MDMA: Biochemistry and Medical Indications

Introduction.

 MDMA (3,4-methylenedioxy-N-methylamphetamine), known by the street names Ecstasy, E, X, or XTC [1] is a semisynthetic entactogen of the phenethylamine family.  MDMA is a ring substituted amphetamine derivative [2] structurally related to the hallucinogens and the stimulants, whose primary effect is the stimulation of secretion as well as inhibition of re-uptake of large amounts of serotonin, dopamine and norepinephrine in the brain [3-8].  An average dose is around 100-150 milligrams is eaten, the physical effects manifest about 45 minutes after ingestion and last about 8 hours.

Snorting, smoking or injecting it produce much more rapid effects. Mental effects trail off over a period of 1-2 days.  MDMA produces physical effects that are similar to those of amphetamines, and include euphoria, hyperexcitability, extreme nervousness, accelerated heartbeat, sweating, dizziness, restlessness, insomnia, tooth grinding, and incessant talking.  Paradoxically, a feeling of relaxation caused by the mental effects entactogenesis and empathogenesis can occur.  Though not classified as a hallucinogen, strange sensory enhancements and distortions can result. Repeated dosages cause the amphetamine-like affects to continue, but the mental effects will start to fade and can only be fully brought back by ceasing intake of the drug for a period of time.  There is a “ceiling effect” beyond which the mental effects will not increase in intensity no matter how much of the drug is taken.

Mechanisms of actions of MDMA.

Pure MDMA is a white, chemically and photolytically stable, crystalline solid, soluble in water, with a distinct, strong and bitter, taste.  It is taken up into the cell via the serotonin uptake channel and/or through diffusion across the membrane. Once inside it depletes stores of tryptophan hydroxylase (TPH (EC 1.14.16.4)) an enzyme involved in the synthesis of serotonin via the amino acid 5-hydroxytryptophan (5-HTP) (Fig. 4) [9-10].  Its structural similarity to endogenous catecholamines makes MDMA chemically similar to SSRI antidepressants [11]. The methylenedioxylation of the catechol ring is responsible for their hallucinogenic activity.

Effects of acute doses of MDMA.

 The acute clinical effects fall into three separate “syndromes”, “serotonin syndrome ” [13-14], severe hyponatremia induced cerebral and pulmonary edema and hepatotoxicity.

Serotonin Syndrome [9] is used to describe the constellation of symptoms observed with abnormally elevated serotonin concentrations. Abnormally elevated concentrations lead to euphoria, drowsiness, sustained rapid eye movement, overreaction of the reflexes, rapid muscle contraction and relaxation in the ankle causing abnormal movements of the foot, clumsiness, restlessness, feeling drunk and dizzy, muscle contraction and relaxation in the jaw, sweating, intoxication, muscle twitching, rigidity, high body temperature, mental status changes, shivering, diarrhea, loss of consciousness, rhabodomyolysis and acidosis and death.   Neurologic effects include confusion agitation, hallucinations, seizures and coma [15]. Pathological findings in fatalities have shown evidence consistent with heat-stroke induced multi-organ damage [16-17]. The true number of patients affected by MDMA induced serotonin syndrome is probably very under reported [14].

Hyponatremia (an electrolyte disturbance when the sodium level in the plasma falls below 135 mmol/l) induced cerebral and pulmonary edema [18-19] can occur. Severe or prolonged electrolyte disturbance due to increased vasopressin release can lead to water intoxication, decreased serum osmolality, hyperkalemia, cardiac problems, neuronal malfunction, respiratory arrest, pulmonary and cerebral edema, organ failure, coma, seizures and ultimately death [20-23].  In addition MDMA can lead to subarachnoid hemorrhage, cerebral infarction, intracranial bleeds, short-term hypertensive surges and subsequent disruption of cerebral blood vessels.

Hepatotoxicity and liver failure even after a single dose of MDMA, but often delayed by 2 to 3 to 15 days after ingestion of MDMA is known [24]. The concentrations of transaminases, enzymes that catalyze reaction between an amino acid and an α-keto acid in the serum become elevated because the hepatocyte cell membrane becomes permeable and the enzymes leak out into the blood stream.

