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

WordNet

a stimulant drug that is chemically related to mescaline and amphetamine and is used illicitly for its euphoric and hallucinogenic effects; it was formerly used in psychotherapy but in 1985 it was declared illegal in the United States; "MDMA is often used at parties because it enables partygoers to remain active for long periods of time" (同)MDMA

Wikipedia preview

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)

wiki ja

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。

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。

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。

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

^ Stimulants, Narcotics, Hallucinogens - Drugs, Pregnancy, and Lactation., Gerald G. Briggs, OB/GYN News, 1 June 2003.
^ “Methylenedioxymethamphetamine (MDMA, ecstasy)”. Drugs and Human Performance Fact Sheets. National Highway Traffic Safety Administration. 2009年4月16日閲覧。
^ 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。
^ 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
^ 138 articles about mdma/ptsd therapy（MAPS、2010年7月30日）

wiki en

[Wiki en表示]

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]

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

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

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

Psychological

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

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

Note: colored text contains article links.

Nuclear pore

Nuclear membrane

Plasma membrane

Ca_v1.2

NMDAR

AMPAR

DRD1

DRD5

DRD2

DRD3

DRD4

G_s

G_i/o

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 cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB 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]}

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/ARDS ... 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 (SIADH), hepatitis, muscular rigidity, rhabdomyolysis, DIC, 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
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^ The first confirmed sample was seized and identified by Chicago Police in 1970, see Sreenivasan VR (1972). "Problems in Identification of Methylenedioxy and Methoxy Amphetamines". Journal of Criminal Law, Criminology & Police Science (The Journal of Criminal Law, Criminology, and Police Science, Vol. 63, No. 2) 63 (2): 304–312. doi:10.2307/1142315. JSTOR 1142315.
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^ "Schedules of Controlled Substances Proposed Placement of 3,4-Methylenedioxymethamphetamine in Schedule I" (PDF). Federal Register 49 (146): 30210. 27 July 1984. Retrieved 15 January 2015.
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^ Erowid MDMA Vault: Info No. 3 on Scheduling. Erowid.org. Retrieved on 11 June 2011.
^ 22nd report of the Expert Committee on Drug Dependence World Health Organization, 1985. (PDF) . Retrieved on 29 August 2012.
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^ Bibliography of Psychedelic Research Studies. collected by the Multidisciplinary Association for Psychedelic Studies^{[dead link]}
^ Susan Donaldson James (23 February 2015). "What Is Molly and Why Is It Dangerous?". NBCNews.com. Retrieved 23 February 2015. Why is it called Molly? That's short for "molecule." "You can put a ribbon and bow on it and call it a cute name like 'Molly' and people are all in," said Paul Doering, professor emeritus of pharmacology at the University of Florida.
^ Aleksander, Irina (21 June 2013). "Molly: Pure, but Not So Simple". The New York Times (The New York Times Company). Retrieved 24 February 2015.
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^ Misuse of Drugs Act 1971. Statutelaw.gov.uk (5 January 1998). Retrieved on 11 June 2011.
^ Schedules of Controlled Substances; Scheduling of 3,4-Methylenedioxymethamphetamine (MDMA) Into Schedule I of the Controlled Substances Act; Remand, 53 Fed. Reg. 5,156 (DEA 22 February 1988).
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UpToDate Contents

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1. MDMA（エクスタシー）中毒 mdma ecstasy intoxication
2. 小児および思春期における類似麻薬の乱用 designer drugs of abuse
3. アンフェタミンおよび合成カチノン（「バスソルト」）による急性中毒 acute amphetamine and synthetic cathinone bath salt intoxication
4. 解離性同一性障害：疫学、病因、臨床症状、経過、評価、および診断 dissociative identity disorder epidemiology pathogenesis clinical manifestations course assessment and diagnosis
5. 違法薬物の急性摂取（体内隠匿による） acute ingestion of illicit drugs body stuffing

English Journal

Oxytocin, cortisol and 3,4-methylenedioxymethamphetamine: neurohormonal aspects of recreational 'ecstasy'.

Parrott AC1.
Behavioural pharmacology.Behav Pharmacol.2016 Dec;27(8):649-658.
Most research into 3,4-methylenedioxymethamphetamine (MDMA) has debated its psychobiological effects in relation to neurotransmission. This article debates the contributory roles of the neurohormones oxytocin and cortisol for their psychobiological effects in humans. The empirical literature on thes
PMID 27681116

Amphetamine and derivatives in natural weight loss pills and dietary supplements by capillary electrophoresis-tandem mass spectrometry.

