MDMA Toxicity


Practice Essentials

The substance 3,4-methylenedioxymethamphetamine (MDMA [ie, ecstasy, XTC, Adam, E, X, clarity, Stacy, Molly]) 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. Individuals who take MDMA describe a sense of euphoria, loss of inhibition, a feeling of closeness and/or empathy, and increased sensuality.

At the root of MDMA's widespread popularity is the mistaken belief that it is a safe drug with little toxicity and a long duration of action. In fact, MDMA has addictive psychoactive properties and unpredictable toxicity, and its abuse has led to an alarming increase in emergency department (ED) visits worldwide.

Patients with MDMA toxicity may present with central nervous system, cardiovascular, gastrointestinal, skin, and other manifestations (see Presentation). They should be evaluated for hyperthermia, dehydration, hyponatremia, seizures, hypertensive crises, cardiac dysrhythmias, and possible signs of serotonin syndrome (see Workup). Most patients with MDMA overdose improve with supportive care, but life-threatening complications may result from severe toxicity (see Treatment).


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.[1]

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.[2] 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[3, 4, 5] . 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”).[6] 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.[7] 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 renally excreted unchanged; the rest is metabolized in the liver, specifically by the hepatic enzyme CYP 2D6 and catechol–O–methyl transferase (COMT).[8] Of note, a small subset of the population is either missing the liver enzyme CYP2D6 and COMT genotypes. Others have decreased function due to inhibition from medications such as the protease inhibitor ritonovir, 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.[9]

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.[9, 3] 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.[10] Further complications include disseminated intravascular coagulation (DIC), hepatotoxicity, and acute kidney injury.[11] Most cases of toxicity have been idiosyncratic and did not depend on massive overdoses.


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).[12, 13] 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.


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.[14]

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.[15] 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.



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 2016 National Survey on Drug Use and Health, 6.9% of those aged 12 years and older had reported using MDMA at least once in their lifetimes.[16]

Estimates by the Drug Abuse Warning Network (DAWN) showed a steady increase in emergency department (ED) visits related to MDMA abuse: 421 ED visits in 1995; 4,026 in 2002; 10,752 in 2005; and 22,498 in 2011.[17] These numbers were collected from participating hospitals in major metropolitan areas throughout the United States and reflect trends of drug abuse and not national numbers.[18]

Data from the National Institute on Drug Abuse (NIDA) show that from 2015 to 2016, lifetime MDMA use declined in those aged 12 to 17 years (from 1.4% to 1.2%) and in those 18 to 25 years old (from 13.1% to 11.6%), and increased in those 26 years and older (from 6.5% to 6.7%).[16] 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%).[19]

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.[20]


The European Centre for Drugs and Drug Addictions (ECDDA) reports a wide variation between countries in the lifetime prevalence of MDMA use in 15- to 34-year-olds, ranging from 0.1% to 12.2%, with a weighted European average of 5.7%. Use of MDMA during the prior year ranges from 0.1% to 3.1%. The ECDDA estimated that about 1.8 million (1.3 %) young Europeans used MDMA in 2012.[21]

The United Nations Office on Drugs and Crime estimates that world wide in 2015, from 9.4 million to 43.1 million people had used MDMA during the past year. MDMA use remained high in Oceania (primarily Australia andNew Zealand), Europe ,and North America, with previous declines in Western and Central Europe, reversing since 2013. The UN estimates the average global prevalence of MDMA use at 0.45%, with higher rates in Oceania (2.42%), North America (0.89%), and Europe (0.69%).[22]


MDMA toxicity has been associated with the following:

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."[23] 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.

Although uncommon, several cardiovascular toxicities have been documented, ranging from arrhythmias to heart failure. Surprisingly, MDMA-induced myocardial infarction is rarely reported.[24] 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-, 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. However, as of 2015, more than 2% of US eighth graders had reported using MDMA at least once.[25] Reports also document MDMA toxicity among patients in the fifth and sixth decades of life.