Long-term consequences of MDMA. The long-term effects of MDMA are related to damage to/depletion of the serotonergic (5-HT) nerve receptors [25-27].  This can cause immediate and delayed word recall, visual, and memory recall.  Persistent psychiatric symptoms [28] include psychosis, panic attacks, depersonalization, depression, flashbacks and obsessive-compulsive symptoms.

Treatment. Certain procedures have been established in order to manage MDMA exposures. Airway, breathing and circulation is the primary medical concern in the emergency room.  GI decontamination (lavage, activated charcoal, etc) doesn’t provide benefit since the time of ingestion is usually several hours previous.  For a recent large ingestion a single dose of activated charcoal – 1 gm/kg in small children, 50 to 100 gm in adolescents and adults is recommended.

To treat hyperthermia, aggressive external cooling, and dantroline – 1 mg/kg by rapid IV injection is given to depress the excitation-contraction coupling in skeletal muscles by decreasing intracellular calcium concentrations. Benzodiazepines (tranquilizers that affect the modulating the GABA_A receptor, one of the two ligand-gated ion channels responsible for mediating the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain) and non-depolarizing paralytics (neuromuscular blocker of skeletal muscle contraction that work by blocking the effect of acetylcholine (ACh) at the neuromuscular junction) may be useful for seizures.

Phenobarbital (an anticonvulsant with sedative and hypnotic properties) and if necessary, followed by phenytoin or fosphenytoin (which damp the unwanted, runaway brain activity by reducing electrical conductance among brain cells) can be used. Since metabolic acidosis (low blood pH (under 7.35)) in MDMA cases is most likely secondary to hyperthermia and/or seizures, sodium bicarbonate therapy at 1-2 mEq/kg is sometimes given.

Hypotension is treated by 10 to 20 ml/kg 0.9% saline and the Trendelenburg [29] position in which the body is laid flat on the back with the head lower than the pelvis.

Hyponatremia is corrected with 0.9% NaCl or slow correction with 3% NaCl in severe cases. For ventricular arrhythmias, lidocaine (which alters the depolarization in neurons, by blocking the fast sodium channels in the cell membrane so it will not depolarize or tramsmit an action potential) followed by a maintenance infusion of 1 to 4 mg per minute is used. Rhabdomyolysis (the breakdown of skeletal muscle due to injury, either mechanical, physical or chemical) is treated by controlling acute metabolic disturbances such as hyperthermia, hyperkalemia, and hypovolemia. Diuretics such as mannitol (an osmotic diuretic agent and a weak renal vasodilator which has a tendency to lose a hydrogen ions in aqueous solutions) or furosemide (a loop diuretic used in the treatment of congestive heart failure and edema) may be needed to maintain urine output.

Serotonin antagonists chlorpromazine (a blocking agent on dopaminergic-receptors, serotonergic-receptors, histaminergic-receptors, alpha1/alpha2-receptors and

on muscarinic (cholinergic) M1/M2-receptors) and cyproheptadine (an antihistaminic and antiserotonergic agent that also blocks calcium channels)  can be effective in mild to moderate cases of serotonin syndrome.

Research. Research indicates that MDMA damages the serotonin system in the brain and produces long-lasting behavioral deficits but limited sample size and difficulties controlling for other illicit substances, age, amount consumed, addiction, and other health conditions make it hard to prove a cause and effect relationship between MDMA use and specific cognitive or psychological damage in humans [30-31]. Laboratory studies of MDMA in humans are subject to ethical and methodological constraints given that the drug is illicit, has potential neurotoxicity and has resulted in some fatalities [34]. Conclusions about the addictive potential of MDMA from volunteers are less reliable than nicotine addiction since tolerance and after effects (‘withdrawal’ effects) seem to occur in some MDMA users who are actually not dependent [32-33].

Problems with verification of acute drug usage and of drug use histories, establishment of baseline (pre-morbid) levels of function, time course of MDMA effects, use of placebo controls and blind conditions, and representativeness of user populations pose other problems for data analyses. Analyses of tablets sold as ‘ecstasy’ has shown that these may contain MDMA at doses ranging from 40 to 150 mg, and may also contain ‘ecstasy-related’ drugs (particularly 3,4-methylenedioxy ethamphetamine and 3,4-methylenedioxyamphetamine), amphetamines, ketamine, LSD or a range of other chemicals and combinations of chemicals, so users’ knowledge of their own drug history can be based on inaccurate information about what they had actually taken [35].