Dos Santos VB1, Daniel D2, Singh M3, do Lago CL4.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.J Chromatogr B Analyt Technol Biomed Life Sci.2016 Dec 1;1038:19-25. doi: 10.1016/j.jchromb.2016.10.019. Epub 2016 Oct 17.
A capillary electrophoresis-tandem mass spectrometry (CE-MS/MS) method for amphetamine (AM), phentermine (PTM), methamphetamine (MAM), methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA), and methylenedioxyethylamphetamine (MDEA) in commercial samples of homeopathic and phytotherap
PMID 27776329

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits.

Abad S1, Camarasa J1, Pubill D1, Camins A1,2, Escubedo E3.
Molecular neurobiology.Mol Neurobiol.2016 Dec;53(10):7271-7283. Epub 2015 Dec 21.
(±)3,4-Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. This study was designed to evaluate whether MDMA exposure affects their recognition memory and hippocampal expression of plasticity markers. Mice were administered with increasing doses of MDMA on
PMID 26687233

Japanese Journal

薬物依存における新たな動向 : 多様化する乱用薬物 (特集アルコール・薬物関連障害)

嶋根卓也
精神医学 54(11), 1119-1126, 2012-11
NAID 40019487330

Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects

Mori Tomohisa,Yoshizawa Kazumi,Shibasaki Masahiro,Suzuki Tsutomu
Journal of Pharmacological Sciences 120(2), 70-76, 2012
… Over the past two decades, the patterns of drug abuse have changed, so that club/recreational drugs such as phencyclidine (PCP), 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), and ketamine, which induce perceptual distortions, like hallucinations, are now more commonly abused, especially in younger generations. …
NAID 130001889167

Related Pictures

★リンクテーブル★

リンク元	「薬物濫用」「セロトニン症候群」「睡眠時歯ぎしり」「エクスタシー」「メチレンジオキシメタンフェタミン」
関連記事	「MD」「MDM」

「薬物濫用」

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	AU: Prohibited (S9); CA: Schedule I; NZ: Class B; UK: Class A; US: Schedule I; UN: Psychotropic Schedule I;
Dependence; liability	Physical: none; Psychological: moderate
Addiction; liability	Moderate
Routes of; administration	Oral, sublingual, insufflation, inhalation (vaporization), injection, rectal
Pharmacokinetic data
Metabolism	Hepatic, CYP450 extensively involved, including CYP2D6
Onset of action	Immediate
Half-life	(R)-MDMA: 5.8 ± 2.2 hours; (S)-MDMA: 3.6 ± 0.9 hours
Excretion	Renal
Identifiers
CAS Registry Number	42542-10-9 [TOXNET]
ATC code	None
PubChem	CID 1615
IUPHAR ligand	4574
DrugBank	DB01454
ChemSpider	1556
UNII	KE1SEN21RM
KEGG	C07577
ChEBI	CHEBI:1391
ChEMBL	CHEMBL43048
Synonyms	3,4-MDMA, Ecstasy, Molly
PDB ligand ID	B41 (PDBe, RCSB PDB)
Chemical data
Formula	C11H15NO2
Molecular mass	193.24 g/mol
	SMILES CC(NC)CC1=CC=C(OCO2)C2=C1;
	InChI InChI=1S/C11H15NO2/c1-8(12-2)5-9-3-4-10-11(6-9)14-7-13-10/h3-4,6,8,12H,5,7H2,1-2H3 ; Key:SHXWCVYOXRDMCX-UHFFFAOYSA-N ;
Physical data
Boiling point	105 °C (221 °F) at 0.4 mmHg (experimental)
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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;
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, 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
	SMILES CC(NC)CC1=CC=C(OCO2)C2=C1;

　　[★]

英: drug abuse, substance abuse
同: 薬物乱用
関: 薬物依存、薬物嗜癖、物質乱用、物質依存症、薬物使用、接着剤吸引

薬物使用が身体に及ぼす効果

濫用 substance abuse：a pattern of abnormal substance use that leads to impairment of occupational, physical, or social functioning(BBS.73)
依存 substance dependence：ub stance abuse puls withdrawal symptoms, tolerance, or a pattern of repetitive use(BBS.73)
離脱 withdrawal：the development of physical or pschological symptoms after the reduction or cessation of intake of a substance(BBS.73)
耐性 tolerance：the need for increased amounts of the substance to achieve the same positive psychological effect(BBS.73)
交差耐性 cross-tolerance：the development of tolerance to one substance as the result of using another substance(BBS.73)