The patient, friends, emergency medical services (EMS), or the authorities may provide history regarding the possibility of drug abuse. These patients usually present on weekends, often late at night or in the early morning hours after many hours of dancing at raves. Emergency Medical Services (EMS) or the authorities can provide information as to the setting in which they were found (eg, clubs, raves, bars).

Sometimes, patients may be carrying MDMA tablets with motif symbols and rave paraphernalia such as neon glow sticks and "smart drinks," which are blended fruit juices with amino acids. However, in the absence of any history, always consider sympathomimetic drugs, such as amphetamines and cocaine, in any young patient who presents with altered mental status and autonomic hyperactivity.

Typically, patients present to the emergency department (ED) either immediately after an ingestion, indicating an acute adverse reaction, or, more commonly, after the euphoric high has subsided and they have tried repeated dosing or co-ingestion with other drugs. Often, patients have mixed toxidromic presentations because of co-ingestion with alcohol, marijuana, ketamine, gamma-hydroxybutyrate (GHB), heroin, or cocaine.

Central nervous system manifestations include the following:

Cardiovascular manifestations include the following:

Gastrointestinal manifestations include the following:

Skin manifestations include the following:

Other manifestations include the following:


Physical examination findings demonstrate sympathomimetic hyperstimulation on various organ systems in the body; they can help focus on the most likely toxidrome; keep in mind that polysubstance abuse is the rule rather than the exception.

Pay particular attention to vital signs. MDMA toxicity results in tachycardia, hypertension, and hyperthermia. Obtain a rectal temperature along with frequent serial checks on the patient's neurologic status.

Head, ears, eyes, nose, and throat findings include the following:

Central nervous system findings include the following:

Cardiovascular findings include the following:

Respiratory findings include the following:

Other findings include the following:

Approach Considerations

If a patient gives a clear history of MDMA ingestion with mild symptoms and is hemodynamically stable, no laboratory studies are indicated. If the history is absent and/or questionable or if the patient exhibits signs of moderate-to-severe toxicity, appropriate laboratory studies include the following:

The urine toxicology screen fails to detect MDMA unless large doses have been ingested. It is nonspecific, and positive test findings only indicate presence of an amphetamine drug class. Confirmation by means of gas chromatography and/or mass spectrometry is strongly recommended when test findings are positive for amphetamines.

Patients complaining of chest pain should undergo electrocardiographic testing and monitoring. Include cardiac enzymes in laboratory studies for chest pain secondary to suspected ischemia.

Send cultures of blood and urine for testing if signs of infection and fever are present. Consider lumbar puncture to exclude meningitis.

Imaging Studies

See the list below:

Other Tests



Prehospital Care

Prehospital care is primarily supportive.

Address the ABCs, administer oxygen, obtain intravenous access, assess blood glucose level, monitor the patient, and perform frequent vital sign checks and serial assessment of consciousness (eg, AVPU [alert, responds to voice, responds to pain, unresponsive], Glasgow Coma Scale).

Anxiety, extreme agitation, panic reactions, and seizures may require short-acting benzodiazepines (eg, lorazepam) administered intravenously or intramuscularly. Restraints may be necessary if patients exhibit complete loss of control and are dangerous to themselves or others.

Emergency Department Care

While most patients with MDMA overdose improve with supportive care, life-threatening complications may result from severe toxicity. Fatalities have been reported because of severe hyperthermia (ie, heat stroke) accompanied by disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Death from cerebral edema and seizures secondary to hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) has also been reported. As in any amphetamine toxicity, the danger of cardiac arrhythmias and cardiovascular instability always must be entertained.

Careful attention to the airway, breathing, and circulation (ABCs) and vital signs is standard in overdoses, and serial neurologic checks are required. Provide oxygen, obtain intravenous access, and perform cardiac monitoring.

A bedside glucose determination is indicated in any patient presenting with altered mental status. If a patient is hypoglycemic, administer thiamine and enough glucose to maintain adequate serum glucose concentrations with frequent monitoring.

