MDMA

出典: meddic

メチレンジオキシメタンフェタミン methylenedioxymethamphetamine

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出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2015/04/21 03:31:57」(JST)

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MDMA
IUPAC命名法による物質名
(RS)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine
臨床データ
胎児危険度分類
  • C[1]
法的規制
  • AU: Prohibited (S9)
  • CA: Schedule III
  • UK: CD Lic
  • US: Schedule I
投与方法 経口, 舌下腺, 吹き入れ, 吸入(蒸気), 注射,[2] 直腸
薬物動態的データ
代謝 肝臓、シトクロムP450オキシダーゼ
半減期 6–10 時間(実際の効果は3–5時間)
排泄 尿
識別
CAS番号 69610-10-2
ATCコード None
PubChem CID 1615
ChemSpider 1556
別名 (±)-1,3-benzodioxolyl-N-methyl-2-propanamine;

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

methylenedioxymethamphetamine
化学的データ
化学式 C11H15NO2 
分子量 193.25 g/mol

3,4-メチレンジオキシメタンフェタミン (3,4-methylenedioxymethamphetamine) は、合成麻薬の一種。略称としてMDMA、ほかエクスタシー(EcstasyまたはXTC)という通称を持つ。

心理学者のラルフ・メッツナー(英語版)がMDMAに対してエンパソーゲン(empathogen、共感をもたらす)という言葉を作った[3]。後により正確な表現としてエンタクトゲン(entactogen、内面のつながりをもたらす)という呼称が提唱され、精神薬理学の分野で採用されている[4]

類似の薬物としてMDA(3,4-メチレンジオキシアンフェタミン)、MDEA(3,4-メチレンジオキシ-N-エチルアンフェタミン)なども知られ、MDMAと同様にエンパソーゲンないしエンタクトゲンへ分類される。

目次

  • 1 生理的作用
  • 2 乱用と医療用途
  • 3 錠剤型麻薬
  • 4 歴史
  • 5 日本での規制
  • 6 脚注

生理的作用

MDMAは脳内のセロトニン等を過剰に放出させることにより、人間の精神に多幸感、他者との共有感などの変化をもたらすとされる。MDMAを経口的に摂取すると30分から1時間ほどで前述のような精神変容が起こり、それが4~6時間程度持続するとされる。

MDMAを摂取すると、体温をコントロールする機能の喪失による高体温や不整脈などによって重篤な症状を引き起こす場合がある。特に暖かい換気の悪い室内、激しい運動を伴う場合、また大量の発汗を伴い水分補給が十分でない場合などに使用すると合併症を生じやすいとされる。低ナトリウム血症、急性腎不全、横紋筋融解症などで死亡することもある。また、摂取後に重度の不安(不安障害)、妄想、気分の障害、記憶障害、睡眠障害、衝動性の亢進、注意集中の困難などが長期間続くことがある。

乱用と医療用途

MDMAは1985年まで主にアメリカにおいて心的外傷後ストレス障害 (PTSD) の治療に用いられてきた。PTSDは患者が自身に起きたトラウマ体験を自己の記憶として受容できないことによる疾患だとされているが、MDMAを摂取した状態でカウンセリングを行うことにより、通常の精神状態では許容しがたいトラウマ体験を想起させ、自己に起きた事実であることを受け入れることによって疾患が軽減もしくは治癒するという理論に基づいたものである。こうしたPTSDに対する医療用途に対する報道はアメリカでは広範になされており、2010年に少なくとも138以上のメディアで取り上げられている[5]

しかしMDMAは嗜好品 (recreational drug) としての側面も持ち、濫用が社会問題化したことを受け米国司法省麻薬取締局はMDMAを規制物質法におけるスケジュールI、すなわち濫用性が高く医療用途の見込みのない違法薬物に指定した。現在ではほとんどの国でMDMAは違法薬物とされている。以降MDMAは嗜好品として違法に濫用され続け今日に至るが、依然としてPTSDへの有用性を主張する声も根強く、2001年にはアメリカ食品医薬品局 (FDA) が、2004年にはDEAがPTSD患者へのMDMAの治験を認める措置が取られることとなり、2008年にはフェイズII治験が終了。続いてイスラエル、スイス、カナダでも臨床試験が行われる。しかし依然としてMDMAが濫用性の高い薬物であることには変わりなく、安全性や依存性の検証、濫用防止などクリアしなければならない問題点は多い。

錠剤型麻薬

錠剤型のMDMA。禁制薬物なので、医薬品なら当然存在する識別用コード番号が打たれていない

「エクスタシー」は本来MDMAを指す隠語である。しかしMDMAは錠剤の形を取って流通する場合が多いため、単に(MDMAを含むと期待される)錠剤型麻薬を総じてエクスタシーと呼ぶことも多い。錠剤型麻薬としては他にも「X」、「E」、「アダム」など多数の俗称を持ち、また日本では、丸い錠剤が多いことから「玉(たま)」、また「X」から転じて「バツ」、「ペケ」の俗称をも持つ。

一般に錠剤型麻薬は違法に製造されるため、MDMA以外の薬物である可能性、また他の成分が混入されている可能性、有害な不純物が残留している可能性などが非常に高く、MDMAの効用を高めるために意図的にパラメトキシアンフェタミンなど、他の薬物を混入することも少なくない。したがって単体としてのMDMAの安全性と錠剤型麻薬の安全性は別個のものとして考えなければならない。錠剤型麻薬の押収量が増加し、世界中で深刻な社会問題となっている。

歴史

  • 1912年、ドイツの化学メーカーメルク社が、食欲抑制剤として初めて合成し、製法特許を取得した(製品化はされなかった)。
  • 1967年、アメリカ軍による機密扱いが解けたことから化学文献への記載が始まり、1970年代から1980年代初頭までは精神科医の間で、PTSDの治療などに頻用された。
  • 1978年、ダウ・ケミカル社の化学者だったアレクサンダー・シュルギンらによる著作『幻覚剤の薬学』が出版され、嗜好品として爆発的な拡大が始まった。
  • 1985年6月、米国司法省麻薬取締局 (DEA) がエクスタシーを非合法とした。現在ではコカイン、ヘロイン、大麻と同様に、アメリカで広く用いられる麻薬の一つとされる。

そのダンス音楽との親近性により、1980年代後半からイギリスなどを中心に起こったセカンド・サマー・オブ・ラブブームやレイヴの代名詞として普及する。欧州では近年では価格の低下により若年層への普及が懸念されている。

日本での規制

日本では、麻薬及び向精神薬取締法によって規制されている。

MDMAの輸入、輸出、製造は1年以上10年以下の懲役。譲受け、譲渡し、所持は7年以下の懲役。施用(しよう、経口摂取など、身体に用いること)は7年以下の懲役となる。</dd>
錠剤型麻薬が覚せい剤(アンフェタミンなど)を含んでいた場合、覚せい剤取締法により、譲受け、譲渡し、所持、使用は10年以下の懲役となる。</dd>

合成麻薬MDMAは記憶系統の混乱を発生させる要因を作り出す。その作用として神経細胞の破壊及び永続的な(数ヶ月~数年とも言われている)後遺症をもたらす。特に混合成分(合成麻薬と言われる由縁)の内、覚醒剤や亜覚醒剤と併用された場合には複雑な精神面・身体面における害反応があり、前述の多様な記憶障害を引き起こす。

海外で行われたレイヴパーティー等ではときどき死亡者がでているが、全体としては少数である。

脚注

  1. ^ Stimulants, Narcotics, Hallucinogens - Drugs, Pregnancy, and Lactation., Gerald G. Briggs, OB/GYN News, 1 June 2003.
  2. ^ “Methylenedioxymethamphetamine (MDMA, ecstasy)”. Drugs and Human Performance Fact Sheets. National Highway Traffic Safety Administration. 2009年4月16日閲覧。
  3. ^ マーティン・トーゴフ 『ドラッグ・カルチャー-アメリカ文化の光と影(1945~2000年)』 宮家あゆみ訳、清流出版2007年。ISBN 978-4860292331。436頁。
  4. ^ Nichols DE. "Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens" J Psychoactive Drugs 18(4), 1986 Oct-Dec, pp. 305-13. PMID 2880944
  5. ^ 138 articles about mdma/ptsd therapy(MAPS、2010年7月30日)



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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[1]
Addiction
liability
Moderate[2]
Routes of
administration
Oral, sublingual, insufflation, inhalation (vaporization), injection,[3] rectal
Pharmacokinetic data
Metabolism Hepatic, CYP450 extensively involved, including CYP2D6
Onset of action Immediate
Half-life (R)-MDMA: 5.8 ± 2.2 hours[4]
(S)-MDMA: 3.6 ± 0.9 hours[4]
Excretion Renal
Identifiers
CAS Registry Number
42542-10-9 Y[TOXNET]
ATC code
None
PubChem CID 1615
IUPHAR ligand 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
193.24 g/mol
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.[5][6] "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.[12]

Possession of MDMA is illegal in most countries. Some limited exceptions exist for scientific and medical research. For 2012, the UNODC estimated between 9.4 and 28.24 million people globally used MDMA at least once in the past year. This was broadly similar to the number of cocaine, substituted amphetamine, and opioid users, but far fewer than the global number of cannabis users.[13] 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.[14]

Medical reviews have noted that MDMA has some limited therapeutic benefits in certain mental health disorders, but has potential adverse effects, such as neurotoxicity and cognitive impairment, associated with its use.[15][16] 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.[15][16]

Contents

  • 1 Uses
    • 1.1 Medical
    • 1.2 Recreational
      • 1.2.1 Recreational effects
      • 1.2.2 Purity and adulterants
  • 2 Adverse effects
    • 2.1 Immediate effects
    • 2.2 After-effects
    • 2.3 Long-term effects
    • 2.4 Dependence and withdrawal
  • 3 Overdose
    • 3.1 Chronic use and addiction
  • 4 Interactions
  • 5 Pharmacology
    • 5.1 Pharmacodynamics
    • 5.2 Pharmacokinetics
  • 6 Physical and chemical properties
    • 6.1 Synthesis
      • 6.1.1 Yield
    • 6.2 Detection in body fluids
  • 7 History
    • 7.1 Early research
    • 7.2 Shulgin's research
    • 7.3 Rising popularity and criminalization
    • 7.4 Post-criminalization
  • 8 Society and culture
    • 8.1 Legal status
    • 8.2 Economics
      • 8.2.1 Europe
      • 8.2.2 North America
      • 8.2.3 Australia
    • 8.3 Controversy
      • 8.3.1 Harm assessment
  • 9 Research
  • 10 References
  • 11 External links

Uses

Medical

See also: MDMA § Research

MDMA currently has no accepted medical uses.[13][17]

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.[18] 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.[19]

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,[20] most of the more common combinations have been given nicknames, such as "candy flipping" for MDMA combined with LSD, "hippie 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 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.

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.[23]

The desired short-term psychoactive effects of MDMA include:

  • Euphoria – a sense of general well-being and happiness[15][24]
  • Increased sociability and feelings of communication being easy or simple[15][24]
  • Entactogenic effects – increased empathy or feelings of closeness with others[15][24]
  • A sense of inner peace[24]
  • Mild hallucination (e.g., colors and sounds are enhanced and mild closed-eye visuals)[24]
  • Enhanced sensation, perception, or sexuality[15][24]

Purity and adulterants

The average tablet contains 60–70 mg (base equivalent) of MDMA, usually as the hydrochloride salt.[17] Powdered MDMA is typically 30–40% pure, due to bulking agents (e.g., lactose) and binding agents.[17] Tablets sold as ecstasy sometimes only contain 3,4-methylenedioxyamphetamine (MDA) instead of MDMA;[4][17] the proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.[17]

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

The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.[24][25] 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.[24][25][26]

The immediate adverse effects of MDMA use can include:

  • Dehydration[18][24][25]
  • Hyperthermia[18][24][25]
  • Bruxism (grinding and clenching of the teeth)[15][18][24]
  • Increased wakefulness or insomnia[24]
  • Increased perspiration and sweating[24][25]
  • Increased heart rate and blood pressure[18][24][25]
  • Loss of appetite[4]
  • Nausea and vomiting[15]
  • Diarrhea[24]
  • Erectile dysfunction[27]
  • Mydriasis[28]

After-effects

The effects that last up to a week[15][29] following cessation of moderate MDMA use include:

Physical</dt>

  • Trismus[15]
  • Loss of appetite[29]
  • Insomnia[29]

Psychological</dt>

  • Anxiety or paranoia[29]
  • Depression[15][29]
  • Irritability[29]
  • Impulsiveness[29]
  • Restlessness[29]
  • Memory impairment[15]
  • Anhedonia[29]

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.[2][4] In addition, long-term exposure to MDMA in humans has been shown to produce marked neurotoxicity in serotonergic axon terminals.[18][24][30] Neurotoxic damage to axon terminals has been shown to persist for more than two years.[30] Brain temperature during MDMA use is positively correlated with MDMA-induced neurotoxicity in animals.[18] Adverse neuroplastic changes to brain microvasculature and white matter also seem to occur in humans using low doses of MDMA.[18] Reduced gray matter density in certain brain structures has also been noted in human MDMA users.[18] In addition, MDMA has immunosuppressive effects in the peripheral nervous system, but pro-inflammatory effects in the central nervous system.[31] 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.[16][32]

MDMA also produces persistent cognitive impairments in human users.[1][15][16] Impairments in multiple aspects of cognition, including memory, visual processing, and sleep have been noted in humans;[15][16] the magnitude of these impairments is correlated with lifetime ecstasy or MDMA usage.[1][15][16] 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).[15][16]

Dependence and withdrawal

Some studies indicate repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug.[33][34][35] Other meta analyses have reported possibility of impairment of executive functioning.[36] Approximately 60% of MDMA users experience withdrawal symptoms, including, but not limited to: fatigue, loss of appetite, depression, and trouble concentrating.[4] Tolerance is expected to occur with consistent MDMA use.[4]

Overdose

Overdose symptoms vary widely with MDMA; they can include:

Overdose symptoms by system
System Symptom
Cardiovascular
  • Disseminated intravascular coagulation[24]
  • Intracranial hemorrhage[24]
  • Severe hypertension[24][37] or hypotension[24]
Central nervous
system
  • Abnormally fast reflexes[38]
  • Agitation[24][37]
  • Cognitive and memory impairment[24] potentially to the point of retrograde or anterograde amnesia[39]
  • Coma[18][37]
  • Convulsions[24][37]
  • Hallucinations[24][37]
  • Loss of consciousness[18]
  • Mental confusion[24]
  • Paranoia[24][37]
  • Serotonin syndrome[18][24][26]
  • Stimulant psychosis[18]
Musculoskeletal
  • Muscle rigidity[24]
  • Rhabdomyolysis (i.e., rapid muscle breakdown)[24][26]
Respiratory
  • Acute respiratory distress syndrome[24]
Urinary
  • Renal failure[24]
Other
  • Cerebral edema[18]
  • Hepatitis[24][26]
  • Hyperpyrexia (a life-threatening elevation of body temperature)[24][26]
  • Hyponatremia (Syndrome of inappropriate antidiuretic hormone)[24][25][26]

Chronic use and addiction

Main article: ΔFosB
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
v · t · e
Note: colored text contains article links.
Nuclear pore
Nuclear membrane
Plasma membrane
Cav1.2
NMDAR
AMPAR
DRD1
DRD5
DRD2
DRD3
DRD4
Gs
Gi/o
cAMP
cAMP
PKA
CaM
CaMKII
DARPP-32
PP1
PP2B
CREB
ΔFosB
JunD
c-Fos
SIRT1
HDAC1
[Color legend 1]
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methylphenidate, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[40][41] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a <abbr title="cyclic adenosine monophosphate">cAMP</abbr> pathway and calcium-dependent pathway that ultimately result in increased <abbr title="cAMP response element-binding protein">CREB</abbr> phosphorylation.[42][43] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors;[43] c-fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[44] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated exposure to stimulants through this process.[45][46] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[45][46] 

MDMA has been shown to induce ΔFosB in the nucleus accumbens.[47] Since MDMA releases dopamine in the mesocorticolimbic projection, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other psychostimulants.[47][48] 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.[48]

Interactions

A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.[4][49] MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors.[4] Concurrent use of MDMA with another serotonergic drug can result in a life-threatening condition called serotonin syndrome.[4] Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors,[4] such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).[50]

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).[4][51][52] 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;[51] 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).[51][53] MDMA inhibits both vesicular monoamine transporters (VMATs), the second of which (VMAT2) is highly expressed within monoamine neurons at vesicular membranes.[52] Once inside a monoamine neuron, MDMA acts as a VMAT2 inhibitor and a TAAR1 agonist.[51][52] Inhibition of VMAT2 by MDMA results in increased concentrations of the associated neurotransmitter (serotonin, norepinephrine, or dopamine) in the cytosol of a monoamine neuron.[52][54] 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.[51] 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.[51]

In summary, MDMA enters monoamine neurons by acting as a monoamine transporter substrate.[51] MDMA activity at VMAT2 moves neurotransmitters out from synaptic vesicles and into the cytosol;[52] MDMA activity at TAAR1 moves neurotransmitters out of the cytosol and into the synaptic cleft.[51]

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.[55][56][57][58] 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.[59](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).[60]

MDMA is a ligand at both sigma receptor subtypes, though its efficacies at the receptors have not yet been elucidated.[61]

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.[62] 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.[63]

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.[64]

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.[28] 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.[65][medical citation needed]

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[66] 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[67] 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).[4] However, because MDMA excretion and metabolism have nonlinear kinetics,[68] the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose[62]).

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.[17] The most common salt of MDMA is the hydrochloride salt;[17] pure MDMA hydrochloride is water soluble and appears as a white or off-white powder or crystal.[17]

Synthesis

There are numerous methods available in the literature to synthesize MDMA via different intermediates.[69][70][71][72] The MDMA synthesis described in Merck's patent involves brominating safrole to 1-(3,4-methylenedioxyphenyl)-2-bromopropane and then reacting this adduct with methylamine.[73][74] 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.[13] 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]

</dd>
</dd>

Yield

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 allows 500 ml of the oil to produce between 150 and 340 grams of MDMA.[75]

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.[76][77][78]

History

Early research

German patent for MDMA (methylsafrylamin) 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.[79] On 24 December 1912, Merck filed two patent applications that described the synthesis of MDMA[80] and its subsequent conversion to methylhydrastinine.[81]

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 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. While researching stimulants in 1959, Wolfgang Fruhstorfer also synthesized MDMA.[79]

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.[82] A 1960 Polish paper describing the synthesis of MDMA was the first published scientific paper on the substance.[79]

Shulgin's research

Alexander Shulgin in March 2010

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.[83] MDMA was being used recreationally in Illinois and Indiana by May 1970.[83][84][85]

Shulgin first heard of the effects of N-methylated MDA in 1975 from a student who reported "amphetamine-like content".[83] Around late May 1976, Shulgin again heard about the effects of N-methylated MDA,[83] this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University.[86][87] Intrigued by her positive report, Shulgin synthesized MDMA and tried it himself in September and October 1976.[83][86] Shulgin also noted the trials of a colleague who had tried the substance before him. Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.[83] 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".[88] Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug "window".[89]

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.[90] 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 proselytize for it. 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.[91][92] Zeff named the drug "Adam", believing it put users in a state of primordial innocence.[86]

Rising popularity and criminalization

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.[93] By the time MDMA was criminalized in 1985, this network of MDMA users consumed an estimated 500,000 doses.[15][94]

A small recreational market for MDMA had developed by the late 1970s.[95] Into the early 1980s, production of MDMA was dominated by a small group of Boston chemists known as the "Boston group".[96] Composed of tenured professors from Harvard and MIT, the group began distributing MDMA in New York City clubs as part of a social experiment to replace cocaine.[97] With demand for MDMA growing, the Southwest distributor for the "Boston group" started the "Texas group"[96] supported by several former cocaine dealers who had experienced MDMA.[94][95] The "Texas group" mass-produced MDMA in a Texas lab[93] or imported it from California[89] 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[93] and advertised as a "fun drug" and "good to dance to".[95] MDMA was openly distributed in Dallas area bars and nightclubs and became popular with yuppies, college students, and gays.[94] "Ecstasy" was recognized as slang for MDMA by 1981,[96] named by "Texas group" leader Michael Clegg[98] over the alternative "empathy" for broader marketing appeal.[93]

The 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.[94] 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.[93] The drug was first proposed for scheduling by the DEA on 27 July 1984 with a request for comments and objections.[99] The DEA was surprised when a number of physicians, therapists, and researchers objected to the proposed scheduling and requested a hearing.[96] In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.[100]

MDMA was classified as a Schedule I controlled substance in the U.S. on 31 May 1985 on an emergency basis.[101] No double blind studies had yet been conducted as to the efficacy of MDMA for psychotherapy. 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.[102]

Post-criminalization

In the late 1980s, MDMA began to be widely used in Ibiza,[103] 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.[89] According to some estimates as of 2004, only marijuana attracts more first time users in the U.S.[89]

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).[104]

"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.[105][106]

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,[107] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.[108]

Society and culture

Global estimates of illicit drug users in 2012
(in millions of users)[13]
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 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,[109] 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.[110] 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.[111] 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."[112]

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.[112][113][114]

In Canada, MDMA is listed as a Schedule 1[115] as it is an analogue of amphetamine.[116] 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.[117] 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.[118]

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.[119] 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.[120] 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.[121]

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.[122]

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.[122][123] A later 2010 UK study which took into account impairment of cognitive functioning placed MDMA at number 17 out of 20 recreational drugs.[124]

Research

MAPS is currently funding pilot studies investigating the use of MDMA in PTSD therapy[125] and social anxiety therapy for autistic adults.[126]

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;[16] however, it emphasized that MDMA is not a safe medical treatment due to lasting neurotoxic and cognition impairing effects in humans.[16] The author noted that oxytocin and D-cycloserine are potentially safer co-drugs in PTSD treatment, albeit with limited evidence of efficacy.[16] 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.[15][16]

References

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    hypertension, aortic dissection, arrhythmias, vasospasm, acute coronary syndrome, hypotension ... Agitation, paranoia, euphoria, hallucinations, bruxism, hyperreflexia, intracerebral haemorrhage ... pulmonary oedema/<abbr title="Adult respiratory distress syndrome">ARDS</abbr> ... Hepatitis, nausea, vomiting, diarrhoea, gastrointestinal ischaemia ... Hyponatraemia (dilutional/SIADH), acidosis ... Muscle rigidity, rhabdomyolysis
    Desired effects
    [entactogen] – euphoria, inner peace, social facilitation, 'heightens sexuality and expands consciousness', mild hallucinogenic effects ...
    Clinical associations
    Bruxism, hyperthermia, ataxia, confusion, hyponatraemia (<abbr title="Syndrome of inappropriate anti-diuretic hormone">SIADH</abbr>), hepatitis, muscular rigidity, rhabdomyolysis, <abbr title="Disseminated intravascular coagulation">DIC</abbr>, renal failure, hypotension, serotonin syndrome, chronic mood/memory disturbances ... human data have shown that long-term exposure to MDMA is toxic to serotonergic neurones.75,76</q>
     
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出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2015/05/16 18:45:35」(JST)

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MDMA
IUPAC命名法による物質名
(RS)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine
臨床データ
胎児危険度分類
  • C[1]
法的規制
  • AU: Prohibited (S9)
  • CA: Schedule III
  • UK: CD Lic
  • US: Schedule I
投与方法 経口, 舌下腺, 吹き入れ, 吸入(蒸気), 注射,[2] 直腸
薬物動態的データ
代謝 肝臓、シトクロムP450オキシダーゼ
半減期 6–10 時間(実際の効果は3–5時間)
排泄 尿
識別
CAS番号 69610-10-2
ATCコード None
PubChem CID 1615
ChemSpider 1556
別名 (±)-1,3-benzodioxolyl-N-methyl-2-propanamine;

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

methylenedioxymethamphetamine
化学的データ
化学式 C11H15NO2 
分子量 193.25 g/mol

3,4-メチレンジオキシメタンフェタミン (3,4-methylenedioxymethamphetamine) は、合成麻薬の一種。略称としてMDMA、ほかエクスタシー(EcstasyまたはXTC)という通称を持つ。

心理学者のラルフ・メッツナー(英語版)がMDMAに対してエンパソーゲン(empathogen、共感をもたらす)という言葉を作った[3]。後により正確な表現としてエンタクトゲン(entactogen、内面のつながりをもたらす)という呼称が提唱され、精神薬理学の分野で採用されている[4]

類似の薬物としてMDA(3,4-メチレンジオキシアンフェタミン)、MDEA(3,4-メチレンジオキシ-N-エチルアンフェタミン)なども知られ、MDMAと同様にエンパソーゲンないしエンタクトゲンへ分類される。

目次

  • 1 生理的作用
  • 2 乱用と医療用途
  • 3 錠剤型麻薬
  • 4 歴史
  • 5 日本での規制
  • 6 脚注

生理的作用

MDMAは脳内のセロトニン等を過剰に放出させることにより、人間の精神に多幸感、他者との共有感などの変化をもたらすとされる。MDMAを経口的に摂取すると30分から1時間ほどで前述のような精神変容が起こり、それが4~6時間程度持続するとされる。

MDMAを摂取すると、体温をコントロールする機能の喪失による高体温や不整脈などによって重篤な症状を引き起こす場合がある。特に暖かい換気の悪い室内、激しい運動を伴う場合、また大量の発汗を伴い水分補給が十分でない場合などに使用すると合併症を生じやすいとされる。低ナトリウム血症、急性腎不全、横紋筋融解症などで死亡することもある。また、摂取後に重度の不安(不安障害)、妄想、気分の障害、記憶障害、睡眠障害、衝動性の亢進、注意集中の困難などが長期間続くことがある。

乱用と医療用途

MDMAは1985年まで主にアメリカにおいて心的外傷後ストレス障害 (PTSD) の治療に用いられてきた。PTSDは患者が自身に起きたトラウマ体験を自己の記憶として受容できないことによる疾患だとされているが、MDMAを摂取した状態でカウンセリングを行うことにより、通常の精神状態では許容しがたいトラウマ体験を想起させ、自己に起きた事実であることを受け入れることによって疾患が軽減もしくは治癒するという理論に基づいたものである。こうしたPTSDに対する医療用途に対する報道はアメリカでは広範になされており、2010年に少なくとも138以上のメディアで取り上げられている[5]

しかしMDMAは嗜好品 (recreational drug) としての側面も持ち、濫用が社会問題化したことを受け米国司法省麻薬取締局はMDMAを規制物質法におけるスケジュールI、すなわち濫用性が高く医療用途の見込みのない違法薬物に指定した。現在ではほとんどの国でMDMAは違法薬物とされている。以降MDMAは嗜好品として違法に濫用され続け今日に至るが、依然としてPTSDへの有用性を主張する声も根強く、2001年にはアメリカ食品医薬品局 (FDA) が、2004年にはDEAがPTSD患者へのMDMAの治験を認める措置が取られることとなり、2008年にはフェイズII治験が終了。続いてイスラエル、スイス、カナダでも臨床試験が行われる。しかし依然としてMDMAが濫用性の高い薬物であることには変わりなく、安全性や依存性の検証、濫用防止などクリアしなければならない問題点は多い。

錠剤型麻薬

錠剤型のMDMA。禁制薬物なので、医薬品なら当然存在する識別用コード番号が打たれていない

「エクスタシー」は本来MDMAを指す隠語である。しかしMDMAは錠剤の形を取って流通する場合が多いため、単に(MDMAを含むと期待される)錠剤型麻薬を総じてエクスタシーと呼ぶことも多い。錠剤型麻薬としては他にも「X」、「E」、「アダム」など多数の俗称を持ち、また日本では、丸い錠剤が多いことから「玉(たま)」、また「X」から転じて「バツ」、「ペケ」の俗称をも持つ。