薬物

1. 中枢神経興奮薬(覚醒剤を含む) stimulants　　身体依存はないとされている

カフェイン caffeine
ニコチン nicotine
amphetamines　精神依存有り。身体依存無し

アンフェタミン amphetamine　精神依存有り。身体依存無し。耐性は連用で出現
デキストロアンフェタミン dextroamphetamine Dexedrine
メタンフェタミン methamphetamine Desoxyn speed ice ヒロポン　精神依存有り。身体依存無し。耐性は連用で出現　　←　以前、日本で多く使われた
メチルフェニデート methylphenidate Ritalin
methylene dioxymethamphetamine MDMA ecstasy

コカイン cocaine crack freebase　精神依存有り。身体依存無し　精神依存生じやすい。耐性発現殆ど無し　コカ

2. sedatives

alcohol　　精神依存有り。身体依存有り。
barbiturates
benzodiazepines

⇔flumazenil Mazicon Romazicon

3. opioids

morphine　精神依存・身体依存有り　けし
heroin　精神依存・身体依存が強い。耐性発現早い。離脱症状激しい
codeine
pethidine
fentanyl
methadone
l-alpha-acetylmethadol acetate LAMM
buprenorphine Temgesic

4. hallucinogens and related agents

cannabis(marijuana(tetrahydrocannabinol THC,hashish)　精神依存有り。身体依存無し　精神依存軽度。耐性は長期使用で軽度出現　大麻草
lysergic acid diethylamide LSD
phencyclidine PCP angel dust
psilocybin
mescaline

精神依存、身体依存

	精神依存	身体依存
コカイン、アンフェタミン類(アンフェタミン、メチルフェタミン)、大麻	○
麻薬(モルヒネ、ヘロイン、コデイン)、バルビツール酸系(フェノバルビタール、チオペンタール)、アルコール	○	○

「セロトニン症候群」

　　[★]

英: serotonin syndrome
関: セロトニン、セロトニン受容体

概念

抗うつ薬(特に SSRI と呼ばれる選択的セロトニン再取り込み阻害薬。≒セロトニン受容体作動薬)などのセロトニン系の薬物を服用中に出現する副作用
精神症状（不安、混乱する、いらいらする、興奮する、動き回るなど）
錐体外路症状（手足が勝手に動く、震える、体が固くなるなど）
自律神経症状（汗をかく、発熱、下痢、脈が速くなるなど）
服薬開始数時間以内に症状が表れることが多い
服薬を中止すれば24時間以内に症状は消失

「不安」、「混乱する」、「いらいらする」に加えて以下の症状がみられる場合に医療機関受診を推奨している(参考1)

｢興奮する｣、「動き回る」、「手足が勝手に動く」、｢眼が勝手に動く｣、｢震える｣、「体が固くなる｣、「汗をかく｣、｢発熱｣、｢下痢｣、「脈が速くなる」

原因となりうる薬剤

トリプトファン、アンフェタミン、コカイン、MDMA、LSD、レボドパ、カルビドパ、トラマドール、ペンタゾシン、メペリジン、SSRI、SNRI、TCA、MAO阻害薬、リネゾリド、5-HT3阻害薬(オンダンセトロン、グラニセトロン)、メトクロプラミド(プリンペラン)、バルプロ酸、カルバマゼピン、シブトラミン(やせ薬)、シクロベンザプリン(中枢性筋弛緩)デキストロメルファン、(メジコン)、ブスピロン(5-HT1A阻害薬、抗不安薬)、トリプタン製剤、エルゴタミン、フェンタニル、リチウム

診断基準

QJM. 2003 Sep;96(9):635-42

Hunter criteria

感度84%, 特異度97%

セロトニン作動薬の内服歴と下記の1つ以上

1. 自発的なミオクローヌス
2. 誘発クローヌスと興奮ないし発汗
3. 眼球クローヌスと興奮ないし発汗
4. 振戦と腱反射亢進
5. 筋強剛
6. BTが38℃以上で眼球クローヌスないし誘発クローヌス