If verbal communication is possible, providing reassurance is important. Avoid physical or pharmacologic restraints if possible. Place the patient in a calm, quiet room. If severe agitation or disruptive behavior persists, sedation using benzodiazepines and/or physical restraints may be necessary.

If acute toxicity caused by ingestion is known, perform gastrointestinal decontamination by administering activated charcoal. Orogastric lavage usually is not necessary unless a life-threatening co-ingestant is involved and the patient presents within 1 hour of ingestion. Whole-bowel irrigation may be indicated if body packing of drugs is suspected.

Although respiratory distress is uncommon, endotracheal intubation and mechanical ventilation may be required in patients who cannot protect their airway or have respiratory compromise because of conditions such as seizures, cardiovascular instability, or trauma.

Patients presenting with severe hyperthermia require aggressive cooling measures and adequate fluid resuscitation. Obtain a rectal temperature. Aggressively cool hyperthermic patients, attempting to reduce the core temperature to 101°F within 30-45 minutes.

. Morbidity is directly related to the severity and duration of hyperthermia. Management considerations are as follows:

Dantrolene (1 mg/kg or 80 mg intravenously [IV]) has been used for the treatment of hyperpyrexia after conventional therapy. Dantrolene is typically used to treat malignant hyperthermia, a genetic disorder of the skeletal muscle due to a defect in the ryanodine receptor that allows for massive release of calcium from the sarcoplasmic reticulum during exposures to general anesthetics.

MDMA-induced hyperthermia is thought to be centrally mediated via serotonin toxicity. Although the mechanism of dantrolene does not seem to correlate with what is known about MDMA-induced hyperthermia, dantrolene was first used to treat hyperthermia in the setting of MDMA-related hyperpyrexia in 1992 due to the similarity of presentation.

A systematic compilation of MDMA case reports suggests possible evidence of benefit in using dantrolene to treat hyperthermia.[27] The study showed decreased morbidity and mortality with rare side effects from the dantrolene itself, especially in patients who present with temperatures above 40°C, and particularly above 42°C. The biggest caveat with using case series and case reports is recognizing the limitations of reporting and publication biases.

A study in an animal model found that clozapine resulted in a marked and immediate reversal of MDMA-induced hyperthermia, via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia, and labetalol was ineffective.[28]

Treat seizures with benzodiazepines. Most seizures are self-limited and respond well to benzodiazepines. Protect the airway and consider phenobarbital or propofol in patients with refractory symptoms. Treat the underlying cause and check electrolytes, especially hyponatremia. Start with fluid restriction, but consider adding hypertonic saline in refractory or severe cases; in these cases, adding 3% saline and furosemide may be indicated but at a rate no greater than 0.5-1 mEq/L/h.

Foley catheter placement is indicated to monitor urine output in patients with rhabdomyolysis. Check urinalysis for myoglobin and creatine kinase for rhabdomyolysis. Recognition and treatment of rhabdomyolysis with fluids, alkalinization of the urine, and furosemide may be indicated to prevent acute renal failure. Alkalinization of the urine with sodium bicarbonate is helpful. Administration of furosemide and mannitol may also be considered.

Obtain cardiac monitoring and an electrocardiogram in patients complaining of chest pain or palpitations. Order appropriate cardiac enzyme measurements if cardiac injury is suggested. Significant cardiac dysrhythmias may require pharmacotherapy or cardioversion and/or defibrillation.

Initially, manage hypertension with benzodiazepine sedation. In patients with refractory symptoms or signs of end-organ damage, nitroprusside or nitroglycerin can be used to lower the blood pressure.

Always perform pregnancy testing in female patients with overdose. MDMA, like all amphetamines, can be toxic to the fetus and may induce miscarriage or premature labor.


