AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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.

A German pharmaceutical company, Merck and Company, originally synthesized MDMA in 1914. At the time of patent application, no use was specified for MDMA. Despite reports to the contrary, MDMA was never marketed as an appetite suppressant by Merck or any other company. In the 1950s, the US military added it to a long list of experimental substances as a possible brainwashing and/or chemical agent. The results were inconclusive, and MDMA did not resurface again until the late 1970s in professional circles as a possible adjunct to psychotherapy. Numerous psychiatric literature and popular press reports during this time concluded that MDMA may have heightened effects for introspection, thus allowing patients to facilitate communication and gain deeper insight into their problems and feelings. Some therapists even used MDMA as an adjunct in marital counseling sessions and in terminally ill patients who had difficulty dealing with their pain.

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 US; 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 Schedule I 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. Young adults ingest 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, always look for signs of hyperthermia, dehydration, hyponatremia, seizures, hypertensive crises, cardiac arrhythmias, and features of the 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 treat and educate patients accordingly.

Pathophysiology

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).

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 ranging from birds (eg, doves), 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. 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 amphetaminelike 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 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. 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

Some evidence suggests that MDMA may harm the liver; reports indicate that hepatitis and jaundice has occurred in some patients. Until recently, only a few reports documented cases of acute hepatitis related to the use of MDMA. Whether liver toxicity was caused by MDMA, another psychoactive compound contained in the ecstasy tablet, a contaminant, or consumption of another drug is unclear. 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. 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 US and western Europe, the exact prevalence remains unknown.

Recent data from the Drug Abuse Warning Network (DAWN) 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. 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.

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.

Some critics have described MDMA as having the "greatest growth potential among all illicit drugs" in the US, 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.

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





• Another major cause of morbidity and mortality is abnormal fluid and/or electrolyte balance. 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 coingest other drugs/stimulants.





• Intracerebral hemorrhage also has 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 1-2% of Asians.

Race

MDMA is now a global phenomenon and is used all over the world. Traditionally, use has been more 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The patient, friends, emergency medical services (EMS), or the authorities may provide history regarding the possibility of abuse. These patients usually present on weekends, often late at night or in the early morning hours after many hours of dancing at raves. 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 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
• • Change in mental status, seizures

  • Anxiety, paranoia

  • Increased psychomotor activity, restlessness

  • Hyperthermia, hot flashes

  • Headache

  • Ataxia

  • Blurred vision, halos

  • Syncope

• Cardiovascular
• • Palpitations

  • Chest pain

• Gastrointestinal
• • Dry mouth

  • Nausea, vomiting

  • Abdominal cramping

  • Anorexia

• Skin
• • Diaphoresis

  • Piloerection

• Other - Pregnancy (Studies have shown that prenatal exposure to MDMA in pregnant rats induces transient and long-term neurochemical and behavioral modifications in dopaminergic and serotonergic functions.)
• Urinary retention, difficulty voiding
• Sexual dysfunction

Physical

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
• • Mydriasis

  • Nystagmus

  • Decreased visual acuity

  • Bruxism (ie, teeth grinding)

  • Trismus, jaw clenching

  • Dry mouth

• Central nervous system
• • Hyperthermia

  • Increased psychomotor agitation

  • Hypervigilance

  • Agitation, anxiety

  • Ataxia

  • Hallucinations (very rare)

  • Hypertensive crisis (can lead to symptoms of stroke)

• Cardiovascular
• • Tachycardia

  • Dysrhythmias (eg, premature ventricular contractions, supraventricular tachycardias, ventricular tachycardia, ventricular fibrillation)

• Respiratory
• • Respiratory distress (rare; patients are usually polysubstance abusers)

  • Respiratory failure, aspiration, noncardiogenic pulmonary edema

• Other
• • Diaphoresis

  • Abdominal cramping

  • Muscle spasm

  • Sexual dysfunction (difficulty having orgasm)

  • Urinary retention

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Polysubstance abuse - Alcohol, marijuana, ketamine, GHB, heroin, and cocaine

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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 labs include the following:
• • Obtain a CBC to exclude infection as a cause of fever and altered mental status.

  • Measure electrolyte levels and pay particular attention to sodium and renal function.

  • A bedside glucose determination is always indicated in patients with altered mental status.

  • Obtain LFTs, prothrombin time and/or activated partial thromboplastin time. Patients manifesting significant or prolonged hyperthermia require evaluation of hepatic and coagulation studies to exclude DIC.

  • Perform pregnancy tests in women of childbearing age.

  • A creatine kinase measurement is helpful to exclude rhabdomyolysis.

  • Dipstick urinalysis findings can be positive for myoglobinuria.

  • 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 labs for chest pain secondary to suspected ischemia.

  • In addition to the tests listed above, labs for altered mental status may include serum osmolality, alcohol, and ketones.

