3,4-Methylenedioxymethamphetamine (MDMA) Toxicity

Etiology

The potential for MDMA toxicity exists with each ingestion, substantiating its designation as a Schedule I drug. MDMA is commonly ingested in tablet form; however, the tablet may be crushed and ingested intranasally. Recreational doses of MDMA can vary significantly from 50 mg to 200 mg per tablet. However, analysis of compounds sold as ecstasy or molly has revealed mixed composition with other substances, including methyl diethanolamine (MDEA, also known as "eve"), 3,4-methylenedioxyamphetamine (MDA, also known as "sally"), ephedrine, ketamine, paracetamol, inactive substitutes, some producing hemodynamic effects.[4][5][6] As a result, significant adverse effects and toxicity can occur with one-time or first-time ingestion due to the unknown dosage and composition of the drug.[7]

MDMA is commonly used with other recreational drugs, which can potentiate or antagonize the toxic effects on the neurological and cardiovascular systems.[3][8] Combined with physical activity in a hot, humid environment, this compounding effect can lead to significant hyperthermia, dehydration, and hyponatremia, mimicking the effects of heat stroke in many cases.[9]

Epidemiology

Trends in MDMA use are well documented throughout the years, with user age ranging from the 8th grade to the collegiate level and adulthood. A review of epidemiological data revealed a significant increase in usage between the 1990s and early 2000s. For example, lifetime MDMA use on one college campus was found to increase from 16% to 24% between the years 1986 and 1990, while a national sample of college students saw a 69% increase between the years 1997 and 1999.[10] From 1999 to 2000, lifetime use among 8th graders increased from 2.7% to 4.3%, while this increase was significantly greater in 12th graders (8%-11%). Also, emergency room visits in the United States increased from 253 to 4511 between 1994 and 2000.[11] A 2002 Monitoring the Future study found that 12.7% of United States college students had used ecstasy once in their lifetime. The 2002 National Survey of Drug Use and Health found a greater than 200% increase in MDMA use by adults 18 to 25 years old from 1996 to 2002.[10]

While the number of users increased significantly from the early 1990s and 2000s, the number of new users varied from 2002 to 2007. Surveys found a decrease in users from 1.2 million in 2002 to 642,000 in 2003, then up to 860,000 from 2006 to 2007.[12] In 2011, data from the National Survey on Drug Use and Health estimated about 14.5 million users aged 12 or older had used MDMA at least once in their lifetime, with approximately 900,000 using it for the first time in 2011. This number increased to 17 million in 2013, with the highest use among young adults aged 18 to 25. Though MDMA use is less prevalent than cannabis, opioid, and other amphetamine use in the United States and worldwide, it remains a significant public health concern due to its adverse effect profile.[8]

Pathophysiology

The difference between MDMA and other amphetamines is due to the attachment of the methylenedioxy group, which is structurally similar to the psychedelic hallucinogen mescaline. MDMA is a compound with characteristics of both amphetamines and hallucinogens.[13] It primarily increases the concentration of norepinephrine, dopamine, and serotonin within the synaptic cleft. MDMA inhibits the reuptake of the neurotransmitter serotonin (5-HT) and stimulates its carrier-mediated release into synapses. Like other amphetamine analogs, MDMA also inhibits monoamine oxidase activity, which further contributes to increased serotonin levels (in addition to dopamine and norepinephrine). Like serotonin, MDMA affects dopamine transporters by promoting release and inhibiting reuptake. The binding of noradrenergic, histaminergic, and muscarinic receptors contributes to the noradrenaline, histamine, gamma-aminobutyric acid (GABA), and acetylcholine effects of the drug. The activity on post-synaptic receptors plays a role in mood, thermoregulation, and the autonomic nervous system.[5][6]

The desired effects of the drug include sympathomimetic arousal, sensual enhancement, feelings of euphoria, and emotional closeness to others. Other effects include nausea, trismus, and bruxism. These effects are attributable to the increased circulation of dopamine and serotonin. Blood pressure and heart rate elevations are secondary to the adrenergic effects of increased circulating norepinephrine acting on α, β-1, and β-2 receptors.[14][15]