See the list below:

Medication Summary

Objectives in pharmacotherapeutic intervention of MDMA toxicity include the following:

  1. Decontamination with activated charcoal/sorbitol
  2. Sedation with benzodiazepines in agitated and anxious patients
  3. Relief of muscle spasms and/or cramping with benzodiazepines
  4. Prevention of rhabdomyolysis with IV fluids (benefit of furosemide or sodium bicarbonate remains controversial)
  5. Seizure control with benzodiazepines
  6. Stabilization of hemodynamic and/or cardiovascular disturbances with nitroprusside or nitroglycerin.

Lorazepam (Ativan)

Clinical Context:  Beneficial for sedative and anticonvulsant effects. Sedation also can lower amphetamine-induced hypertension. DOC for initial treatment of status epilepticus.

Diazepam (Valium, Diazemuls, Diastat)

Clinical Context:  Depresses all levels of CNS, possibly by increasing activity of GABA; individualize dosage and increase cautiously to avoid adverse effects.

Class Summary

These agents are important for sedation, muscle relaxation, and seizure management.

Phenobarbital (Luminal, Barbita, Solfoton)

Clinical Context:  Exhibits anticonvulsant activity in anesthetic doses. In status epilepticus, important to achieve therapeutic levels as quickly as possible. IV dose may require approximately 15 min to attain peak levels in brain.

If IM route is chosen, administer into areas such as one of the large muscles (eg, gluteus maximus, vastus lateralis, other areas with little risk of encountering a nerve trunk or major artery); permanent neurologic deficit may result from injection into or near peripheral nerves.

Restrict IV use to conditions in which other routes are not possible, either because patient is unconscious or because prompt action is required; if used to terminate generalized convulsive status epilepticus, administer up to 15-20 mg/kg.

Ventilation and intubation may be necessary; hypotension may require treatment; a trend exists in recommendations to use agents other than phenobarbital (propofol, midazolam, other barbiturates) for refractory status epilepticus.

Class Summary

Class of anticonvulsants useful when phenytoin and benzodiazepines fail.

Sodium bicarbonate (Neut)

Clinical Context:  Useful in alkalization of urine to prevent acute myoglobinuric renal failure; titrate dose to increase pH to 7.45-7.55; onset of action is within minutes and lasts approximately 15-30 min; monitor blood pH to avoid excess alkalosis. Maintain normal serum potassium level because urinary alkalinization impossible if patient is hypokalemic.

Class Summary

These agents are used to facilitate treatment of rhabdomyolysis.

Mannitol (Osmitrol)

Clinical Context:  Alternative diuretic used when urine output is inadequate despite aggressive fluid therapy.

Initially assess for adequate renal function in adults by administering test dose of 200 mg/kg IV over 3-5 min; should produce urine flow of at least 30-50 mL/h of urine over 2-3 h.

In children, assess for adequate renal function by administering test dose of 200 mg/kg IV over 3-5 min; should produce urine flow of at least 1 mL/h over 1-3 h.

Class Summary

These agents increase osmolarity of glomerular filtrate and induce diuresis. They hinder tubular reabsorption of water, causing sodium and chloride excretion to increase.

Phentolamine (Regitine)

Clinical Context:  Alpha1 and alpha2 adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension that results from catecholamine effects on alpha-receptors.

Sodium nitroprusside (Nitropress)

Clinical Context:  Produces vasodilation and increases inotropic activity of heart; at higher dosages, may exacerbate myocardial ischemia by increasing heart rate.

Nitroglycerin (Nitro-Bid, Nitrostat, Deponit)

Clinical Context:  Decreases coronary vasospasm, which increases coronary blood flow; in addition, induces vessel dilatation, decreasing cardiac workload.

Class Summary

Design treatment of hypertension to reduce the blood pressure and other risk factors of coronary heart disease. Individualize pharmacologic therapy based on a patient's age, race, known pathophysiologic variables, and concurrent conditions. Design treatment not only to lower blood pressure safely and effectively but also to avoid or reverse hyperlipidemia, glucose intolerance, and left ventricular hypertrophy.