一般に錠剤型麻薬は違法に製造されるため、MDMA以外の薬物である可能性、また他の成分が混入されている可能性、有害な不純物が残留している可能性などが非常に高く、MDMAの効用を高めるために意図的にパラメトキシアンフェタミンなど、他の薬物を混入することも少なくない。したがって単体としてのMDMAの安全性と錠剤型麻薬の安全性は別個のものとして考えなければならない。錠剤型麻薬の押収量が増加し、世界中で深刻な社会問題となっている。

歴史

  • 1912年、ドイツの化学メーカーメルク社が、食欲抑制剤として初めて合成し、製法特許を取得した(製品化はされなかった)。
  • 1967年、アメリカ軍による機密扱いが解けたことから化学文献への記載が始まり、1970年代から1980年代初頭までは精神科医の間で、PTSDの治療などに頻用された。
  • 1978年、ダウ・ケミカル社の化学者だったアレクサンダー・シュルギンらによる著作『幻覚剤の薬学』が出版され、嗜好品として爆発的な拡大が始まった。
  • 1985年6月、米国司法省麻薬取締局 (DEA) がエクスタシーを非合法とした。現在ではコカイン、ヘロイン、大麻と同様に、アメリカで広く用いられる麻薬の一つとされる。

そのダンス音楽との親近性により、1980年代後半からイギリスなどを中心に起こったセカンド・サマー・オブ・ラブブームやレイヴの代名詞として普及する。欧州では近年では価格の低下により若年層への普及が懸念されている。

日本での規制

日本では、麻薬及び向精神薬取締法によって規制されている。

MDMAの輸入、輸出、製造は1年以上10年以下の懲役。譲受け、譲渡し、所持は7年以下の懲役。施用(しよう、経口摂取など、身体に用いること)は7年以下の懲役となる。</dd>
錠剤型麻薬が覚せい剤(アンフェタミンなど)を含んでいた場合、覚せい剤取締法により、譲受け、譲渡し、所持、使用は10年以下の懲役となる。</dd>

合成麻薬MDMAは記憶系統の混乱を発生させる要因を作り出す。その作用として神経細胞の破壊及び永続的な(数ヶ月~数年とも言われている)後遺症をもたらす。特に混合成分(合成麻薬と言われる由縁)の内、覚醒剤や亜覚醒剤と併用された場合には複雑な精神面・身体面における害反応があり、前述の多様な記憶障害を引き起こす。

海外で行われたレイヴパーティー等ではときどき死亡者がでているが、全体としては少数である。

脚注

  1. ^ Stimulants, Narcotics, Hallucinogens - Drugs, Pregnancy, and Lactation., Gerald G. Briggs, OB/GYN News, 1 June 2003.
  2. ^ “Methylenedioxymethamphetamine (MDMA, ecstasy)”. Drugs and Human Performance Fact Sheets. National Highway Traffic Safety Administration. 2009年4月16日閲覧。
  3. ^ マーティン・トーゴフ 『ドラッグ・カルチャー-アメリカ文化の光と影(1945~2000年)』 宮家あゆみ訳、清流出版2007年。ISBN 978-4860292331。436頁。
  4. ^ Nichols DE. "Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens" J Psychoactive Drugs 18(4), 1986 Oct-Dec, pp. 305-13. PMID 2880944
  5. ^ 138 articles about mdma/ptsd therapy(MAPS、2010年7月30日)



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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[1]
Addiction
liability
Moderate[2]
Routes of
administration
Oral, sublingual, insufflation, inhalation (vaporization), injection,[3] rectal
Pharmacokinetic data
Metabolism Hepatic, CYP450 extensively involved, including CYP2D6
Onset of action Immediate
Half-life (R)-MDMA: 5.8 ± 2.2 hours[4]
(S)-MDMA: 3.6 ± 0.9 hours[4]
Excretion Renal
Identifiers
CAS Registry Number
42542-10-9 Y[TOXNET]
ATC code
None
PubChem CID 1615
IUPHAR ligand 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
193.24 g/mol
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.[5][6] "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.[12]

Possession of MDMA is illegal in most countries. Some limited exceptions exist for scientific and medical research. For 2012, the UNODC estimated between 9.4 and 28.24 million people globally used MDMA at least once in the past year. This was broadly similar to the number of cocaine, substituted amphetamine, and opioid users, but far fewer than the global number of cannabis users.[13] 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.[14]

Medical reviews have noted that MDMA has some limited therapeutic benefits in certain mental health disorders, but has potential adverse effects, such as neurotoxicity and cognitive impairment, associated with its use.[15][16] 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.[15][16]

Contents

  • 1 Uses
    • 1.1 Medical
    • 1.2 Recreational
      • 1.2.1 Recreational effects
      • 1.2.2 Purity and adulterants
  • 2 Adverse effects
    • 2.1 Immediate effects
    • 2.2 After-effects
    • 2.3 Long-term effects
    • 2.4 Dependence and withdrawal
  • 3 Overdose
    • 3.1 Chronic use and addiction
  • 4 Interactions
  • 5 Pharmacology
    • 5.1 Pharmacodynamics
    • 5.2 Pharmacokinetics
  • 6 Physical and chemical properties
    • 6.1 Synthesis
      • 6.1.1 Yield
    • 6.2 Detection in body fluids
  • 7 History
    • 7.1 Early research
    • 7.2 Shulgin's research
    • 7.3 Rising use
    • 7.4 Scheduling
    • 7.5 Post-scheduling
  • 8 Society and culture
    • 8.1 Legal status
    • 8.2 Economics
      • 8.2.1 Europe
      • 8.2.2 North America
      • 8.2.3 Australia
    • 8.3 Controversy
      • 8.3.1 Harm assessment
  • 9 Research
  • 10 References
  • 11 External links

Uses

Medical

See also: MDMA § Research

MDMA currently has no accepted medical uses.[13][17]

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.[18] 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.[19]

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,[20] most of the more common combinations have been given nicknames, such as "candy flipping" for MDMA combined with LSD, "hippie 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 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.

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.[23]

The desired short-term psychoactive effects of MDMA include:

  • Euphoria – a sense of general well-being and happiness[15][24]
  • Increased sociability and feelings of communication being easy or simple[15][24]
  • Entactogenic effects – increased empathy or feelings of closeness with others[15][24]
  • A sense of inner peace[24]
  • Mild hallucination (e.g., colors and sounds are enhanced and mild closed-eye visuals)[24]
  • Enhanced sensation, perception, or sexuality[15][24]

Purity and adulterants

The average tablet contains 60–70 mg (base equivalent) of MDMA, usually as the hydrochloride salt.[17] Powdered MDMA is typically 30–40% pure, due to bulking agents (e.g., lactose) and binding agents.[17] Tablets sold as ecstasy sometimes only contain 3,4-methylenedioxyamphetamine (MDA) instead of MDMA;[4][17] the proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.[17]

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

The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.[24][25] 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.[24][25][26]

The immediate adverse effects of MDMA use can include:

  • Dehydration[18][24][25]
  • Hyperthermia[18][24][25]
  • Bruxism (grinding and clenching of the teeth)[15][18][24]
  • Increased wakefulness or insomnia[24]
  • Increased perspiration and sweating[24][25]
  • Increased heart rate and blood pressure[18][24][25]
  • Loss of appetite[4]
  • Nausea and vomiting[15]
  • Diarrhea[24]
  • Erectile dysfunction[27]
  • Mydriasis[28]

After-effects

The effects that last up to a week[15][29] following cessation of moderate MDMA use include:

Physical</dt>

  • Trismus[15]
  • Loss of appetite[29]
  • Insomnia[29]

Psychological</dt>

  • Anxiety or paranoia[29]
  • Depression[15][29]
  • Irritability[29]
  • Impulsiveness[29]
  • Restlessness[29]
  • Memory impairment[15]
  • Anhedonia[29]

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.[2][4] In addition, long-term exposure to MDMA in humans has been shown to produce marked neurotoxicity in serotonergic axon terminals.[18][24][30] Neurotoxic damage to axon terminals has been shown to persist for more than two years.[30] Brain temperature during MDMA use is positively correlated with MDMA-induced neurotoxicity in animals.[18] Adverse neuroplastic changes to brain microvasculature and white matter also seem to occur in humans using low doses of MDMA.[18] Reduced gray matter density in certain brain structures has also been noted in human MDMA users.[18] In addition, MDMA has immunosuppressive effects in the peripheral nervous system, but pro-inflammatory effects in the central nervous system.[31] 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.[16][32]

MDMA also produces persistent cognitive impairments in human users.[1][15][16] Impairments in multiple aspects of cognition, including memory, visual processing, and sleep have been noted in humans;[15][16] the magnitude of these impairments is correlated with lifetime ecstasy or MDMA usage.[1][15][16] 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).[15][16]

Dependence and withdrawal

Some studies indicate repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug.[33][34][35] Other meta analyses have reported possibility of impairment of executive functioning.[36] Approximately 60% of MDMA users experience withdrawal symptoms, including, but not limited to: fatigue, loss of appetite, depression, and trouble concentrating.[4] Tolerance is expected to occur with consistent MDMA use.[4]

Overdose

Overdose symptoms vary widely with MDMA; they can include:

Overdose symptoms by system
System Symptom
Cardiovascular
  • Disseminated intravascular coagulation[24]
  • Intracranial hemorrhage[24]
  • Severe hypertension[24][37] or hypotension[24]
Central nervous
system
  • Abnormally fast reflexes[38]
  • Agitation[24][37]
  • Cognitive and memory impairment[24] potentially to the point of retrograde or anterograde amnesia[39]
  • Coma[18][37]
  • Convulsions[24][37]
  • Hallucinations[24][37]
  • Loss of consciousness[18]
  • Mental confusion[24]
  • Paranoia[24][37]
  • Serotonin syndrome[18][24][26]
  • Stimulant psychosis[18]
Musculoskeletal
  • Muscle rigidity[24]
  • Rhabdomyolysis (i.e., rapid muscle breakdown)[24][26]
Respiratory
  • Acute respiratory distress syndrome[24]
Urinary
  • Renal failure[24]
Other
  • Cerebral edema[18]
  • Hepatitis[24][26]
  • Hyperpyrexia (a life-threatening elevation of body temperature)[24][26]
  • Hyponatremia (Syndrome of inappropriate antidiuretic hormone)[24][25][26]

Chronic use and addiction

Main article: ΔFosB
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
v · t · e
Note: colored text contains article links.
Nuclear pore
Nuclear membrane
Plasma membrane
Cav1.2
NMDAR
AMPAR
DRD1
DRD5
DRD2
DRD3
DRD4
Gs
Gi/o
cAMP
cAMP
PKA
CaM
CaMKII
DARPP-32
PP1
PP2B
CREB
ΔFosB
JunD
c-Fos
SIRT1
HDAC1
[Color legend 1]
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methylphenidate, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[40][41] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a <abbr title="cyclic adenosine monophosphate">cAMP</abbr> pathway and calcium-dependent pathway that ultimately result in increased <abbr title="cAMP response element-binding protein">CREB</abbr> phosphorylation.[42][43][44] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors;[43] c-fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[45] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated exposure to stimulants through this process.[46][47] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[46][47] 

MDMA has been shown to induce ΔFosB in the nucleus accumbens.[48] Since MDMA releases dopamine in the mesocorticolimbic projection, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other psychostimulants.[48][49] 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.[49]

Interactions

A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.[4][50] MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors.[4] Concurrent use of MDMA with another serotonergic drug can result in a life-threatening condition called serotonin syndrome.[4] Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors,[4] such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).[51]

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).[4][52][53] 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;[52] 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).[52][54] MDMA inhibits both vesicular monoamine transporters (VMATs), the second of which (VMAT2) is highly expressed within monoamine neurons at vesicular membranes.[53] Once inside a monoamine neuron, MDMA acts as a VMAT2 inhibitor and a TAAR1 agonist.[52][53] Inhibition of VMAT2 by MDMA results in increased concentrations of the associated neurotransmitter (serotonin, norepinephrine, or dopamine) in the cytosol of a monoamine neuron.[53][55] 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.[52] 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.[52]

In summary, MDMA enters monoamine neurons by acting as a monoamine transporter substrate.[52] MDMA activity at VMAT2 moves neurotransmitters out from synaptic vesicles and into the cytosol;[53] MDMA activity at TAAR1 moves neurotransmitters out of the cytosol and into the synaptic cleft.[52]

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.[56][57][58][59] 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.[60](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).[61]

MDMA is a ligand at both sigma receptor subtypes, though its efficacies at the receptors have not yet been elucidated.[62]

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.[63] 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.[64]

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.[65]

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.[28] 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.[66][non-primary source needed]

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[67] 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[68] 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).[4] However, because MDMA excretion and metabolism have nonlinear kinetics,[69] the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose[63]).