参考

1. 重篤副作用疾患別対応マニュアル

http://www.pmda.go.jp/files/000144659.pdf

「睡眠時歯ぎしり」

　　[★]

英: sleep bruxism
関: 睡眠時ブラキシズム、sleep-related bruxism。覚醒時歯ぎしり wakeful bruxism

睡眠時に咀嚼筋の運動が活発になり、歯の食いしばりと歯の摩耗を生じる(いわゆる歯ぎしり)。
睡眠時歯ぎしりの有病率は小児期に最も多く、その後年齢とともに次第に減少する。有病率としては子供では15-40%、成人では8-10%といわれている。
睡眠障害(閉塞性睡眠時無呼吸、睡眠時随伴症)を有するときに認められやすい。
リスク因子は閉塞性睡眠時無呼吸(OR 1.8)、アルコール多飲(OR 1.8)、イビキ(OR 1.4)、カフェイン摂取(OR 1.4)、喫煙(OR 1.4)、不安(OR 1.3)、ストレス環境下(OR 1.3)とされている。
薬剤により誘発されるものとしても報告がある；アンフェタミン、抗精神病薬、SSRI、SNRI、MDMA
精神・神経疾患との関連も報告あり；ダウン症候群、レット症候群、脳性麻痺、注意欠陥多動性障害
多くの場合治療の必要はない。
小児発症の場合は成長に伴い消失する場合がある。
歯の摩耗を伴うような場合には、マウスピースで歯を保護する必要があります。
薬物が原因の場合には薬物の調節により改善する場合がある。
難治例に対しての薬物療法の報告がなされているが括弧としたものはなさそう；クロナゼパム、ジアゼパムなどのベンゾジアゼピン系薬。アミトリプチリン、ブロモクリプチン、クロニジン、プロプラノロール、レボドパ、トリプトファン

「エクスタシー」

　　[★]

英: ecstasy、club drug、methylenedioxymethamphetamine、MDMA
関: 恍惚、メチレンジオキシメタンフェタミン、クラブドラッグ、N-メチル-3,4-メチレンジオキシアンフェタミン

「メチレンジオキシメタンフェタミン」

　　[★]

英: methylenedioxymethamphetamine、MDMA
同: エクスタシー ecstasy、N-メチル-3,4-メチレンジオキシアンフェタミン N-methyl-3,4-methylenedioxyamphetamine 3,4-methylenedioxymethamphetamine

「MD」

　　[★]

「MDM」

　　[★] ミデカマイシン midecamycin

[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）

[HSDB_Toxnet-1] "3,4-METHYLENEDIOXYMETHAMPHETAMINE". Hazardous Substances Data Bank. National Library of Medicine. 28 August 2008. Retrieved 22 August 2014. /EPIDEMIOLOGY STUDIES/ /Investigators/ compared the prevalence of Diagnostic and Statistical Manual version IV (DSM-IV) mental disorders in 30 current and 29 former ecstasy users, 29 polydrug and 30 drug-naive controls. Groups were approximately matched by age, gender and level of education. The current ecstasy users reported a life-time dose of an average of 821 and the former ecstasy users of 768 ecstasy tablets. Ecstasy users did not significantly differ from controls in the prevalence of mental disorders, except those related to substance use. Substance-induced affective, anxiety and cognitive disorders occurred more frequently among ecstasy users than polydrug controls. The life-time prevalence of ecstasy dependence amounted to 73% in the ecstasy user groups. More than half of the former ecstasy users and nearly half of the current ecstasy users met the criteria of substance-induced cognitive disorders at the time of testing. Logistic regression analyses showed the estimated life-time doses of ecstasy to be predictive of cognitive disorders, both current and life-time. ... Cognitive disorders still present after over 5 months of ecstasy abstinence may well be functional consequences of serotonergic neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA) [Thomasius R et al; Addiction 100(9):1310-9 (2005)] **PEER REVIEWED** PubMed Abstract

[NHM-MDMA-2] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 375. ISBN 9780071481274. MDMA has been proven to produce lesions of serotonin neurons in animals and humans.

[3] "Methylenedioxymethamphetamine (MDMA, ecstasy)". Drugs and Human Performance Fact Sheets. National Highway Traffic Safety Administration.

[Toxnet_MDMA-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m "3,4-METHYLENEDIOXYMETHAMPHETAMINE". Hazardous Substances Data Bank. National Library of Medicine. 28 August 2008. Retrieved 22 August 2014.