Furosemide (Lasix)

Clinical Context:  Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule; potent vasodilator of medullary vessels serving to wash out concentration gradient of countercurrent system, resulting in marked diuresis.

Class Summary

Diuretics facilitate diuresis during treatment of rhabdomyolysis.

Activated charcoal (Liqui-Char, Actidose-Aqua)

Clinical Context:  Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal; does not dissolve in water; for maximum effect, administer within 30 min of poison ingestion; may administer as aqueous suspension or combined with cathartic (usually sorbitol 70%) and with presence of active bowel sounds; may need to be repeated (without cathartic) to adsorb large pill masses or drug packages.

Class Summary

Activated charcoal adsorbs MDMA after acute ingestions and limits absorption into systemic circulation. Most beneficial if administered within 4 hours of ingestion.

Dextrose (Glucose-D)

Clinical Context:  Monosaccharide, absorbed from intestine and distributed, stored, and used by tissues. Parenterally injected dextrose is used in patients unable to obtain adequate oral intake; direct oral absorption results in rapid increase of blood glucose concentrations. Effective in small doses; no evidence indicates that it may cause toxicity; concentrated infusions provide higher amounts of glucose and increased caloric intake with minimum fluid volume.

Class Summary

This agent is used to raise the patient's serum glucose level.

Thiamine (Vitamin B-1)

Clinical Context:  Supplementation ensures adequate cofactor for maintenance of cellular aerobic respiration. CNS depletion of thiamine may result in Wernicke encephalopathy.

Class Summary

Vitamins are indicated to correct thiamine deficiency and prevent Wernicke-Korsakoff encephalopathy.

Further Outpatient Care

Refer the patient for drug abuse counseling and treatment.

Further Inpatient Care

Admission to an intensive care unit may be needed in patients with any of the following:


Patients may require transfer to a psychiatric facility for evaluation and treatment if they exhibit dangerous behavior or psychosis refractory to general supportive measures. However, patients must be stable, without hemodynamic instability and with no evidence of cardiac, cerebral, renal, hepatic, or pulmonary complications.


Hyperthermia and the risk of serotonin syndrome can result in increased mortality with complications of disseminated intravascular coagulation, rhabdomyolysis, and acute kidney injury. Institute general cooling measures and treat rhabdomyolysis with generous intravenous hydration and alkalinization of the urine.

Monitor hyponatremia as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and excessive water intake for resultant cerebral edema and seizures. In severe cases, administration of 3% saline and furosemide may be indicated to correct the hyponatremia, but at a rate no greater than 0.5-1 mEq/L/h.

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.

Although the causal relationship between MDMA and liver toxicity has not been shown definitively, case reports document hepatotoxicity resulting in self-limited hepatitis and fulminant liver failure following MDMA use.

Always keep in mind the possibility of other drug ingestions. MDMA users often co-ingest other drugs, and ecstasy tablets can also contain other drugs. Heroin, ketamine, cocaine, alcohol, and marijuana have been implicated, and the patient may present with a mixed toxidromic clinical picture.

Patient Education

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.