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.[17] The most common salt of MDMA is the hydrochloride salt;[17] pure MDMA hydrochloride is water soluble and appears as a white or off-white powder or crystal.[17]

Synthesis

There are numerous methods available in the literature to synthesize MDMA via different intermediates.[70][71][72][73] 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.[74][75] 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.[13] 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]

</dd>
</dd>

Yield

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 allows 500 ml of the oil to produce between 150 and 340 grams of MDMA.[76]

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.[77][78][79]

History

Early research

German patent for MDMA (methylsafrylamin) 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.[80] On 24 December 1912, Merck filed two patent applications that described the synthesis of MDMA[81] and its subsequent conversion to methylhydrastinine.[82]

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.[80]

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.[83] A 1960 Polish paper describing the synthesis of MDMA was the first published scientific paper on the substance.[80]

Shulgin's research

Alexander Shulgin in March 2010

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.[84] MDMA was being used recreationally in the Chicago area by August 1970.[84][85]

Shulgin first heard of the effects of N-methylated MDA in 1975 from a student acquaintance who reported "amphetamine-like content".[84] Around late May 1976, Shulgin again heard about the effects of N-methylated MDA,[84] this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University.[86][87] 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.[84][86] Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.[84] 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".[88] Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug "window".[89]

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.[90] 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.[91][92] Zeff named the drug "Adam", believing it put users in a state of primordial innocence.[86]

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.[93] By the time MDMA was criminalized in 1985, this network of MDMA users consumed an estimated 500,000 doses.[15][94]

A small recreational market for MDMA had developed by the late 1970s.[95] Into the early 1980s, production of MDMA was dominated by a small group of Boston chemists known as the "Boston group".[96] With demand for MDMA growing, the Southwest distributor for the "Boston group" started the "Texas group"[96] supported by several former cocaine dealers who had experienced MDMA.[94][95] The "Texas group" mass-produced MDMA in a Texas lab[93] or imported it from California[89] 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[93] and advertised as a "fun drug" and "good to dance to".[95] MDMA was openly distributed in Dallas area bars and nightclubs and became popular with yuppies, college students, and gays.[94] "Ecstasy" was recognized as slang for MDMA by 1981,[96] named by "Texas group" leader Michael Clegg[97] over the alternative "empathy" for broader marketing appeal.[93]

Scheduling

The 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.[94] 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.[93] The drug was first proposed for scheduling by the DEA on 27 July 1984 with a request for comments and objections.[98] The DEA was surprised when a number of physicians, therapists, and researchers objected to the proposed scheduling and requested a hearing.[96] In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.[99]

MDMA was classified as a Schedule I controlled substance in the U.S. on 31 May 1985 on an emergency basis.[100] 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.[96] 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.[96][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.[101]

Post-scheduling

In the late 1980s, MDMA began to be widely used in Ibiza,[102] 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.[89] According to some estimates as of 2004, only marijuana attracts more first time users in the U.S.[89]

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).[103]

"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.[104][105]

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,[106] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.[107]

Society and culture

Global estimates of illicit drug users in 2012
(in millions of users)[13]
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 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,[108] 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.[109] 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.[110] 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."[111]

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.[111][112][113]

In Canada, MDMA is listed as a Schedule 1[114] as it is an analogue of amphetamine.[115] 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.[116] 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.[117]

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.[118] 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.[119] 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.[120]

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.[121]

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.[121][122] A later 2010 UK study which took into account impairment of cognitive functioning placed MDMA at number 17 out of 20 recreational drugs.[123]

Research

MAPS is currently funding pilot studies investigating the use of MDMA in PTSD therapy[124] and social anxiety therapy for autistic adults.[125]

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;[16] however, it emphasized that MDMA is not a safe medical treatment due to lasting neurotoxic and cognition impairing effects in humans.[16] The author noted that oxytocin and D-cycloserine are potentially safer co-drugs in PTSD treatment, albeit with limited evidence of efficacy.[16] 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.[15][16]

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    Desired effects
    [entactogen] – euphoria, inner peace, social facilitation, 'heightens sexuality and expands consciousness', mild hallucinogenic effects ...
    Clinical associations
    Bruxism, hyperthermia, ataxia, confusion, hyponatraemia (<abbr title="Syndrome of inappropriate anti-diuretic hormone">SIADH</abbr>), hepatitis, muscular rigidity, rhabdomyolysis, <abbr title="Disseminated intravascular coagulation">DIC</abbr>, renal failure, hypotension, serotonin syndrome, chronic mood/memory disturbances ... human data have shown that long-term exposure to MDMA is toxic to serotonergic neurones.75,76</q>
     
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  123. ^ 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. 
  124. ^ Zarembo, Alan (15 March 2014). "Exploring therapeutic effects of MDMA on post-traumatic stress". Los Angeles Times (Los Angeles Times). Retrieved 22 February 2015. 
  125. ^ 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. 
  1. ^
      Ion channel
      G proteins & linked receptors
      (Text color) Transcription factors

External links

  • MDMA Facts and Statistics



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Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2017/03/02 12:38:04」(JST)

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<raw>
MDMA
IUPAC命名法による物質名
臨床データ
胎児危険度分類
  • C[1]
法的規制
  • <abbr title="オーストラリア">AU</abbr>: Prohibited (S9)
  • <abbr title="カナダ">CA</abbr>: Schedule III
  • <abbr title="イギリス">UK</abbr>: 規制薬物 Lic
  • <abbr title="アメリカ合衆国">US</abbr>: スケジュールI
投与方法 経口, 舌下腺, 吹き入れ, 吸入(蒸気), 注射,[2] 直腸
薬物動態データ
代謝 肝臓、シトクロムP450オキシダーゼ
半減期 6–10 時間(実際の効果は3–5時間)
排泄 尿
識別
CAS番号
(MeSH)
69610-10-2
ATCコード none
PubChem CID: 1615
ChemSpider 1556
別名 (±)-1,3-benzodioxolyl-N-methyl-2-propanamine;

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

methylenedioxymethamphetamine
化学的データ
化学式 C11H15NO2
分子量 193.25 g/mol

3,4-メチレンジオキシメタンフェタミン (英:3,4-methylenedioxymethamphetamine)、あるいはMDMAは、アンフェタミンと類似した化学構造を持つ化合物である[3]。愛の薬などと呼ばれ共感作用がある。幻覚剤に分類される[4][5][6]。心的外傷後ストレス障害(PTSD)に対し、MDMAを併用した心理療法の臨床試験が米国で進行している[7]

俗にエクスタシーあるいはモリーと呼ばれている[3]。エクスタシーなどとして街角で売られる薬物は、様々な純度であり、時にはMDMAはまったく含まれない[3]。何がどれくらい含まれているか不明であり、過剰摂取の危険性が高い[8]。一部では休みなく踊ることが原因で高熱や脱水から死亡し、逆に、それに対処しようと水をとりすぎて低ナトリウム血症で死亡している[8]

心理学者のラルフ・メッツナー(英語版)がMDMAに対してエンパソーゲン(empathogen、共感をもたらす)という言葉を作った[9]。同種の作用のある薬物としてMDA(3,4-メチレンジオキシアンフェタミン)、MDEA(3,4-メチレンジオキシ-N-エチルアンフェタミン)なども知られ、エンタクトゲン(entactogen、内面に触れる)と呼ばれる[10]

目次

  • 1 用語
    • 1.1 俗称
  • 2 分類
  • 3 化学的性質
  • 4 作用
  • 5 作用量
  • 6 薬物動態
  • 7 医療用途
    • 7.1 法的規制
    • 7.2 臨床試験
  • 8 乱用
  • 9 依存性
  • 10 エクスタシー錠剤
  • 11 副作用
  • 12 死亡
  • 13 歴史
  • 14 日本での規制
  • 15 出典
  • 16 参考文献
  • 17 外部リンク

用語

MDMAを臨床現場にて初めて使ったレオ・ゼフ(英語版)は、患者に投与する際にMDMAをアダムと呼んだ[3]

俗称

MDMAは、俗にエクスタシー(Ecstacy)と呼ばれ、英語圏では21世紀初頭には本来の高揚感の意味と同じように定着している[10]。初期の娯楽使用のための提供者は、作用を適切に説明するエンパシー(Empathy、共感の意味)と呼んだが、後に潜在的な顧客により訴えかけるためにエクスタシーに決めた[10]。他にEとか、X、あるいはEXCと呼ばれる[10]

モリー(Molly)とも呼ばれている[3]。これは2010年以降の呼称であり、混ざり物のない粉末のMDMAを指しているが、しばしば別の薬物であるという報道がなされている。

このような呼称で、街角で手に入る錠剤は、時にはMDMAをまったく含んでいない[3]

日本では、丸い錠剤が多いことから(たま)、またXから転じてバツペケの俗称をも持つ。

分類

世界保健機関の1994年の薬物に関する用語集[4]、世界保健機関の『疾病及び関連保健問題の国際統計分類』第10版(ICD-10)[5]、アメリカ精神医学会の『精神障害の診断と統計マニュアル』第4版(DSM-IV)において [6]、幻覚剤に分類されている。

なお化学構造からは、精神刺激薬のアンフェタミン類に分類される。

MDMA、MDA、MDE、MBDBはフェネチルアミンの一群に属し、それらは同様の作用を持つことからエンタクトゲン(entactogens[11]、内面に触れる)と呼ばれる[10]

化学的性質

常温では白色の結晶または粉末。分子構造はメタンフェタミンに類似し、メタンフェタミンのフェニル基の一部を置換したものと同一である。このためMDMAもメタンフェタミンと同じく光学異性体を持つ。

作用

MDMAは脳内のセロトニン等を過剰に放出させることにより、人間の精神に多幸感、他者との共感などの変化をもたらすとされる。MDMAを経口的に摂取すると30分から1時間ほどで前述のような精神変容が起こり、それが4~6時間程度持続するとされる。

典型的な幻覚剤とは異なる心理的作用を有する[7]

MDMAは認知と社会的相互作用に影響を与え、開放性や感情への反応性を増加させ、他者への親近感を生じさせる[7]。使用者はおしゃべりで友好的な感じになったことを報告するが、一方、制御できないという不安を経験することもある[7]

MDMAはオキシトシンの放出を増加させる[7]。並行して、神経生物学的領域における研究、神経プチペドのオキシトシンとバソプレッシンによる人間のつながりと触れ合いの影響についてのものが進行している[7]。オキシトシンは哺乳類における、つがいの形成や社会的所属と関連している[7]

作用量

ヒトでの作用量を挙げる。

臨床試験の、治療抵抗性の心的外傷後ストレス障害(PTSD)における使用量は、体重1キログラムあたり、約2ミリグラム以下である[3]。同1ミリグラムから、知覚や認知や気分に変化を生じさせる[7]

PiHKAL(英語版)には、80から150mgと書かれている[12]

街角のエクスタシー錠剤では、1錠ごとにも含有量が異なり、最も少ないものと多いものでは7倍の差がある[3]。経験豊富な使用者では増やす場合があるが、動物実験にて耐性が生じるため、耐性が原因であると考えられる[3]。MDMAの過剰摂取は重篤な状態や死亡につながることがある[3]。またエクスタシー錠剤が、混じりもののないMDMAを含んでいることは少ない[7]。未知の薬物では、致命的な過剰摂取につながることがある[13]

薬物動態

作用開始は投与から30~45分後であり、ピークは90~120分、3~6時間後に投与前に戻る[7]

MDMAの半減期は約7時間であるが、代謝産物のMDAは16~38時間である[7]

抗レトロウイルス薬やモノアミン酸化酵素阻害薬(MAOI)との併用は、命に関わるような高血圧を引き起こすことがある[7]

MDMAは、CYP2D6で代謝される[7]

医療用途

過去には、様々に用いられたこともあったが、それらは二重盲検など、現在の科学的研究における最良の慣行が行われていない[7]

法的規制

その初期から治療の可能性のある薬として認識されていたが、MDMAは「医療用途がない」というスケジュールIに分類されており、しかし証拠はスケジュールIIに移動させるのに十分であり、そうすることで治療抵抗性PTSDを有する人など深刻な精神障害のある人々への医薬品を解放することになる[14]

臨床試験

アメリカでは、心的外傷後ストレス障害(PTSD)に対するMDMAを併用した心理療法の臨床試験が進行しており、第II相の4つの試験では慢性的(長期の)PTSDを患う退役軍人や警察官や消防士を含んでいる[7]。2016年11月には、第III相の臨床試験が承認されている[15]

CAPSというPTSDの症状の評価尺度にて、79点台の症状は、MDMA支援心理療法53.7点の低下、心理療法のみでは20.5点の低下であった[7]。さらに症状の改善は3.8年継続されている[7]。比較として、セルトラリン(ゾロフト)のPTSDのためのFDAの臨床試験では、10.2点の低下である[7]。これらのPTSDは平均19.5年の治療抵抗の期間を持ち、MDMA支援心理療法の治療から4年後に2人が再発したが、症状の改善は維持されていた[16]

こうしたPTSDに対する医療用途に対する報道はアメリカでは広範になされており、2010年に少なくとも138以上のメディアで取り上げられている[17]

イスラエル、スイス、カナダでも臨床試験が行われている。イギリスでも標準的な国民保健サービスの診療所にてこのような治療を提供できるようにと研究が進んでいる[18]。試験はテレビで放映もされた[19]。薬物に関する独立科学評議会#ドラッグス・ライブ参照。

アメリカで、成人の自閉症の患者の社交不安[7]、および、がん患者の抑うつに用いる臨床試験も行われている[20]

自閉症の中核症状である社会性の問題は、集中的な行動介入によく反応し鍛えることが可能であることが実証されているが、薬としては見つかっておらず、社会的動機と社会的認知を高めるような向社会的化合物(Prosocial Compounds)として、オキシトシンとバソプレッシンと共にMDMAは注目される[21]

乱用

MDMAは、娯楽薬としての側面も持ち、乱用が社会問題化したことをもって、各国では規制されている。

アメリカでの2011年の全国調査から、12歳以上の約1450万人が、生涯においてMDMAを一度は使用していると推定される[3]

依存性

アカゲザルにおける動物実験では、MDMAの自己投与は継続的に維持されなかった[22]。他の研究では、げっ歯類にてコカインにて報告されている強い強化因子とは異なり弱いとしている[23]。霊長類および、げっ歯類におけるMDMA自己投与の研究を探索し、大半の研究にて他の薬物よりも強化因子として弱いことが見いだされた[24]

頻繁に使用する人でも、他の薬物に見られるように集中的に使用するということは見られない[7]。MDMAは、アルコールやタバコ、ヘロインなどと比較したとき依存性が低い[8]

エクスタシー錠剤

エクスタシー錠剤。こうした街角で入手されるエクスタシー錠剤はMDMAがまったく含まれない場合がある[3]。エクスタシーの名での販売は、錠剤か粉末か、様々な成分、また色や形、ブランド名によって発展してきた[10]
結晶状の MDMA。変質前は典型的には白色。

1990年前後の初期の時代には、エクスタシーは白や色のついた小さな錠剤であったが、1990年代後半から世紀が変わる頃には、多種多様な色や形を持ったブランディング現象が生じた[10]。こうしたマーケティング現象は、エクスタシーがはじめてではなくLSDの長い歴史を持っている[10]。LSDでは虹やピースマークの記号といったヒッピー風であるのに対し、エクスタシーではルイ・ヴィトン、モトローラや三菱といったブランドであり中流階級的な社会が反映され、特定のブランドに人気を示す場合がある[10]。サンフランシスコのベイエリアでは、混ざりもののないMDMAだと供給者が主張する粉末状のエクスタシーには、錠剤以上の人気がある[10]