[5] Luciano, Randy L.; Perazella, Mark A. (25 March 2014). "Nephrotoxic effects of designer drugs: synthetic is not better!". Nature Reviews Nephrology 10 (6): 314–324. doi:10.1038/nrneph.2014.44. Retrieved 2 December 2014.

[6] "DrugFacts: MDMA (Ecstasy or Molly)". http://www.drugabuse.gov. National Institute on Drug Abuse. Retrieved 2 December 2014.

[7] ttp://www.nytimes.com/2014/09/01/nyregion/safer-electric-zoo-festival-brings-serious-beats-and-tight-security.html?_r=0

[8] ttp://nypost.com/2013/09/12/drug-dealers-tricking-club-kids-with-deadly-bath-salts-not-molly/

[9] ttp://online.wsj.com/news/articles/SB10001424127887324755104579073524185820910

[10] ttp://www.mixmag.net/words/features/drug-molly-everything-but-the-girl

[11] ttp://www.dailyprogress.com/news/dea-molly-use-akin-to-playing-russian-roulette/article_944a6886-1d8a-11e3-ac75-001a4bcf6878.html

[12] [7]^[8]^[9]^[10]^[11]

[World_Drug_Report_2014-13] Mohan, J, ed. (June 2014). World Drug Report 2014 (PDF). Vienna, Austria: United Nations Office on Drugs and Crime. pp. 2, 3, 123–152. ISBN 978-92-1-056752-7. Retrieved 1 December 2014.

[WHO2004-14] World Health Organization (2004). Neuroscience of Psychoactive Substance Use and Dependence. World Health Organization. pp. 97–. ISBN 978-92-4-156235-5.

[current_perspectives-15] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r Meyer JS (2013). "3,4-methylenedioxymethamphetamine (MDMA): current perspectives". Subst Abuse Rehabil 4: 83–99. doi:10.2147/SAR.S37258. PMC 3931692. PMID 24648791.

[Pharmacotherapy_dangers-16] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Parrott AC (2014). "The potential dangers of using MDMA for psychotherapy". J Psychoactive Drugs 46 (1): 37–43. doi:10.1080/02791072.2014.873690. PMID 24830184. Human Psychopharmacology recently published my review into the increase in empirical knowledge about the human psychobiology of MDMA over the past 25 years (Parrott, 2013a). Deficits have been demonstrated in retrospective memory, prospective memory, higher cognition, complex visual processing, sleep architecture, sleep apnoea, pain, neurohormonal activity, and psychiatric status. Neuroimaging studies have shown serotonergic deficits, which are associated with lifetime Ecstasy/MDMA usage, and degree of neurocognitive impairment. Basic psychological skills remain intact. Ecstasy/MDMA use by pregnant mothers leads to psychomotor impairments in the children. Hence, the damaging effects of Ecstasy/MDMA were far more widespread than was realized a few years ago. ... Rogers et al. (2009) concluded that recreational ecstasy/MDMA is associated with memory deficits, and other reviews have come to similar conclusions. Nulsen et al. (2010) concluded that 'ecstasy users performed worse in all memory domains'. Laws and Kokkalis (2007) concluded that abstinent Ecstasy/MDMA users showed deficits in both short-term and long-term memory, with moderate to large effects sizes. Neither of these latter reviews suggested that the empirical literature they were reviewing was of poor quality (Laws and Kokkalis, 2007; Nulsen et al., 2010).

[EMCDDA-17] ^ ^a ^b ^c ^d ^e ^f ^g ^h "Methylenedioxymethamphetamine (MDMA or 'Ecstasy')". EMCDDA. European Monitoring Centre for Drugs and Drug Addiction. Retrieved 17 October 2014.

