methylenedioxymethamphetamine

出典: meddic

メチレンジオキシメタンフェタミン <quote_text ori="WordNet" license="license_wordnet" syno="MDMA">a stimulant drug that is chemically related to mescaline and amphetamine and is used illicitly for its euphoric and hallucinogenic effects; it was formerly used in psychotherapy but in 1985 it was declared illegal in the United States; "MDMA is often used at parties because it enables partygoers to remain active for long periods of time"</quote_text>

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出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2013/10/20 04:23:30」(JST)

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MDMA
Systematic (IUPAC) name
(RS)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine
Clinical data
Pregnancy cat. C[1]
Legal status Prohibited (S9) (AU) Schedule I (CA) CD Lic (UK) Schedule I (US)
Dependence liability Moderate
Routes Oral, sublingual, insufflation, inhalation (vaporization), injection,[2] rectal
Pharmacokinetic data
Metabolism Hepatic, CYP450 extensively involved, especially CYP2D6
Half-life 6–10 hours (though duration of effects is typically actually 3–5 hours)
Excretion Renal
Identifiers
CAS number 42542-10-9 N
ATC code N/A
PubChem CID 1615
DrugBank DB01454
ChemSpider 1556 Y
UNII KE1SEN21RM Y
ChEBI CHEBI:1391 Y
ChEMBL CHEMBL43048 Y
Synonyms (±)-1,3-benzodioxolyl-N-methyl-2-propanamine;

(±)-3,4-methylenedioxy-N-methyl-α-methyl-2-phenethylamine;
DL-3,4-methylenedioxy-N-methamphetamine;

methylenedioxymethamphetamine
Chemical data
Formula C11H15NO2 
Mol. mass 193.25 g/mol
 N (what is this?)  (verify)

MDMA (3,4-methylenedioxy-N-methylamphetamine) is an empathogenic drug of the phenethylamine and amphetamine classes of drugs. MDMA has become widely known as "ecstasy" (shortened to "E", "X", or "XTC"), usually referring to its street pill form, although this term may also include the presence of possible adulterants. The terms "mandy" or "molly" colloquially refer to MDMA in powder or crystalline form, usually implying a higher level of purity.[3]

MDMA can induce euphoria, a sense of intimacy with others, diminished anxiety, and mild psychedelia. Many studies, particularly in the fields of psychology and cognitive therapy, have suggested MDMA has therapeutic benefits and facilitates therapy sessions in certain individuals, a practice for which it had been formally used in the past. Clinical trials are now testing the therapeutic potential of MDMA for post-traumatic stress disorder, anxiety associated with terminal cancer[4][5] and addiction.[6]

MDMA is criminalized in most countries (though some civil society initiatives—such as the Global Commission on Drug Policy—consider educating the public about the drug more important than curtailing supply[7]) and its possession, manufacture, or sale may result in criminal prosecution. Some limited exceptions exist for scientific and medical research. For 2008, the UN estimated between 10 and 25 million people globally used MDMA at least once in the past year. This was broadly similar to the number of cocaine, amphetamine, and opioid users, but far fewer than the global number of cannabis users.[8] It is taken in a variety of contexts far removed from its roots in psychotherapeutic settings, and is commonly associated with dance parties (or "raves") and electronic dance music.[9]

Regulatory authorities in several locations around the world have approved scientific studies administering MDMA to humans to examine its therapeutic potential and its effects.[10]

Contents

  • 1 Medical use
  • 2 Recreational use
    • 2.1 Subjective effects
  • 3 Adverse effects
    • 3.1 Aftereffects
    • 3.2 Overdose
    • 3.3 Chronic use
    • 3.4 Short-term health concerns
    • 3.5 Long-term effects on serotonin and dopamine
    • 3.6 Purity and dosage of "ecstasy"
    • 3.7 Harm assessment
    • 3.8 Drug interactions
    • 3.9 Sassafras oil
  • 4 Chemistry
  • 5 Pharmacology
  • 6 Pharmacokinetics
    • 6.1 Detection of use
  • 7 History
  • 8 Legal status
    • 8.1 United Kingdom
    • 8.2 United States
    • 8.3 Netherlands
    • 8.4 Canada
    • 8.5 World Health Organization
  • 9 Environmental concerns
  • 10 Cost and distribution
    • 10.1 Australia
  • 11 References
  • 12 Further reading
  • 13 External links

Medical use[edit]

MDMA has been indicated as possibly useful in psychotherapy, facilitating self-examination with reduced fear.[11][12][13] Indeed, some therapists, including Leo Zeff, Claudio Naranjo, George Greer, Joseph Downing, and Philip Wolfson, used MDMA in their practices until it was made illegal. George Greer synthesized MDMA in the lab of Alexander Shulgin and administered it to about 80 of his clients over the course of the remaining years preceding MDMA's Schedule I placement in 1985. In a published summary of the effects,[14] the authors reported patients felt improved in various mild psychiatric disorders and experienced other personal benefits, especially improved intimate communication with their significant others. In a subsequent publication on the treatment method, the authors reported one patient with severe pain from terminal cancer experienced lasting pain relief and improved quality of life.[15]

Recently,[when?] two randomized, controlled trials of MDMA-assisted psychotherapy for post-traumatic stress disorder were published. Although small, these trials are consistent with earlier results. The patients treated with two or three sessions of MDMA-psychotherapy showed greater improvement than the ones treated by placebo-psychotherapy[16] or placebo-inactive dose of MDMA.[17] This improvement was generally maintained on a follow-up several years later.[18]

Recreational use[edit]

Tablets containing MDMA

Small doses of MDMA are used as an entheogen to enhance prayer or meditation by some religious practitioners.[19]

MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and parties. In the rave environment, the sensorial effects from the music and setup such as lasers are often highly synergistic with the drug. The psychedelic amphetamine quality of MDMA lends it to variable reasons as to why it appeals to users in the "rave" setting. Some users enjoy the feeling of mass communion from the inhibition-depressing effects of the drug, while others use it as party fuel because of the drug's stimulatory effects.[20]

MDMA is occasionally known for being taken in conjunction with psychedelic drugs, such as LSD or psilocybin mushrooms, or even common drugs such as cannabis. 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, "hippy flipping" for MDMA with psilocybin mushrooms, or "kitty flipping" for MDMA with ketamine.[21] The term "flipping" may come from the subjective effects of using MDMA with a psychedelic in which the user may shift rapidly between a more lucid state and a more psychedelic state several times during the course of their experiences. Many users use mentholated products while taking MDMA for its cooling sensation while experiencing the drug's effects. Examples include menthol cigarettes, Vicks VapoRub, NyQuil,[22] and lozenges.

Subjective effects[edit]

The primary effects attributable to MDMA consumption are predictable and fairly consistent among users. In general, users begin reporting subjective effects within 30–60 minutes of consumption, hitting a peak at about 75–120 minutes, reaching a plateau that lasts about 3.5 hours.[23] This is followed by a comedown of a few hours. After the drug has run its course, many users report feeling fatigue.

The following subjective effects of MDMA were statistically significant in a placebo-controlled trial, using Altered States of Consciousness rating scale: derealization, depersonalization, altered perception of space and time, positive basic mood, mania-like experience, anxious derealization, thought disorder, fears of loss of thought or body control, visual hallucinations or pseudo-hallucinations, synesthesia, changed meaning of percepts, facilitated recollection or imagination. On an Adjective Mood rating scale, the following measurements were significantly increased: self-confidence, heightened mood, apprehension-anxiety, thoughtfulness-contemplativeness, extroversion, dazed state, sensitivity and emotional excitation.[23]

Adverse effects[edit]

In January 2001, an overview of the subjective side effects of MDMA was based on clinical research conducted over several years involving 74 healthy volunteers. The researchers found a number of common side effects, and many of the effects seemed to occur in different amounts based on the sex of the user. The top side effects reported were difficulty concentrating, jaw clenching/grinding of the teeth during sleep, lack of appetite, and dry mouth/thirst (all occurring in more than 50% of the 74 volunteers). They also measured some of the test subjects for blood pressure, heart rate, and body temperature against a placebo control, but no statistically significant changes were seen.[23][24]

A 2008 study found a slight but significant correlation of cognitive deficiency in MDMA users, but admitted these data may be confounded by other illicit drug use. The significant finding of the article was the serotonergic neurotoxicity in stacked doses and a lasting serotonin reuptake inhibition (SERT). At high doses and in high temperatures, in rats, serotonergic neurotoxicity is limited, but dopaminergic neurotoxicity occurs. However, rats may not be a generalizable model for human neurotoxicity studies.[25]

A 2010 study found EEG measured brain activity believed to confirm neurotoxicity to serotonergic neurotransmission systems, and noted that the recorded brain activity data were "in line with the observation of attentional and memory impairments in Ecstasy users with moderate to high misuse".[26]

However, a 2011 study found no signs of cognitive impairment due to MDMA use, nor a decrease in any mental ability. The report also raised concerns that previous methods used to conduct research on the drug chose subjects not consistent with the general population, such as previous substance abusers, and therefore not necessarily average cognitive function, and thereby overstated the cognitive differences between users and nonusers.[27]

Aftereffects[edit]

Effects reported by some users once the acute effects of MDMA have worn off include:

  • Psychological
    • Anxiety and paranoia
    • Depression[28][29][30][31]
    • Irritability[29]
    • Fatigue[30][31]
    • Impaired attention, focus, and concentration, as well as drive and motivation (due to depleted serotonin levels)[28]
    • Residual feelings of empathy, emotional sensitivity, and a sense of closeness to others (afterglow)
  • Physiological
    • Dizziness, lightheadedness, or vertigo[31]
    • Loss of appetite[28]
    • Gastrointestinal disturbances, such as diarrhea or constipation
    • Insomnia[28]
    • Aches and pains, usually from excessive physical activity (e.g., dancing)[28][30]
    • Exhaustion[29][31]
    • Jaw soreness, from bruxism[31][32][33]

A slang term given to the depressive period following MDMA consumption is Tuesday Blues (or "Suicide Tuesday"), referring to the low mood that can be experienced midweek by depleted serotonin levels following MDMA use on the previous Friday or Saturday when raves or dance concerts were frequently scheduled. Some users reported consuming 5-HTP, L-tryptophan and vitamins the day after use can reduce the depressive effect by replenishing serotonin levels (magnesium supplements are also used prior to or during use, in an attempt to prevent jaw/muscle clenching).[34]

Overdose[edit]

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

  • Psychological
    • Disorientation and/or confusion
    • Agitation,[35][36] restlessness[36] and paranoia[35]
    • Hallucinations[29][35][36] and/or delusions[37]
    • Thought disorder or disorganized thinking
    • Cognitive and memory impairment potentially to the point of retrograde or anterograde amnesia[38]
  • Physiological
    • Muscle rigidity[36]
    • Convulsions[35]
    • Hyperreflexia or overresponsive or overreactive reflexes[39]
    • Hyperactivity[35]
    • Hypertension[35][36] or hypotension[36]
    • Tachycardia[36]
    • Tachypnoea or rapid breathing and/or dyspnea or shortness of breath
    • Palpitations[36]
    • Angina pectoris or severe chest pain, as well as pulmonary hypertension (PH)[40]
    • Vasculitis or destruction of blood vessels[41]
    • Cardiotoxicity or damage to the heart[42]
    • Cardiac dysfunction, arrest, myocardial infarction, and/or heart failure[43][44][45]
    • Hemorrhage and/or stroke[46][47]
    • Severe hyperthermia, potentially resulting in organ failure[48][49]
    • Loss of consciousness[50]
    • Renal failure[36]
    • Coma[35] or death[50]

Chronic use[edit]

Some studies indicate repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug.[51][52][53] Other meta analyses have reported possibility of impairment of executive functioning.[54] Despite these findings, many factors, including total lifetime MDMA consumption, the duration of abstinence between uses, dosage, the environment of use, multiple drug use/abuse, quality of mental health, various lifestyle choices, and predispositions to develop clinical depression and other disorders, have made the results of many studies difficult to verify. A study that attempted to eliminate these confounding factors found few differences in the cognitive functioning of MDMA-using ravers versus non-MDMA-using ravers, "In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings-including our own-and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users."[55] MDMA use has been occasionally associated with liver damage,[56] excessive wear of teeth,[57] and (very rarely) hallucinogen persisting perception disorder.[58]

Comparison of physical harm and dependence regarding various drugs.[59]
Relative physical harm and dependence of ecstasy (the British medical journal The Lancet)[60]

Short-term health concerns[edit]

Short-term physical health risks of MDMA consumption include hyperthermia,[61][62] and hyponatremia.[63] 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.[citation needed]

Long-term effects on serotonin and dopamine[edit]

MDMA causes a reduction in the reuptake concentration of serotonin transporters in the brain. The rate at which the brain recovers from serotonergic changes is unclear. One study demonstrated lasting serotonergic changes in some animals exposed to MDMA.[64] Other studies have suggested that the brain may recover from serotonergic damage.[65][66]

Some studies show MDMA may be neurotoxic in humans.[67][68] Other studies, however, suggest that any potential brain damage may be at least partially reversible following prolonged abstinence from MDMA.[66][69] Depression and deficits in memory have been shown to occur more frequently in long-term MDMA users.[70][71] However, some recent studies have suggested MDMA use may not be associated with chronic depression.[72][73]

One study on MDMA toxicity, by George A. Ricaurte of Johns Hopkins School of Medicine, which claimed 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.[74] Ricaurte blamed this mistake on a labeling error by the chemical supply company that sold the material to his lab, but the supply company responded there was no evidence of a labeling error on their end. Most studies have found the levels of the dopamine transporter (or other markers of dopamine function) in MDMA users deserve further study or are normal.[75][76][77][78][79][80][81]

Several studies have indicated a possible mechanism for neurotoxicity of a metabolite of MDMA, through the reaction of alpha-methyldopamine, a principal metabolite, and glutathione, the major antioxidant in the human body. One possible product of this reaction, 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine, has been demonstrated to produce the same toxic effects observed in MDMA, while MDMA, and alpha-methyldopamine themselves have been shown to be non-neurotoxic. It is, however, impossible to avoid the metabolism of MDMA in the body, and the production of this toxic metabolite.[82][83][84] Some studies have demonstrated possible ways to minimize the production of this particular metabolite, though evidence at this point is sparse at best.

