthol cigarettes, Vicks lozenges, etc. This sometimes has deleterious results on the upper respiratory tract.

See also

• Amphetamine
• MDEA
• paramethoxyamphetamine (PMA), a different, more dangerous drug sometimes sold deceptively as "ecstasy"
• Leah Betts & Anna Wood (people who have died as a result of drinking too much water while on ecstasy)
• paramethoxyamphetamine
• Eleusis/Zwitterion (Famous underground ecstasy chemist)
• Psychedelic therapy
• RAVE Act
• Retracted article on neurotoxicity of ecstasy
• Sextasy
• Otto Snow (Author of chemistry books concerning ecstasy)
• Template:ChemicalSources

References

• Adam, David. Truth about ecstasy's unlikely trip from lab to dance floor: Pharmaceutical company unravels drug's chequered past, Guardian Unlimited, 2006-08-18.

• Baggott, Matthew, and John Mendelson. “MDMA Neurotoxicity”. Ecstasy: The Complete Guide. Ed. Julie Holland. Spring 2001 from www.erowid.com.

• de la Torre, Rafael et al. (2000), Non-linear pharmacokinetics of MDMA (`ecstasy') in humans. Br J Clin Pharmacol, 2000; 49(2):104-9

• de la Torre, Rafael & Farré, Magí (2004). Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans. Trends in Pharmacological Sciences 25, 505-508.

• Eisner, Bruce. "Ecstasy: The MDMA Story-2nd ed." Berkeley, CA: Ronin Publishing, 1994.

• Erowid, Earth. “Do Antioxidants Protect Against MDMA Hangover, Tolerance, and Neurotoxicity?” Erowid Extracts. December 2001; 2:6-11.

• Jennings, Peter. Ecstasy Rising, ABC television documentary. 2004-01-04.

• Jones, Douglas C. et al. (2004). Thioether Metabolites of 3,4-Methylenedioxyamphetamine and 3,4-Methylenedioxymethamphetamine Inhibit Human Serotonin Transporter (hSERT) Function and Simultaneously Stimulate Dopamine Uptake into hSERT-Expressing SK-N-MC Cells. J Pharmacol Exp Ther 311, 298-306.

• Kalant H. (2001) The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ. October 2;165(7):917-28. Review. PMID 11599334 Full Text

• Miller, R.T. et al. (1997). 2,5-Bis-(glutathione-S-yl)-alpha-methyldopamine, a putative metabolite of (+/-)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations. Eur J Pharmaco. 323(2-3), 173-80. Abstract retrieved April 17, 2005, from PubMed.

• Monks, T.J. et al. (2004). The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and 3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity. Ther Drug Monit 26(2), 132-136.

• Morgan, Michael John (2000). Ecstasy (MDMA): a review of its possible persistent psychological effects. Psychopharmacology 152, 230-248.

• Shankaran, Mahalakshmi, Bryan K. Yamamoto, and Gary A. Gudelsky. “Ascorbic Acid Prevents 3,4,-Methylenedioxymethamphetamine (MDMA)- Induced Hydroxyl Radical Formation and the Behavioral and Neurochemical Consequences of the Depletion of Brain 5-HT”. Synapse. 2001; 40:55-64.

• Strote, Jared et al. (2002). Increasing MDMA use among college students: results of a national survey. Journal of Adolescent Health 30, 64-72.

• Sumnall, Harry R. & Cole, Jon C. (2005). Self-reported depressive symptomatology in community samples of polysubstance misusers who report Ecstasy use: a meta-analysis. Journal of Psychopharmacology 19(1), 84-92.

• Vollmer, Grit. "Crossing the Barrier." Scientific American Mind. June/July 2006, 34-39.

• Yeh, S. Y. “Effects of Salicylate on 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Neurotoxicity in Rats”. Pharmacology Biochemistry and Behavior. 1997; Vol. 58, No. 3: 701-708.

• Gerra G, Zaimovic A, Ampollini R, Giusti F, Delsignore R, Raggi MA, Laviola G, Macchia T, Brambilla F. "Experimentally induced aggressive behavior in subjects with 3,4-methylenedioxy-methamphetamine ("Ecstasy") use history: psychobiological correlates." J Subst Abuse. 2001;13(4):471-91

• Reid LW, Elifson KW, Sterk CE. "Hug drug or thug drug? Ecstasy use and aggressive behavior". Violence Vict. 2007;22(1):104-19.

• Ksir, Charles, Carl L. Hart, and Oakley Ray. "Drugs, Society and Human Behavior-12th ed." NY,NY: McGraw Hills, 2006.

External links

• Jennings, Peter. "Primetime Special: Peter Jennings - Ecstasy Rising." ABC News, April 1, 2004.
• Conant, Eve. "Ecstasy: A Possible New Role for a Banned Club Drug." Newsweek, May 2, 2005.
• This is your brain on Ecstasy - A slideshow that illustrates the neuropharmacokinetics of Ecstasy (how the drug affects the brain.) Some of the information on this page is at present (July 2005) outdated.
• Multidisciplinary Association for Psychedelic Studies - A non-profit organization currently conducting FDA-approved studies with MDMA.
• EcstasyData.org A database of photos and lab-test results of over 1500 pills of "Ecstasy."
• American Council for Drug Education factsheet on Ecstasy
• Ecstasy.org