エクスタシーとして街角で売られる錠剤は様々な純度であり、時にはMDMAはほとんど含まれないか、まったく含まれない[3]。北米での2007年の調査ではわずか3%だけが混じりもののないMDMAを含んでいた[7]

EcstasyData.org[25]のデータから推定可能であり、2012年12月から、2013年4月の間の65種類の錠剤およびカプセルからは、およそ半分は67%以上のMDMAを含み、半分はそれ以下で多くの場合はまったく含んでいない[3]

世界の多くの地域で、2010年代にエクスタシーとして販売された多くの錠剤には、MDMA以外の物質が含まれている[26]。それは既存の違法な薬物や、新規向精神薬(NPS)、またカフェインやエフェドリンである[10]

MDMAでなくMDA、MDEやMBDBを含むことがある[10]。また、まったく作用が異なる薬物を含むことがある。2014年の国連の報告書では、アジア、アメリカ、欧州とで、メタンフェタミンやケタミン、アメリカでは2C-B、アジアではJWH-018(英語版)などが検出されている[26]

ダンスセーフ(英語版)という団体は、薬物の使用が避けられないという前提の上で悪影響を最小化するためのハーム・リダクションや、教育を重視しており、サイト上で薬物を検査したり、ナイトスポットで活動している[27]。音楽フェスティバルにおける、そうした取り組み関するドキュメンタリーも作成されており、売人から買った薬物にはメフェドロン、カフェインなど何が混ぜられているかは不明であり、モリーとして買った薬物から合成カチノン類が検出された[28]

副作用

1994年のアメリカの第I相の臨床試験では、体温、心拍数や血圧の上昇が報告されたが、一過性で許容できる範囲である[7]。2014年11月の時点で、第I相と第II相にて合計1,133人の被験者に投与されており、重篤な有害事象は、継続的な調査の中では報告されていない[7]

エクスタシーの使用者は、翌日の抑うつ気分を報告する。異常高熱は、水の入手手段がない暑い空間で活発に踊るなど、医学的監督下にないエクスタシーの使用によって生じ、稀なものであるが最も頻繁に報告されている[7]。その一方これも稀であるが、必要な電解質を摂取せずに水を摂取しすぎて水中毒となり、低ナトリウム血症にて致命的となりうる[7]。また過剰摂取は重篤となりうる。

議論の中心はMDMAに脳損傷を引き起こす神経毒性があるかどうかである[7]。動物実験ではヒトでの娯楽薬としての使用よりもはるかに多い使用量で生じることが見いだされているし、感情や記憶の障害を含む器質的な損傷や、精神医学的な損傷を報告しているが、頻繁に欠陥のある研究手法、疑わしいデータの解析、偏った結論から引き出されている[7]

定期的なエクスタシーの使用者に関する報告が否定的な影響を示唆しているが、エクスタシー錠剤にはMDMA以外の薬物が含まれ、またそうした使用者はエクスタシー以外の多剤を乱用しているため、MDMAが特異的な原因となっているのかは不明確である[3]。エクスタシーの使用者は多くの場合、違法合法を問わず、アルコールやタバコ、大麻やメタンフェタミン、幻覚剤など、多剤の使用者である[3]

死亡

海外で行われたレイヴパーティー等では、ときどき死亡者がでているが、全体としては少数である。(しかし、こうした報道はエクスタシー錠剤がMDMAを含有していたかが不明である)

日本では、2010年に東京23区内で死亡した死因不明の異常死が司法解剖された、5年間で計13,499名の調査がある[29]。2006年から2010年の5年間でMDMA6件、比較のために挙げると、多いものは、医薬品3,337件で睡眠薬や精神科の薬が多く、アルコールは3,018件である[29]

歴史

1912年、ドイツの化学メーカーメルク社によって、抗凝固薬を特定するためのプロジェクトの際に合成され、特許が取得された[3]。後に、合成した化学者による、特性の試験が行われたが、会社の関心を引かず、それ以上のことはなかった[3]。(製品化はされなかった)。食欲抑制剤としてという説もある。

動物における毒性研究は、1950年代に米軍の支援によってミシガン大学でが行われ、後に機密解除が解け、1973年にハードマンが出版する[3]。1967年にアメリカ軍による機密扱いが解けた。

元ダウ・ケミカル社の化学者であったアレクサンダー・シュルギンによって、MDMAが「再発見」されることになる[3]。1978年には、アレクサンダー・シュルギンらによる『幻覚剤の精神薬理学』(The Psychopharmacology of Hallucinogens)にて、ヒトにおける主観的な作用に関する、初の報告が行われた[3]

シュルギンは先に1967年にMDAが深層にある感情への接近を容易にするため、心理療法に有益である可能性を報告していたが、この点でMDMAはMDAより優れていたと評価した[3]。心理学者のレオ・ゼフ(英語版)に紹介し、臨床現場での使用が始まった[3]。1970年代のなかばに研究が開始され、初期の研究者は、従来の治療に反応しないうつ病や心的外傷後ストレス障害(PTSD)といった治療に用い、数千の患者に投与されたが、系統的な研究はなかった[7]

1980年代初期には、アメリカでの娯楽薬(英語版)としての使用が広まる[3]。1985年(5月)に、アメリカ麻薬取締局 (DEA) が、MDMAを(規制物質法の)スケジュールIに分類し、1987年から1988年の短期間を除き、アメリカではこの分類が継続されている[3]

ラブパレード:1990年代には100万人以上を動員した大規模なレイブは、ドイツのベルリンにて行われる[30]。1989年にベルリンの壁は取り壊されたが、それまで壁は1945年から資本主義の西ドイツと、共産主義の東ドイツを分断していた。

その後に、スペインのイビザ島での使用から世界的に広がり、イギリスのクラブシーンやレイヴでは、若者の第一選択薬となった[10]。(セカンド・サマー・オブ・ラブも参照)アメリカでは10年後に国内のレイブシーンが登場するまで、主流の位置は占めなかった[10]

欧州では近年では価格の低下により若年層への普及が懸念されている。

2010年代では、マイリー・サイラスやヒップホップのスヌープ・ドッグなど多くの歌手が歌詞にモリーを登場させている[31]。エレクトロニック・ダンス・ミュージック(EDM)のウルトラ・ミュージック・フェスティバル・マイアミでは、歌手のマドンナは聴衆に向かって「この中でモリーを見たことがある人はどれくらいいる?」と語りかけた[32]。彼女は『MDNA』というアルバムを出していた[32]。2013年には、アメリカで6回分摂取したロトンドが死亡し、音楽フェスティバルが閉鎖された[33]

2015年にはオランダの青年自由民主党は、音楽フェスティバルでのエクスタシーによる死亡を踏まえて、危険性をアピールするために、アムステルダムに1日限定で「XTC shop」を開店した[34]。偽薬が販売されたが、アピールには非犯罪化の議論が含まれ、違法な売人から買うよりも、害を最小化できるというハーム・リダクションの考えを議論するための署名を求めた[34]

2016年夏には、ダンスセーフの創始者エマニュエル・スフェリオスの作成したドキュメンタリー映画『MDMAザ・ムービー』(日本では未定)が公開される。映画は、PTSDに対するMDMAを併用した治療の研究や、MDMAの歴史を取り扱う。

日本での規制

日本では、麻薬及び向精神薬取締法によって規制されている。 MDMAの輸入、輸出、製造は1年以上10年以下の懲役。譲受け、譲渡し、所持は7年以下の懲役。施用(しよう、経口摂取など、身体に用いること)は7年以下の懲役となる。

出典

  1. ^ Stimulants, Narcotics, Hallucinogens - Drugs, Pregnancy, and Lactation., Gerald G. Briggs, OB/GYN News, 1 June 2003.
  2. ^ “Methylenedioxymethamphetamine (MDMA, ecstasy)”. Drugs and Human Performance Fact Sheets. National Highway Traffic Safety Administration. 2009年4月16日閲覧。
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y MDMA current perspectives 2013.
  4. ^ a b 世界保健機関 (1994) (pdf). Lexicon of alchol and drug term. World Health Organization. ISBN 92-4-154468-6. http://whqlibdoc.who.int/publications/9241544686.pdf.  (HTML版 introductionが省略されている)
  5. ^ a b 世界保健機関 『ICD‐10精神および行動の障害:臨床記述と診断ガイドライン』 医学書院、2005年、新訂版、39頁。ISBN 978-4-260-00133-5
  6. ^ a b アメリカ精神医学会 『DSM-IV-TR 精神疾患の診断・統計マニュアル(新訂版)』 医学書院、2004年、§幻覚剤関連障害。ISBN 978-0890420256
  7. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Danforth, Struble & Yazar-KlosinskiGrob 2016.
  8. ^ a b c MDMA / 'Ecstasy' (英語) 薬物に関する独立科学評議会、LastUpdate:2013-9-4日
  9. ^ マーティン・トーゴフ 『ドラッグ・カルチャー-アメリカ文化の光と影(1945~2000年)』 宮家あゆみ訳、清流出版2007年。ISBN 978-4860292331。436頁。
  10. ^ a b c d e f g h i j k l m n What's in a Label? 2009.
  11. ^ Nichols DE. "Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens" J Psychoactive Drugs 18(4), 1986 Oct-Dec, pp. 305-13. PMID 2880944
  12. ^ Alexander and Ann Shulgin (1991). PiHKAL:A Chemical Love Story. ISBN 0963009605. 
  13. ^ 薬物に関する独立科学評議会 (Last updated 2014-04-04). “'Legal Highs'/NPS”. Independent Scientific Committee on Drugs. 2014年7月25日閲覧。
  14. ^ Nutt, D.; Sessa, B. (2015). “Making a medicine out of MDMA”. The British Journal of Psychiatry 206 (1): 4–6. doi:10.1192/bjp.bp.114.152751. PMID 25561485. 
  15. ^ MDMA approved for final trials to treat PTSD before possible legalization (2016-12-1) ガーディアン - 2016年12月12日閲覧
  16. ^ Frood, Arran (2012). “MDMA keeps severe stress at bay”. Nature. doi:10.1038/nature.2012.11864. 
  17. ^ 138 articles about mdma/ptsd therapy(MAPS、2010年7月30日)
  18. ^ Sessa B (July 2012). “Shaping the renaissance of psychedelic research”. Lancet 380 (9838): 200–1. doi:10.1016/S0140-6736(12)60600-X. PMID 22817963. 
  19. ^ Helen Brown (2012年9月27日). “Drugs Live: the Ecstasy Trial, Channel 4, review”. Telegraph. http://www.telegraph.co.uk/culture/tvandradio/9569797/Drugs-Live-the-Ecstasy-Trial-Channel-4-review.html 2015年10月1日閲覧。 
  20. ^ Krystle Mitchell (2015年5月29日). “FDA and DEA Approve MDMA Studies”. Guardian Liberty Voice. http://guardianlv.com/2015/05/fda-and-dea-approve-mdma-studies/ 2015年10月1日閲覧。 
  21. ^ Insel, T. R. (October 2012). “Next-Generation Treatments for Mental Disorders”. Science Translational Medicine 4 (155): 155ps19–155ps19. doi:10.1126/scitranslmed.3004873. PMID 23052292. 
  22. ^ Fantegrossi, William E. (2006). “Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?”. Psychopharmacology 189 (4): 471–482. doi:10.1007/s00213-006-0320-8. PMID 16555062. 
  23. ^ De La Garza, R.; Fabrizio, K. R.; Gupta, A. (2006). “Relevance of rodent models of intravenous MDMA self-administration to human MDMA consumption patterns”. Psychopharmacology 189 (4): 425–434. doi:10.1007/s00213-005-0255-5. PMID 16470404. 
  24. ^ Schenk, Susan (2009). “MDMA Self-Administration in Laboratory Animals: A Summary of the Literature and Proposal for Future Research”. Neuropsychobiology 60 (3-4): 130–136. doi:10.1159/000253549. PMID 19893330. 
  25. ^ EcstasyData.org (英語)
  26. ^ a b 国連薬物犯罪事務所 (2014). 2014 Global Synthetic Drugs Assessment (Report). p. 23. http://www.unodc.org/documents/scientific/2014_Global_Synthetic_Drugs_Assessment_web.pdf 2014年10月1日閲覧。. 
  27. ^ Nick Wing (2015年5月20日). “This Music Festival Knows It Can't Stop People From Doing Drugs, So It's Trying To Keep Them Safe Instead”. Huffington Post. http://www.huffingtonpost.com/2015/05/20/lightning-in-a-bottle-festival-drugs_n_7336290.html 2015年10月1日閲覧。 
  28. ^ Ryan Bassil (2014年9月17日). “What's in My Baggie? Well, the MDMA You've Been Taking at Festivals This Summeri s Probably Bath Salts”. Noisey by VICE. https://noisey.vice.com/blog/whats-in-my-baggie-well-the-mdma-youve-been-taking-at-festivals-this-summer-is-probably-bath-salts-interview-documentary-2014 2015年10月1日閲覧。 
  29. ^ a b 福永龍繁「監察医務院から見えてくる多剤併用」、『精神科治療学』第27巻第1号、2012年1月、 149-154頁。 抄録
  30. ^ M. Ter Bogt, Tom F.; M. E. Engels, Rutger C. (2005). ““Partying” Hard: Party Style, Motives for and Effects of MDMA Use at Rave Parties”. Substance Use & Misuse 40 (9-10): 1479–1502. doi:10.1081/JA-200066822. PMID 16048829. 
  31. ^ “Molly Is A Drug & There Are A Lot Of Songs About Molly”. Huffpost Entertainment. (2013年9月5日). http://www.huffingtonpost.com/2013/09/05/molly-drug-songs_n_3874047.html 2015年10月1日閲覧。 
  32. ^ a b Kia Makarechi (2012年3月26日). “Deadmau5 Slams Madonna Over 'Molly,' Ecstasy Reference At Ultra Music Festival”. Huffington Post. http://www.huffingtonpost.com/2012/03/26/deadmau5--madonna-molly-ultra-_n_1379437.html 2015年10月1日閲覧。 
  33. ^ Hollie McKay (2013年9月5日). “Are pop stars who glorify the drug molly responsible when fans use it?”. FoxNews. http://www.foxnews.com/entertainment/2013/09/05/are-pop-stars-who-glorify-dangerous-drug-molly-responsible-when-fans-use-it/ 2015年10月1日閲覧。 
  34. ^ a b “World's first Ecstasy shop to open in Amsterdam on Monday”. mixmag. (2015年5月16日). http://www.mixmag.net/read/worlds-first-ecstasy-shop-to-open-in-amsterdam-on-monday-news 2015年10月1日閲覧。 