In addition to its effects on neurotransmitters, MDMA increases the levels of arginine vasopressin (antidiuretic hormone), leading to fluid retention. This effect, coupled with excessive water intake, is implicated in the development of life-threatening hyponatremia and coma.[16]

Toxicokinetics

When ingested, MDMA is readily absorbed through the gastrointestinal tract with an onset between 20 minutes and 1 hour and peak concentrations occurring at 2 hours. MDMA is primarily metabolized hepatically through CYP2D6. The elimination half-life of MDMA is moderately slow at about 8 hours. MDMA takes about 40 hours (ie, 5 half-lives) to achieve over 95% drug clearance. Since some metabolites of MDMA are pharmacologically active, such as MDA, the duration of clinical effects may continue after clearance from the body.[6][17][18]

History and Physical

The presentation of acute MDMA toxicity is similar to amphetamines and includes tachycardia, hypertension, dysrhythmias, anxiety, agitation, hallucinations, seizures, mydriasis, diaphoresis, and hyperthermia. However, MDMA has less stimulant and more serotonergic effects compared to amphetamines and methamphetamines.[19] At low doses, adverse effects include increased muscle activity, such as bruxism, restless legs, jaw clenching, hyperactivity, insomnia, difficulty concentrating, and feelings of restlessness.[14] 

Significant life-threatening complications include serotonin syndrome, cardiac dysrhythmias, rhabdomyolysis, disseminated intravascular coagulation, aortic dissection, and intracranial hemorrhages.[8][20][21] Since MDMA undergoes metabolism via hepatic CYP2D6, severe hepatoxicity may occur, leading to fulminant liver failure.[22]  Central nervous system (CNS) hyperactivity can lead to agitated delirium and seizures.[23][24] 

Because MDMA is a popular rave drug, the combination of intense physical activity with the sympathomimetic effects of the drug leads to an increase in body temperature that resembles heat stroke and could result in rhabdomyolysis.[25] Significant increases in fluid consumption by users coupled with the development of the syndrome of inappropriate diuretic syndrome (SIADH) may potentially contribute to the development of severe hyponatremia, leading to cerebral edema, seizures, and death.[26][27]

Evaluation

Diagnostic testing should be guided by the clinical presentation (history and physical exam). Initially, evaluation of the altered patient must include intravenous (IV) access, vital signs, rapid glucose check, and complete physical examination. Obtaining a core body temperature (rectal or bladder) is critical to diagnose life-threatening hyperthermia (>105 °F or >40.5 °C). 

Recommended lab tests are as follows:

1. Basic metabolic panel (BMP) to evaluate for:
   • Electrolyte abnormalities such as hyponatremia and hyperkalemia
   • Acute kidney injury - blood urea nitrogen (BUN) and creatinine (Cr) levels
   • Rhabdomyolysis - creatine phosphokinase (CPK) levels
2. Liver function tests (LFTs) to evaluate fulminant hepatic failure
3. Electrocardiogram (EKG) for screening tachyarrhythmias
4. Complete blood count (CBC), urinalysis, coagulation profile, chest radiography, computed tomography (CT) head scan, or lumbar puncture in the undifferentiated altered mental status patient
5. Qualitative urine immunoassays (urine drug screens) for amphetamines should not guide the clinical management of patients. The major limitation of amphetamine immunoassays is the high rate of false positives and false negatives. An actual positive result means that the patient used a certain amphetamine within the past several days and did not distinguish acute or recent use. The gold standard of drug testing, gas chromatography-mass spectrometry analysis, may misidentify isomeric substances such as l-methamphetamine (present in nasal inhalers) versus d-methamphetamine. 
   • Xenobiotics that cause false-positive qualitative amphetamine screens include pseudoephedrine, L-ephedrine, procainamide, mexiletine, selegiline, bupropion, trazodone, and amantadine.
   • Xenobiotics known to cause false negatives include MDMA and cathinones. 