Purity and dosage of "ecstasy"[edit]

MDMA powder

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, mephedrone, methamphetamine, ephedrine, caffeine, all of which may be comparatively cheap to produce and can help to boost overall profits. In some cases, tablets sold as ecstasy do not even contain any MDMA. Instead they may contain an assortment of undesirable drugs and substances, such as paracetamol, ibuprofen, talcum powder, etc.[85]

A number of deaths have been attributed to para-methoxyamphetamine (PMA), a hallucinogenic amphetamine, being sold as ecstasy.[86][87] PMA is unique in its ability to quickly elevate body temperature and heart rate at relatively low doses, especially in comparison to MDMA. Hence, users believing they are 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 it also acts as a monoamine oxidase inhibitor. When combined with an MDMA or an MDMA-like substance, serotonin syndrome can result.[88] Combining MAO inhibitors with certain legal prescription and over-the-counter medications can also lead to (potentially fatal) serotonin syndrome.

Harm assessment[edit]

The UK 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. They did not evaluate or rate the negative impact of 'ecstasy' on the cognitive health of ecstasy users, e.g., impaired memory and concentration. Based on these factors, the study placed MDMA at number 18 in the list of 20 harmful drugs.[89]

David Nutt, a former chairman of the UK Advisory Council on the Misuse of Drugs, stated in the Journal of Psychopharmacology in January 2009, that 'ecstasy' use compared favorably with horse riding in terms of risk, with the drug leading to around 30 deaths a year in the UK compared to about 10 from horse riding, and "acute harm to person" occurring in about one in 10,000 episodes of 'ecstasy' use compared to about one in 350 episodes of horse riding.[90] Dr. Nutt noted the lack of a balanced risk assessment in public discussions of MDMA:[90]

The general public, especially the younger generation, are disillusioned with the lack of balanced political debate about drugs. This lack of rational debate can undermine the trust in government in relation to drug misuse and thereby undermining the government's message in public information campaigns. The media in general seem to have an interest in scare stories about illicit drugs, though there are some exceptions (Horizon, 2008).[91] A telling review of 10-year media reporting of drug deaths in Scotland illustrates the distorted media perspective very well (Forsyth, 2001).[92] During this decade, the likelihood of a newspaper reporting a death from paracetamol was in [sic] per 250 deaths, for diazepam it was 1 in 50, whereas for amphetamine it was 1 in 3 and for ecstasy every associated death was reported.

A spokesperson for the ACMD said, "The recent article by Professor David Nutt published in the Journal of Psychopharmacology was done in respect of his academic work and not as chair of the ACMD."[93]

The most carefully designed study so far,[55] compared the effect on cognitive skills in 52 'ecstasy' users against 59 very closely matched nonusers. The study eliminated potential confounding factors such as the use of other drugs and history of drug use. The study found no short- or long-term differences in cognitive skills in the test group (users) versus the control group (nonusers).

Drug interactions[edit]

A number of reported potentially dangerous possible interactions occur between MDMA and other drugs, including serotonergic drugs.[94] Several cases have been reported of death in individuals who ingested MDMA while taking ritonavir (Norvir), which inhibits multiple CYP450 enzymes. Toxicity or death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors, such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).[95] Conversely, MAOB inhibitors such as selegiline (Deprenyl; Eldepryl, Zelapar, Emsam) do not seem to carry these risks when taken at selective doses, and have been used to completely block neurotoxicity in rats.[96]

Sassafras oil[edit]

Commercial sassafras oil generally is a byproduct of camphor production in Asia or comes from related trees in Brazil. Safrole is a precursor for the clandestine manufacture of MDMA, and as such, its transport is monitored internationally. Roots of Sassafras can also be steeped to make tea and were used in the flavoring of traditional root beer until being banned for mass production by the FDA. Laboratory animals that were given oral doses of sassafras tea or sassafras oil that contained large doses of safrole developed permanent liver damage or various types of cancer. In humans, liver damage can take years to develop, and it may not have obvious signs.[citation needed] While sassafras oil is an important ingredient in clandestine manufacture of MDMA, MDMA itself does not contain any sassafras oil.

Chemistry[edit]

Reactors used to synthesize MDMA on an industrial scale in a chemical factory in Cikande, Indonesia.

Safrole, a colorless or slightly yellow oily liquid, extracted from the root-bark or the fruit of the sassafras tree 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.[97][98][99][100] One common route is via the MDP2P (3,4-methylenedioxyphenyl-2-propanone, also known as piperonyl acetone) intermediate, which can be produced in at least two different ways. One method is to isomerize safrole to isosafrole in the presence of a strong base, and then oxidize isosafrole to MDP2P. Another, reportedly better,[citation needed] method is to make use of the Wacker process to oxidize safrole directly to the MDP2P (3,4-methylenedioxy phenyl-2-propanone) intermediate. This can be done with a palladium catalyst. Once the MDP2P intermediate has been prepared, a reductive amination leads to MDMA, a racemate {1:1 mixture of (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine and (S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine}. Another method for the synthesis of racemic MDMA is addition of hydrogen bromide to safrole and reaction of the adduct with methylamine. Safrole is not required for MDMA production, and other precursor chemicals are often used instead, for example piperonal.

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Relatively small quantities of essential oil are required to make large amounts of MDMA. The essential oil of Ocotea cymbarum typically contains between 80 and 94% safrole. This would allow 500 ml of the oil, which retails at between $20 and $100, to be used to produce between 150 and 340 grams of MDMA.[101]

Pharmacology[edit]

MDMA acts as a releasing agent of serotonin, norepinephrine, and dopamine.[102] It enters neurons via carriage by the monoamine transporters.[102] Once inside, MDMA inhibits the vesicular monoamine transporter, which results in increased concentrations of serotonin, norepinephrine, and dopamine in the cytoplasm,[103] and induces their release by reversing their respective transporters through a process known as phosphorylation.[104]

MDMA has been identified as a potent agonist of TAAR1, a newly discovered GPCR important for regulation of monoaminergic systems in the brain.[105] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits transporter function.[105][106][107][108][109] These effects increase monoamine efflux and prolong the amount of time monoamines remain in the synapse. It also acts as a weak 5-HT1 and 5-HT2 receptor agonist, and its more efficacious metabolite MDA likely augments this action.[110][111][112][113]

MDMA's unusual entactogenic effects have been hypothesized to be, at least partly, the result of indirect oxytocin secretion via activation of the serotonin system.[114] Oxytocin is a hormone released following events such as hugging, orgasm, and childbirth, and is thought to facilitate bonding and the establishment of trust.[115] Based on studies in rats, MDMA is believed to cause the release of oxytocin, at least in part, by both directly and indirectly agonizing the serotonin 5-HT1A receptor. A placebo-controlled study in 15 human volunteers found 100 mg MDMA increased blood levels of oxytocin, and the amount of oxytocin increase was correlated with the subjective prosocial effects of MDMA.[116]

Three neurobiological mechanisms for the therapeutic effects of MDMA have been suggested: "1) MDMA increases oxytocin levels, which may strengthen the therapeutic alliance; 2) MDMA increases ventromedial prefrontal activity and decreases amygdala activity, which may improve emotional regulation and decrease avoidance, and 3) MDMA increases norepinephrine (NE) release and circulating cortisol levels, which may facilitate emotional engagement and enhance extinction of learned fear associations."[117]

Pharmacokinetics[edit]

Tan MDMA crystals

MDMA reaches maximal concentrations in the blood stream between 1.5 and 3 hr after ingestion.[118] It is then slowly metabolized and excreted, with levels of MDMA and its metabolites decreasing to half their peak concentration over approximately 8 hours.[119] Thus, there are still high MDMA levels in the body when the experiential effects have mostly ended, indicating acute tolerance has developed to the actions of MDMA. Taking additional supplements of MDMA at this point, therefore, produces higher concentrations of MDMA in the blood and brain than might be expected based on the perceived effects.

Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-dihydroxyamphetamine (DHA) (also called alpha-methyldopamine (α-Me-DA)), 3,4-methylenedioxyphenylacetone (MDP2P), and 3,4-Methylenedioxy-N-hydroxyamphetamine (MDOH). The contributions of these metabolites to the psychoactive and toxic effects of MDMA are an area of active research. Sixty-five percent of MDMA is excreted unchanged in the urine (in addition, 7% is metabolized into MDA) during the 24 hours after ingestion.[120]

MDMA is known to be metabolized by two main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The metabolism may be primarily by cytochrome P450 (CYP450) enzymes (CYP2D6 (in humans, but CYP2D1 in mice), and CYP3A4) and COMT. Complex, nonlinear pharmacokinetics arise via autoinhibition of CYP2D6 and CYP2D8, resulting in zeroth order kinetics at higher doses. It is thought that this can result in sustained and higher concentrations of MDMA if the user takes consecutive doses of the drug.

Because the enzyme CYP2D6 is deficient or totally absent in some people,[121] it was once hypothesized that these people might have elevated risk when taking MDMA. However, there is still no evidence for this theory and available evidence argues against it.[122] It is now thought that the contribution of CYP2D6 to MDMA metabolism in humans is less than 30% of the metabolism. Indeed, an individual lacking CYP2D6 was given MDMA in a controlled clinical setting and a larger study gave MDMA to healthy volunteers after inhibiting CYP2D6 with paroxetine. Lack of the enzyme caused a modest increase in drug exposure and decreases in some metabolites, but physical effects did not appear appreciably elevated. While there is little or no evidence that low CYP2D6 activity increases risks from MDMA, it is likely that MDMA-induced CYP2D inhibition will increase risk of those prescription drugs that are metabolized by this enzyme. MDMA-induced CYP2D inhibition appears to last for up to a week after MDMA exposure.

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[123]

The (R)/(-)-enantiomer (top) and the (S)/(+)-enantiomer of MDMA

MDMA is a chiral compound and has been almost exclusively administered as a racemate. However, the two enantiomers have been shown to exhibit different kinetics. (S)-MDMA is more effective in eliciting 5-HT, NE, and DA release, while (D)-MDMA is overall less effective, and more selective for 5-HT and NE release (having only a very faint efficacy on DA release).[124] The disposition of MDMA may also be stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. Evidence suggests[125] that the area under the blood plasma concentration versus time curve (AUC) was two to four times higher for the (R)-enantiomer than the (S)-enantiomer after a 40 mg oral dose in human volunteers. Likewise, the plasma half-life of (R)-MDMA was significantly longer than that of the (S)-enantiomer (5.8 ± 2.2 hours vs 3.6 ± 0.9 hours). However, because MDMA excretion and metabolism have nonlinear kinetics,[126] the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose[118]). Given as the racemate MDMA has a half-life of around 8 hours.

Detection of use[edit]

MDMA and MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDMA or its major metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10% those of the parent drug.[127][128][129]

History[edit]

MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch. At the time, Merck was interested in developing substances that stopped abnormal bleeding. Merck wanted to evade an existing patent, held by Bayer, for one such compound: hydrastinine. At the behest of his superiors Walther Beckh and Otto Wolfes, Köllisch developed a preparation of a hydrastinine analogue, methylhydrastinine. MDMA was an intermediate compound in the synthesis of methylhydrastinine, and Merck was not interested in its properties at the time.[130] On 24 December 1912, Merck filed two patent applications that described the synthesis of MDMA[131] and its subsequent conversion to methylhydrastinine.[132]

Merck records indicate that its researchers returned to the compound sporadically. In 1927, Max Oberlin studied the pharmacology of MDMA and observed that its effects on blood sugar and smooth muscles were similar to ephedrine's. Researchers at Merck conducted experiments with MDMA in 1952 and 1959.[130] In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals of injected mescaline and several analogues, including MDMA. The Army experimented with MDMA as an interrogation tool in Project MKUltra.[133] These originally classified investigations were declassified and published in 1973.[134] MDMA was being used recreationally in the United States by 1970.[135] In the mid-1970s, Alexander Shulgin, then at University of California, Berkeley, heard from his students about unusual effects of MDMA; among others, the drug had helped one of them to overcome his stutter. Intrigued, Shulgin synthesized MDMA and tried it himself in 1976.[136] Two years later, he and David E. Nichols published the first report on the drug's psychotropic effect in humans. They described "altered state of consciousness with emotional and sensual overtones" that can be compared "to marijuana, and to psilocybin devoid of the hallucinatory component".[137]

Shulgin took to occasionally using MDMA for relaxation, referring to it as "my low-calorie martini", and giving the drug to his friends, researchers, and other people whom he thought could benefit from it. One such person was psychotherapist Leo Zeff, who had been known to use psychedelics in his practice. Zeff was so impressed with the effects of MDMA that he came out of his semi-retirement to proselytize for it. Over the following years, Zeff traveled around the U.S. and occasionally to Europe, training other psychotherapists in the use of MDMA.[136][138][139] Among underground psychotherapists, MDMA developed a reputation for enhancing communication during clinical sessions, reducing patients' psychological defenses, and increasing capacity for therapeutic introspection.[140]

In the early 1980s in the U.S., MDMA rose to prominence as "Adam" in trendy nightclubs and gay dance clubs in the Dallas area.[141] From there, use spread to raves in major cities around the country,[citation needed] and then to mainstream society. "Ecstasy" was recognized as slang for MDMA as early as June 1982.[142] The drug was first proposed for scheduling by the Drug Enforcement Administration (DEA) in July 1984[143] and was classified as a Schedule I controlled substance in the U.S. on 31 May 1985.[144]

In the late 1980s, MDMA began to be widely used in the UK and other parts of Europe, becoming an integral element of rave culture and other psychedelic-influenced music scenes. Spreading along with rave culture, illicit MDMA use became increasingly widespread among young adults in universities and later in high schools. MDMA became one of the four most widely used illicit drugs in the U.S., along with cocaine, heroin, and cannabis.[145] According to some estimates as of 2004, only marijuana attracts more first time users in the U.S.[145]

After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent legally approved MDMA studies in humans have taken place in the U.S. in Detroit (Wayne State University), Chicago (University of Chicago), San Francisco (UCSF and California Pacific Medical Center), Baltimore (NIDA–NIH Intramural Program), and South Carolina, as well as in Switzerland (University Hospital of Psychiatry, Zürich), the Netherlands (Maastricht University), and Spain (Universitat Autònoma de Barcelona).[146]

In 2010, the BBC reported that use of MDMA had decreased in the UK in previous years. This is thought to be due to increased seizures and decreased production of the precursor chemicals used to manufacture MDMA. Unwitting substitution with other drugs, such as mephedrone and methamphetamine,[147] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.[148]

Legal status[edit]

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 and limited medical use. In general, the unlicensed use, sale or manufacture of MDMA are all criminal offenses.