参考文献

  • Meyer, Jerry (2013). “3,4-methylenedioxymethamphetamine (MDMA): current perspectives”. Substance Abuse and Rehabilitation: 83. doi:10.2147/SAR.S37258. PMC 3931692. PMID 24648791. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931692/. 
  • Nutt, David J.; Carhart-Harris, Robin L.; Murphy, Kevin; Leech, Robert; Erritzoe, David; Wall, Matthew B.; Ferguson, Bart; Williams, Luke T.J. et al. (2015). “The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level–Dependent Resting State Functional Connectivity”. Biological Psychiatry 78 (8): 554–562. doi:10.1016/j.biopsych.2013.12.015. PMID 24495461. http://www.biologicalpsychiatryjournal.com/article/S0006-3223(14)00005-5/fulltext. 
  • Carhart-Harris, Robin L.; Roseman, Leor; Leech, Robert; Feilding, Amanda; Nutt, David J. (2014). “The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers”. Frontiers in Human Neuroscience 8: 204. doi:10.3389/fnhum.2014.00204. PMC 4034428. PMID 24904346. http://journal.frontiersin.org/article/10.3389/fnhum.2014.00204/full. 
  • Danforth, Alicia L.; Struble, Christopher M.; Yazar-Klosinski, Berra; Grob, Charles S. (2016). “MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults”. Progress in Neuro-Psychopharmacology and Biological Psychiatry 64: 237–249. doi:10.1016/j.pnpbp.2015.03.011. PMID 25818246. http://www.sciencedirect.com/science/article/pii/S0278584615000603. 
  • Duterte, Micheline; Jacinto, Camille; Sales, Paloma; Murphy, Sheigla (2009). “What's in a Label? Ecstasy Sellers' Perceptions of Pill Brands”. Journal of Psychoactive Drugs 41 (1): 27–37. doi:10.1080/02791072.2009.10400672. PMC 2717897. PMID 19455907. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717897/. 
  • doi:10.1016/j.biopsych.2010.08.003:Empathogenですか?とする実際の作用の研究。

映画</dt>

  • MDMA the Movie、2016年夏公開

外部リンク

  • MDMA / 'Ecstasy' (英語) 薬物に関する独立科学評議会
  • Treating PTSD with MDMA-Assisted Psychotherapy (英語) PTSDに対するMDMA支援心理療法の情報ページ

成分データ</dt>

  • EcstasyData.org (英語) ダンスセーフとエロウィドによる実際の薬物と含有成分のデータベース
  • Pill Reports - Ecstasy Test Results Database by Enlighten (英語)


</raw> </toggledisplay>

wiki en

<toggledisplay showtext="[Wiki en表示]" hidetext="[隠す]">

<raw>
Not to be confused with MDA, EDMA or 2,3-MDMA.
MDMA
Clinical data
Pronunciation methylenedioxy­methamphetamine:

/ˈmɛ.θɪ.ln.d.ˈɒk.si./

/ˌmɛθæmˈfɛtəmn/
AHFS/Drugs.com MDMA
Dependence
liability
Physical: not typical[1]
Psychological: moderate
Addiction
liability
Low–moderate[2][3][4]
Routes of
administration
Common: by mouth[5]
Uncommon: snorting,[5] inhalation (vaporization),[5] injection,[5][6] rectal
Drug class empathogen–entactogen
stimulant
ATC code
  • none
Legal status
Legal status
  • <abbr title="Australia">AU</abbr>: S9 (Prohibited)
  • <abbr title="Canada">CA</abbr>: Schedule I
  • <abbr title="Germany">DE</abbr>: Anlage I (Controlled)
  • <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
Pharmacokinetic data
Metabolism Liver, CYP450 extensively involved, including CYP2D6
Metabolites MDA, HMMA, HMA, DHA, MDP2P, MDOH[7]
Onset of action 30–45 minutes (by mouth)[8]
Biological half-life (R)-MDMA: 5.8 ± 2.2 hours[9]
(S)-MDMA: 3.6 ± 0.9 hours[9]
Duration of action 4–6 hours[3][8]
Excretion Kidney
Identifiers
Synonyms <abbr title="3,4-Methylenedioxymethamphetamine">3,4-MDMA</abbr>, ecstasy (E, X, XTC), molly, mandy[10][11]
CAS Number
  • 42542-10-9 Y[TOXNET]
PubChem <abbr title="Compound ID">CID</abbr>
  • 1615
IUPHAR/BPS
  • 4574
DrugBank
  • DB01454 Y
ChemSpider
  • 1556 Y
UNII
  • KE1SEN21RM
KEGG
  • C07577 Y
ChEBI
  • CHEBI:1391 Y
ChEMBL
  • CHEMBL43048 Y
PDB ligand
  • B41 (PDBe, RCSB PDB)
Chemical and physical data
Formula C11H15NO2
Molar mass 193.25 g·mol−1
3D model (Jmol)
  • Interactive image
Chirality Racemic mixture
Boiling point 105 °C (221 °F) at 0.4 mmHg (experimental)
  (verify)

3,4-Methylenedioxymethamphetamine (MDMA),[note 1] commonly known as ecstasy (E), is a psychoactive drug used primarily as a recreational drug. Desired effects include increased empathy, euphoria, and heightened sensations.[12][13][14] When taken by mouth, effects begin after 30–45 minutes and last 3–6 hours.[8][15] It is also sometimes snorted or smoked.[14] As of 2017, MDMA has no accepted medical uses.[5]

Adverse effects of MDMA use include addiction, memory problems, paranoia, difficulty sleeping, teeth grinding, blurred vision, sweating, and a rapid heartbeat. Use may also lead to depression and fatigue. Deaths have been reported due to increased body temperature and dehydration.[14] MDMA increases the release and slows the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine in parts of the brain. It has stimulant and psychedelic effects.[1][16] The initial increase is followed by a short-term decrease in the neurotransmitters.[14][15] MDMA belongs to the substituted methylenedioxyphenethylamine and substituted amphetamine classes of drugs.

MDMA was first made in 1912.[14] It was used to improve psychotherapy beginning in the 1970s and became popular as a street drug in the 1980s.[14][15][17] MDMA is commonly associated with dance parties, raves, and electronic dance music.[18] It is often sold mixed with other substances such as ephedrine, amphetamine, and methamphetamine.[14] In 2014, between 9 and 29 million people between the ages of 15 and 64 used ecstasy (0.2% to 0.6% of the world population). This was broadly similar to the percentage of people who use cocaine, amphetamines, and opioids, but fewer than for cannabis.[19] In the United States, about 0.9 million people used ecstasy in 2010.[14]

MDMA is generally illegal in most countries.[14][20] Limited exceptions are sometimes made for research.[15] Researchers are investigating whether a few low doses of MDMA may assist in treating severe, treatment-resistant posttraumatic stress disorder (PTSD).[12][21] In November 2016, phase 3 clinical trials for PTSD were approved by the United States Food and Drug Administration to assess effectiveness and safety.[22]

Contents

  • 1 Use
    • 1.1 Medical
    • 1.2 Alternative medicine
    • 1.3 Recreational
    • 1.4 Forms
  • 2 Effects
  • 3 Adverse effects
    • 3.1 Short-term
    • 3.2 Long-term
    • 3.3 During pregnancy
    • 3.4 Reinforcement disorders
    • 3.5 Harm assessment
  • 4 Overdose
  • 5 Interactions
  • 6 Pharmacology
    • 6.1 Pharmacodynamics
    • 6.2 Pharmacokinetics
  • 7 Chemistry
    • 7.1 Synthesis
    • 7.2 Detection in body fluids
  • 8 History
    • 8.1 Early research and use
    • 8.2 Shulgin's research and therapeutic use
    • 8.3 Rising recreational use
    • 8.4 Media attention and scheduling
      • 8.4.1 United States
      • 8.4.2 United Nations
    • 8.5 Post-scheduling
  • 9 Society and culture
    • 9.1 Legal status
      • 9.1.1 Australia
      • 9.1.2 United Kingdom
      • 9.1.3 United States
      • 9.1.4 Netherlands
      • 9.1.5 Canada
    • 9.2 Demographics
    • 9.3 Economics
      • 9.3.1 Europe
      • 9.3.2 North America
      • 9.3.3 Australia
      • 9.3.4 Corporate logos on pills
  • 10 Research
  • 11 Notes
  • 12 References
  • 13 External links

Use

Medical

See also: MDMA § Research

As of 2017, MDMA has no accepted medical indications.[5][23] Before it was widely banned, it saw limited use in therapy.[3][5][24]

Alternative medicine

A small number of therapists continue to use MDMA in therapy despite its illegal status.[25][26]

Recreational

MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and house parties.[7] 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 appeal 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.[27] MDMA is used less frequently than other stimulants, typically less than once per week.[28]

MDMA is sometimes taken in conjunction with other psychoactive drugs, such as LSD, psilocybin mushrooms, and ketamine. Users sometimes use mentholated products while taking MDMA for its cooling sensation.[29]

Forms

Ecstasy tablets which allegedly contain MDMA, but may contain adulterants
A salt of MDMA (typically white) with impurities, resulting in a tan discoloration
Crushed MDMA (1 gram) crystals made into a line
High purity MDMA in capsules

MDMA has become widely known as ecstasy (shortened "E", "X", or "XTC"), usually referring to its tablet form, although this term may also include the presence of possible adulterants or dilutants. The UK term "mandy" and the US term "molly" colloquially refer to MDMA in a crystalline powder form that is thought to be free of adulterants.[10][11][30] MDMA is also sold in the form of the hydrochloride salt, either as loose crystals or in gelcaps.[31][32]

In part due to the global supply shortage of sassafras oil, substances that are sold as molly frequently contain no MDMA and instead contain methylone, ethylone, MDPV, mephedrone, or any other of the group of compounds commonly known as bath salts.[11][30][31][32] Powdered MDMA is typically 30–40% pure, due to bulking agents that are added to dilute the drug and increase profits (e.g., lactose) and binding agents.[5] Tablets sold as ecstasy sometimes contain 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), other amphetamine derivatives, caffeine, opiates, or painkillers.[3] Some tablets contain little or no MDMA.[3][9][5] The proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.[5] The average content of MDMA in a preparation is 70 to 120 mg with the purity having increased since the 1990s.[3]

Effects

In general, MDMA users begin reporting subjective effects within 30 to 60 minutes of consumption, reaching the peak at about 75 to 120 minutes which plateaus for about 3.5 hours.[33]

The desired short-term psychoactive effects of MDMA have been reported to include:

  • Euphoria – a sense of general well-being and happiness[12][13]
  • Increased self-confidence, sociability and feelings of communication being easy or simple[12][13][3]
  • Entactogenic effects – increased empathy or feelings of closeness with others[12][13] and oneself[3]
  • Relaxation and reduced anxiety[3]
  • Increased emotionality[3]
  • A sense of inner peace[13]
  • Mild hallucination[13]
  • Enhanced sensation, perception, or sexuality[12][13][3]
  • Altered sense of time[15]

The experience elicited by MDMA depends on the dose, setting, and user.[3] The variability of the induced altered state by MDMA is lower compared to other psychedelics. For example, MDMA used at parties is associated with high motor activity, reduced sense of self-identity as well as poor awareness of the background surroundings. Use of MDMA individually or in a small groups in a quiet environment and when concentrating, is associated with increased lucidity, capability of concentration, sensitivity of aesthetic aspects of the background and emotions, as well as greater capability of communication with others.[7][34] In psychotherapeutic settings MDMA effects have been described by infantile ideas, alternating phases of mood, sometimes memories and moods connected with childhood experiences.[34][35]

Sometimes MDMA is labelled as an “empathogenic” drug, because of its empathy-producing effects.[36][37] Results of different studies show its effects of powerful empathy with others.[36] When testing the MDMA for medium and high dosage ranges it showed increase on hedonic as well as arousal continuum.[38][39] The effect of MDMA increasing sociability is consistent, however effects on empathy have been more mixed.[40]

Adverse effects

Short-term

The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.[13][41] 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.[13][41][42]

The immediate adverse effects of MDMA use can include:

  • Dehydration[7][13][41]
  • Hyperthermia[3][7][41]
  • Bruxism (grinding and clenching of the teeth)[3][7][12]
  • Increased wakefulness or insomnia[13][3]
  • Increased perspiration and sweating[13][41]
  • Increased heart rate and blood pressure[3][7][41]
  • Increased psychomotor activity[3]
  • Loss of appetite[3][9]
  • Nausea and vomiting[12]
  • Diarrhea[13]
  • Erectile dysfunction[3][43]
  • Visual and auditory hallucinations (rarely)[3]
  • Mydriasis[3]

The adverse effects that last up to a week[12][44] following cessation of moderate MDMA use include:

Physiological</dt>

  • Trismus[12]
  • Loss of appetite[44]
  • Insomnia[44]
  • Tiredness or lethargy[45][46]

Psychological</dt>

  • Anxiety or paranoia[44]
  • Depression[12][44]
  • Irritability[44]
  • Impulsiveness[44]
  • Restlessness[44]
  • Memory impairment[12]
  • Anhedonia[44]

