Mdma (ecstasy) intoxication

Robert J Hoffman, MD

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INTRODUCTION — MDMA (3,4-methylenedioxymethamphetamine) is a synthetic compound with structural and pharmacologic similarities to both amphetamines and mescaline. First developed in 1914 as an appetite suppressant, MDMA found use as a psychotherapeutic agent during the 1970s [1,2]. Its potential for abuse, however, was quickly recognized, leading government agencies to place tight restrictions on its use [3,4]. Although no longer used in psychiatry or psychotherapy, MDMA has become a common drug of abuse, particularly among young party-goers at "raves" and "circuit parties," due to its capacity to elicit feelings of euphoria, wakefulness, intimacy, sexual arousal, and disinhibition [5].

MDMA continues to gain popularity as a substance of abuse, particularly among adolescents and young adults. Among US high school seniors in 1999, 5.9 percent admitted to using ecstasy; in 2001, that figure climbed to 11 percent [6]. Erroneously believed to be a "safe" drug compared with amphetamine, MDMA actually shares the toxicity of amphetamine and possesses unique toxicities, both acute and chronic. With abuse on the rise and clear evidence of the drug's dangers, clinicians face a growing challenge of recognizing and managing acute MDMA toxicity.

Acute MDMA intoxication will be discussed here. A summary table to facilitate emergent management is provided (show table 1). Detailed discussions of related issues, such as serotonin syndrome, severe hyperthermia, and a general discussion of the poisoned patient are found elsewhere. (See "Serotonin syndrome", and see "Severe hyperthermia: Heat stroke and malignant hyperthermia" , see "General approach to drug intoxication in adults", and see "Approach to the child with occult toxic exposure").

PHARMACOLOGY AND CELLULAR TOXICOLOGY — MDMA (3,4-methylenedioxymethamphetamine) is a sympathomimetic amphetamine that causes release of endogenous catecholamines (particularly norepinephrine and dopamine) and blocks their reuptake into presynaptic vesicles.

MDMA differs somewhat from traditional amphetamines in that it is structurally similar to serotonin. This difference likely accounts for an increased release of serotonin and inhibition of serotonin reuptake [4,7,8].

This results in a toxicity profile for MDMA that is different from that of traditional amphetamines. Although typical findings of amphetamine toxicity (hypertension, tachycardia, hyperthermia, CNS stimulation) are often seen in MDMA toxicity, serotonergic toxicity (serotonin syndrome, SIADH) may be seen as well.

KINETICS — MDMA (3,4-methylenedioxymethamphetamine) is typically ingested as a tablet in dosages ranging from 50 mg to 200 mg, and it is readily absorbed from the gastrointestinal tract. Peak effects occur within two hours of ingestion and typically last four to six hours [8]. Up to 75 percent of MDMA is excreted in the urine unchanged, while the remainder is primarily metabolized by the hepatic enzyme CYP2D6 [9,10].

The concentrations of MDMA contained in illicitly produced pills vary widely [4]. Major toxicity and death may occur after ingestion of a single tablet; ingestion of larger quantities carries greater risk of toxicity.

CLINICAL FEATURES — MDMA (3,4-methylenedioxymethamphetamine) increases alertness, reduces fatigue, and leads to feelings of increased physical and mental powers, and euphoria. Users typically begin to experience the desired effects of MDMA approximately one hour following oral administration [7]. Minor adverse reactions such as agitation, nausea, bruxism (grinding teeth), ataxia, diaphoresis, blurry vision, tachycardia, and hypertension can also occur at typical MDMA doses. These effects are usually self-limited and resolve within hours [11]. More serious effects are uncommon and described below.

Vital signs — MDMA can cause hypertension, tachycardia, and hyperthermia.

Cardiovascular stimulation — Life-threatening increases in heart rate and blood pressure may occur. Cardiovascular toxicity can include hypertensive emergencies, intracranial hemorrhage, myocardial infarction, aortic dissection, and dysrhythmia [12-18].

Hyperthermia and related effects — Hyperthermia may result from drug effects on the central nervous system (CNS), prolonged physical exertion (eg, dancing all night at a "rave"), and environmental conditions (eg, dancing in a densely populated, hot room). Both the stimulant effect of amphetamines and serotonin syndrome may contribute to severe hyperthermia in these patients [16,19]. Hyperthermia can lead to disseminated intravascular coagulation and rhabdomyolysis. (See "Hyperthermia" below).