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

Imaging Studies

• Patients demonstrating only mild symptoms without any hemodynamic instability do not require imaging studies. Observation and supportive care is recommended.
• Obtain a chest x-ray in patients complaining of chest pain, demonstrating low oxygen saturations, or experiencing respiratory distress.
• Patients presenting with a seizure or prolonged mental status changes despite initial resuscitation should undergo cranial CT scan. Metabolic causes such as hyponatremia should be found quickly and corrected cautiously.

Other Tests

• Patients complaining of chest pain should undergo electrocardiographic testing and monitoring.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Prehospital care is primarily supportive.

• Address the ABCs, administer oxygen, obtain IV access, assess blood glucose, 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 IV or IM. 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 DIC, rhabdomyolysis, and acute renal failure. Death by cerebral edema and seizures secondary to hyponatremia and SIADH also has been reported. As in any amphetamine toxicity, the danger of cardiac arrhythmias and cardiovascular instability always must be entertained. Careful attention to the airway and vital signs is standard in overdoses, and serial neurologic checks are required.

• Establish ABCs, provide oxygen, obtain IV 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 contact is possible, it is important to provide reassurance. 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 GI 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 to 102°F. Morbidity is directly related to the severity and duration of hyperthermia.
• • Undress the patient.

  • Apply evaporative cooling with water and a fan.

  • Apply ice packs to the groin and axilla.

  • Iced gastric lavage may be considered.

  • Control shivering with a benzodiazepine.

  • Antipyretics are not useful.

• Treat seizures with benzodiazepines. Most seizures are self-limited and respond well to benzodiazepines. Protect the airway and consider phenytoin and phenobarbital in patients with refractory symptoms. Treat the underlying cause and check electrolytes, especially hyponatremia. Start with fluid restriction, but consider adding 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 also may be considered.

• Obtain cardiac monitoring and ECG in patients complaining of chest pain or palpitations. Order appropriate cardiac enzymes 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 patients with overdose. MDMA, like all amphetamines, can be toxic to the fetus and may induce miscarriage or premature labor.

Consultations

• A regional poison control center and medical toxicologist can provide valuable information and instructions for handling complex ingestions. Bedside consultation or admission (if necessary) by a medical toxicologist may be beneficial in these situations.
• Obtain psychiatric consultation for patients who demonstrate suicidal thoughts or behavior.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Objectives in pharmacotherapeutic intervention of MDMA toxicity include the following: (1) decontamination with activated charcoal/sorbitol, (2) sedation in agitated and anxious patients with benzodiazepines, (3) relief of muscle spasms and/or cramping with benzodiazepines, (4) prevention of rhabdomyolysis with furosemide or sodium bicarbonate, (5) seizure control with benzodiazepines, and (6) stabilization of hemodynamic and/or cardiovascular disturbances with nitroprusside or nitroglycerin.

Drug Category: Benzodiazepines

Important for sedation, muscle relaxation, and seizure management.

Drug Name	Diazepam (Valium, Diazemuls, Diastat)
Description	Depresses all levels of CNS, possibly by increasing activity of GABA; individualize dosage and increase cautiously to avoid adverse effects.
Adult Dose	0.2 mg/kg IV at 2 mg/min; not to exceed 20 mg as a single dose; may repeat, monitoring for respiratory depression
Pediatric Dose	<5 years: 0.2-0.5 mg/kg IV; not to exceed 5 mg >5 years: 0.2-0.5 mg/kg IV; not to exceed 10 mg
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; altered mental status; low BP or respiratory rate
Interactions	Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, cimetidine, alcohols, and MAOIs
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause altered mental status, respiratory depression, and hypotension; caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)

Drug Category: Anticonvulsants

Used to terminate clinical and electrical seizure activity as rapidly as possible and to prevent seizure recurrence.

Drug Category: Barbiturates

Class of anticonvulsants useful when phenytoin and benzodiazepines fail.

Drug Category: Alkalinizing agent

To facilitate treatment of rhabdomyolysis.

Drug Category: Osmotic diuretics

Increase osmolarity of glomerular filtrate and induce diuresis. Hinder tubular reabsorption of water, causing sodium and chloride excretion to increase.

Drug Category: Antihypertensives

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.

Drug Name	Sodium nitroprusside (Nitropress)
Description	Produces vasodilation and increases inotropic activity of heart; at higher dosages, may exacerbate myocardial ischemia by increasing heart rate.
Adult Dose	0.1-8 mcg/kg/min IV; titrate to effect
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; subaortic stenosis; idiopathic hypertrophic; atrial fibrillation or flutter; hypovolemia; sildenafil (Viagra) use within 24 h
Interactions	Coadministration with indomethacin may increase nitrate serum concentrations; sildenafil coadministration causes severe hypotension
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in increased intracranial pressure, hepatic failure, severe renal impairment, and hypothyroidism; in renal or hepatic insufficiency, nitroprusside levels may increase and can cause cyanide toxicity; monitor for thiocyanate and cyanide or limit use to <24 h (risk of cyanide toxicity is increased with infusions > 2 mcg/kg/min); cyanide toxicity can be prevented with prolonged nitroprusside infusions by adding 1 g sodium thiosulfate to each 250 cm3 bag of nitroprusside for infusion; has ability to lower blood pressure (thus, use only in patients with mean arterial pressures >70 mm Hg); not a first-line drug for use in pregnant women unless hypertensive emergency

