MDMA Toxicity 

The substance 3,4-methylenedioxymethamphetamine (MDMA [ie, ecstasy, XTC, Adam, E, X, clarity, Stacy]) is an amphetamine derivative that has gained significant popularity in recent years and has become the recreational drug of choice for many adolescents and young adults. The drug has various addictive psychoactive properties, and its abuse has led to an alarming increase in emergency department (ED) visits worldwide. This designer drug must be recognized by the ED physician because of its tremendous abuse potential and unpredictable toxicity. At the root of its widespread popularity is the mistaken belief that it is a safe drug with little toxicity and a long duration of action. Individuals who take MDMA describe a sense of euphoria, loss of inhibition, a feeling of closeness and/or empathy, and increased sensuality.

The first synthesis of MDMA was by Köllisch in 1912 at a German pharmaceutical company, Merck and Company, with the German patent 274350. At the time of patent application, no use was specified for MDMA and it was called "methylsafrylamin" in the annual report. MDMA was discovered while in the pursuit of hemostatic substances, not appetite suppressants. The erroneous association is due to MDA, 3,4-methylenedioxyamphetamine, a close analogue studied for its antidepressive and appetite suppressant effects developed in 1949-1957 by Smith, Kline, and French.

In 1927, Max Oberlin at Merck noticed the chemical similarity between MDMA and ephetonine-like and adrenalin-like substances. He conducted the first pharmacologic testing and noted that MDMA did not have pure sympathetic effects because it was devoid of the local effects on the eye. In 1978, Shulgin and colleagues reported human study results concerning the pharmacokinetic and psychotropic effects of MDMA. Before MDMA became a Schedule I drug, some therapists used MDMA as an experimental therapeutic aid in marriage counseling and psychoanalysis due to its enactogenic effects, the ability to “touch within” and for increasing self-awareness.

Inevitably, as public awareness grew, some members of the public began to use MDMA for recreational purposes, and its use began to increase on the streets. Recreational MDMA use began insidiously among middle class professionals and was confined to small groups. However, as the potential for huge profits appeared, MDMA soon spread to a younger crowd and became prevalent in bars, clubs, and college campuses across the country. During the early 1980s, this subculture of house music and house parties was found in major cities throughout the United States; at the same time, MDMA use spread throughout Europe in hideaways such as Ibiza, Spain, and the famed underground club scene in London.

In 1985, published reports stated that MDMA and its demethylated metabolite 3,4-methylenedioxyamphetamine (MDA) had long-term neurotoxic effects in laboratory animals. As a result of the study and concern over MDMA's increasing recreational use, the Drug Enforcement Agency placed MDMA in the Schedule I category of the Controlled Substance Act, hence declaring the drug illegal. Despite its illegal status as of 1986, the use of MDMA has continued to increase and has risen dramatically since the arrival of the "rave" phenomenon.

Raves occur in dance halls and clubs. Typically, young adults ingest tablets of MDMA and dance all night to electronic music and laser lights. People gather by the thousands and dance for many hours in hot crowded venues or clubs; they may present to the ED, usually complaining of symptoms of dehydration and hyperthermia. While most improve with supportive treatment alone, the patient should be evaluated for signs of hyperthermia, dehydration, hyponatremia, seizures, hypertensive crises, cardiac dysrhythmias, and possible signs of serotonin syndrome.

MDMA use has increased dramatically, becoming a global phenomenon. The misconception that MDMA is a safe drug continues to be a major problem. Many of the myths concern the fact that it was once legal as a psychotherapeutic adjunct and that it has few adverse effects. The medical community's awareness of MDMA has increased, and conclusive evidence indicates that significant morbidity and mortality are associated with its use. Physicians must be able to recognize these symptoms and to treat and educate patients accordingly.