United Kingdom[edit]

MDMA was made illegal in 1977 by a modification order to the existing Misuse of Drugs Act 1971. Although MDMA was not named explicitly in this legislation, the order extended the definition of Class A drugs to include various ring-substituted phenethylamines,[149] thereby making it illegal to sell, buy, or possess the drug without a licence. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking. See list of drugs illegal in the UK for more information. In February 2009 an official independent scientific advisory board to the UK government recommended that MDMA be re-classified to Class B, but this recommendation was immediately rejected by the government. This 2009 report on MDMA stated:[150]

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

In 2000, the UK Police Foundation issued the Runciman Report, which reviewed the medical and social harms of MDMA and recommended: "Ecstasy and related compounds should be transferred from Class A to Class B."[151] In 2002, the Home Affairs Committee of the UK House of Commons, issued a report, The Government's Drugs Policy: Is it working?, which also recommended that MDMA should be reclassified to a Class B drug.[152] The UK government rejected both recommendations, saying that re-classification of MDMA would not be considered without a recommendation from the Advisory Council on the Misuse of Drugs, the official UK scientific advisory board on drug abuse issues.[153]

In February 2009, the UK Advisory Council on the Misuse of Drugs issued A review of MDMA ('ecstasy'), its harms and classification under the Misuse of Drugs Act 1971, which recommended that MDMA be re-classified in the UK from a class A drug to a class B drug.[150]

From the Discussion section of the ACMD report on MDMA:

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

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

The UK Home Office rejected the recommendation of its independent scientific advisory board to downgrade MDMA to Class B, "saying it is not prepared to send a message to young people that it takes ecstasy less seriously".[154][155]

The government's veto was criticized in scientific publications. Colin Blakemore, Professor of Neuroscience, Oxford, stated in the British Medical Journal, "The government's decisions compromise its commitment to evidence based policy".[156] Also in response, an editorial in the New Scientist noted "A much larger percentage of people suffer a fatal acute reaction to peanuts than to MDMA.... Sadly, perspective is something that is generally lacking in the long and tortuous debate over illegal drugs."[157]

United States[edit]

In the U.S., MDMA was legal and unregulated until 31 May 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 Administrative Law Judge (ALJ) overseeing the hearings, Francis Young, also recommended that MDMA be placed in Schedule III. The DEA however classified MDMA as Schedule I.[158][159] However, in Grinspoon v. Drug Enforcement Administration, 828 F.2d 881 (1st Cir. 1987), the First Circuit Court of Appeals remanded the scheduling determination for reconsideration by the DEA.[160] MDMA was temporarily removed from Schedule I.[161] Ultimately, in 1988, the DEA re-evaluated its position on remand and subsequently placed MDMA into Schedule I of the Controlled Substances Act.[162]

In a 2011 federal court hearing the American Civil Liberties Union successfully argued that the sentencing guideline for MDMA/ecstasy is based on outdated science, leading to excessive prison sentences.[163]

Netherlands[edit]

The Expert Committee on the List (Expertcommissie Lijstensystematiek Opiumwet) of the Netherlands issued a report in June 2011 which discussed the evidence for harm and the legal status of MDMA.[164] From the English-language summary:[165]

As regards MDMA, better known as XTC, the committee concludes that investigations show that damage to the health of the individual in the long term is less serious than was initially assumed. But the extent of the illegal production and involvement of organised crime leads to damage to society, including damage to the image of the Netherlands abroad. This argues in favour of maintaining MDMA on List I.

The Committee noted that research had found the health risks of MDMA were less serious than previously assumed (citing the 2009 UK ACMD report), and so they considered moving MDMA out of the Dutch List I ('hard drugs') to List II ('soft drugs' such as cannabis), but this was not acceptable because the criminal black market would continue to produce all the MDMA. Note, the Committee did not discuss permitting legally regulated production of MDMA for non-medical use because this is not allowed under the UN 1971 Convention on Psychotropic Substances (See Drug decriminalization vs. legalization).

Canada[edit]

Listed as a Schedule 1 [166] as it is an analogue of amphetamine.[167] The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule 3 to Schedule 1.[168]

World Health Organization[edit]

In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 Convention on Psychotropic Substances, despite noting:[169]

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

The decision to recommend scheduling of MDMA was not unanimous:[169]

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

The 1971 Convention has a provision in Article 7(a) that allows use of Schedule I drugs for "scientific and very limited medical purposes." The committee's report stated:[169][170]

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.

Environmental concerns[edit]

Demand for safrole, a substance used in the manufacture of MDMA, is causing rapid and illicit harvesting of the Cinnamomum parthenoxylon tree in Southeast Asia, in particular the Cardamom Mountains in Cambodia.[171] Demand for safrole, mostly for industrial use but also for MDMA production, depletes around 500,000 trees per year in China, Brazil, Cambodia, Vietnam, and Laos.[172][better source needed] In 2008 alone, Australian and Cambodian authorities blocked and destroyed the export of 33 tons of safrole, capable of producing 245 million ecstasy tablets with a street value of 7.6 billion dollars.[173] Only a small proportion of illicitly harvested safrole is going toward MDMA production, as over 90% of the global safrole supply (approx 2000 metric tons per year) is used to manufacture pesticides, fragrances, and other chemicals.[173][174] Sustainable harvesting of safrole is possible from leaves and sticks of certain plants.[173][174] Safrole is not required for MDMA production, and other precursor chemicals are often used instead.

Cost and distribution[edit]

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.[175] The United Nations Office on Drugs and Crime claimed in its 2008 World Drug Report that typical U.S. retail prices are US$20 to $25 per tablet, or from $3 to $10 per tablet if bought in batches.[176]

Australia[edit]

MDMA is expensive in Australia, costing A$20–A$50 per tablet. In terms of purity data for Australian MDMA, the average is around 34%, ranging from less than 1% to about 85%. The majority of tablets contain 70–85 mg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the U.S.[177]

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Further reading[edit]

  • Julie Holland – "Ecstasy: The Complete Guide: A Comprehensive Look at the Risks and Benefits of MDMA" Park Street Press (2001).
  • Jerome Beck, Marsha Rosenbaum – "Pursuit of Ecstasy: The MDMA Experience" SUNY Press (1994).
  • Leslie Iversen – "Speed, Ecstasy, Ritalin: The Science of Amphetamines" Oxford University Press (2008).
  • David Pearce – "Utopian Pharmacology: Mental Health in the Third Millenium: MDMA and Beyond" (2008).
  • Earth Erowid – "Do Antioxidants Protect Against MDMA Hangover, Tolerance, and Neurotoxicity?" Erowid Extracts (2001).
  • Marsha Rosenbaum, Rick Doblin – "Why MDMA Should Not Have Been Made Illegal" SAGE Publications (1991).
  • Nature News – "Ecstasy Could Augment the Benefits of Psychotherapy" (2008).
  • Nature News – "Party drug could ease trauma long term" (2010).
  • Reuters Health – "Ecstasy May Help PTSD Victims Get Better" (2009).
  • The Economist – "Agony and Ecstasy: Ecstasy May Be Good For Those Who Can’t Get Over Something Truly Horrible" (2008).
  • New Scientist – "Ecstasy's Long-Term Effects Revealed" (2009).
  • Matt Palmquist Miller-McCune – "The Ecstasy and the Agony" (August 2009).
  • ACMD – "MDMA (Ecstasy): A Review of its Harms and Classification Under the Misuse of Drugs Act 1971" UK Home Office (2009).
  • NIDA InfoFacts – "MDMA (Ecstasy)" (August 2008).

External links[edit]

  • Alexander Shulgin & Ann Shulgin – PiHKAL: "No. 109 MDMA: MDM; ADAM; Ecstasy; 3,4-Methylenedioxy-N-methylamphetamine" (1991).
  • ABC News – "Primetime Special: Peter Jennings – Ecstasy Rising" (2004).
  • The Vaults of Erowid: "MDMA ("Ecstasy")".
  • Erowid Experience Vaults: "MDMA ("Ecstasy", "E", "X") Reports".
  • DanceSafe: ": What is Ecstasy?".
  • MAPS: "R&D Medicines > MDMA".
  • EcstasyData.org: Providing Access to Lab Testing Results for Street Ecstasy Tablets.
  • PillReports.com: Ecstasy Test Results Database by Enlighten.
  • Fifteen Minutes: E is for Ecstasy
  • Jessica Winter, "Can a Single Pill Change Your Life?" O Magazine, 15 February 2011



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出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2015/06/29 23:35:20」(JST)

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Not to be confused with other meanings of the word Ecstasy.
MDMA
Systematic (IUPAC) name
(RS)-1-(Benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine
Clinical data
AHFS/Drugs.com entry
Legal status
  • <abbr title="Australia">AU</abbr>: Prohibited (S9)
  • <abbr title="Canada">CA</abbr>: Schedule I
  • <abbr title="New Zealand">NZ</abbr>: Class B
  • <abbr title="United Kingdom">UK</abbr>: Class A
  • <abbr title="United States">US</abbr>: Schedule I
  • <abbr title="United Nations">UN</abbr>: Psychotropic Schedule I
Dependence
liability
Physical: none
Psychological: moderate[2]
Addiction
liability
Moderate[1]
Routes of
administration
Common: oral
Uncommon: sublingual, insufflation, inhalation (vaporization), injection,[3] rectal
Pharmacokinetic data
Metabolism Hepatic, CYP450 extensively involved, including CYP2D6
Metabolites MDA, HMMA, HMA, DHA, MDP2P, MDOH[4]
Onset of action 30–45 minutes (oral)[5]
Biological half-life (R)-MDMA: 5.8 ± 2.2 hours[6]
(S)-MDMA: 3.6 ± 0.9 hours[6]
Duration of action 4–6 hours[5]
Excretion Renal
Identifiers
CAS Registry Number 42542-10-9 Y[TOXNET]
ATC code None
PubChem CID: 1615
IUPHAR/BPS 4574
DrugBank DB01454 Y
ChemSpider 1556 Y
UNII KE1SEN21RM Y
KEGG C07577 Y
ChEBI CHEBI:1391 Y
ChEMBL CHEMBL43048 Y
Synonyms <abbr title="3,4-Methylenedioxymethamphetamine">3,4-MDMA</abbr>, Ecstasy, Molly
PDB ligand ID B41 (PDBe, RCSB PDB)
Chemical data
Formula C11H15NO2
Molecular mass 193.25 g·mol−1
Physical data
Boiling point 105 °C (221 °F) at 0.4 mmHg (experimental)
 Y (what is this?)  (verify)

MDMA (contracted from 3,4-methylenedioxy-methamphetamine) is a psychoactive drug of the substituted methylenedioxyphenethylamine and substituted amphetamine classes of drugs that is consumed primarily for its euphoric and empathogenic effects. Pharmacologically, MDMA acts as a serotonin-norepinephrine-dopamine releasing agent and reuptake inhibitor.

MDMA has become widely known as "ecstasy" (shortened to "E", "X", or "XTC"), usually referring to its tablet street form, although this term may also include the presence of possible adulterants. The UK term "Mandy" and the US term "Molly" colloquially refer to MDMA in a crystalline powder form that is relatively free of adulterants.[7][8] "Molly" can sometimes also refer to the related drugs methylone, MDPV, mephedrone or any other of the pharmacological group of compounds commonly known as bath salts.[14]

Possession of MDMA is illegal in most countries. Some limited exceptions exist for scientific and medical research. In 2013 between 9 and 28 million people used used ecstasy recreationally (0.2% to 0.6% of the global population between the ages of 15 and 65).[15] This was broadly similar to the number for cocaine, substituted amphetamine, and opioids, but fewer than the number of cannabis users.[16] It is taken in a variety of contexts far removed from its roots in psychotherapeutic settings, and is commonly associated with dance parties (or "raves") and electronic dance music.[17]

MDMA may have some limited health benefits in certain mental disorders, but has potential adverse effects, such as neurotoxicity and cognitive impairment.[18][19] More research is needed in order to determine if its potential usefulness in posttraumatic stress disorder (PTSD) treatment outweighs the risk of persistent neuropsychological harm to a patient.[18][19]

Contents

  • 1 Uses
    • 1.1 Medical
    • 1.2 Recreational
      • 1.2.1 Recreational effects
    • 1.3 Available forms
  • 2 Adverse effects
    • 2.1 Immediate effects
    • 2.2 After-effects
    • 2.3 Long-term effects
    • 2.4 Dependence and withdrawal
    • 2.5 Overdose
    • 2.6 Chronic use and addiction
  • 3 Interactions
  • 4 Pharmacology
    • 4.1 Pharmacodynamics
    • 4.2 Pharmacokinetics
  • 5 Physical and chemical properties
    • 5.1 Synthesis
      • 5.1.1 Yield
    • 5.2 Detection in body fluids
  • 6 History
    • 6.1 Early research
    • 6.2 Shulgin's research
    • 6.3 Rising use
    • 6.4 Scheduling
    • 6.5 Post-scheduling
  • 7 Society and culture
    • 7.1 Legal status
    • 7.2 Economics
      • 7.2.1 Europe
      • 7.2.2 North America
      • 7.2.3 Australia
    • 7.3 Controversy
      • 7.3.1 Harm assessment
  • 8 Research
  • 9 References
  • 10 External links

Uses

Medical

See also: MDMA § Research

MDMA currently has no accepted medical uses.[16][20]

Recreational

Ecstasy is commonly consumed at raves. Above, a rave in Austria in 2005.

MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and house parties.[21] In the rave environment, the sensory effects from the music and lighting are often highly synergistic with the drug. The psychedelic amphetamine quality of MDMA offers multiple reasons for its appeals to users in the "rave" setting. Some users enjoy the feeling of mass communion from the inhibition-reducing effects of the drug, while others use it as party fuel because of the drug's stimulatory effects.[22]

MDMA is occasionally known for being taken in conjunction with psychedelic drugs the more common combinations include MDMA combined with LSD, MDMA with psilocybin mushrooms, and MDMA with ketamine. Many users use mentholated products while taking MDMA for its cooling sensation while experiencing the drug's effects. Examples include menthol cigarettes, Vicks VapoRub, NyQuil,[23] and lozenges.

Recreational effects

In general, MDMA users begin reporting subjective effects within 30 to 60 minutes of consumption, hitting a peak at about 75 to 120 minutes which plateaus for about 3.5 hours.[24]

The desired short-term psychoactive effects of MDMA include:

  • Euphoria – a sense of general well-being and happiness[18][25]
  • Increased sociability and feelings of communication being easy or simple[18][25]
  • Entactogenic effects – increased empathy or feelings of closeness with others[18][25]
  • A sense of inner peace[25]
  • Mild hallucination (e.g., colors and sounds are enhanced and mild closed-eye visuals)[25]
  • Enhanced sensation, perception, or sexuality[18][25]

Available forms

The average ecstasy tablet contains 60–70 mg (base equivalent) of MDMA, usually as the hydrochloride salt.[20] Powdered MDMA is typically 30–40% pure, due to bulking agents (e.g., lactose) and binding agents.[20] Tablets sold as ecstasy sometimes only contain 3,4-methylenedioxyamphetamine (MDA) instead of MDMA;[6][20] the proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.[20]

Ecstasy tablets which allegedly contain MDMA, but may contain adulterants
A salt of MDMA (typically white) with impurities, resulting in a tan discoloration

Adverse effects

Immediate effects

Bruxism can be a side effect of MDMA prompting some users to suck on pacifiers to avoid teeth grinding.

The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.[25][26] Cases of life-threatening or fatal hyponatremia (excessively low sodium concentration in the blood) have developed in MDMA users attempting to prevent dehydration by consuming excessive amounts of water without replenishing electrolytes.[25][26][27] Even without excessive water intake, MDMA can increase water retention through syndrome of inappropriate antidiuretic hormone secretion,[28] so that water intake must be restricted (unless heavy sweating occurs).[29][non-primary source needed] The resultant hypervolumia can simultaneously cause both dilutional hyponatremia (which can cause seizures) and hypertension (which can cause stroke). In the case of excessive water intake, salt can be administered to increase osmotic pressure, but while this improves hyponatremia it can also further worsen hypertension. Both are associated with a sensation of intracranial pressure, either in the brain's arteries as in hypertension, or in the brain's tissues as in hyponatremia.[medical citation needed]

The immediate adverse effects of MDMA use can include:

  • Dehydration[21][25][26]
  • Hyperthermia[21][25][26]
  • Bruxism (grinding and clenching of the teeth)[18][21][25]
  • Increased wakefulness or insomnia[25]
  • Increased perspiration and sweating[25][26]
  • Increased heart rate and blood pressure[21][25][26]
  • Loss of appetite[6]
  • Nausea and vomiting[18]
  • Diarrhea[25]
  • Erectile dysfunction[30]
  • Mydriasis[31]

After-effects

The effects that last up to a week[18][32] following cessation of moderate MDMA use include:

Physical</dt>

  • Trismus[18]
  • Loss of appetite[32]
  • Insomnia[32]

Psychological</dt>

  • Anxiety or paranoia[32]
  • Depression[18][32]
  • Irritability[32]
  • Impulsiveness[32]
  • Restlessness[32]
  • Memory impairment[18]
  • Anhedonia[32]

Long-term effects

MDMA use has been shown to produce brain lesions, a form of brain damage, in the serotonergic neural pathways of humans and other animals.[1][6] In addition, long-term exposure to MDMA in humans has been shown to produce marked neurotoxicity in serotonergic axon terminals.[21][25][33] Neurotoxic damage to axon terminals has been shown to persist for more than two years.[33] Brain temperature during MDMA use is positively correlated with MDMA-induced neurotoxicity in animals.[21] Adverse neuroplastic changes to brain microvasculature and white matter also seem to occur in humans using low doses of MDMA.[21] Reduced gray matter density in certain brain structures has also been noted in human MDMA users.[21] In addition, MDMA has immunosuppressive effects in the peripheral nervous system, but pro-inflammatory effects in the central nervous system.[34] Babies of mothers who used MDMA during pregnancy exhibit impaired motor function at 4 months of age, which may reflect either a delay in development or a persistent neurological deficit.[19][35]

MDMA also produces persistent cognitive impairments in human users.[2][18][19] Impairments in multiple aspects of cognition, including memory, visual processing, and sleep have been noted in humans;[18][19] the magnitude of these impairments is correlated with lifetime ecstasy or MDMA usage.[2][18][19] Memory is significantly impacted by ecstasy use, which is associated with marked impairments in all forms of memory (e.g., long-term, short-term, working).[18][19]

Dependence and withdrawal

Some studies indicate repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug.[36][37][38] Other meta analyses have reported possibility of impairment of executive functioning.[39] Approximately 60% of MDMA users experience withdrawal symptoms, including, but not limited to: fatigue, loss of appetite, depression, and trouble concentrating.[6] Tolerance is expected to occur with consistent MDMA use.[6]

Overdose

Overdose symptoms vary widely with MDMA; they can include:

Symptoms of overdose
System Minor or moderate overdose[31] Severe overdose[31]
Cardiovascular
  • Disseminated intravascular coagulation[25]
  • Intracranial hemorrhage[25]
  • Severe hypertension[25][40] or hypotension[25]
Central nervous
system
  • Abnormally fast reflexes[41]
  • Agitation[25][40]
  • Mental confusion[25]
  • Paranoia[25][40]
  • Stimulant psychosis[21]
  • Cognitive and memory impairment[25] potentially to the point of retrograde or anterograde amnesia[42]
  • Coma[21][40]
  • Convulsions[25][40]
  • Hallucinations[25][40]
  • Loss of consciousness[21]
  • Serotonin syndrome[21][25][27]
Musculoskeletal
  • Muscle rigidity[25]
  • Rhabdomyolysis (i.e., rapid muscle breakdown)[25][27]
Respiratory
  • Acute respiratory distress syndrome[25]
Urinary
  • Renal failure[25]
Other
  • Cerebral edema[21]
  • Hepatitis[25][27]
  • Hyperpyrexia (a life-threatening elevation of body temperature)[25][27]
  • Hyponatremia (Syndrome of inappropriate antidiuretic hormone)[25][26][27]

Chronic use and addiction

See also: ΔFosB

MDMA has been shown to induce ΔFosB in the nucleus accumbens.[43] Since MDMA releases dopamine in the mesocorticolimbic projection, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other psychostimulants.[43][44] Therefore, chronic use of MDMA at high doses can result in altered brain structure and drug addiction, which occur as a consequence of ΔFosB overexpression in the nucleus accumbens.[44]

Interactions

A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.[6][45] MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors.[6] Concurrent use of MDMA with another serotonergic drug can result in a life-threatening condition called serotonin syndrome.[6] Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors,[6] such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).[46]

Pharmacology

Pharmacodynamics

MDMA acts primarily as a presynaptic releasing agent of serotonin, norepinephrine, and dopamine, which arises from its activity at trace amine-associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (VMAT2).[6][47][48] MDMA is a monoamine transporter substrate (i.e., a substrate for DAT, NET, and SERT), so it enters monoamine neurons via these neuronal membrane transport proteins;[47] by acting as a monoamine transporter substrate, MDMA produces competitive reuptake inhibition at the neuronal membrane transporters (i.e., it competes with endogenous monoamines for reuptake).[47][49] MDMA inhibits both vesicular monoamine transporters (VMATs), the second of which (VMAT2) is highly expressed within monoamine neurons at vesicular membranes.[48] Once inside a monoamine neuron, MDMA acts as a VMAT2 inhibitor and a TAAR1 agonist.[47][48] Inhibition of VMAT2 by MDMA results in increased concentrations of the associated neurotransmitter (serotonin, norepinephrine, or dopamine) in the cytosol of a monoamine neuron.[48][50] Activation of TAAR1 by MDMA triggers protein kinase A and protein kinase C signaling events which then phosphorylates the associated monoamine transporters – DAT, NET, or SERT – of the neuron.[47] In turn, these phosphorylated monoamine transporters either reverse transport direction – i.e., move neurotransmitters from the cytosol to the synaptic cleft – or withdraw into the neuron, respectively producing neurotransmitter efflux and noncompetitive reuptake inhibition at the neuronal membrane transporters.[47]

In summary, MDMA enters monoamine neurons by acting as a monoamine transporter substrate.[47] MDMA activity at VMAT2 moves neurotransmitters out from synaptic vesicles and into the cytosol;[48] MDMA activity at TAAR1 moves neurotransmitters out of the cytosol and into the synaptic cleft.[47]

MDMA also has weak agonist activity at postsynaptic serotonin receptors 5-HT1 and 5-HT2 receptors, and its more efficacious metabolite MDA likely augments this action.[51][52][53][54] A placebo-controlled study in 15 human volunteers found 100 mg MDMA increased blood levels of oxytocin, and the amount of oxytocin increase was correlated with the subjective prosocial effects of MDMA.[55](S)-MDMA is more effective in eliciting 5-HT, NE, and DA release, while (D)-MDMA is overall less effective, and more selective for 5-HT and NE release (having only a very faint efficacy on DA release).[56]

MDMA is a ligand at both sigma receptor subtypes, though its efficacies at the receptors have not yet been elucidated.[57]

Pharmacokinetics

(R)/(–)-enantiomer of MDMA (top)

(S)/(+)-enantiomer of MDMA (bottom)

MDMA reaches maximal concentrations in the blood stream between 1.5 and 3 hr after ingestion.[58] It is then slowly metabolized and excreted, with levels of MDMA and its metabolites decreasing to half their peak concentration over the next several hours.[59]

Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-dihydroxyamphetamine (DHA) (also called alpha-methyldopamine (α-Me-DA)), 3,4-methylenedioxyphenylacetone (MDP2P), and 3,4-Methylenedioxy-N-hydroxyamphetamine (MDOH). The contributions of these metabolites to the psychoactive and toxic effects of MDMA are an area of active research. Sixty-five percent of MDMA is excreted unchanged in the urine (in addition, 7% is metabolized into MDA) during the 24 hours after ingestion.[4]

MDMA is known to be metabolized by two main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine.[31] The metabolism may be primarily by cytochrome P450 (CYP450) enzymes CYP2D6 and CYP3A4 and COMT. Complex, nonlinear pharmacokinetics arise via autoinhibition of CYP2D6 and CYP2D8, resulting in zeroth order kinetics at higher doses. It is thought that this can result in sustained and higher concentrations of MDMA if the user takes consecutive doses of the drug.[60][non-primary source needed]

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[61] MDMA is a chiral compound and has been almost exclusively administered as a racemate. However, the two enantiomers have been shown to exhibit different kinetics. The disposition of MDMA may also be stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. Evidence suggests[62] that the area under the blood plasma concentration versus time curve (AUC) was two to four times higher for the (R)-enantiomer than the (S)-enantiomer after a 40 mg oral dose in human volunteers. Likewise, the plasma half-life of (R)-MDMA was significantly longer than that of the (S)-enantiomer (5.8 ± 2.2 hours vs 3.6 ± 0.9 hours).[6] However, because MDMA excretion and metabolism have nonlinear kinetics,[63] the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose[58]).

Physical and chemical properties

A powdered salt of MDMA
Reactors used to synthesize MDMA on an industrial scale in a chemical factory in Cikande, Indonesia

The free base of MDMA is a colorless oil that is insoluble in water.[20] The most common salt of MDMA is the hydrochloride salt;[20] pure MDMA hydrochloride is water-soluble and appears as a white or off-white powder or crystal.[20]

Synthesis

There are numerous methods available in the literature to synthesize MDMA via different intermediates.[64][65][66][67] The original MDMA synthesis described in Merck's patent involves brominating safrole to 1-(3,4-methylenedioxyphenyl)-2-bromopropane and then reacting this adduct with methylamine.[68][69] Most illicit MDMA is synthesized using MDP2P (3,4-methylenedioxyphenyl-2-propanone) as a precursor. MDP2P in turn is generally synthesized from piperonal, safrole or isosafrole.[16] One method is to isomerize safrole to isosafrole in the presence of a strong base, and then oxidize isosafrole to MDP2P. Another method uses the Wacker process to oxidize safrole directly to the MDP2P intermediate with a palladium catalyst. Once the MDP2P intermediate has been prepared, a reductive amination leads to racemic MDMA (an equal parts mixture of (R)-MDMA and (S)-MDMA).[citation needed]

Synthesis of MDMA from piperonal
Synthesis of MDMA and related analogs from safrole

Yield

Relatively small quantities of essential oil are required to make large amounts of MDMA. The essential oil of Ocotea cymbarum, for example, typically contains between 80 and 94% safrole. This allows 500 ml of the oil to produce between 150 and 340 grams of MDMA.[70]

Detection in body fluids

MDMA and MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDMA or its major metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10% those of the parent drug.[71][72][73]

History

Early research

German patents for MDMA (methylsafrylamin) synthesis and the subsequent methylhydrastinine synthesis filed by Merck in 1912 and issued in 1914.

MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch. At the time, Merck was interested in developing substances that stopped abnormal bleeding. Merck wanted to avoid an existing patent held by Bayer for one such compound: hydrastinine. Köllisch developed a preparation of a hydrastinine analogue, methylhydrastinine, at the request of his coworkers, Walther Beckh and Otto Wolfes. MDMA was an intermediate compound in the synthesis of methylhydrastinine and Merck was not interested in its properties at the time.[74] On 24 December 1912, Merck filed two patent applications that described the synthesis of MDMA[75] and its subsequent conversion to methylhydrastinine.[76]

Merck records indicate its researchers returned to the compound sporadically. In 1927, Max Oberlin studied the pharmacology of MDMA and observed that its effects on blood sugar and smooth muscles were similar to those of ephedrine. Research was stopped "particularly due to a strong price increase of safrylmethylamine". Albert van Schoor performed simple toxicological tests with the drug in 1952, most likely while researching new stimulants or circulatory medications. Seven years later, in 1959, Wolfgang Fruhstorfer also synthesized MDMA while researching stimulants.[74]

Outside of Merck, other researchers began to investigate MDMA. In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals injected with mescaline and several analogues, including MDMA. Conducted at the University of Michigan in Ann Arbor, these investigations were declassified in October 1969 and published in 1973.[77] A 1960 Polish paper describing the synthesis of MDMA was the first published scientific paper on the substance.[74]

Shulgin's research

Alexander and Ann Shulgin in December 2011

Chemist Alexander Shulgin reported that he synthesized MDMA in 1965 while researching methylenedioxy compounds at Dow Chemical Company, but did not test the psychoactivity of the compound at this time. Around 1970, Shulgin sent instructions for N-methylated MDA (MDMA) synthesis to the founder of a Los Angeles chemical company who had requested them. This individual later provided these instructions to a client in the Midwest.[78] MDMA was being used recreationally in the Chicago area by August 1970.[78][79]

Shulgin first heard of the effects of N-methylated MDA in 1975 from a student acquaintance who reported "amphetamine-like content".[78] Around late May 1976, Shulgin again heard about the effects of N-methylated MDA,[78] this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University.[80][81] Following the self-trials of a colleague at the University of San Francisco, Shulgin synthesized MDMA and tried it himself in September and October 1976.[78][80] Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.[78] Two years later, he and David E. Nichols published a report on the drug's psychotropic effect in humans. They described MDMA as inducing "an easily controlled altered state of consciousness with emotional and sensual overtones" comparable "to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA".[82] Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug "window".[83]

Shulgin took to occasionally using MDMA for relaxation, referring to it as "my low-calorie martini", and giving the drug to his friends, researchers, and other people whom he thought could benefit from it.[84] One such person was psychotherapist Leo Zeff, who had been known to use psychedelics in his practice. When he tried the drug in 1977, Zeff was so impressed with the effects of MDMA that he came out of his semi-retirement to promote its use in psychotherapy. Over the following years, Zeff traveled around the U.S. and occasionally to Europe, eventually introducing roughly four thousand psychotherapists to the use of MDMA in therapy.[85][86] Zeff named the drug "Adam", believing it put users in a state of primordial innocence.[80]

Rising use

In the late seventies and early eighties, MDMA spread through personal networks of psychotherapists, psychiatrists, users of psychedelics, and yuppies. Hoping MDMA could avoid criminalization like LSD and mescaline, psychotherapists and experimenters attempted to limit the spread of MDMA and information about it while conducting informal research.[87] By the time MDMA was criminalized in 1985, this network of MDMA users consumed an estimated 500,000 doses.[18][88]

A small recreational market for MDMA had developed by the late 1970s.[89] Into the early 1980s, production of MDMA was dominated by a small group of Boston chemists known as the "Boston group".[90] With demand for MDMA growing, the Southwest distributor for the "Boston group" started the "Texas group"[90] supported by several former cocaine dealers who had experienced MDMA.[88][89] The "Texas group" mass-produced MDMA in a Texas lab[87] or imported it from California[83] and marketed tablets using pyramid sales structures and toll-free numbers with credit card purchase options. Under the brand name "Sassyfras", MDMA was sold in brown bottles[87] and advertised as a "fun drug" and "good to dance to".[89] MDMA was openly distributed in Dallas area bars and nightclubs and became popular with yuppies, college students, and gays.[88] "Ecstasy" was recognized as slang for MDMA by 1981,[90] named by "Texas group" leader Michael Clegg[91] over the alternative "empathy", for broader marketing appeal.[87]

Scheduling

In the United Kingdom, MDMA was made illegal in 1977 by a modification order to the existing Misuse of Drugs Act 1971. Although MDMA was not named explicitly in this legislation, the order extended the definition of Class A drugs to include various ring-substituted phenethylamines.[92]

John C. Lawn in 2003

The United States Drug Enforcement Administration (DEA) began collecting information about MDMA in 1982 with the intention of banning the drug if enough evidence for abuse could be found.[88] By mid-1984, MDMA use was becoming more noticed. Bill Mandel reported on "Adam" in a June 10 San Francisco Chronicle article, but misidentified the drug as methyloxymethylenedioxyamphetamine (MMDA). In the next month, the World Health Organization identified MDMA as the only substance out of twenty phenethylamines to be seized a significant number of times.[87] The drug was first proposed for scheduling by the DEA on 27 July 1984 with a request for comments and objections.[93] The DEA was surprised when a number of physicians, therapists, and researchers objected to the proposed scheduling and requested a hearing.[90] In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.[94]

MDMA was classified as a Schedule I controlled substance in the U.S. on 31 May 1985 on an emergency basis.[95] No double blind studies had yet been conducted as to the efficacy of MDMA for psychotherapy. However, as a result of several expert witnesses testifying that MDMA had an accepted medical usage, the administrative law judge presiding over the hearings recommended that MDMA was classified as a Schedule III substance. Despite this, DEA administrator John C. Lawn overruled and classified the drug as Schedule I.[90] Later Harvard psychiatrist Lester Grinspoon sued the DEA, claiming that the DEA had ignored the medical uses of MDMA, and the federal court sided with Grinspoon, calling Lawn's argument "strained" and "unpersuasive", and vacated MDMA's Schedule I status. Despite this, less than a month later Lawn reviewed the evidence and reclassified MDMA as Schedule I again, claiming that the expert testimony of several psychiatrists claiming over 200 cases where MDMA had been used in a therapeutic context with positive results could be dismissed because they weren't published in medical journals.[90][citation needed]

In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 Convention on Psychotropic Substances, which is its current status.[96]

Post-scheduling

In the late 1980s, MDMA began to be widely used in Ibiza,[97] the UK and other parts of Europe, becoming an integral element of rave culture and other psychedelic-influenced music scenes. Spreading along with rave culture, illicit MDMA use became increasingly widespread among young adults in universities and later, in high schools. MDMA became one of the four most widely used illicit drugs in the U.S., along with cocaine, heroin, and cannabis.[83] According to some estimates as of 2004, only marijuana attracts more first time users in the U.S.[83]

After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later,[when?] Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent legally-approved MDMA studies in humans have taken place in the U.S. in Detroit (Wayne State University), Chicago (University of Chicago), San Francisco (UCSF and California Pacific Medical Center), Baltimore (NIDA–NIH Intramural Program), and South Carolina, as well as in Switzerland (University Hospital of Psychiatry, Zürich), the Netherlands (Maastricht University), and Spain (Universitat Autònoma de Barcelona).[98]

"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.[99][100]

In 2010, the BBC reported that use of MDMA had decreased in the UK in previous years. This may be due to increased seizures during use and decreased production of the precursor chemicals used to manufacture MDMA. Unwitting substitution with other drugs, such as mephedrone and methamphetamine,[101] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.[102]

Society and culture

Global estimates of illicit drug users in 2012
(in millions of users)[103]
Substance Mean
estimate
Low
estimate
High
estimate
Cannabis 177.63 125.30 227.27
Cocaine 17.24 13.99 20.92
MDMA 18.75 9.4 28.24
Opiates 16.37 12.80 20.23
Opioids 33.04 28.63 38.16
Substituted
amphetamines
34.40 13.94 54.81

Legal status

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 and limited medical use. In general, the unlicensed use, sale or manufacture of MDMA are all criminal offences.

In Australia, MDMA was declared illegal in 1986 because of its harmful effects and potential for abuse. It is classed as a Schedule 9 Prohibited Substance in the country, meaning it is available for scientific research purposes only. Any other type of sale, use or manufacture is strictly prohibited by law. Permits for research uses on humans must be approved by a recognized ethics committee on human research.

In the United Kingdom, MDMA is illegal under a 1977 modification to the Misuse of Drugs Act 1971[92] thereby making it illegal to sell, buy, or possess the drug without a licence. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking.

In the United States, MDMA is currently placed in Schedule I of the Controlled Substances Act.[104] In a 2011 federal court hearing the American Civil Liberties Union successfully argued that the sentencing guideline for MDMA/ecstasy is based on outdated science, leading to excessive prison sentences.[105] Other courts have upheld the sentencing guidelines. The United States District Court for the Eastern District of Tennessee explained its ruling by noting that "an individual federal district court judge simply cannot marshal resources akin to those available to the Commission for tackling the manifold issues involved with determining a proper drug equivalency."[106]

In the Netherlands, the Expert Committee on the List (Expertcommissie Lijstensystematiek Opiumwet) issued a report in June 2011 which discussed the evidence for harm and the legal status of MDMA, arguing in favor of maintaining it on List I.[106][107][108]

In Canada, MDMA is listed as a Schedule 1[109] as it is an analogue of amphetamine.[110] The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule III to Schedule I in March 2012.

Economics

Worldwide consumption of ecstasy by country in 2012 according to the UNODC 2014 World Drugs Report

Europe

In 2008 the European Monitoring Centre for Drugs and Drug Addiction noted that although there were some reports of tablets being sold for as little as €1, most countries in Europe then reported typical retail prices in the range of €3 to €9 per tablet, typically containing 25–65 mg of MDMA.[111] By 2014 the EMCDDA reported that the range was more usually between €5 and €10 per tablet, typically containing 57–102 mg of MDMA, although MDMA in powder form was becoming more common.[112]

North America

The United Nations Office on Drugs and Crime stated in its 2014 World Drug Report that U.S. ecstasy retail prices range from US$1 to $70 per pill, or from $15,000 to $32,000 per kilogram.[113] A new research area named Drug Intelligence aims to automatically monitor distribution networks based on image processing and machine learning techniques, in which an Ecstasy pill picture is analyzed to detect correlations among different production batches.[114] These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks.

Australia

MDMA is particularly expensive in Australia, costing A$15–A$30 per tablet. In terms of purity data for Australian MDMA, the average is around 34%, ranging from less than 1% to about 85%. The majority of tablets contain 70–85 mg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the U.S.[115]

Controversy

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Ecstasy was ranked 16th in addictiveness, harmfulness, and social harm.[116]

Harm assessment

Some scientists such as David Nutt have disagreed with the categorization of MDMA with other drugs they view as more harmful. A 2007 UK study ranked MDMA 18th in harmfulness out of 20 recreational drugs. Rankings for each drug were based 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. The authors did not evaluate or rate the negative impact of 'ecstasy' on the cognitive health of ecstasy users, e.g., impaired memory and concentration.[116][117] A later 2010 UK study which took into account impairment of cognitive functioning placed MDMA at number 17 out of 20 recreational drugs.[118]

Research

MAPS is currently funding pilot studies investigating the use of MDMA in PTSD therapy[119] and social anxiety therapy for autistic adults.[120] MDMA has also been proposed as an adjunct to substance abuse treatment.[121]

A review of the safety and efficacy of MDMA as a treatment for various disorders, particularly PTSD, indicated that MDMA has therapeutic efficacy in some patients;[19] however, it emphasized that MDMA is not a safe medical treatment due to lasting neurotoxic and cognition impairing effects in humans.[19] The author noted that oxytocin and D-cycloserine are potentially safer co-drugs in PTSD treatment, albeit with limited evidence of efficacy.[19] This review and a second corroborating review by a different author both concluded that, because of MDMA's demonstrated potential to cause lasting harm in humans (e.g., serotonergic neurotoxicity and persistent memory impairment), "considerably more research must be performed" on its efficacy in PTSD treatment to determine if the potential treatment benefits outweigh its potential to cause long-term harm to a patient.[18][19]

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  78. ^ a b c d e f Benzenhöfer, Udo; Passie, Torsten (9 July 2010). "Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin". Addiction 105 (8): 1355–1361. doi:10.1111/j.1360-0443.2010.02948.x. 
  79. ^ The first confirmed sample was seized and identified by Chicago Police in 1970, see Sreenivasan VR (1972). "Problems in Identification of Methylenedioxy and Methoxy Amphetamines". Journal of Criminal Law, Criminology & Police Science (The Journal of Criminal Law, Criminology, and Police Science, Vol. 63, No. 2) 63 (2): 304–312. doi:10.2307/1142315. JSTOR 1142315. 
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  81. ^ "Alexander ‘Sasha’ Shulgin". http://shulginresearch.org. Alexander Shulgin Research Institute. Retrieved 8 January 2015. 
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  83. ^ a b c d Jennings, Peter (1 April 2004). "Ecstasy Rising". Primetime Thursday (Special edition) (ABC News). 
  84. ^ Shulgin, Alexander; Shulgin, Ann (1991). "Part I, Chapter 12". PiHKAL : A Chemical Love Story (7th printing, 1st ed.). Berkeley, CA: Transform Press. ISBN 0963009605. 
  85. ^ Bennett, Drake (30 January 2005). "Dr. Ecstasy.". New York Times Magazine. 
  86. ^ Shulgin, Ann (2004). "Tribute to Jacob". In Doblin, Rick. The Secret Chief Revealed (PDF) (2nd ed.). Sarasota, Fl: Multidisciplinary Association for Psychedelic Studies. pp. 17–18. ISBN 0-9660019-6-6. Retrieved 7 January 2015. 
  87. ^ a b c d e Eisner, Bruce (1994). Ecstasy : The MDMA Story (Expanded 2nd ed.). Berkeley, CA: Ronin Publishing. ISBN 0914171682. 
  88. ^ a b c d Doblin, Rick; Rosenbaum, Marsha (1991). "Chapter 6: Why MDMA Should Not Have Been Made Illegal". In Inciardi, James A. The Drug Legalization Debate (2nd ed.). London: Sage Publications, Inc. ISBN 0803936788. Retrieved 5 January 2015. 
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  96. ^ 22nd report of the Expert Committee on Drug Dependence World Health Organization, 1985. (PDF) . Retrieved on 29 August 2012.
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  98. ^ Bibliography of Psychedelic Research Studies. collected by the Multidisciplinary Association for Psychedelic Studies[dead link]
  99. ^ Susan Donaldson James (23 February 2015). "What Is Molly and Why Is It Dangerous?". NBCNews.com. Retrieved 23 February 2015. <q>Why is it called Molly? That's short for "molecule." "You can put a ribbon and bow on it and call it a cute name like 'Molly' and people are all in," said Paul Doering, professor emeritus of pharmacology at the University of Florida.</q> 
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  105. ^ Court Rejects Harsh Federal Drug Sentencing Guideline as Scientifically Unjustified | American Civil Liberties Union. Aclu.org (15 July 2011). Retrieved on 29 August 2012.
  106. ^ a b "An Examination of Federal Sentencing Guidelines' Treatment of MDMA ('Ecstasy') by Alyssa C. Hennig :: SSRN". 
  107. ^ Rapport Drugs in Lijsten | Rapport. Rijksoverheid.nl (27 June 2011). Retrieved on 29 August 2012.
  108. ^ "Committee: the current system of the Opium Act does not have to be changed". government.nl. 24 June 2011. Retrieved 29 August 2012. <q>As regards MDMA, better known as XTC, the committee concludes that investigations show that damage to the health of the individual in the long term is less serious than was initially assumed. But the extent of the illegal production and involvement of organised crime leads to damage to society, including damage to the image of the Netherlands abroad. This argues in favour of maintaining MDMA on List I.</q> 
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  112. ^ European Drug Report 2014, page 26
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  117. ^ Scientists want new drug rankings, BBC News (23 March 2007).
  118. ^ Nutt, David J; King, Leslie A; Phillips, Lawrence D (November 2010). "Drug harms in the UK: a multicriteria decision analysis". The Lancet 376 (9752): 1558–1565. doi:10.1016/S0140-6736(10)61462-6. PMID 21036393. Retrieved 1 February 2015. 
  119. ^ Zarembo, Alan (15 March 2014). "Exploring therapeutic effects of MDMA on post-traumatic stress". Los Angeles Times (Los Angeles Times). Retrieved 22 February 2015. 
  120. ^ Danforth, Alicia L.; Struble, Christopher M.; Yazar-Klosinski, Berra; Grob, Charles S. (March 2015). "MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults". Progress in Neuro-Psychopharmacology and Biological Psychiatry. doi:10.1016/j.pnpbp.2015.03.011. Retrieved 17 April 2015. 
  121. ^ Jerome, Lisa; Schuster, Shira; Berra Yazar-Klosinski, B. (March 2013). "Can MDMA Play a Role in the Treatment of Substance Abuse?". Current Drug Abuse Reviews 6 (1): 54–62. doi:10.2174/18744737112059990005. PMID 23627786. Retrieved 18 June 2015. 