What is MDMA toxicity?What is MDMA?What is the pathophysiology of MDMA?What are the routes of MDMA administration?What is the role of metabolism in the pathophysiology of MDMA toxicity?What is the role of tolerance in the pathophysiology of MDMA toxicity?How does the purity of MDMA affect toxicity?What are the adverse effects of MDMA toxicity?What are the cardiovascular effects of MDMA toxicity?What is the pathophysiology of serotonin syndrome due to MDMA toxicity?What is the pathophysiology of hyponatremia in MDMA toxicity?What are neurologic effects of MDMA toxicity?What is the pathophysiology of hepatotoxicity caused by MDMA?What are long-term neuropsychiatric effects of MDMA toxicity?What is the prevalence of MDMA toxicity in the US?What is the global prevalence of MDMA toxicity?What is the mortality and morbidity associated with MDMA toxicity?Which patient groups are at highest risk for MDMA toxicity?Which clinical history findings are characteristic of MDMA toxicity?What are the CNS signs and symptoms of MDMA toxicity?What are the cardiovascular signs and symptoms of MDMA toxicity?What are the GI signs and symptoms of MDMA toxicity?What are the cutaneous signs and symptoms of MDMA toxicity?What are the genitourinary and dental signs and symptoms of MDMA toxicity?What is included in the physical exam to evaluate MDMA toxicity?Which ENT findings are characteristic of MDMA toxicity?Which CNS findings are characteristic of MDMA toxicity?Which cardiovascular findings are characteristic of MDMA toxicity?Which respiratory findings are characteristic of MDMA toxicity?Which GI and genitourinary findings are characteristic of MDMA toxicity?Which adulterants and MDMA substitutes should be considered in the differential diagnoses of MDMA toxicity?What are the differential diagnoses for MDMA Toxicity?What is the role of lab tests in the workup of MDMA toxicity?What is the role of cardiac testing and monitoring in the workup of MDMA toxicity?What is the role of lumbar puncture in the workup of MDMA toxicity?What is the role of imaging studies in the workup of MDMA toxicity?What is included in prehospital care for MDMA toxicity?What causes morbidity in MDMA toxicity?How is MDMA toxicity treated?How is hyperthermia treated in MDMA toxicity?What is the role of dantrolene in the treatment of MDMA toxicity?How are seizures treated in MDMA toxicity?How is rhabdomyolysis treated in MDMA toxicity?How are the cardiovascular manifestation of MDMA toxicity treated?How does MDMA toxicity affect a pregnancy?Which specialist consultations are beneficial to patients with MDMA toxicity?What are the objectives of medical treatment of MDMA toxicity?Which medications in the drug class Vitamin supplementation are used in the treatment of MDMA Toxicity?Which medications in the drug class Glucose supplement are used in the treatment of MDMA Toxicity?Which medications in the drug class GI decontamination are used in the treatment of MDMA Toxicity?Which medications in the drug class Diuretic are used in the treatment of MDMA Toxicity?Which medications in the drug class Antihypertensives are used in the treatment of MDMA Toxicity?Which medications in the drug class Osmotic diuretics are used in the treatment of MDMA Toxicity?Which medications in the drug class Alkalinizing agent are used in the treatment of MDMA Toxicity?Which medications in the drug class Barbiturates are used in the treatment of MDMA Toxicity?Which medications in the drug class Benzodiazepines are used in the treatment of MDMA Toxicity?Where should patients be referred following treatment for MDMA toxicity?When is inpatient treatment indicated for MDMA toxicity?When is patient transfer considered in the treatment of MDMA toxicity?What are the possible complications of MDMA toxicity?What is included in patient education about MDMA toxicity?


In-Hei Hahn, MD, FACEP, FACMT, Attending Physician, Department of Emergency Medicine, NYU Langone-Cobble Hill

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John G Benitez, MD, MPH, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

Disclosure: Nothing to disclose.

Chief Editor

Jeter (Jay) Pritchard Taylor, III, MD, Assistant Professor, Department of Surgery, University of South Carolina School of Medicine; Attending Physician, Clinical Instructor, Compliance Officer, Department of Emergency Medicine, Palmetto Richland Hospital

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Employed contractor - Chief Editor for Medscape.

Additional Contributors

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Peter MC DeBlieux, MD, Professor of Clinical Medicine and Pediatrics, Section of Pulmonary and Critical Care Medicine, Program Director, Department of Emergency Medicine, Louisiana State University School of Medicine in New Orleans

Disclosure: Nothing to disclose.


The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author David Yew, MD, to the original writing and development of this article.