Long-term

As of 2015, the long-term effects of MDMA on human brain structure and function have not been fully determined.[47] However, there is consistent evidence of structural and functional deficits in MDMA users with a high lifetime exposure.[47][48] In contrast, there is no evidence of structural or functional changes in MDMA users with only a moderate (<50 doses used and <100 tablets consumed) lifetime exposure.[48] MDMA use at high doses has been shown to produce brain lesions, a form of brain damage, in the serotonergic neural pathways of humans and animals.[2][9] It is unclear if typical MDMA users may develop neurotoxic brain lesions.[49] Long-term exposure to MDMA in humans has been shown to produce marked neurodegeneration in striatal, hippocampal, prefrontal, and occipital serotonergic axon terminals.[47][50] Neurotoxic damage to serotonergic axon terminals has been shown to persist for more than two years.[50] Elevations in brain temperature from MDMA use are positively correlated with MDMA-induced neurotoxicity.[7][47] Adverse neuroplastic changes to brain microvasculature and white matter also occur in humans using low doses of MDMA.[7][47] Reduced gray matter density in certain brain structures has also been noted in human MDMA users.[7][47] Global reductions in gray matter volume, thinning of the parietal and orbitofrontal cortices, and decreased hippocampal activity have been observed in long term users.[3] The effects established so far for recreational use of ecstasy lie in the range of moderate to large effects for SERT reduction.[51]

MDMA can also produce cognitive impairments in humans.[12][21][47] Impairments in multiple aspects of cognition, including attention, learning, memory, visual processing, and sleep have been found in regular MDMA users.[3][12][21][47] The magnitude of these impairments is correlated with lifetime MDMA usage[12][21][47] and are partially reversible with abstinence.[3] MDMA use is also associated with increased impulsivity and depression.[3] Several forms of memory are impaired by chronic ecstasy use;[12][21] however, the effect sizes for memory impairments in ecstasy users are generally small overall.[52][53]

Serotonin depletion following MDMA use can cause depression in subsequent days. In some cases depressive symptoms persist for longer.[3] Some studies indicate repeated recreational users of ecstasy have increased rates of depression and anxiety, even after quitting the drug.[54] Depression is one of the main factors for cessation of use.[3]

At high doses, MDMA induces a neuroimmune response which, through several mechanisms, increases the permeability of the blood-brain barrier, thereby making the brain more susceptible to environmental toxins and pathogens.[55][56][page needed] In addition, MDMA has immunosuppressive effects in the peripheral nervous system and pro-inflammatory effects in the central nervous system.[57]

During pregnancy

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 dependence, physical harm, and social harm.[58]

MDMA is a moderately teratogenic drug (i.e., it is toxic to the fetus).[59][60] In utero exposure to MDMA is associated with a neuro- and cardiotoxicity[60] and impaired motor functioning. Motor delays may be temporary during infancy or long-term. The severity of these developmental delays increases with heavier MDMA use.[21][61]

Reinforcement disorders

Approximately 60% of MDMA users experience withdrawal symptoms when they stop taking MDMA.[9] Some of these symptoms include fatigue, loss of appetite, depression, and trouble concentrating.[9] Tolerance to some of the desired and adverse effects of MDMA is expected to occur with consistent MDMA use.[9] A 2007 analysis estimated MDMA to have a psychological dependence and physical dependence potential roughly three fourths and four fifths that of cannabis.[58]

MDMA has been shown to induce ΔFosB in the nucleus accumbens.[62] Since MDMA releases dopamine in the striatum, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other dopaminergic psychostimulants.[62][63] 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.[63] MDMA is less addictive than other stimulants such as methamphetamine and cocaine.[64][65] Compared with amphetamine, MDMA and its metabolite MDA are less reinforcing.[66]

One study found approximately 15% of chronic MDMA users met the DSM-IV diagnostic criteria for substance dependence.[67] However, there is little evidence for a specific diagnosable MDMA dependence syndrome since MDMA is typically used relatively infrequently.[28]

There are currently no medications to treat MDMA addiction.[68]

Harm assessment

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[58]

Overdose

MDMA overdose symptoms vary widely due to the involvement of multiple organ systems. Some of the more overt overdose symptoms are listed in the table below. The number of instances of fatal MDMA intoxication is low relative to its usage rates. In most fatalities MDMA was not the only drug involved. Acute toxicity is mainly caused by serotonin syndrome and sympathomimetic effects.[67] MDMA's toxicity in overdose may be exacerbated by caffeine, which it is frequently cut with(mixed with to increase volume).[69]

Symptoms of overdose
System Minor or moderate overdose[70] Severe overdose[70]
Cardiovascular
  • Disseminated intravascular coagulation[13]
  • Intracranial hemorrhage[13]
  • Severe hypertension[13][71] or hypotension[13]
  • Hypotensive bleeding[3]
Central nervous
system
  • Abnormally fast reflexes[72]
  • Agitation[13][71]
  • Mental confusion[13]
  • Paranoia[13][71]
  • Stimulant psychosis[3][7]
  • Cognitive and memory impairment[13] potentially to the point of retrograde or anterograde amnesia[73]
  • Coma[7][71]
  • Convulsions[13][71]
  • Hallucinations[13][71]
  • Loss of consciousness[7]
  • Serotonin syndrome[7][13][42]
Musculoskeletal
  • Muscle rigidity[13]
  • Rhabdomyolysis (i.e., rapid muscle breakdown)[13][42]
Respiratory
  • Acute respiratory distress syndrome[13]
Urinary
  • Acute kidney injury[13][74]
Other
  • Cerebral edema[7]
  • Hepatitis[13][42]
  • Hyperpyrexia (a life-threatening elevation of body temperature)[13][42]
  • Hyponatremia (Syndrome of inappropriate antidiuretic hormone)[13][41][42]

Interactions

A number of drug interactions can occur between MDMA and other drugs, including serotonergic drugs.[9][75] MDMA also interacts with drugs which inhibit CYP450 enzymes, like ritonavir (Norvir), particularly CYP2D6 inhibitors.[9] Concurrent use of MDMA high dosages with another serotonergic drug can result in a life-threatening condition called serotonin syndrome.[3][9] Severe overdose resulting in death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors,[3][9] such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix).[76]

Pharmacology

Pharmacodynamics

MDMA binds to serotonin transporters.

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).[9][77][78] 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;[77] 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).[77][79] MDMA inhibits both vesicular monoamine transporters (VMATs), the second of which (VMAT2) is highly expressed within monoamine neurons at vesicular membranes.[78] Once inside a monoamine neuron, MDMA acts as a VMAT2 inhibitor and a TAAR1 agonist.[77][78]

Inhibition of VMAT2 by MDMA results in increased concentrations of the associated neurotransmitter (serotonin, norepinephrine, or dopamine) in the cytosol of a monoamine neuron.[78][80] 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.[77] 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.[77] MDMA has ten times more affinity for uptake at serotonin transporters compared to dopamine and norepinephrine transporters and consequently has mainly serotonergic effects.[81]:1080

In summary, MDMA enters monoamine neurons by acting as a monoamine transporter substrate.[77] MDMA activity at VMAT2 moves neurotransmitters out from synaptic vesicles and into the cytosol;[78] MDMA activity at TAAR1 moves neurotransmitters out of the cytosol and into the synaptic cleft.[77]

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.[82][83][84][85] Cortisol, prolactin, and oxytocin quantities in serum are increased by MDMA.[3] 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.[86](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).[87]

MDMA is a ligand at both sigma receptor subtypes, though its efficacies at the receptors have not yet been elucidated.[88]

Pharmacokinetics

Diagram showing the sequence of MDMA metabolization.

MDMA reaches maximal concentrations in the blood stream between 1.5 and 3 hr after ingestion.[89] 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.[90] The duration of action of MDMA is usually four to six hours, after which serotonin levels in the brain are depleted.[3] Serotonin levels typically return to normal within 24–48 hours.[3]

Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (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. 80% of MDMA is metabolised in the liver, and about 20% is excreted unchanged in the urine.[7]

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.[70] 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.[91][non-primary source needed]

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[92] 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[93] 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).[9] However, because MDMA excretion and metabolism have nonlinear kinetics,[94] the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose[89]).

Chemistry

(R)-MDMA
(S)-MDMA
MDMA is a racemic mixture and exists as two enantiomers: (R)- and (S)-MDMA.
A powdered salt of MDMA
Reactors used to synthesize MDMA on an industrial scale in a chemical factory in Cikande, Indonesia

MDMA is in the substituted methylenedioxyphenethylamine and substituted amphetamine classes of chemicals. As a free base, MDMA is a colorless oil insoluble in water.[5] The most common salt of MDMA is the hydrochloride salt;[5] pure MDMA hydrochloride is water-soluble and appears as a white or off-white powder or crystal.[5]

Synthesis

There are numerous methods available in the literature to synthesize MDMA via different intermediates.[95][96][97][98] 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.[99][100] 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.[101] 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] 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.[102]

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

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.[103][104][105]

History

Early research and use

German patents for MDMA synthesis and the subsequent methylhydrastinine synthesis filed by Merck on 24 December 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 fellow lab members, Walther Beckh and Otto Wolfes. MDMA (called methylsafrylamin, safrylmethylamin or N-Methyl-a-Methylhomopiperonylamin in Merck laboratory reports) was an intermediate compound in the synthesis of methylhydrastinine. Merck was not interested in MDMA itself at the time.[106] On 24 December 1912, Merck filed two patent applications that described the synthesis and some chemical properties of MDMA[107] and its subsequent conversion to methylhydrastinine.[108]

Merck records indicate its researchers returned to the compound sporadically. A 1920 Merck patent describes a chemical modification to MDMA.[109] In 1927, Max Oberlin studied the pharmacology of MDMA while searching for substances with effects similar to adrenaline or ephedrine, the latter being structurally similar to MDMA. Compared to ephedrine, Oberlin observed that it had similar effects on vascular smooth muscle tissue, stronger effects at the uterus, and no "local effect at the eye". MDMA was also found to have effects on blood sugar levels comparable to high doses of ephedrine. Oberlin concluded that the effects of MDMA were not limited to the sympathetic nervous system. Research was stopped "particularly due to a strong price increase of safrylmethylamine", which was still used as an intermediate in methylhydrastinine synthesis. Albert van Schoor performed simple toxicological tests with the drug in 1952, most likely while researching new stimulants or circulatory medications. After pharmacological studies, research on MDMA was not continued. In 1959, Wolfgang Fruhstorfer synthesized MDMA for pharmacological testing while researching stimulants. It is unclear if Fruhstorfer investigated the effects of MDMA in humans.[106]

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.[110][111] A 1960 Polish paper by Biniecki and Krajewski describing the synthesis of MDMA as an intermediate was the first published scientific paper on the substance.[106][111][112]

MDMA may have been in non-medical use in the western United States in 1968.[113] An August 1970 report at a meeting of crime laboratory chemists indicates MDMA was being used recreationally in the Chicago area by 1970.[111][114] MDMA likely emerged as a substitute for its analog methylenedioxyamphetamine (MDA),[115] a drug at the time popular among users of psychedelics[116] which was made a Schedule 1 substance in the United States in 1970.[117][118]

Shulgin's research and therapeutic use

Alexander and Ann Shulgin in December 2011

American chemist and psychopharmacologist Alexander Shulgin reported 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. Shulgin may have suspected he played a role in the emergence of MDMA in Chicago.[111]

Shulgin first heard of the psychoactive effects of N-methylated MDA around 1975 from a young student who reported "amphetamine-like content".[111] Around 30 May 1976, Shulgin again heard about the effects of N-methylated MDA,[111] this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University[116][119] who directed him to the University of Michigan study.[120] She and two close friends had consumed 100 mg of MDMA and reported positive emotional experiences.[111] 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.[111][116] Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.[111] In 1978, he and David E. Nichols published a report on the drug's psychoactive 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".[121]

While not finding his own experiences with MDMA particularly powerful,[120][122] Shulgin was impressed with the drug's disinhibiting effects and thought it could be useful in therapy.[122] Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug "window".[120][123] Shulgin occasionally used MDMA for relaxation, referring to it as "my low-calorie martini", and gave the drug to friends, researchers, and others who he thought could benefit from it.[120] One such person was Leo Zeff, a psychotherapist who had been known to use psychedelic substances in his practice. When he tried the drug in 1977, Zeff was impressed with the effects of MDMA and came out of his semi-retirement to promote its use in therapy. Over the following years, Zeff traveled around the US and occasionally to Europe, eventually training an estimated four thousand psychotherapists in the therapeutic use of MDMA.[122][124] Zeff named the drug "Adam", believing it put users in a state of primordial innocence.[116]

Psychotherapists who used MDMA believed the drug eliminated the typical fear response and increased communication. Sessions were usually held in the home of the patient or the therapist. The role therapist was minimized in favor of patient self-discovery accompanied by MDMA induced feelings of empathy. Depression, substance abuse, relationship problems, premenstrual syndrome, and autism were among several psychiatric disorders MDMA assisted therapy was reported to treat.[118] According to psychiatrist George Greer, therapists who used MDMA in their practice were impressed by the results. Anecdotally, MDMA was said to greatly accelerate therapy.[122]

Rising recreational use

In the late 1970s and early 1980s, "Adam" 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.[118][125] Early MDMA distributors were deterred from large scale operations by the threat of possible legislation.[126] Between the 1970s and the mid-1980s, this network of MDMA users consumed an estimated 500,000 doses.[12][127]

A small recreational market for MDMA developed by the late 1970s,[128] consuming perhaps 10,000 doses in 1976.[117] By the early 1980s MDMA was being used in Boston and New York City nightclubs such as Studio 54 and Paradise Garage.[129][130] Into the early 1980s, as the recreational market slowly expanded, production of MDMA was dominated by a small group of therapeutically minded Boston chemists. Having commenced production in 1976, this "Boston Group" did not keep up with growing demand and shortages frequently occurred.[126]

Perceiving a business opportunity, Michael Clegg, the Southwest distributor for the Boston Group, started his own "Texas Group" backed financially by Texas friends.[126][131] In 1981,[126] Clegg had coined "Ecstasy" as a slang term for MDMA to increase its marketability.[123][125] Starting in 1983,[126] the Texas Group mass-produced MDMA in a Texas lab[125] or imported it from California[123] and marketed tablets using pyramid sales structures and toll-free numbers.[127] MDMA could be purchased via credit card and taxes were paid on sales.[126] Under the brand name "Sassyfras", MDMA tablets were sold in brown bottles.[125] The Texas Group advertised "Ecstasy parties" at bars and discos, describing MDMA as a "fun drug" and "good to dance to".[126] MDMA was openly distributed in Austin and Dallas-Fort Worth area bars and nightclubs, becoming popular with yuppies, college students, and gays.[115][126][127]