Drug Name	Nitroglycerin (Nitro-Bid, Nitrostat, Deponit)
Description	Decreases coronary vasospasm, which increases coronary blood flow; in addition, induces vessel dilatation, decreasing cardiac workload.
Adult Dose	400 mcg SL or 5 mcg/min IV; titrate to effect May administer bolus of 12.5-25 mcg or give 400-mcg tab SL as bolus before continuous infusion; initial infusion rate of 10-20 mcg/min may be increased 5-10 mcg/min q5-10min until desired clinical or hemodynamic response is achieved; infusion rates of 500 mcg/min occasionally have been required
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe anemia; shock; postural hypotension; head trauma; closed-angle glaucoma; cerebral hemorrhage; hypovolemia; constrictive pericarditis; pericardial effusion; hypertrophic cardiomyopathy; sildenafil (Viagra) use within previous 24 h
Interactions	Aspirin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in coronary artery disease, low systolic BP, recent AMI, glaucoma, hepatic disease, and hyperthyroidism

Drug Category: Diuretic

Facilitates diuresis during treatment of rhabdomyolysis.

Drug Category: GI decontamination

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

Drug Category: Glucose supplement

Used to raise the patient's serum glucose.

Drug Category: Vitamin supplementation

Indicated to correct thiamine deficiency and prevent Wernicke-Korsakoff encephalopathy.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admission to an intensive care unit may be needed if evidence suggests presence of significant hyperthermia, altered mental status, seizures, severe hyponatremia, respiratory depression, or acute renal failure secondary to rhabdomyolysis.

Further Outpatient Care

• Patients can be offered referral to outpatient detoxification centers for drug rehabilitation.

Transfer

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

Complications

• Hyperthermia and the risk of serotonin syndrome can result in increased mortality with complications of DIC, rhabdomyolysis, and acute renal failure. Institute general cooling measures and treat rhabdomyolysis with generous IV hydration and alkalinization of the urine.
• Monitor hyponatremia as a result of 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 be combined with 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 perceived as a "safe" drug with few adverse effects and a long duration of action. However, tolerance develops quickly, and, with increasing doses, patients place themselves further at risk for complications of sympathetic hyperactivity leading to possible cardiac arrhythmias, hyperthermia, and hemodynamic instability. Patients must 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 excellent patient education resources, visit eMedicine's Substance Abuse Center, Poisoning - First Aid and Emergency Center, and Mental Health and Behavior Center. Also, see eMedicine's patient education articles Club Drugs, Drug Dependence & Abuse, Substance Abuse, Poisoning, and Activated Charcoal.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The pure ecstasy user is a rare entity. The overwhelming majority of persons who take ecstasy also use other drugs. In addition, ecstasy tablets may be mixed or cut with other substances. Always keep in mind the possibility of co-ingestion with opiates, ketamine, GHB, cocaine, alcohol, marijuana, and other drugs.
• Hypoglycemia is always a possibility in patients presenting with neuropsychiatric symptoms. A rapid bedside glucose determination always is indicated; if needed, administer thiamine and glucose.
• Failure to monitor core temperature and provide sedation, cooling measures, and adequate IV hydration is a potential pitfall. Monitor for rhabdomyolysis and treat it with alkalinization of the urine.
• Failure to recognize hyponatremia as a severe complication of MDMA use is a potential pitfall. Numerous reports have demonstrated significant morbidity and mortality associated with hyponatremia-induced cerebral edema and seizures.
• A negative urine toxicology screen does not exclude the possibility of MDMA abuse. Toxicology screens usually fail to detect MDMA unless large amounts are ingested.

Special Concerns

• Beware of specific drug interactions that are potentially life threatening.
• • Patients with HIV who are taking protease inhibitors and ingest MDMA have had near-fatal reactions secondary to alterations in the cytochrome P-450 systems, resulting in an inability to metabolize MDMA.

  • Patients taking monoamine oxidase inhibitors (MAOIs) have had near-fatal outcomes when ingesting MDMA. Sympathomimetic-MAOI interactions can cause excessive serotonin and norepinephrine release, resulting in hypertensive crises, intracranial hemorrhage, and severe hyperthermia.

• Pregnancy presents special concerns.
• • MDMA, like other amphetamines, can cross the placental fetal blood barrier.

  • Infants born to mothers who used MDMA during pregnancy are at increased risk of congenital birth defects. Prospective follow-up studies of 136 babies exposed to ecstasy in utero indicated that the drug may be associated with a significantly increased risk of congenital defects (15.4%). Cardiovascular anomalies (26 per 1000 live births) and musculoskeletal anomalies (38 per 1000 live births) were predominant.

• Acidification of the urine no longer is recommended for amphetamine toxicity. An increased risk of acute renal failure exists secondary to the precipitation of ferrihemate in the renal tubules.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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