[pmid22392347-18] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L (August 2012). "Toxicity of amphetamines: an update". Arch. Toxicol. 86 (8): 1167–1231. doi:10.1007/s00204-012-0815-5. PMID 22392347. MDMA has become a popular recreational drug of abuse at nightclubs and rave or techno parties, where it is combined with intense physical activity (all-night dancing), crowded conditions (aggregation), high ambient temperature, poor hydration, loud noise, and is commonly taken together with other stimulant club drugs and/or alcohol (Parrott 2006; Von Huben et al. 2007; Walubo and Seger 1999). This combination is probably the main reason why it is generally seen an increase in toxicity events at rave parties since all these factors are thought to induce or enhance the toxicity (particularly the hyperthermic response) of MDMA. ... Another report showed that MDMA users displayed multiple regions of grey matter reduction in the neocortical, bilateral cerebellum, and midline brainstem brain regions, potentially accounting for previously reported neuropsychiatric impairments in MDMA users (Cowan et al. 2003). Neuroimaging techniques, like PET, were used in combination with a 5-HTT ligand in human ecstasy users, showing lower density of brain 5-HTT sites (McCann et al. 1998, 2005, 2008). Other authors correlate the 5-HTT reductions with the memory deficits seen in humans with a history of recreational MDMA use (McCann et al. 2008). A recent study prospectively assessed the sustained effects of ecstasy use on the brain in novel MDMA users using repeated measurements with a combination of different neuroimaging parameters of neurotoxicity. The authors concluded that low MDMA dosages can produce sustained effects on brain microvasculature, white matter maturation, and possibly axonal damage (de Win et al. 2008).

[19] Reynolds, Simon (1999). Generation Ecstasy: Into the World of Techno and Rave Culture. Routledge. p. 81. ISBN 0415923735.

[Mixing-20] "Mixing". The Good Drugs Guide. Retrieved 17 October 2014.

[21] University of Maryland, College Park Center for Substance Abuse Research. "Ecstasy:CESAR".

[22] "Director's Report to the National Advisory Council on Drug Abuse". National Institute on Drug Abuse. May 2000. ^{[dead link]}

[mcn-23] Liechti ME, Gamma A, Vollenweider FX (2001). "Gender Differences in the Subjective Effects of MDMA". Psychopharmacology 154 (2): 161–168. doi:10.1007/s002130000648. PMID 11314678.

[Acute_amph_toxicity-24] ^ ^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 ^ac ^ad ^ae ^af ^ag ^ah Greene SL, Kerr F, Braitberg G (October 2008). "Review article: amphetamines and related drugs of abuse". Emerg. Med. Australas 20 (5): 391–402. doi:10.1111/j.1742-6723.2008.01114.x. PMID 18973636. Clinical manifestation ...
hypertension, aortic dissection, arrhythmias, vasospasm, acute coronary syndrome, hypotension ... Agitation, paranoia, euphoria, hallucinations, bruxism, hyperreflexia, intracerebral haemorrhage ... pulmonary oedema/ARDS ... 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 (SIADH), hepatitis, muscular rigidity, rhabdomyolysis, DIC, 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

[Hyponatremia-25] ^ ^a ^b ^c ^d ^e ^f ^g Keane M (February 2014). "Recognising and managing acute hyponatraemia". Emerg Nurse 21 (9): 32–6; quiz 37. doi:10.7748/en2014.02.21.9.32.e1128. PMID 24494770.

[hyperpyrexia-26] ^ ^a ^b ^c ^d ^e ^f Michael White C (March 2014). "How MDMA's pharmacology and pharmacokinetics drive desired effects and harms". J Clin Pharmacol 54 (3): 245–52. doi:10.1002/jcph.266. PMID 24431106. Hyponatremia can occur from free water uptake in the collecting tubules secondary to the ADH effects and from over consumption of water to prevent dehydration and overheating. ... Hyperpyrexia resulting in rhabdomyolysis or heat stroke has occurred due to serotonin syndrome or enhanced physical activity without recognizing clinical clues of overexertion, warm temperatures in the clubs, and dehydration.1,4,9 ... Hepatic injury can also occur secondary to hyperpyrexia with centrilobular necrosis and microvascular steatosis.

[27] Zemishlany, Z; Aizenberg, D; Weizman, A (March 2001). "Subjective effects of MDMA (‘Ecstasy’) on human sexual function". European Psychiatry 16 (2): 127–130. doi:10.1016/S0924-9338(01)00550-8. |accessdate= requires |url= (help)

[pmid15228154-28] Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J (2004). "Human pharmacology of MDMA: Pharmacokinetics, metabolism, and disposition". Therapeutic drug monitoring 26 (2): 137–144. doi:10.1097/00007691-200404000-00009. PMID 15228154.

