MDMA Toxicity

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. More recently, MDMA has shown efficacy in the treatment of posttraumatic stress disorder (PTSD). ^{[1, 2]} MDMA-assisted psychotherapy received breakthrough therapy status from the US Food and Drug Administration (FDA) in 2017. A phase 3 clinical trial of MDMA-assisted therapy demonstrated statistically significant improvement in PTSD symptoms after three sessions, and FDA approval by late 2023 is possible. ^{[3, 4, 5]}

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 rose dramatically with 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. ^[6] 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 ^{[7, 8, 9]} . 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); 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 capsule or tablet form. The pure crystalline powder form of MDMA is usually sold in capsules and is popularly known as Molly (slang for “molecular”). ^[10] 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).

MDMA is usually swallowed, although reports of smoking, snorting, and injecting MDMA have been found. Users may place a crushed or powdered dose of MDMA in a small piece of soft paper (eg, toilet paper) and swallow it—so-called parachuting—to speed onset of the drug's effect. ^[11] Following oral intake, the 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.

About 75% is excreted unchanged by the kidneys; the rest is metabolized in the liver, specifically by the liver enzyme CYP2D6 and catechol–O–methyl transferase (COMT). ^[12] Of note, a small subset of the population has a CYP2D6 genotype that results in absent or low CYP2D6 enzyme activity, or a COMT genotype that results in low COMT enzyme activity. Decreased enzyme function may also be due to inhibition from medications such as the protease inhibitor ritonavir, which may be implicated in severe toxicity such as serotonin syndrome, hepatitis, disseminated intravascular coagulation, hyponatremia, and fatalities caused by the inability to metabolize MDMA. ^[13]

Typically, a 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 have included 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. ^{[13, 7]} 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. ^[14] Further complications include disseminated intravascular coagulation (DIC), hepatotoxicity, and acute kidney injury. ^[15] 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). ^{[16, 17]} 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 potentially 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. ^[18]

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

The 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, persistent 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. ^[19] 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. 

Data from the National Institute on Drug Abuse (NIDA) show that from 2015 to 2021, lifetime MDMA use declined in those aged 12 to 17 years (from 1.4% to 0.6%) and in those 18 to 25 years old (from 13.1% to 7.9%), and increased in those 26 years and older (from 6.5% to 8.3%). ^[20] However, a review of 2014 NIDA data by Palamar et al suggested that MDMA use by high school students may have been underreported, because of failure to include the term "Molly" on some survey forms. The surveys that included "Molly" in the definition of MDMA returned significantly higher rates of lifetime use (8.0% vs. 5.5%) and 12-month use (5.1% vs. 3.6%). ^[21]

In a survey conducted at a large university in the mid-Atlantic United States and published in 2006, 9% of students reported lifetime MDMA use; in addition, MDMA users were more likely than marijuana users to have used inhalants, LSD, cocaine, and heroin in the past year. ^[22]

The 2021 Annual Report of the American Association of Poison Control Centers' National Poison Data System reported 12 deaths attributed to MDMA. ^[23]

International

The European Centre for Drugs and Drug Addictions (ECDDA) estimated that in 2021, about 1.9 million (1.9%) young Europeans (ages 15-34) used MDMA, with higher prevalence among those aged 15-24 (2.2%). ^[24]

The United Nations Office on Drugs and Crime estimates that world wide, 20 million people had used MDMA in 2020 and estimates the average global prevalence of MDMA use at 0.4%. MDMA use is highest in Asia (10 million users) followed by North America (2.9 million users) and Africa (2 million users). ^[25]

In addition, the UNODC reports that illicit fentanyl and its analogues are reportedly mixed into heroin and other drugs, such as cocaine and MDMA,  and sold as counterfeit prescription opioids. Users are often unaware of the contents of the substance they are taking, which inevitably leads to a great number of fatal overdoses. ^[25]  

Race-, Sex-, and Age-related Demographics

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 more females and large percentages of Asian, African American, and Hispanic persons.

Typically, most users are 16-25 years of age. In 2022 lifetime prevalence remained steady from 2021 with more than 0.6% of US eighth graders and 1.4% of twelth graders reported using MDMA at least once. ^[26] Reports also document MDMA toxicity among patients in the fifth and sixth decades of life.

MDMA toxicity has been associated with the following:

• Seizures
• Hyperthermia
• Coagulopathies
• Arrhythmias
• Heart failure
• Stroke
• Renal failure
• 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 stay adequately hydrated and take cooling measures as needed.

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." ^[27]  This, in turn, puts them at higher risk for hyperthermia and the serotonin syndrome.

Another major cause of morbidity and mortality is abnormal fluid balance, 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.

As with any amphetamine, the risk of stroke, cardiac arrhythmia, and heart failure always is possible. The risk is especially high in patients with congenital abnormalities (eg, arteriovenous malformations, cardiomyopathy) or underlying heart and pulmonary disease. Surprisingly, MDMA-induced myocardial infarction is rarely reported. ^[28]  

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.

Patient education is essential in communicating the short- and long-term risks of MDMA use. MDMA long has been misperceived as a safe drug with few adverse effects and a long duration of action. However, tolerance develops quickly, and users who respond by taking larger doses place themselves further at risk for complications of sympathetic hyperactivity leading to possible cardiac arrhythmias, hyperthermia, and hemodynamic instability.

Patients must also be informed of long-term psychiatric implications associated with regular use. Depression, anxiety, paranoia, and insomnia have been reported to last for years after cessation of MDMA use. In addition, studies have demonstrated impairment in concentration and memory associated with MDMA use.

For patient education information, see the First Aid and Injuries Center and Mental Health Center, as well as Club Drugs, Drug Dependence & Abuse, Substance Abuse, Poisoning, and Activated Charcoal.