MDMA is a member of a family of amphetamine derivatives known as MDA. Structurally, MDMA is similar to the stimulant methamphetamine and the hallucinogen mescaline. Like other amphetamines (in particular, dopamine and norepinephrine), it causes catecholamine release from presynaptic vesicles. However, MDMA also is a selective serotonergic neurotoxin that causes massive release of serotonin (ie, 5-hydroxytryptamine [5-HT]) and is postulated to inhibit its uptake. In animal models, it has been demonstrated to cause long-term destruction of 5-HT axons and axon terminals. No randomized clinical human studies exist, and one always must be cautious when extrapolating animal study data and applying it to human models. However, studies demonstrate lowered concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid of regular MDMA users. This correlates with a similar decrease reported in primates with brain damage induced by MDMA.

The effects of MDMA can be described as those of a hallucinogenic amphetamine, combining some effects of amphetamine (ie, speed) with that of LSD (ie, acid). However, many of the effects are dose dependent, and auditory and/or visual hallucinations are not commonly observed. Much of the abuse potential lies in its pleasurable subjective effects (eg, empathy, euphoria, disinhibition, increased sensuality). Hence, MDMA is often described as the “hug drug,” due to the amplified desire to be touched and socialize.

MDMA is available as a tablet, capsule, powder, and liquid; however, it most commonly is used in tablet form. These tablets often are engraved with various motif symbols and brands, ranging from birds (eg, doves) and animals (eg, blue elephants), numbers (eg, 8 1/2), cartoon characters (eg, Bugs Bunny), and cars (eg, Ferrari). It usually is swallowed, although reports of smoking, snorting, and injecting MDMA have been found. Following oral intake, its duration of action is 8-24 hours with a half-life of 12-34 hours, though this can depend on the purity of the drug ingested. It is metabolized in the liver and excreted renally. Of note, a small subset of the population is missing the liver enzyme CYP2D6, which may be implicated in fatalities caused by the inability to metabolize MDMA.

Each tablet contains approximately 50-100 mg of MDMA and costs approximately $20-25. Effective doses are 1-2 mg/kg, and initial effects occur in 30-60 minutes. Peak effects occur at 90 minutes and may persist 4-8 hours. Tolerance to the psychoactive properties of MDMA develops rapidly, and an increase in adverse effects is reported because of frequent use. Repeated doses cause sympathomimetic responses to predominate and can result in amphetamine-like toxicity. Severe hyperthermia has been reported at doses of 4-5 mg/kg.

One of the problems in assessing the causes and effects of MDMA toxicity is determining the purity of the ingested substance. Synthesis of MDMA is relatively simple, and it often is produced in illicit laboratories or clandestine locations, such as basements and garages. In addition to the less than ideal quality control measures, these synthesized tablets also may be cut or mixed with other psychoactive substances. Substances found mixed with MDMA include heroin, ketamine, and ephedrine (ie, herbal ecstasy).

General medical adverse effects

The acute effects of MDMA have an initial onset of 30 minutes after oral intake and are characterized by anxiety, tachycardia, and elevated blood pressures. Associated symptoms include diaphoresis, bruxism, jaw clenching, paresthesias, dry mouth, increased psychomotor activity, and blurred vision. Within 1 hour, these sympathomimetic effects are replaced by feelings of relaxation, euphoria, and increased empathy and communication. While overt auditory and/or visual hallucinations are uncommon, patients report increased sensory tactile enhancement and mild visual distortions, such as halos. These effects plateau for up to 90 minutes and then diminish over 3-4 hours.

Many users attempt to prolong these effects by taking additional doses of the drug. However, when too much additional MDMA is consumed in a single session, individuals report unpleasant symptoms of autonomic hyperarousal associated with feelings of restlessness, paranoia, and anxiety. Tolerance to the psychoactive properties of MDMA develops rapidly, and the user is unable to restore the euphoric effects with repeated doses. Instead, sympathomimetic effects predominate, placing the patient at risk for cardiovascular instability, arrhythmias, and hyperthermia. In addition, following the acute effects of MDMA, users often report a 24- to 48-hour period characterized by lethargy, anorexia, and dysphoria. This period of lethargy is known as the blues or colloquially “suicide Tuesday” after weekend ecstasy use and is dangerous because other drugs often are co-ingested to help ease the "crash" after psychostimulant administration.