External links

  • MDMA Facts and Statistics



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Not to be confused with other meanings of the word Ecstasy.
MDMA
Systematic (IUPAC) name
(RS)-1-(Benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine
Clinical data
AHFS/Drugs.com entry
Legal status
  • <abbr title="Australia">AU</abbr>: Prohibited (S9)
  • <abbr title="Canada">CA</abbr>: Schedule I
  • <abbr title="New Zealand">NZ</abbr>: Class B
  • <abbr title="United Kingdom">UK</abbr>: Class A
  • <abbr title="United States">US</abbr>: Schedule I
  • <abbr title="United Nations">UN</abbr>: Psychotropic Schedule I
Dependence
liability
Physical: none
Psychological: moderate[2]
Addiction
liability
Moderate[1]
Routes of
administration
Common: oral
Uncommon: sublingual, insufflation, inhalation (vaporization), injection,[3] rectal
Pharmacokinetic data
Metabolism Hepatic, CYP450 extensively involved, including CYP2D6
Metabolites MDA, HMMA, HMA, DHA, MDP2P, MDOH[4]
Onset of action 30–45 minutes (oral)[5]
Biological half-life (R)-MDMA: 5.8 ± 2.2 hours[6]
(S)-MDMA: 3.6 ± 0.9 hours[6]
Duration of action 4–6 hours[5]
Excretion Renal
Identifiers
CAS Registry Number 42542-10-9 Y[TOXNET]
ATC code None
PubChem CID: 1615
IUPHAR/BPS 4574
DrugBank DB01454 Y
ChemSpider 1556 Y
UNII KE1SEN21RM Y
KEGG C07577 Y
ChEBI CHEBI:1391 Y
ChEMBL CHEMBL43048 Y
Synonyms <abbr title="3,4-Methylenedioxymethamphetamine">3,4-MDMA</abbr>, Ecstasy, Molly
PDB ligand ID B41 (PDBe, RCSB PDB)
Chemical data
Formula C11H15NO2
Molecular mass 193.25 g·mol−1
Physical data
Boiling point 105 °C (221 °F) at 0.4 mmHg (experimental)
 Y (what is this?)  (verify)

MDMA (contracted from 3,4-methylenedioxy-methamphetamine) is a psychoactive drug of the substituted methylenedioxyphenethylamine and substituted amphetamine classes of drugs that is consumed primarily for its euphoric and empathogenic effects. Pharmacologically, MDMA acts as a serotonin-norepinephrine-dopamine releasing agent and reuptake inhibitor.

MDMA has become widely known as "ecstasy" (shortened to "E", "X", or "XTC"), usually referring to its tablet street form, although this term may also include the presence of possible adulterants. The UK term "Mandy" and the US term "Molly" colloquially refer to MDMA in a crystalline powder form that is relatively free of adulterants.[7][8] "Molly" can sometimes also refer to the related drugs methylone, MDPV, mephedrone or any other of the pharmacological group of compounds commonly known as bath salts.[14]

Possession of MDMA is illegal in most countries. Some limited exceptions exist for scientific and medical research. In 2013 between 9 and 28 million people used ecstasy recreationally (0.2% to 0.6% of the global population between the ages of 15 and 65).[15] This was broadly similar to the number for cocaine, substituted amphetamine, and opioids, but fewer than the number of cannabis users.[16] It is taken in a variety of contexts far removed from its roots in psychotherapeutic settings, and is commonly associated with dance parties (or "raves") and electronic dance music.[17]

MDMA may have some limited health benefits in certain mental disorders, but has potential adverse effects, such as neurotoxicity and cognitive impairment.[18][19] More research is needed in order to determine if its potential usefulness in posttraumatic stress disorder (PTSD) treatment outweighs the risk of persistent neuropsychological harm to a patient.[18][19]

Contents

  • 1 Uses
    • 1.1 Medical
    • 1.2 Recreational
      • 1.2.1 Recreational effects
    • 1.3 Available forms
  • 2 Adverse effects
    • 2.1 Immediate effects
    • 2.2 After-effects
    • 2.3 Long-term effects
    • 2.4 Dependence and withdrawal
    • 2.5 Overdose
    • 2.6 Chronic use and addiction
  • 3 Interactions
  • 4 Pharmacology
    • 4.1 Pharmacodynamics
    • 4.2 Pharmacokinetics
  • 5 Physical and chemical properties
    • 5.1 Synthesis
      • 5.1.1 Yield
    • 5.2 Detection in body fluids
  • 6 History
    • 6.1 Early research
    • 6.2 Shulgin's research
    • 6.3 Rising use
    • 6.4 Scheduling
    • 6.5 Post-scheduling
  • 7 Society and culture
    • 7.1 Legal status
    • 7.2 Economics
      • 7.2.1 Europe
      • 7.2.2 North America
      • 7.2.3 Australia
    • 7.3 Controversy
      • 7.3.1 Harm assessment
  • 8 Research
  • 9 References
  • 10 External links

Uses

Medical

See also: MDMA § Research

MDMA currently has no accepted medical uses.[16][20]

Recreational

Ecstasy is commonly consumed at raves. Above, a rave in Austria in 2005.

MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and house parties.[21] In the rave environment, the sensory effects from the music and lighting are often highly synergistic with the drug. The psychedelic amphetamine quality of MDMA offers multiple reasons for its appeals to users in the "rave" setting. Some users enjoy the feeling of mass communion from the inhibition-reducing effects of the drug, while others use it as party fuel because of the drug's stimulatory effects.[22]

MDMA is occasionally known for being taken in conjunction with psychedelic drugs the more common combinations include MDMA combined with LSD, MDMA with psilocybin mushrooms, and MDMA with ketamine. Many users use mentholated products while taking MDMA for its cooling sensation while experiencing the drug's effects. Examples include menthol cigarettes, Vicks VapoRub, NyQuil,[23] and lozenges.

Recreational effects

In general, MDMA users begin reporting subjective effects within 30 to 60 minutes of consumption, hitting a peak at about 75 to 120 minutes which plateaus for about 3.5 hours.[24]

The desired short-term psychoactive effects of MDMA include:

  • Euphoria – a sense of general well-being and happiness[18][25]
  • Increased sociability and feelings of communication being easy or simple[18][25]
  • Entactogenic effects – increased empathy or feelings of closeness with others[18][25]
  • A sense of inner peace[25]
  • Mild hallucination (e.g., colors and sounds are enhanced and mild closed-eye visuals)[25]
  • Enhanced sensation, perception, or sexuality[18][25]

Available forms

The average ecstasy tablet contains 60–70 mg (base equivalent) of MDMA, usually as the hydrochloride salt.[20] Powdered MDMA is typically 30–40% pure, due to bulking agents (e.g., lactose) and binding agents.[20] Tablets sold as ecstasy sometimes only contain 3,4-methylenedioxyamphetamine (MDA) instead of MDMA;[6][20] the proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.[20]

Ecstasy tablets which allegedly contain MDMA, but may contain adulterants
A salt of MDMA (typically white) with impurities, resulting in a tan discoloration

Adverse effects

Immediate effects

Bruxism can be a side effect of MDMA prompting some users to suck on pacifiers to avoid teeth grinding.

The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.[25][26] Cases of life-threatening or fatal hyponatremia (excessively low sodium concentration in the blood) have developed in MDMA users attempting to prevent dehydration by consuming excessive amounts of water without replenishing electrolytes.[25][26][27] Even without excessive water intake, MDMA can increase water retention through syndrome of inappropriate antidiuretic hormone secretion,[28] so that water intake must be restricted (unless heavy sweating occurs).[29][non-primary source needed] The resultant hypervolumia can simultaneously cause both dilutional hyponatremia (which can cause seizures) and hypertension (which can cause stroke). In the case of excessive water intake, salt can be administered to increase osmotic pressure, but while this improves hyponatremia it can also further worsen hypertension. Both are associated with a sensation of intracranial pressure, either in the brain's arteries as in hypertension, or in the brain's tissues as in hyponatremia.[medical citation needed]

The immediate adverse effects of MDMA use can include:

  • Dehydration[21][25][26]
  • Hyperthermia[21][25][26]
  • Bruxism (grinding and clenching of the teeth)[18][21][25]
  • Increased wakefulness or insomnia[25]
  • Increased perspiration and sweating[25][26]
  • Increased heart rate and blood pressure[21][25][26]
  • Loss of appetite[6]
  • Nausea and vomiting[18]
  • Diarrhea[25]
  • Erectile dysfunction[30]
  • Mydriasis[31]

After-effects

The effects that last up to a week[18][32] following cessation of moderate MDMA use include:

Physical</dt>

  • Trismus[18]
  • Loss of appetite[32]
  • Insomnia[32]

Psychological</dt>

  • Anxiety or paranoia[32]
  • Depression[18][32]
  • Irritability[32]
  • Impulsiveness[32]
  • Restlessness[32]
  • Memory impairment[18]
  • Anhedonia[32]

Long-term effects

MDMA use has been shown to produce brain lesions, a form of brain damage, in the serotonergic neural pathways of humans and other animals.[1][6] In addition, long-term exposure to MDMA in humans has been shown to produce marked neurotoxicity in serotonergic axon terminals.[21][25][33] Neurotoxic damage to axon terminals has been shown to persist for more than two years.[33] Brain temperature during MDMA use is positively correlated with MDMA-induced neurotoxicity in animals.[21] Adverse neuroplastic changes to brain microvasculature and white matter also seem to occur in humans using low doses of MDMA.[21] Reduced gray matter density in certain brain structures has also been noted in human MDMA users.[21] In addition, MDMA has immunosuppressive effects in the peripheral nervous system, but pro-inflammatory effects in the central nervous system.[34] Babies of mothers who used MDMA during pregnancy exhibit impaired motor function at 4 months of age, which may reflect either a delay in development or a persistent neurological deficit.[19][35]

MDMA also produces persistent cognitive impairments in human users.[2][18][19] Impairments in multiple aspects of cognition, including memory, visual processing, and sleep have been noted in humans;[18][19] the magnitude of these impairments is correlated with lifetime ecstasy or MDMA usage.[2][18][19] Memory is significantly impacted by ecstasy use, which is associated with marked impairments in all forms of memory (e.g., long-term, short-term, working).[18][19]

Dependence and withdrawal

Some studies indicate repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug.[36][37][38] Other meta analyses have reported possibility of impairment of executive functioning.[39] Approximately 60% of MDMA users experience withdrawal symptoms, including, but not limited to: fatigue, loss of appetite, depression, and trouble concentrating.[6] Tolerance is expected to occur with consistent MDMA use.[6]

Overdose

Overdose symptoms vary widely with MDMA; they can include:

Symptoms of overdose
System Minor or moderate overdose[31] Severe overdose[31]
Cardiovascular
  • Disseminated intravascular coagulation[25]
  • Intracranial hemorrhage[25]
  • Severe hypertension[25][40] or hypotension[25]
Central nervous
system
  • Abnormally fast reflexes[41]
  • Agitation[25][40]
  • Mental confusion[25]
  • Paranoia[25][40]
  • Stimulant psychosis[21]
  • Cognitive and memory impairment[25] potentially to the point of retrograde or anterograde amnesia[42]
  • Coma[21][40]
  • Convulsions[25][40]
  • Hallucinations[25][40]
  • Loss of consciousness[21]
  • Serotonin syndrome[21][25][27]
Musculoskeletal
  • Muscle rigidity[25]
  • Rhabdomyolysis (i.e., rapid muscle breakdown)[25][27]
Respiratory
  • Acute respiratory distress syndrome[25]
Urinary
  • Renal failure[25]
Other
  • Cerebral edema[21]
  • Hepatitis[25][27]
  • Hyperpyrexia (a life-threatening elevation of body temperature)[25][27]
  • Hyponatremia (Syndrome of inappropriate antidiuretic hormone)[25][26][27]