  1. Sessa B. MDMA and PTSD treatment: "PTSD: From novel pathophysiology to innovative therapeutics". Neurosci Lett. 2017 May 10. 649:176-180. [View Abstract]
  2. Armenian P, Mamantov TM, Tsutaoka BT, Gerona RR, Silman EF, Wu AH, et al. Multiple MDMA (Ecstasy) overdoses at a rave event: a case series. J Intensive Care Med. 2013 Jul-Aug. 28 (4):252-8. [View Abstract]
  3. McCann UD, Eligulashvili V, Ricaurte GA. (+/-)3,4-Methylenedioxymethamphetamine ('Ecstasy')-induced serotonin neurotoxicity: clinical studies. Neuropsychobiology. 2000. 42(1):11-6. [View Abstract]
  4. Ricaurte GA, Martello AL, Katz JL, Martello MB. Lasting effects of (+-)-3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther. 1992 May. 261(2):616-22. [View Abstract]
  5. Steele TD, McCann UD, Ricaurte GA. 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"): pharmacology and toxicology in animals and humans. Addiction. 1994 May. 89(5):539-51. [View Abstract]
  6. Schwartz RH, Miller NS. MDMA (ecstasy) and the rave: a review. Pediatrics. 1997 Oct. 100(4):705-8. [View Abstract]
  7. Boels D, Grall-Bronnec M, Guerlais M, Le Roux G, Spiers A, Gerardin M, et al. Parachuting: a dangerous trend in recreational psychoactive substance delivery. Expert Opin Drug Deliv. 2017 Apr. 14 (4):491-498. [View Abstract]
  8. Aitchison KJ, Tsapakis EM, Huezo-Diaz P, Kerwin RW, Forsling ML, Wolff K. Ecstasy (MDMA)-induced hyponatraemia is associated with genetic variants in CYP2D6 and COMT. J Psychopharmacol. 2012 Mar. 26(3):408-18. [View Abstract]
  9. Nadkarni GN, Hoskote SS, Piotrkowski J, Annapureddy N. Serotonin Syndrome, Disseminated Intravascular Coagulation, and Hepatitis After a Single Ingestion of MDMA in an Asian Woman. Am J Ther. 2012 Jun 16. [View Abstract]
  10. Cunningham M. Ecstasy-induced rhabdomyolysis and its role in the development of acute renal failure. Intensive Crit Care Nurs. 1997 Aug. 13(4):216-23. [View Abstract]
  11. Fahal IH, Sallomi DF, Yaqoob M, Bell GM. Acute renal failure after ecstasy. BMJ. 1992 Jul 4. 305(6844):29. [View Abstract]
  12. Henry JA, Fallon JK, Kicman AT, Hutt AJ, Cowan DA, Forsling M. Low-dose MDMA ("ecstasy") induces vasopressin secretion. Lancet. 1998 Jun 13. 351(9118):1784. [View Abstract]
  13. Holden R, Jackson MA. Near-fatal hyponatraemic coma due to vasopressin over-secretion after "ecstasy" (3,4-MDMA). Lancet. 1996 Apr 13. 347(9007):1052. [View Abstract]
  14. Carvalho M, Pontes H, Remiao F, Bastos ML, Carvalho F. Mechanisms underlying the hepatotoxic effects of ecstasy. Curr Pharm Biotechnol. 2010 Aug. 11(5):476-95. [View Abstract]
  15. Reneman L, Booij J, Schmand B, van den Brink W, Gunning B. Memory disturbances in "Ecstasy" users are correlated with an altered brain serotonin neurotransmission. Psychopharmacology (Berl). 2000 Feb. 148(3):322-4. [View Abstract]
  16. National Institute on Drug Abuse. National Survey of Drug Use and Health. Available at Accessed: December 20, 2017.
  17. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Substance Abuse and Mental Health Services Administration. 2013. Available at
  18. Drug Abuse Warning Network (DAWN) Reports 2005. [Electronic Version]. Retrieved June 8, 2008 from
  19. Palamar JJ, Keyes K, Cleland CM. Underreporting of ecstasy use among high school seniors in the US. Drug Alcohol Depend. 2016 Jun 6. [View Abstract]