Cardiovascular effects

Autonomic hyperactivity is a major feature in patients presenting with MDMA toxicity and is dose-dependent. Typically, MDMA has only 1/10 the CNS stimulant effect of amphetamine. The proposed mechanism is the amphetamine-induced catecholamine and 5-HT surge that causes tachycardia, hypertension, and hyperthermia. Hyperthermia is especially dangerous because many cases involve patients dancing for prolonged periods with inadequate fluid intake in crowded dance halls with hot temperatures and poor ventilation.

As with any amphetamine, the risk of cardiac dysrhythmias and cardiovascular collapse is always a possibility. Fatal dysrhythmias have been reported following MDMA use, resulting in ventricular fibrillation and asystole. Individuals with underlying cardiac and/or pulmonary disease and preexisting conditions such as Wolff-Parkinson-White syndrome are especially at risk for heart failure and fatal arrhythmias.

Serotonin syndrome

Serotonin syndrome is a condition in which central 5-HT receptor hyperstimulation results in classic findings of hyperthermia, mental status changes, autonomic instability, and altered muscle tone and/or rigidity. MDMA causes massive serotonin release, and numerous case reports link MDMA toxicity to the serotonin syndrome. The mechanism is unclear, but a direct effect by MDMA on the thermoregulatory centers may be potentiated by sustained physical activity, high temperatures, and inadequate fluid intake as observed at rave parties. Vigorous dancing for long hours in these conditions can predispose patients to hyperthermia, dehydration, and muscle breakdown leading to rhabdomyolysis. Further complications include disseminated intravascular coagulation (DIC), hepatotoxicity, and acute renal failure. Most cases of toxicity have been idiosyncratic and did not depend on massive overdoses.

Hyponatremia

Various cases of seizure and death secondary to hyponatremia have been reported. The occurrence of hyponatremia after MDMA use is multifactorial, stemming from increased water intake, excessive sweating with physical exertion, and the release of vasopressin leading to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In severe cases of hyponatremia, patients can develop cerebral edema with subsequent seizures and, possibly, coma. These patients invariably show high urine osmolarity and continued sodium excretion despite low serum osmolality and hyponatremia, which is consistent with the criteria for diagnosis of SIADH. In the ED, always consider hyponatremia with resultant cerebral edema in any patient with known MDMA ingestion who presents with an altered mental status or seizure.

Neurologic effects

MDMA, like other amphetamines, can lead to a variety of fatal neurologic outcomes, including subarachnoid hemorrhage, cerebral infarction, or intracranial bleeds. Underlying mechanisms involve the short-term hypertensive surges and subsequent disruption of cerebral blood vessels, especially in patients with congenital arteriovenous malformations or cerebral angiomas. While these fatalities are rare, always consider amphetamine use as a possible cause of stroke.

Hepatotoxicity

Growing evidence suggests that MDMA may harm the liver. Hepatotoxicity ranges from asymptomatic liver injury with confirmation of elevation of the liver function tests to fulminant acute hepatic failure. Different patterns of liver injury are recognized, including benign lesions, viral hepatitis, extensive or focal hepatic necrosis, total loss of liver parenchyma and function with accompanying encephalopathy, cerebral edema, and multiorgan system failure.

In the setting of grade III or IV hepatic encephalopathy, without a liver transplant, the mortality rate is more than 50%. The presentation of MDMA hepatotoxicity varies. The timing of ingestion and onset of symptoms, as well as doses, do not seem to correlate with the clinical severity, and recurrence can also occur due to chronic use. Chronic use of MDMA leads to fibrotic changes that are related to an increase of collagen I production by the stellate cells.