Chronic use and addiction

See also: ΔFosB

MDMA has been shown to induce ΔFosB in the nucleus accumbens.[43] Since MDMA releases dopamine in the mesocorticolimbic projection, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other psychostimulants.[43][44] Therefore, chronic use of MDMA at high doses can result in altered brain structure and drug addiction, which occur as a consequence of ΔFosB overexpression in the nucleus accumbens.[44]

Interactions

A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.[6][45] MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors.[6] Concurrent use of MDMA with another serotonergic drug can result in a life-threatening condition called serotonin syndrome.[6] Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors,[6] such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).[46]

Pharmacology

Pharmacodynamics

MDMA acts primarily as a presynaptic releasing agent of serotonin, norepinephrine, and dopamine, which arises from its activity at trace amine-associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (VMAT2).[6][47][48] MDMA is a monoamine transporter substrate (i.e., a substrate for DAT, NET, and SERT), so it enters monoamine neurons via these neuronal membrane transport proteins;[47] by acting as a monoamine transporter substrate, MDMA produces competitive reuptake inhibition at the neuronal membrane transporters (i.e., it competes with endogenous monoamines for reuptake).[47][49] MDMA inhibits both vesicular monoamine transporters (VMATs), the second of which (VMAT2) is highly expressed within monoamine neurons at vesicular membranes.[48] Once inside a monoamine neuron, MDMA acts as a VMAT2 inhibitor and a TAAR1 agonist.[47][48] Inhibition of VMAT2 by MDMA results in increased concentrations of the associated neurotransmitter (serotonin, norepinephrine, or dopamine) in the cytosol of a monoamine neuron.[48][50] Activation of TAAR1 by MDMA triggers protein kinase A and protein kinase C signaling events which then phosphorylates the associated monoamine transporters – DAT, NET, or SERT – of the neuron.[47] In turn, these phosphorylated monoamine transporters either reverse transport direction – i.e., move neurotransmitters from the cytosol to the synaptic cleft – or withdraw into the neuron, respectively producing neurotransmitter efflux and noncompetitive reuptake inhibition at the neuronal membrane transporters.[47]

In summary, MDMA enters monoamine neurons by acting as a monoamine transporter substrate.[47] MDMA activity at VMAT2 moves neurotransmitters out from synaptic vesicles and into the cytosol;[48] MDMA activity at TAAR1 moves neurotransmitters out of the cytosol and into the synaptic cleft.[47]

MDMA also has weak agonist activity at postsynaptic serotonin receptors 5-HT1 and 5-HT2 receptors, and its more efficacious metabolite MDA likely augments this action.[51][52][53][54] A placebo-controlled study in 15 human volunteers found 100 mg MDMA increased blood levels of oxytocin, and the amount of oxytocin increase was correlated with the subjective prosocial effects of MDMA.[55](S)-MDMA is more effective in eliciting 5-HT, NE, and DA release, while (D)-MDMA is overall less effective, and more selective for 5-HT and NE release (having only a very faint efficacy on DA release).[56]

MDMA is a ligand at both sigma receptor subtypes, though its efficacies at the receptors have not yet been elucidated.[57]

Pharmacokinetics

(R)/(–)-enantiomer of MDMA (top)

(S)/(+)-enantiomer of MDMA (bottom)

MDMA reaches maximal concentrations in the blood stream between 1.5 and 3 hr after ingestion.[58] It is then slowly metabolized and excreted, with levels of MDMA and its metabolites decreasing to half their peak concentration over the next several hours.[59]

Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-dihydroxyamphetamine (DHA) (also called alpha-methyldopamine (α-Me-DA)), 3,4-methylenedioxyphenylacetone (MDP2P), and 3,4-Methylenedioxy-N-hydroxyamphetamine (MDOH). The contributions of these metabolites to the psychoactive and toxic effects of MDMA are an area of active research. Sixty-five percent of MDMA is excreted unchanged in the urine (in addition, 7% is metabolized into MDA) during the 24 hours after ingestion.[4]

MDMA is known to be metabolized by two main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine.[31] The metabolism may be primarily by cytochrome P450 (CYP450) enzymes CYP2D6 and CYP3A4 and COMT. Complex, nonlinear pharmacokinetics arise via autoinhibition of CYP2D6 and CYP2D8, resulting in zeroth order kinetics at higher doses. It is thought that this can result in sustained and higher concentrations of MDMA if the user takes consecutive doses of the drug.[60][non-primary source needed]

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[61] MDMA is a chiral compound and has been almost exclusively administered as a racemate. However, the two enantiomers have been shown to exhibit different kinetics. The disposition of MDMA may also be stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. Evidence suggests[62] that the area under the blood plasma concentration versus time curve (AUC) was two to four times higher for the (R)-enantiomer than the (S)-enantiomer after a 40 mg oral dose in human volunteers. Likewise, the plasma half-life of (R)-MDMA was significantly longer than that of the (S)-enantiomer (5.8 ± 2.2 hours vs 3.6 ± 0.9 hours).[6] However, because MDMA excretion and metabolism have nonlinear kinetics,[63] the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose[58]).

Physical and chemical properties

A powdered salt of MDMA
Reactors used to synthesize MDMA on an industrial scale in a chemical factory in Cikande, Indonesia

The free base of MDMA is a colorless oil that is insoluble in water.[20] The most common salt of MDMA is the hydrochloride salt;[20] pure MDMA hydrochloride is water-soluble and appears as a white or off-white powder or crystal.[20]

Synthesis

There are numerous methods available in the literature to synthesize MDMA via different intermediates.[64][65][66][67] The original MDMA synthesis described in Merck's patent involves brominating safrole to 1-(3,4-methylenedioxyphenyl)-2-bromopropane and then reacting this adduct with methylamine.[68][69] Most illicit MDMA is synthesized using MDP2P (3,4-methylenedioxyphenyl-2-propanone) as a precursor. MDP2P in turn is generally synthesized from piperonal, safrole or isosafrole.[16] One method is to isomerize safrole to isosafrole in the presence of a strong base, and then oxidize isosafrole to MDP2P. Another method uses the Wacker process to oxidize safrole directly to the MDP2P intermediate with a palladium catalyst. Once the MDP2P intermediate has been prepared, a reductive amination leads to racemic MDMA (an equal parts mixture of (R)-MDMA and (S)-MDMA).[citation needed]

Synthesis of MDMA from piperonal
Synthesis of MDMA and related analogs from safrole

Yield

Relatively small quantities of essential oil are required to make large amounts of MDMA. The essential oil of Ocotea cymbarum, for example, typically contains between 80 and 94% safrole. This allows 500 ml of the oil to produce between 150 and 340 grams of MDMA.[70]

Detection in body fluids

MDMA and MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDMA or its major metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10% those of the parent drug.[71][72][73]

History

Early research

German patents for MDMA (methylsafrylamin) synthesis and the subsequent methylhydrastinine synthesis filed by Merck in 1912 and issued in 1914.

MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch. At the time, Merck was interested in developing substances that stopped abnormal bleeding. Merck wanted to avoid an existing patent held by Bayer for one such compound: hydrastinine. Köllisch developed a preparation of a hydrastinine analogue, methylhydrastinine, at the request of his coworkers, Walther Beckh and Otto Wolfes. MDMA was an intermediate compound in the synthesis of methylhydrastinine and Merck was not interested in its properties at the time.[74] On 24 December 1912, Merck filed two patent applications that described the synthesis of MDMA[75] and its subsequent conversion to methylhydrastinine.[76]

Merck records indicate its researchers returned to the compound sporadically. In 1927, Max Oberlin studied the pharmacology of MDMA and observed that its effects on blood sugar and smooth muscles were similar to those of ephedrine. Research was stopped "particularly due to a strong price increase of safrylmethylamine". Albert van Schoor performed simple toxicological tests with the drug in 1952, most likely while researching new stimulants or circulatory medications. Seven years later, in 1959, Wolfgang Fruhstorfer also synthesized MDMA while researching stimulants.[74]

Outside of Merck, other researchers began to investigate MDMA. In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals injected with mescaline and several analogues, including MDMA. Conducted at the University of Michigan in Ann Arbor, these investigations were declassified in October 1969 and published in 1973.[77] A 1960 Polish paper describing the synthesis of MDMA was the first published scientific paper on the substance.[74]

Shulgin's research

Alexander and Ann Shulgin in December 2011

Chemist Alexander Shulgin reported that he synthesized MDMA in 1965 while researching methylenedioxy compounds at Dow Chemical Company, but did not test the psychoactivity of the compound at this time. Around 1970, Shulgin sent instructions for N-methylated MDA (MDMA) synthesis to the founder of a Los Angeles chemical company who had requested them. This individual later provided these instructions to a client in the Midwest.[78] MDMA was being used recreationally in the Chicago area by August 1970.[78][79]

Shulgin first heard of the effects of N-methylated MDA in 1975 from a student acquaintance who reported "amphetamine-like content".[78] Around late May 1976, Shulgin again heard about the effects of N-methylated MDA,[78] this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University.[80][81] Following the self-trials of a colleague at the University of San Francisco, Shulgin synthesized MDMA and tried it himself in September and October 1976.[78][80] Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.[78] Two years later, he and David E. Nichols published a report on the drug's psychotropic effect in humans. They described MDMA as inducing "an easily controlled altered state of consciousness with emotional and sensual overtones" comparable "to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA".[82] Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug "window".[83]

Shulgin took to occasionally using MDMA for relaxation, referring to it as "my low-calorie martini", and giving the drug to his friends, researchers, and other people whom he thought could benefit from it.[84] One such person was psychotherapist Leo Zeff, who had been known to use psychedelics in his practice. When he tried the drug in 1977, Zeff was so impressed with the effects of MDMA that he came out of his semi-retirement to promote its use in psychotherapy. Over the following years, Zeff traveled around the U.S. and occasionally to Europe, eventually introducing roughly four thousand psychotherapists to the use of MDMA in therapy.[85][86] Zeff named the drug "Adam", believing it put users in a state of primordial innocence.[80]

Rising use

In the late seventies and early eighties, MDMA spread through personal networks of psychotherapists, psychiatrists, users of psychedelics, and yuppies. Hoping MDMA could avoid criminalization like LSD and mescaline, psychotherapists and experimenters attempted to limit the spread of MDMA and information about it while conducting informal research.[87] By the time MDMA was criminalized in 1985, this network of MDMA users consumed an estimated 500,000 doses.[18][88]

A small recreational market for MDMA had developed by the late 1970s.[89] Into the early 1980s, production of MDMA was dominated by a small group of Boston chemists known as the "Boston group".[90] With demand for MDMA growing, the Southwest distributor for the "Boston group" started the "Texas group"[90] supported by several former cocaine dealers who had experienced MDMA.[88][89] The "Texas group" mass-produced MDMA in a Texas lab[87] or imported it from California[83] and marketed tablets using pyramid sales structures and toll-free numbers with credit card purchase options. Under the brand name "Sassyfras", MDMA was sold in brown bottles[87] and advertised as a "fun drug" and "good to dance to".[89] MDMA was openly distributed in Dallas area bars and nightclubs and became popular with yuppies, college students, and gays.[88] "Ecstasy" was recognized as slang for MDMA by 1981,[90] named by "Texas group" leader Michael Clegg[91] over the alternative "empathy", for broader marketing appeal.[87]

Scheduling

In the United Kingdom, MDMA was made illegal in 1977 by a modification order to the existing Misuse of Drugs Act 1971. Although MDMA was not named explicitly in this legislation, the order extended the definition of Class A drugs to include various ring-substituted phenethylamines.[92]

John C. Lawn in 2003

The United States Drug Enforcement Administration (DEA) began collecting information about MDMA in 1982 with the intention of banning the drug if enough evidence for abuse could be found.[88] By mid-1984, MDMA use was becoming more noticed. Bill Mandel reported on "Adam" in a June 10 San Francisco Chronicle article, but misidentified the drug as methyloxymethylenedioxyamphetamine (MMDA). In the next month, the World Health Organization identified MDMA as the only substance out of twenty phenethylamines to be seized a significant number of times.[87] The drug was first proposed for scheduling by the DEA on 27 July 1984 with a request for comments and objections.[93] The DEA was surprised when a number of physicians, therapists, and researchers objected to the proposed scheduling and requested a hearing.[90] In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.[94]

MDMA was classified as a Schedule I controlled substance in the U.S. on 31 May 1985 on an emergency basis.[95] No double blind studies had yet been conducted as to the efficacy of MDMA for psychotherapy. However, as a result of several expert witnesses testifying that MDMA had an accepted medical usage, the administrative law judge presiding over the hearings recommended that MDMA was classified as a Schedule III substance. Despite this, DEA administrator John C. Lawn overruled and classified the drug as Schedule I.[90] Later Harvard psychiatrist Lester Grinspoon sued the DEA, claiming that the DEA had ignored the medical uses of MDMA, and the federal court sided with Grinspoon, calling Lawn's argument "strained" and "unpersuasive", and vacated MDMA's Schedule I status. Despite this, less than a month later Lawn reviewed the evidence and reclassified MDMA as Schedule I again, claiming that the expert testimony of several psychiatrists claiming over 200 cases where MDMA had been used in a therapeutic context with positive results could be dismissed because they weren't published in medical journals.[90][citation needed]

In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 Convention on Psychotropic Substances, which is its current status.[96]

Post-scheduling

In the late 1980s, MDMA began to be widely used in Ibiza,[97] the UK and other parts of Europe, becoming an integral element of rave culture and other psychedelic-influenced music scenes. Spreading along with rave culture, illicit MDMA use became increasingly widespread among young adults in universities and later, in high schools. MDMA became one of the four most widely used illicit drugs in the U.S., along with cocaine, heroin, and cannabis.[83] According to some estimates as of 2004, only marijuana attracts more first time users in the U.S.[83]

After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later,[when?] Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent legally-approved MDMA studies in humans have taken place in the U.S. in Detroit (Wayne State University), Chicago (University of Chicago), San Francisco (UCSF and California Pacific Medical Center), Baltimore (NIDA–NIH Intramural Program), and South Carolina, as well as in Switzerland (University Hospital of Psychiatry, Zürich), the Netherlands (Maastricht University), and Spain (Universitat Autònoma de Barcelona).[98]

"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.[99][100]

In 2010, the BBC reported that use of MDMA had decreased in the UK in previous years. This may be due to increased seizures during use and decreased production of the precursor chemicals used to manufacture MDMA. Unwitting substitution with other drugs, such as mephedrone and methamphetamine,[101] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.[102]

Society and culture

Global estimates of illicit drug users in 2012
(in millions of users)[103]
Substance Mean
estimate
Low
estimate
High
estimate
Cannabis 177.63 125.30 227.27
Cocaine 17.24 13.99 20.92
MDMA 18.75 9.4 28.24
Opiates 16.37 12.80 20.23
Opioids 33.04 28.63 38.16
Substituted
amphetamines
34.40 13.94 54.81

Legal status

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 and limited medical use. In general, the unlicensed use, sale or manufacture of MDMA are all criminal offences.