Hyponatremia — Users of MDMA experience an elevation in antidiuretic hormone levels, which may cause symptomatic hyponatremia and hypoosmolality [20]. Other factors that may contribute to hyponatremia include psychogenic polydipsia and the repletion of volume losses with free water [21]. Some MDMA users believe they can avoid hyperthermia by drinking large amounts of water.

Seizures, cerebral edema, cerebral herniation, and death have been reported as a result of hyponatremia and hypoosmolality [20,22]. Data from case reports and one small case series suggest symptomatic ecstasy users presenting to the emergency department typically have serum sodium levels on the order of 110 to 125 meq/dL [20,21]. A serum sodium level as low as 101 meq/dL has been reported [23].

Neurologic — Stimulation of the CNS is common and can manifest as agitation, hyperactivity, anxiety, and even delirium [19]. Seizures and status epilepticus can occur. Psychomotor agitation may be associated with hyperthermia as well as rhabdomyolysis.

Serotonin syndrome findings — Serotonin syndrome is a potentially life-threatening condition characterized by the triad of autonomic dysfunction, abnormal neuromuscular activity, and altered mental status. MDMA use can cause serotonin syndrome, presumably via stimulation of massive serotonin release. Individuals who use MDMA in combination with selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), or other drugs that increase 5-HT1A receptor activity (such as meperidine, tryptophan, or lithium) are at greater risk of developing serotonin syndrome [24-27]. (See "Serotonin syndrome").

DIFFERENTIAL DIAGNOSIS — Other sympathomimetic drugs of abuse, such as cocaine, amphetamine, and methamphetamine, may present with a clinical syndrome that is indistinguishable from MDMA (3,4-methylenedioxymethamphetamine) toxicity.

Anticholinergic toxicity can present with delirium, dilated pupils, hyperthermia, tachycardia, and hypertension. Skin findings are helpful in distinguishing the two syndromes: patients with anticholinergic toxicity generally present with reduced or absent sweating, whereas patients with MDMA toxicity are usually diaphoretic. The typical pattern of speech is also different for the two poisonings, frequently being clear but pressured for MDMA and resembling a "mouthful of marbles" with anticholinergic toxicity.

Other causes of altered mental status, such as hypoglycemia, electrolyte disorders, intracranial hemorrhage, and infection should be considered. In particular, patients with hyperthermia and alteration in mental status who do not have a history strongly suggestive of MDMA or other drug intoxication should undergo lumbar puncture to rule out a CNS infection.

LABORATORY EVALUATION — Routine laboratory evaluation of the poisoned patient should include the following:

• Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

• Acetaminophen and salicylate levels, to rule out these common coingestions

• Electrocardiogram (ECG), to rule out conduction system poisoning by drugs that effect the QRS or QTc intervals

• Pregnancy test in women of childbearing age

For patients in whom significant toxicity related to use of MDMA (3,4-methylenedioxymethamphetamine) is suspected, the clinician should also obtain the following [4,8]:

• Basic serum electrolytes; if hyponatremia is present, a serum osmolality is recommended

• Creatine kinase and urine myoglobin, to evaluate for rhabdomyolysis (see "Rhabdomyolysis")

• Serum creatinine, to assess for kidney damage

• Serum aminotransferase concentrations, to assess for liver damage

• Coagulation studies (ie, aPTT, PT, INR, platelet count, d-dimer), to assess for disseminated intravascular coagulation (see "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults")

Although there are specific serum and urine assays for MDMA, we advise against the use of these assays to guide clinical management. A positive MDMA screening test cannot confirm that a patient's symptoms are the result of MDMA toxicity. A negative test can occur despite the presence of MDMA congeners, of which there are over 100. Such congeners may cause clinical symptoms that are indistinguishable from MDMA toxicity. Regardless of whether the inciting agent is MDMA or a related drug, management is identical and based solely on the patient's clinical status.

MANAGEMENT — The general approach to any poisoned patient must always begin with stabilization of the airway, breathing, and circulation. General discussions of the basic facets of the management of poisonings are found elsewhere. Detailed management of MDMA (3,4-methylenedioxymethamphetamine) intoxication is discussed immediately below. A summary table to facilitate emergent management is provided (show table 1). (See "General approach to drug intoxication in adults", and see "Decontamination of poisoned adults" and see "Enhanced elimination of poisons").