Histopathologically, hepatotoxicity associated with hyperthermia demonstrates a picture of centrolobular necrosis and microvesicular steatosis. Without hyperthermia present, hepatotoxic changes noted are consistent with acute cholestatic hepatitis with eosinophils and macrophage infiltrates. The reasons for the different patterns of injury are still not completely understood, although theories include hyperthermia, increased efflux of neurotransmitters, oxidation of biogenic amines, mitochondrial impairment, apoptosis, and genetic polymorphisms.^[1]

CYP2D6 catalyzes the metabolism of MDMA in the liver via O-demethylenation pathway. So atypical responses to MDMA may be related to genetic polymorphisms of this isoenzyme. Subjects known to be slow metabolizers had elevated levels of MDMA and lower levels of the demethylenated product after being administered two 100-mg doses with a 24-hour interval period in a clinical trial. Clinically, a slow metabolizer may be at greater risk for developing acute MDMA toxicity.

Finally, MDMA is synthesized, and often the source as well as well as the purity of the drug is unknown. One must consider whether the liver toxicity was caused by MDMA, another psychoactive compound contained in the ecstasy tablet, a contaminant, or coingestion of another drug. Nevertheless, MDMA may exert harmful effects on the liver and may cause significant damage, especially when combined with other hepatotoxic substances.

Long-term neuropsychiatric effects

Recent literature suggests the possibility of long-term psychiatric complications involving regular use of MDMA. The long-term effects may be related to the decrease in serotonin reuptake transporter (SERT) function and numbers. Recovery of SERT may take weeks and months; ultimately, chronic use may lead to permanent serotonergic damage of the axons and terminals sparing the cell bodies. Patients have reported symptoms of depression, anxiety, panic attacks, and insomnia after ending MDMA use. Further studies report that patients using MDMA have difficulty concentrating and short-term memory impairment. Although much of the focus in the ED involves managing the acute toxic effects of MDMA, educate patients that long-term neurologic and psychiatric complications may occur.

Frequency

United States

Although various estimates have been given on the extent of current illicit MDMA use in the United States and western Europe, the exact prevalence remains unknown. According to the 2004 National Drug Use and Health, more than 11 million persons aged 12 years and older have reported using MDMA at least once in their lifetimes.^[2] Drug Abuse Warning Network (DAWN) data have shown a steady increase in emergency department (ED) visits from MDMA abuse. The DAWN estimates have shown a greater than 800% increase since 1995 from 421 ED visits to 4,026 in 2002 and another 167% increase in 2005 with 10,752 ED visits. These numbers are collected from participating hospitals in major metropolitan areas throughout the United States and reflect trends of drug abuse and not national numbers.^[3]

According to a 1993 National Institute on Drug Abuse survey, 2% of all US college students admitted to taking MDMA in the previous 12 months. An interview study of Stanford University undergraduate students reported that 39% had taken MDMA at least once in their lives. A Tulane University survey of more than 1200 students revealed that 24% had used MDMA.^[4]

Some critics have described MDMA as having the "greatest growth potential among all illicit drugs" in the United States, with tens of thousands of new users introduced to the drug scene every month, particularly within the context of raves. In support of this statement, a 1999 national study reported statistically significant changes regarding MDMA use among 10th and 12th graders. Use of MDMA increased from 3.3% in 1998 to 4.4% in 1999 among 10th graders. The percentage of 12th graders using MDMA rose from 3.6% in 1998 to 5.6% in 1999. Lifetime use increased from 5.8% in 1998 to 8% in 1999.

However, there is some good news, recent data from the annual NIDA Monitoring the Future survey has shown a decline in MDMA use in middle school and high school students. Between 2001 and 2005, annual ecstasy use was down 52% in 8^th graders, 58 % in 10^th graders, and 67% in 12^th graders.^[2] The 2004 National Survey on Drug Use and Health estimates that the number of current adolescent and adult MDMA abusers in the United States declined from 676,000 in 2002 to 450,000 in 2004.