Regular MDMA users often report that the positive effects of the drug decrease over time, while the more negative aspects increase in frequency. A pre-disposition to psychiatric illness may be a mediating factor in determining whether someone experiences psychopathology following MDMA use. Sometimes users won’t divulge the extent of their drug use given fears about confidentiality of information about an illegal activity. Retrospective accounts of drug history rely on memory, and when participants have used drugs like MDMA their recall of drug history may be unreliable.  Hair analysis can now detect drugs like ecstasy and offers potential for objectively verifying drug history.

Research studies also must deal with the fact that the MDMA users may differ from controls (nonusers or other drug users) regardless of having used ecstasy. For example, impulsiveness and sensation seeking would be predictably higher in young people who go on to use MDMA than in those who stick to the more ‘traditional’ drugs like alcohol, and people with higher levels of depression or aggression [36] may be more prone to use MDMA as a form of self-medication. So, things like memory function may be poorer initially in people who go on to use MDMA than in those who do not. Many ethical committees would feel that assessing people before they were about to take MDMA would, in effect, mean the researcher is condoning the use of this illicit substance, and they would not wish their own institution to be associated with this. Further, even predrug testing with regular users may pick up the residual effects of the last MDMA ingestion.

Other problems arise from the lack of information about how long subjects abstained from MDMA before testing takes place. Blood and urine samples can detect drugs like cannabis 2–3 weeks after use, but MDMA and other amphetamine derivatives can be detected only 24–48 h after the last dose, even though they have psychological and somatic effects which last longer. So, in studies where participants are asked to abstain from taking psychoactive drugs for several weeks prior to assessment, this cannot be objectively confirmed from bodily fluids taken only once before the study. Many studies of psychological function or psychiatric symptomatology do not provide even self-report information on time since last dose of MDMA.

Challenges and Future Directions.

According to studies in the United States, MDMA use is heaviest among youth and young adults. The U.S. Department of Health and Human Services’ National Household Survey on Drug Abuse found that 9.7% of 18- to 25-year-olds surveyed in 2000 had used MDMA at least once in their lifetimes. More than 6.4 million people age 12 and older reported that they had used MDMA at least once during their lifetimes. This is up from 5.1 million lifetime users in 1999. In a 2002 survey conducted by the CDC, 676,000 people had used MDMA during the month before they were surveyed.

To help prevent the use of MDMA Healthy People 2010 works with peer leaders to help and teach people who take this drug the harmful side effects of it and what it does to one’s body. Drug prevention programs at high school and colleges are also being started to help try and reduce the use of this drug all over the world today. MDMA is a leading indicator because it can eventually lead to substance abuse.

Law enforcement has a key role [37-38] since MDMA is most often manufactured clandestinely in Western Europe, primarily in the Netherlands and Belgium. The majority of the MDMA produced in other countries is trafficked to the United States by Israeli and Russian organized crime syndicates that recruit American, Israeli, and Western European nationals as couriers using express mail services, commercial flights, and airfreight shipments to deliver their merchandise. All major airports in Europe act as shipping points for MDMA destined for the United States. Currently, Los Angeles, Miami, and New York are the major gateway cities for the influx of MDMA from abroad.

 In the United States, the Drug Enforcement Administration’s (DEA’s) Chemical Control Program is working to prevent the diversion of precursor chemicals used to produce these substances. DEA registration, record keeping, and suspicious order reporting requirements apply to those who import, export, manufacture, and distribute the chemicals being watched by DEA. The United States and other governments use the annual meetings of the United Nations Commission on Narcotic Drugs to promote international acceptance of chemical control and to highlight emerging chemical control concerns. As a result of the 1988 United Nations Drug Convention, parties to the convention became obligated to control their chemical commerce and to cooperate with each other in their efforts to prevent chemical diversion.

Conclusion.  MDMA is a psychoactive chemical substance that may have additive and neurotoxic effects that manifest both in short term and long term use. The use of this mood-enhancing drug has increased in recent years due to its popularity among young in dance clubs. It is manufactured illegally and many deaths may be associated with impurities as well as by primary poisoning of the substance. Systematic research is impeded by ethical concerns of administering such a substance to humans, and other factors including pre-existing conditions, other drug use, and environmental factors can exacerbate the drug’s effects.

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