[Toxnet_MDMA_after-effects-29] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ "3,4-METHYLENEDIOXYMETHAMPHETAMINE". Hazardous Substances Data Bank. National Library of Medicine. 28 August 2008. Retrieved 22 August 2014. Over the course of a week following moderate use of the drug, many MDMA users report feeling a range of emotions, including anxiety, restlessness, irritability, and sadness that in some individuals can be as severe as true clinical depression. Similarly, elevated anxiety, impulsiveness, and aggression, as well as sleep disturbances, lack of appetite, and reduced interest in and pleasure from sex have been observed in regular MDMA users.

[Meth_MDMA_NTox-30] Halpin LE, Collins SA, Yamamoto BK (February 2014). "Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine". Life Sci. 97 (1): 37–44. doi:10.1016/j.lfs.2013.07.014. PMID 23892199. In contrast, MDMA produces damage to serotonergic, but not dopaminergic axon terminals in the striatum, hippocampus, and prefrontal cortex (Battaglia et al., 1987, O'Hearn et al., 1988). The damage associated with Meth and MDMA has been shown to persist for at least 2 years in rodents, non-human primates and humans (Seiden et al., 1988, Woolverton et al., 1989, McCann et al., 1998, Volkow et al., 2001a, McCann et al., 2005)

[31] Boyle NT, Connor TJ (September 2010). "Methylenedioxymethamphetamine ('Ecstasy')-induced immunosuppression: a cause for concern?" (PDF). British Journal of Pharmacology 161 (1): 17–32. doi:10.1111/j.1476-5381.2010.00722.x. PMC 2962814. PMID 20718737.

[pmid22387807-32] Singer LT, Moore DG, Fulton S, Goodwin J, Turner JJ, Min MO, Parrott AC (2012). "Neurobehavioral outcomes of infants exposed to MDMA (Ecstasy) and other recreational drugs during pregnancy". Neurotoxicol Teratol 34 (3): 303–10. doi:10.1016/j.ntt.2012.02.001. PMC 3367027. PMID 22387807.

[MDMAchronic2-33] Verheyden SL, Henry JA, Curran HV (2003). "Acute, sub-acute and long-term subjective consequences of 'ecstasy' (MDMA) consumption in 430 regular users". Hum Psychopharmacol 18 (7): 507–17. doi:10.1002/hup.529. PMID 14533132.

[MDMAchronic3-34] Verheyden SL, Maidment R, Curran HV (2003). "Quitting ecstasy: an investigation of why people stop taking the drug and their subsequent mental health". J. Psychopharmacol. (Oxford) 17 (4): 371–8. doi:10.1177/0269881103174014. PMID 14870948.

[35] Laws KR, Kokkalis J (2007). "Ecstasy (MDMA) and memory function: a meta-analytic update". Human Psychopharmacology: Clinical and Experimental 22 (6): 381–88. doi:10.1002/hup.857. PMID 17621368.

[MDMAchronic4-36] Rodgers J, Buchanan T, Scholey AB, Heffernan TM, Ling J, Parrott AC (2003). "Patterns of drug use and the influence of gender on self-reports of memory ability in ecstasy users: a web-based study". J. Psychopharmacol. (Oxford) 17 (4): 389–96. doi:10.1177/0269881103174016. PMID 14870950.

[oxford-37] ^ ^a ^b ^c ^d ^e ^f John; Gunn, Scott; Singer, Mervyn; Webb, Andrew Kellum. Oxford American Handbook of Critical Care. Oxford University Press (2007). ASIN: B002BJ4V1C. Page 464.

[38] Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J (2004). "Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition". Ther Drug Monit 26 (2): 137–144. doi:10.1097/00007691-200404000-00009. PMID 15228154.

[39] Chummun H, Tilley V, Ibe J (2010). "3,4-methylenedioxyamfetamine (ecstasy) use reduces cognition". Br J Nurs 19 (2): 94–100. PMID 20235382.

[Glutamate-dopamine_cotransmission_review-41] Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950.

[Glutamate-dopamine_cotransmission_review_2-42] Descarries L, Berube-Carriere N, Riad M, Bo GD, Mendez JA, Trudeau LE (August 2008). "Glutamate in dopamine neurons: synaptic versus diffuse transmission". Brain Res. Rev. 58 (2): 290–302. doi:10.1016/j.brainresrev.2007.10.005. PMID 18042492.

[Amphetamine_KEGG_.CE.94FosB-43] Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.

[Nestler-Renthal_Figure_2-44] Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3): 257–268. PMC 2834246. PMID 19877494. Retrieved 21 July 2014.

[c-Fos_repression-45] Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924.

[Nestler1-46] Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity.

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MDMA