  20. Wish ED, Fitzelle DB, O'Grady KE, Hsu MH, Arria AM. Evidence for significant polydrug use among ecstasy-using college students. J Am Coll Health. 2006 Sep-Oct. 55(2):99-104. [View Abstract]
  21. European Monitoring Centre for Drugs and Drug Addiction. Methylenedioxymethamphetamine (MDMA or 'Ecstasy'). EMCDDA. Available at January 8, 2015; Accessed: December 20, 2017.
  22. United Nations Office on Drugs and Crime. World Drug Report 2017. UNODC. Available at Accessed: December 20, 2017.
  23. O'Shea E, Escobedo I, Orio L, et al. Elevation of ambient room temperature has differential effects on MDMA-induced 5-HT and dopamine release in striatum and nucleus accumbens of rats. Neuropsychopharmacology. 2005 Jul. 30(7):1312-23. [View Abstract]
  24. Lai TI, Hwang JJ, Fang CC, Chen WJ. Methylene 3, 4 dioxymethamphetamine-induced acute myocardial infarction. Ann Emerg Med. 2003 Dec. 42(6):759-62. [View Abstract]
  25. Monitoring the Future Study: Trends in Prevalence of Various Drugs. National Institute on Drug Abuse. Available at Accessed: July 6, 2016.
  26. Papaseit E, Pérez-Mañá C, Mateus JA, Pujadas M, Fonseca F, Torrens M, et al. Human Pharmacology of Mephedrone in Comparison to MDMA. Neuropsychopharmacology. 2016 May 20. [View Abstract]
  27. Grunau BE, Wiens MO, Brubacher JR. Dantrolene in the treatment of MDMA-related hyperpyrexia: a systematic review. CJEM. 2010 Sep. 12(5):435-42. [View Abstract]
  28. Kiyatkin EA, Ren S, Wakabayashi KT, Baumann MH, Shaham Y. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction. Neuropsychopharmacology. 2016 Jan. 41 (2):549-59. [View Abstract]
  29. McElhatton PR, Bateman DN, Evans C, Pughe KR, Thomas SH. Congenital anomalies after prenatal ecstasy exposure. Lancet. 1999 Oct 23. 354(9188):1441-2. [View Abstract]
  30. Andreu V, Mas A, Bruguera M, et al. Ecstasy: a common cause of severe acute hepatotoxicity. J Hepatol. 1998 Sep. 29(3):394-7. [View Abstract]
  31. Burgess C, O'Donohoe A, Gill M. Agony and ecstasy: a review of MDMA effects and toxicity. Eur Psychiatry. 2000 Aug. 15(5):287-94. [View Abstract]
  32. Freudenmann RW, Oxler F, Bernschneider-Reif S. The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction. 2006 Sep. 101(9):1241-5. [View Abstract]
  33. Galineau L, Belzung C, Kodas E, Bodard S, Guilloteau D, Chalon S. Prenatal 3,4-methylenedioxymethamphetamine (ecstasy) exposure induces long-term alterations in the dopaminergic and serotonergic functions in the rat. Brain Res Dev Brain Res. 2005 Feb 8. 154(2):165-76. [View Abstract]
  34. Joseph M. Ecstasy - Its History and Lore. Carlton Books; 2000. 1-96.
  35. Maxwell DL, Polkey MI, Henry JA. Hyponatraemia and catatonic stupor after taking "ecstasy". BMJ. 1993 Nov 27. 307(6916):1399. [View Abstract]
  36. Saadat KS, O'shea E, Colado MI, Elliott JM, Green AR. The role of 5-HT in the impairment of thermoregulation observed in rats administered MDMA ('ecstasy') when housed at high ambient temperature. Psychopharmacology (Berl). 2005 Jun. 179(4):884-90. [View Abstract]
  37. Amoroso T. The Psychopharmacology of ±3,4 Methylenedioxymethamphetamine and its Role in the Treatment of Posttraumatic Stress Disorder. J Psychoactive Drugs. 2015 Nov-Dec. 47 (5):337-44. [View Abstract]