Treatment / Management

Initial management includes continuous cardiac monitoring, maintaining a patent airway, and prioritizing breathing and circulation. For the agitated patient, temporary physical restraints may help gain pharmacologic control. They should be discontinued as soon as possible to avoid the development or worsening of rhabdomyolysis and heat generation. A core temperature (rectally or bladder) greater than 105 °F (40.5 °C) represents rapid life-threatening hyperthermia and takes precedence after initial airway evaluation.[25] Treatment of hyperthermia involves both rapid sedation to control agitation and external cooling. External cooling with whole-body ice-water immersion is effective for treating life-threatening hyperthermia.[28][29][30] (B3)

Sedation with IV benzodiazepines such as diazepam (10 mg) or lorazepam (2 mg) is the first-line treatment for agitation secondary to acute amphetamine toxicity.[31]  The predictable pharmacokinetics, high therapeutic index, and anti-epileptic activity of benzodiazepines make for an effective treatment for undifferentiated agitated patients. If IV access is unavailable, intramuscular doses of midazolam are effective. Sedation should be titrated rapidly until the patient is calm.[32](B3)

Rhabdomyolysis from acute amphetamine toxicity occurs from psychomotor agitation and hyperthermia. Supportive care with IV hydration should maintain a urine output of at least 1 to 2 mL/kg/h. Urine acidification may increase elimination and decrease the half-life of amphetamines. Still, it is not recommended since it does not decrease toxicity and increases the risk of acute kidney injury (AKI) from rhabdomyolysis.[33][34] Hemodialysis may be required in patients with renal failure, severe acidemia, and hyperkalemia. Given the limited evidence and potential harms, dantrolene is not recommended to treat amphetamine-induced hyperthermia.[35]  (A1)

Differential Diagnosis

Differential diagnoses include the following:

1. Anticholinergic toxicity
2. Cholinergic toxicity
3. Neuroleptic malignant syndrome
4. Malignant hyperthermia
5. Serotonin syndrome
6. Monoamine oxidase inhibitor toxicity
7. Meningitis
8. Encephalitis
9. Heatstroke
10. Heat exhaustion
11. Rhabdomyolysis
12. Amphetamine toxicity
13. Cocaine toxicity

Prognosis

The 2 most frequently reported causes of death include hyperthermia and hyponatremia. While toxicity can be severe, a literature review reveals deaths related to MDMA toxicity are rare. Confounding factors include co-ingested drugs, making it challenging to determine if MDMA was the cause of death.

Though deaths are rare, animal and radiological studies have demonstrated the potential for long-term adverse effects. In MDMA-treated monkeys, a loss of serotonin axon terminal markers was observed, leading to deficits in emotion, memory, and high-order cognitive processes. Positron emission tomography (PET) scans in baboons showed significant decreases in radioactivity levels in various brain areas. Similarly, human volunteers with a history of MDMA use underwent PET scanning and were found to have a global dose-related reduction in a structural element of serotonin. Further studies on PET scans of volunteers with a history of MDMA abuse showed similar effects, along with changes in the amygdala and neocortex regions. Deficits in short-term memory, visual memory, verbal memory, and reasoning seem to be associated. The cerebrovascular systems may also be affected, causing a decline in cognitive abilities that can resemble dementia.[36][37]

Complications

Complications of MDMA toxicity include the following:

• Neurologic complications include delirium and seizures [23]
• Cardiovascular complications include cardiac dysrhythmias, myocardial infarction, aortic dissection, and intracranial hemorrhages [8][20][21]
• Gastrointestinal complications include severe hepatotoxicity, which can lead to fulminant liver failure [22]
• Renal complications include rhabdomyolysis and acute renal failure [25]
• Endocrine complications include the development of a syndrome of inappropriate diuretic hormone (SIADH), resulting in life-threatening hyponatremia and seizures
• Patients can also present with life-threatening hyperthermia mimicking heat stroke [25][26][27]
• Other complications include increased psychomotor agitation or muscle activity (such as bruxism, restless legs, and jaw clenching), hyperactivity, insomnia, difficulty concentrating, and feelings of restlessness [14]