Government raids on MDMA also have shown a drastic increase in MDMA drug trafficking. In the late 1990s, government seizures of MDMA increased by 450%. In 1997, 400,000 tablets were seized, and, in 1999, 3.3 million tablets were seized. The US government's projected numbers for the next few years are between 7 and 8 million tablets.

International

A 1992 Harris Opinion Poll for the British Broadcasting Corporation (BBC) in Great Britain presented data that 31% of people aged 16-25 years admitted using MDMA. In a survey of school children across England, 6% of those aged 14-15 years reported using MDMA. In 1996, the popular British press reported that an estimated 500,000-1,000,000 young people in Great Britain use MDMA every weekend.

Throughout the 1990s, raves have become increasingly common, spreading throughout Europe, Spain, Portugal, Australia, and even India and Asia. One published report from 1998 estimated that 3% of the adult European population had tried ecstasy. Although the exact numbers in other countries are not known, MDMA truly has become a global phenomenon and is continuing to spread because of its easy availability and the misconception that it is a relatively safe drug.

Mortality/Morbidity

MDMA toxicity has been associated with seizures, hyperthermia, coagulopathies, arrhythmias, heart failure, stroke, and renal and/or liver failure.

Most MDMA-related fatalities have been attributed to symptoms of heat stroke and hyperthermia. Many of these patients exhibited features of the serotonin syndrome. Hyperthermia results from the catecholamine surge caused by MDMA and is exacerbated in the setting of raves. Increased body temperatures with vigorous dancing in crowded hot clubs can cause dehydration, DIC, rhabdomyolysis, and acute renal failure. MDMA users are informed at raves to keep adequate hydration and take cooling measures as needed.

Recent studies in rats have shown that high ambient temperatures enhance MDMA-induced locomotor activity suggesting that the high temperatures seen at raves may serve as an incentive to users to prolong and enhance their "high."^[5] This, in turn, puts them at higher risk for hyperthermia and the serotonin syndrome.

Another major cause of morbidity and mortality is abnormal fluid, electrolyte balance, or both. MDMA stimulates vasopressin release, resulting in SIADH. This, in conjunction with too much water intake during profuse sweating and salt loss (eg, during raves), can lead to severe hyponatremia with subsequent cerebral edema and seizures.

Although uncommon, several cardiovascular toxicities have been documented ranging from arrhythmias to heart failure. Surprisingly, MDMA-induced myocardial infarction is rarely reported. Despite the low frequency of cardiovascular-related deaths from MDMA, it must be emphasized that any amphetamine has the potential to induce fatal arrhythmias. This is especially true in patients with underlying cardiac/pulmonary disease and in those who co-ingest other drugs/stimulants.

Intracerebral hemorrhage has also been reported but is uncommon. Patients with underlying conditions such as arteriovenous malformations and cerebral angiomas have an increased risk. Elderly patients and those with a history of hypertension also have an increased risk of intracerebral hemorrhage following MDMA use.

Hepatitis and liver failure have been reported, although whether MDMA has a direct toxic effect to the liver is unclear. Interestingly, a subset of the population may be at risk for liver toxicity. These patients are missing a liver enzyme called CYP2D6, which is necessary to metabolize MDMA. It is deficient or totally absent in 5-10% of whites and African Americans and in 1-2% of Asians.

Race

MDMA is now a global phenomenon and is used all over the world. Traditionally, use has been associated with white males; however, the demographic has changed with the popularity of raves and now includes large percentages of Asian, African American, and Hispanic persons.

Sex

MDMA use is most common among single white males aged 16-25 years. However, with the advent of raves, MDMA use has increased across all ethnic, age, and gender boundaries.

Age

Typically, most users are aged 16-25 years. However, incidence of MDMA use in younger age groups is increasing. Reports also document MDMA toxicity among patients in the fifth and sixth decades of life.