In Australia, MDMA was declared illegal in 1986 because of its harmful effects and potential for abuse. It is classed as a Schedule 9 Prohibited Substance in the country, meaning it is available for scientific research purposes only. Any other type of sale, use or manufacture is strictly prohibited by law. Permits for research uses on humans must be approved by a recognized ethics committee on human research.

In the United Kingdom, MDMA is illegal under a 1977 modification to the Misuse of Drugs Act 1971[92] thereby making it illegal to sell, buy, or possess the drug without a licence. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking.

In the United States, MDMA is currently placed in Schedule I of the Controlled Substances Act.[104] In a 2011 federal court hearing the American Civil Liberties Union successfully argued that the sentencing guideline for MDMA/ecstasy is based on outdated science, leading to excessive prison sentences.[105] Other courts have upheld the sentencing guidelines. The United States District Court for the Eastern District of Tennessee explained its ruling by noting that "an individual federal district court judge simply cannot marshal resources akin to those available to the Commission for tackling the manifold issues involved with determining a proper drug equivalency."[106]

In the Netherlands, the Expert Committee on the List (Expertcommissie Lijstensystematiek Opiumwet) issued a report in June 2011 which discussed the evidence for harm and the legal status of MDMA, arguing in favor of maintaining it on List I.[106][107][108]

In Canada, MDMA is listed as a Schedule 1[109] as it is an analogue of amphetamine.[110] The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule III to Schedule I in March 2012.

Economics

Worldwide consumption of ecstasy by country in 2012 according to the UNODC 2014 World Drugs Report

Europe

In 2008 the European Monitoring Centre for Drugs and Drug Addiction noted that although there were some reports of tablets being sold for as little as €1, most countries in Europe then reported typical retail prices in the range of €3 to €9 per tablet, typically containing 25–65 mg of MDMA.[111] By 2014 the EMCDDA reported that the range was more usually between €5 and €10 per tablet, typically containing 57–102 mg of MDMA, although MDMA in powder form was becoming more common.[112]

North America

The United Nations Office on Drugs and Crime stated in its 2014 World Drug Report that U.S. ecstasy retail prices range from US$1 to $70 per pill, or from $15,000 to $32,000 per kilogram.[113] A new research area named Drug Intelligence aims to automatically monitor distribution networks based on image processing and machine learning techniques, in which an Ecstasy pill picture is analyzed to detect correlations among different production batches.[114] These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks.

Australia

MDMA is particularly expensive in Australia, costing A$15–A$30 per tablet. In terms of purity data for Australian MDMA, the average is around 34%, ranging from less than 1% to about 85%. The majority of tablets contain 70–85 mg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the U.S.[115]

Controversy

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Ecstasy was ranked 16th in addictiveness, harmfulness, and social harm.[116]

Harm assessment

Some scientists such as David Nutt have disagreed with the categorization of MDMA with other drugs they view as more harmful. A 2007 UK study ranked MDMA 18th in harmfulness out of 20 recreational drugs. Rankings for each drug were based 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. The authors did not evaluate or rate the negative impact of 'ecstasy' on the cognitive health of ecstasy users, e.g., impaired memory and concentration.[116][117] A later 2010 UK study which took into account impairment of cognitive functioning placed MDMA at number 17 out of 20 recreational drugs.[118]

Research

MAPS is currently funding pilot studies investigating the use of MDMA in PTSD therapy[119] and social anxiety therapy for autistic adults.[120] MDMA has also been proposed as an adjunct to substance abuse treatment.[121]

A review of the safety and efficacy of MDMA as a treatment for various disorders, particularly PTSD, indicated that MDMA has therapeutic efficacy in some patients;[19] however, it emphasized that MDMA is not a safe medical treatment due to lasting neurotoxic and cognition impairing effects in humans.[19] The author noted that oxytocin and D-cycloserine are potentially safer co-drugs in PTSD treatment, albeit with limited evidence of efficacy.[19] This review and a second corroborating review by a different author both concluded that, because of MDMA's demonstrated potential to cause lasting harm in humans (e.g., serotonergic neurotoxicity and persistent memory impairment), "considerably more research must be performed" on its efficacy in PTSD treatment to determine if the potential treatment benefits outweigh its potential to cause long-term harm to a patient.[18][19]

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External links

  • MDMA Facts and Statistics



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出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2015/07/26 02:58:08」(JST)

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Not to be confused with other meanings of the word Ecstasy.
MDMA
Systematic (IUPAC) name
(RS)-1-(Benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine
Clinical data
AHFS/Drugs.com entry
Legal status
  • <abbr title="Australia">AU</abbr>: Prohibited (S9)
  • <abbr title="Canada">CA</abbr>: Schedule I
  • <abbr title="New Zealand">NZ</abbr>: Class B
  • <abbr title="United Kingdom">UK</abbr>: Class A
  • <abbr title="United States">US</abbr>: Schedule I
  • <abbr title="United Nations">UN</abbr>: Psychotropic Schedule I
Dependence
liability
Physical: none
Psychological: moderate[2]
Addiction
liability
Moderate[1]
Routes of
administration
Common: oral
Uncommon: sublingual, insufflation, inhalation (vaporization), injection,[3] rectal
Pharmacokinetic data
Metabolism Hepatic, CYP450 extensively involved, including CYP2D6
Metabolites MDA, HMMA, HMA, DHA, MDP2P, MDOH[4]
Onset of action 30–45 minutes (oral)[5]
Biological half-life (R)-MDMA: 5.8 ± 2.2 hours[6]
(S)-MDMA: 3.6 ± 0.9 hours[6]
Duration of action 4–6 hours[5]
Excretion Renal
Identifiers
CAS Registry Number 42542-10-9 Y[TOXNET]
ATC code None
PubChem CID: 1615
IUPHAR/BPS 4574
DrugBank DB01454 Y
ChemSpider 1556 Y
UNII KE1SEN21RM Y
KEGG C07577 Y
ChEBI CHEBI:1391 Y
ChEMBL CHEMBL43048 Y
Synonyms <abbr title="3,4-Methylenedioxymethamphetamine">3,4-MDMA</abbr>, Ecstasy, Molly
PDB ligand ID B41 (PDBe, RCSB PDB)
Chemical data
Formula C11H15NO2
Molecular mass 193.25 g·mol−1
Physical data
Boiling point 105 °C (221 °F) at 0.4 mmHg (experimental)
 Y (what is this?)  (verify)

MDMA (contracted from 3,4-methylenedioxy-methamphetamine) is a psychoactive drug of the substituted methylenedioxyphenethylamine and substituted amphetamine classes of drugs that is consumed primarily for its euphoric and empathogenic effects. Pharmacologically, MDMA acts as a serotonin-norepinephrine-dopamine releasing agent and reuptake inhibitor.

MDMA has become widely known as "ecstasy" (shortened to "E", "X", or "XTC"), usually referring to its tablet street form, although this term may also include the presence of possible adulterants. The UK term "Mandy" and the US term "Molly" colloquially refer to MDMA in a crystalline powder form that is relatively free of adulterants.[7][8] "Molly" can sometimes also refer to the related drugs methylone, MDPV, mephedrone or any other of the pharmacological group of compounds commonly known as bath salts.[14]

Possession of MDMA is illegal in most countries. Some limited exceptions exist for scientific and medical research. In 2013 between 9 and 28 million people used ecstasy recreationally (0.2% to 0.6% of the global population between the ages of 15 and 65).[15] This was broadly similar to the number for cocaine, substituted amphetamine, and opioids, but fewer than the number of cannabis users.[16] It is taken in a variety of contexts far removed from its roots in psychotherapeutic settings, and is commonly associated with dance parties (or "raves") and electronic dance music.[17]

MDMA may have some limited health benefits in certain mental disorders, but has potential adverse effects, such as neurotoxicity and cognitive impairment.[18][19] More research is needed in order to determine if its potential usefulness in posttraumatic stress disorder (PTSD) treatment outweighs the risk of persistent neuropsychological harm to a patient.[18][19]

Contents

  • 1 Uses
    • 1.1 Medical
    • 1.2 Recreational
      • 1.2.1 Recreational effects
    • 1.3 Available forms
  • 2 Adverse effects
    • 2.1 Immediate effects
    • 2.2 After-effects
    • 2.3 Long-term effects
    • 2.4 Dependence and withdrawal
    • 2.5 Overdose
    • 2.6 Chronic use and addiction
  • 3 Interactions
  • 4 Pharmacology
    • 4.1 Pharmacodynamics
    • 4.2 Pharmacokinetics
  • 5 Physical and chemical properties
    • 5.1 Synthesis
      • 5.1.1 Yield
    • 5.2 Detection in body fluids
  • 6 History
    • 6.1 Early research
    • 6.2 Shulgin's research
    • 6.3 Rising use
    • 6.4 Scheduling
    • 6.5 Post-scheduling
  • 7 Society and culture
    • 7.1 Legal status
    • 7.2 Economics
      • 7.2.1 Europe
      • 7.2.2 North America
      • 7.2.3 Australia
    • 7.3 Controversy
      • 7.3.1 Harm assessment
  • 8 Research
  • 9 References
  • 10 External links

Uses

Medical

See also: MDMA § Research

MDMA currently has no accepted medical uses.[16][20]

Recreational

Ecstasy is commonly consumed at raves. Above, a rave in Austria in 2005.

MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and house parties.[21] In the rave environment, the sensory effects from the music and lighting are often highly synergistic with the drug. The psychedelic amphetamine quality of MDMA offers multiple reasons for its appeals to users in the "rave" setting. Some users enjoy the feeling of mass communion from the inhibition-reducing effects of the drug, while others use it as party fuel because of the drug's stimulatory effects.[22]

MDMA is occasionally known for being taken in conjunction with psychedelic drugs the more common combinations include MDMA combined with LSD, MDMA with psilocybin mushrooms, and MDMA with ketamine. Many users use mentholated products while taking MDMA for its cooling sensation while experiencing the drug's effects. Examples include menthol cigarettes, Vicks VapoRub, NyQuil,[23] and lozenges.

Recreational effects

In general, MDMA users begin reporting subjective effects within 30 to 60 minutes of consumption, hitting a peak at about 75 to 120 minutes which plateaus for about 3.5 hours.[24]

The desired short-term psychoactive effects of MDMA include:

  • Euphoria – a sense of general well-being and happiness[18][25]
  • Increased sociability and feelings of communication being easy or simple[18][25]
  • Entactogenic effects – increased empathy or feelings of closeness with others[18][25]
  • A sense of inner peace[25]
  • Mild hallucination (e.g., colors and sounds are enhanced and mild closed-eye visuals)[25]
  • Enhanced sensation, perception, or sexuality[18][25]

Available forms

The average ecstasy tablet contains 60–70 mg (base equivalent) of MDMA, usually as the hydrochloride salt.[20] Powdered MDMA is typically 30–40% pure, due to bulking agents (e.g., lactose) and binding agents.[20] Tablets sold as ecstasy sometimes only contain 3,4-methylenedioxyamphetamine (MDA) instead of MDMA;[6][20] the proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.[20]

Ecstasy tablets which allegedly contain MDMA, but may contain adulterants
A salt of MDMA (typically white) with impurities, resulting in a tan discoloration

Adverse effects

Immediate effects

Bruxism can be a side effect of MDMA prompting some users to suck on pacifiers to avoid teeth grinding.

The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.[25][26] Cases of life-threatening or fatal hyponatremia (excessively low sodium concentration in the blood) have developed in MDMA users attempting to prevent dehydration by consuming excessive amounts of water without replenishing electrolytes.[25][26][27] Even without excessive water intake, MDMA can increase water retention through syndrome of inappropriate antidiuretic hormone secretion,[28] so that water intake must be restricted (unless heavy sweating occurs).[29][non-primary source needed] The resultant hypervolumia can simultaneously cause both dilutional hyponatremia (which can cause seizures) and hypertension (which can cause stroke). In the case of excessive water intake, salt can be administered to increase osmotic pressure, but while this improves hyponatremia it can also further worsen hypertension. Both are associated with a sensation of intracranial pressure, either in the brain's arteries as in hypertension, or in the brain's tissues as in hyponatremia.[medical citation needed]

The immediate adverse effects of MDMA use can include:

  • Dehydration[21][25][26]
  • Hyperthermia[21][25][26]
  • Bruxism (grinding and clenching of the teeth)[18][21][25]
  • Increased wakefulness or insomnia[25]
  • Increased perspiration and sweating[25][26]
  • Increased heart rate and blood pressure[21][25][26]
  • Loss of appetite[6]
  • Nausea and vomiting[18]
  • Diarrhea[25]
  • Erectile dysfunction[30]
  • Mydriasis[31]

After-effects

The effects that last up to a week[18][32] following cessation of moderate MDMA use include:

Physical</dt>

  • Trismus[18]
  • Loss of appetite[32]
  • Insomnia[32]

Psychological</dt>

  • Anxiety or paranoia[32]
  • Depression[18][32]
  • Irritability[32]
  • Impulsiveness[32]
  • Restlessness[32]
  • Memory impairment[18]
  • Anhedonia[32]

Long-term effects

MDMA use has been shown to produce brain lesions, a form of brain damage, in the serotonergic neural pathways of humans and other animals.[1][6] In addition, long-term exposure to MDMA in humans has been shown to produce marked neurotoxicity in serotonergic axon terminals.[21][25][33] Neurotoxic damage to axon terminals has been shown to persist for more than two years.