Recreational use also increased after several cocaine dealers switched to distributing MDMA following experiences with the drug.[127] A California laboratory that analyzed confidentially submitted drug samples first detected MDMA in 1975. Over the following years the number of MDMA samples increased, eventually exceeding the number of MDA samples in the early 1980s.[132][133] By the mid-1980s, MDMA use had spread to colleges around the United States.[126]:33

Media attention and scheduling

United States

27 July 1984 Federal Register notice of the proposed MDMA scheduling

In an early media report on MDMA published in 1982, a Drug Enforcement Administration (DEA) spokesman stated the agency would ban the drug if enough evidence for abuse could be found.[126] By mid-1984, MDMA use was becoming more noticed. Bill Mandel reported on "Adam" in a 10 June 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.[125]

After a year of planning and data collection, MDMA was proposed for scheduling by the DEA on 27 July 1984 with a request for comments and objections.[125][134] The DEA was surprised when a number of psychiatrists, psychotherapists, and researchers objected to the proposed scheduling and requested a hearing.[118] In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.[135] An initial hearing was held on 1 February 1985 at the DEA offices in Washington, D.C. with administrative law judge Francis L. Young presiding.[125] It was decided there to hold three more hearings that year: Los Angeles on 10 June, Kansas City, Missouri on 10–11 July, and Washington, D.C. on 8–11 October.[118][125]

Sensational media attention was given to the proposed criminalization and the reaction of MDMA proponents, effectively advertising the drug.[118] In response to the proposed scheduling, the Texas Group increased production from 1985 estimates of 30,000 tablets a month to as many as 8,000 per day, potentially making two million ecstasy tablets in the months before MDMA was made illegal.[136] By some estimates the Texas Group distributed 500,000 tablets per month in Dallas alone.[123] According to one participant in an ethnographic study, the Texas Group produced more MDMA in eighteen months than all other distribution networks combined across their entire histories.[126] By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States.[113][137] According to the DEA there was evidence of use in twenty-eight states[138] and Canada.[113] Urged by Senator Lloyd Bentsen, the DEA announced an emergency Schedule I classification of MDMA on 31 May 1985. The agency cited increased distribution in Texas, escalating street use, and new evidence of MDA (an analog of MDMA) neurotoxicity as reasons for the emergency measure.[137][139][140] The ban took effect one month later on 1 July 1985[136] in the midst of Nancy Reagan's "Just Say No" campaign.[141][142]

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 be classified as a Schedule III substance. Despite this, DEA administrator John C. Lawn overruled and classified the drug as Schedule I.[118][143] 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.[118][citation needed] No double blind studies had yet been conducted as to the efficacy of MDMA for therapy.[citation needed]

United Nations

While engaged in scheduling debates in the United States, the DEA also pushed for international scheduling.[136] In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 United Nations Convention on Psychotropic Substances. The committee made this recommendation on the basis of the pharmacological similarity of MDMA to previously scheduled drugs, reports of illicit trafficking in Canada, drug seizures in the United States, and lack of well-defined therapeutic use. While intrigued by reports of psychotherapeutic uses for the drug, the committee viewed the studies as lacking appropriate methodological design and encouraged further research. Committee chairman Paul Grof dissented, believing international control was not warranted at the time and a recommendation should await further therapeutic data.[144] The Commission on Narcotic Drugs added MDMA to Schedule I of the convention on 11 February 1986.[145]

Post-scheduling

A 1995 Vibe Tribe rave in Erskineville, New South Wales, Australia being broken up by police. MDMA use spread globally along with rave culture.
Play media
A 2000 United States Air Force video dramatizing the dangers of MDMA abuse.

The use of MDMA in Texas clubs declined rapidly after criminalization, although by 1991 the drug remained popular among young middle-class whites and in nightclubs.[126]:46 In 1985, MDMA use became associated with Acid House on the Spanish island of Ibiza.[126]:50[146] Thereafter in the late 1980s, the drug spread alongside rave culture to the UK and then to other European and American cities.[126]:50 Illicit MDMA use became increasingly widespread among young adults in universities and later, in high schools. Since the mid-1990s, MDMA has become the most widely used amphetamine-type drug by college students and teenagers.[81]:1080 MDMA became one of the four most widely used illicit drugs in the US, along with cocaine, heroin, and cannabis.[123] According to some estimates as of 2004, only marijuana attracts more first time users in the US.[123]

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 US. 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).[147]

"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.[148][149]

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,[150] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.[151]

Society and culture

Global estimates of illegal drug users in 2014
(in millions of users)[152]
Substance Best
estimate
Low
estimate
High
estimate
Amphetamine-
type stimulants
35.65 15.34 55.90
Cannabis 182.50 127.54 233.65
Cocaine 18.26 14.88 22.08
Ecstasy 19.40 9.89 29.01
Opiates 17.44 13.74 21.59
Opioids 33.12 28.57 38.52

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.

Australia

In Australia, MDMA was declared an illegal substance 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 Western Australia under the Misuse of Drugs Act 1981 4.0g of MDMA is the amount required determining a court of trial, 2.0g is considered a presumption with intent to sell or supply and 28.0g is considered trafficking under Australian law.[153]

United Kingdom

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.[154][155] The drug is therefore illegal to sell, buy, or possess the drug without a licence in the UK. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking.

Some researchers such as David Nutt have criticized the current scheduling of MDMA, what he determined to be a relatively harmless drug.[156][157] An editorial he wrote in the Journal of Psychopharmacology, where he compared the risk of harm for horse riding (1 adverse event in 350) to that of ecstasy (1 in 10,000) resulted in his dismissal as well as the resignation of his colleagues from the ACMD.[158]

United States

In the United States, MDMA is currently placed in Schedule I of the Controlled Substances Act.[159] 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.[160] 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."[161]

Netherlands

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.[161][162][163]

Canada

In Canada, MDMA is listed as a Schedule 1[164] as it is an analogue of amphetamine.[165] The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule III to Schedule I in March 2012.

Demographics

UNODC map showing the use of ecstasy by country in 2014 for the global population aged 15–64.

In 2014, 3.5% of 18 to 25 year-olds had used MDMA in the United States.[3] In Europe, an estimated 37% of regular club-goers aged 14 to 35 used MDMA in the past year according to the 2015 European Drug report.[3] The highest one-year prevalence of MDMA use in Germany in 2012 was 1.7% among people aged 25 to 29 compared with a population average of 0.4%.[3] Among adolescent users in the United States between 1999 and 2008, girls were more likely to use MDMA than boys.[166]

Economics

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.[167] 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.[168]

North America

The United Nations Office on Drugs and Crime stated in its 2014 World Drug Report that US ecstasy retail prices range from US$1 to $70 per pill, or from $15,000 to $32,000 per kilogram.[169] 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.[170] These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks.

As of October 2015, most of the MDMA in the United States is produced in British Columbia, Canada and imported by Canada-based Asian transnational criminal organizations.[30] The market for MDMA in the United States is relatively small compared to methamphetamine, cocaine, and heroin.[30]

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 US.[171]

Corporate logos on pills

A number of ecstasy manufacturers brand their pills with a logo, often being a corporate logo,[172] to help distinguish between suppliers; one of the most notable logos which appeared on pills is the Mitsubishi logo which was popular.[173] Some pills depict logos of products or shows popular with children, such as Shaun the Sheep.[174]

Research

The Multidisciplinary Association for Psychedelic Studies (MAPS) is currently funding pilot studies or clinical trials investigating the use of MDMA in psychotherapy to treat posttraumatic stress disorder (PTSD),[26] social anxiety in autistic adults,[3][175] and anxiety in terminal illness.[176][177] In November 2016, the United States Food and Drug Administration (FDA) approved large-scale phase 3 clinical trials involving the use of MDMA for the treatment of PTSD in individuals who do not respond to traditional prescription drugs or psychotherapy — a final step before the possible approval of MDMA as a prescription drug in the United States.[22] MDMA has also been proposed as an adjunct to substance abuse treatment.[4] MDMA is taken only a few times in a therapeutic setting, unlike approved psychiatric medications which require ongoing treatment.[178]

The potential for MDMA to be used as a rapid-acting antidepressant has been studied in clinical trials, but as of 2017 the evidence on efficacy and safety were insufficient to reach a conclusion.[179] A 2014 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;[21] however, it emphasized that issues regarding the control-ability of MDMA-induced experiences and neurochemical recovery must be addressed.[21] The author noted that oxytocin and D-cycloserine are potentially safer co-drugs in PTSD treatment, albeit with limited evidence of efficacy.[21] 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 harm to a patient.[12][21]

Notes

  1. ^ The term MDMA is a contraction of 3,4-methylenedioxy-methamphetamine; it is also known as ecstasy (shortened to "E", "X", or "XTC"), mandy, and molly.[10][11]

References

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  30. ^ a b c d "MDMA (3,4-Methylenedioxymethamphetamine)". 2015 National Drug Threat Assessment Summary (PDF). Drug Enforcement Administration. United States Department of Justice: Drug Enforcement Administration. October 2015. pp. 85–88. Retrieved 10 April 2016. <q>MDMA, a synthetic Schedule I drug commonly referred to as “ecstasy” and “molly”, is available throughout the United States. Compared to marijuana, cocaine, heroin, and other illicit drugs, the MDMA market in the United States is small. Most of the MDMA seized in the United States is manufactured in clandestine laboratories in Canada and smuggled across the Northern Border. Canada-based Asian TCOs are the primary suppliers of MDMA in the United States ... MDMA production takes place predominantly in British Columbia; however, it is also manufactured in smaller quantities in Ontario and Quebec. ... The drug “molly” is purported to be a pure form of MDMA—free of any added substances—but the true chemical make-up of “molly” varies. Drugs marketed or sold as “molly” are often made up of several different substances, including synthetic cathinones such as methylone, and do not always contain MDMA. ... Intelligence indicates that some tablets sold as “ecstasy” or “molly” may not be MDMA at all, but another chemical or a mixture of various chemicals which may or may not contain MDMA. DEA laboratories have analyzed samples that have contained methamphetamine, ketamine, caffeine, dimethylsulfone, N-benzylpiperazine (BZP), and trifluoromethylpiperazine (TFMPP), in addition to MDMA</q> 
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    • Chronic MDMA use results in serotonergic toxicity, thereby altering the regional cerebral blood flow that can be studied using fMRI.
    • The effects of chronic MDMA use have been analysed in various neurocognitive domains such as working memory, episodic memory, semantic memory, visual stimulation, motor function and impulsivity. ...
    Structural neuroimaging in MDMA users has shown reduction in brain 5-HT transporter (5-HTT) [18-21] and 5-HT2a receptor levels [22-24] using positron emission tomography (PET) or single photon emission computed tomography (SPECT) and reduced grey matter density in various brain regions using voxel based morphometry method (VBM) [25]. Chemical Neuroimaging, assaying the levels of myoinositol (MI) and N-acetylaspartate (NAA) in the brains of MDMA users using proton magnetic resonance spectroscopy (MRS), has not revealed any consistent results [17, 26-29]. Functional magnetic resonance imaging (fMRI) studies have shown task evoked differences in regional brain activation, measured as blood oxygen level dependent (BOLD) signal intensity and/or spatial extent of activation, in MDMA users and controls [30-33]. ... Neurocognitive studies, in MDMA users, have consistently revealed dose related memory and learning problems [35-38] ... Serotonergic innervation is known to regulate the cerebral microvasculature. Chronic MDMA use results in serotonin toxicity, therefore MDMA users are expected to have altered regional blood flow detectable in fMRI [17]. ... Animal data has suggested that MDMA is selectively more toxic to the axons more distal to the brainstem cell bodies, that is, those present mainly in the occipital cortex [54, 55]. Also, human PET and SPECT studies have revealed significant reductions in serotonin transporter binding, most evident in the occipital cortex [18, 20] ... The effects of poly-drug exposure may result in additive neurotoxicity or mutual neuro-protection. MDMA is known to induce hyperthermia which is a prooxidant neurotoxic condition [65]. Hyperthermia is known to accentuate the neurotoxic potential of MDMA as well as methamphetamine [66, 67]. On the other hand, lowering of the core body temperature has been shown to have a neuroprotective effect.</q>
     
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  64. ^ Mack, Avram H.; Brady, Kathleen T.; Miller, Sheldon I.; Frances, Richard J. Clinical Textbook of Addictive Disorders. Guilford Publications. p. 169. ISBN 9781462521692. <q>MDMA's addictive liability appears to be lower than that of other drugs of abuse....</q> 
  65. ^ Favrod-Coune, Thierry; Broers, Barbara (22 July 2010). "The Health Effect of Psychostimulants: A Literature Review". Pharmaceuticals. pp. 2333–2361. doi:10.3390/ph3072333. <q>It seems to present a smaller addiction potential than cocaine or methamphetamine.</q> 
  66. ^ Saiz, senior editor Richard K. Ries ; associate editors David A. Fiellin, Shannon C. Miller, Richard (2009). Principles of addiction medicine. (4th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. p. 226. ISBN 9780781774772. <q>MDA and MDMA are less reinforcing than amphetamine...</q> 
  67. ^ a b Steinkellner, Thomas; Freissmuth, Michael; Sitte, Harald H.; Montgomery, Therese (1 January 2011). "The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), methamphetamine and d-amphetamine". Biological Chemistry. 392 (1–2). doi:10.1515/BC.2011.016. <q>...approximately 15% of routine MDMA users recently fit the diagnostic criteria for MDMA dependence [note that the DSM-IV diagnostic criteria for substance dependence is actually a diagnostic criteria for addiction] according to the Diagnostic and Statistical Manual, fourth edition/DSMIV.</q> 
  68. ^ Mack, Avram H.; Brady, Kathleen T.; Miller, Sheldon I.; Frances, Richard J. Clinical Textbook of Addictive Disorders. Guilford Publications. p. 171. ISBN 9781462521692. <q>There are no known pharmacological treatments for MDMA addiction.</q> 
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