Continuing Education Activity

This activity reviews the FDA-class 1 drug 3,4 - methylenedioxymethamphetamine, also known as MDMA, ecstasy, or molly. The drug is known to promote a sense of euphoria and facilitate empathy and communication. Unfortunately, it can have dangerous effects on the cardiovascular, neurologic, renal, and hepatic systems and can lead to devastating consequences, including death. This activity reviews the potential for 3,4 -methylenedioxymethamphetamine toxicity, treatment approaches to patients who have overdosed on it, and the role of the interprofessional care team in improving outcomes for patients that use 3,4 -methylenedioxymethamphetamine.

Objectives:

• Describe the signs and symptoms that a patient with 3,4 -methylenedioxymethamphetamine toxicity might exhibit.
• Outline the treatment strategy for a patient with 3,4 -methylenedioxymethamphetamine toxicity.
• Identify rapid sequence intubation agents that should be avoided if a patient with 3,4 -methylenedioxymethamphetamine toxicity presents in a hyper-adrenergic state or if rhabdomyolysis is a consideration.
• Explain why 3,4 -methylenedioxymethamphetamine toxicity requires an interprofessional team approach.

Introduction

MDMA (3,4 - methylenedioxymethamphetamine), or more commonly known as Molly or Ecstasy, is a synthetic substance first developed in 1912 as a precursor to the synthesis of hemostatic agents (not as an appetite suppressant as incorrectly reported).[1] Due to its effects on promoting empathy and facilitating communication, the drug became popular in the early 1970s among psychiatrists for its therapeutic potential. The drug would later find heavy use in dance parties and festivals as it became prominently associated with rave culture due to its heightened euphoric effects. The DEA subsequently classified it as a schedule 1 drug in 1985 as the potential for harm and abuse was recognized. To this day, ecstasy continues to be used by millions. Its effects on the cardiovascular, neurologic, renal, and hepatic systems can be devastating, and recognizing its toxicity is essential to medical providers.[2][3]

Etiology

The potential for MDMA toxicity exists with every ingestion. MDMA is commonly ingested orally through tablet form; however, the powder itself can be snorted.  Recreational doses of the drug can vary significantly. During the 1990s and early 2000s, doses ranged between 73 mg to 103 mg, while doses have also been reported to be as low as 50 mg to as high as 150 mg per tablet. Analysis of compounds sold as ecstasy/molly has also revealed the variability of composition with other substances aside from MDMA, including MDEA, MDA, ephedrine, ketamine, paracetamol, and other inactive substitutes and others that may have profound 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 random dosage and composition of the drug.[7]

Ecstasy is also often taken with other illicit drugs, which can potentially compound each drug’s individual effects on the neurologic and cardiovascular system.[3][8] This compounding effect in combination with physical activity in a hot, humid environment such as a rave can lead to significant hyperthermia and dehydration.[9]

Epidemiology

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

While the number of users increased significantly from the early 1990s and 2000s, the number of new users was variable from the period of 2002 to 2007.  Surveys found a decrease in users from 1.2 million in 2002 down to 642000 in 2003 then up to 860000 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 ecstasy at least once in their lifetime, with approximately 900000 using it for the first time in 2011. This number increased to 17 million in 2013, with the highest use among individuals aged 18 to 25 years. Though MDMA still falls behind cannabis, opioids, 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

MDMA differs from other amphetamines due to the attachment of the methylenedioxy group, which is structurally similar to the psychedelic hallucinogen mescaline. Because of this, MDMA is a chemical compound that shares properties of both amphetamines and hallucinogens.[13] It primarily acts to increase the overall concentration of norepinephrine, dopamine, and serotonin within the synaptic cleft. MDMA inhibits the re-uptake of the neurotransmitter serotonin, thereby stimulating its carrier-mediated release.  In addition to the depletion of serotonin-containing vesicles, this action results in increased synaptic levels of serotonin. 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 promoting their release and inhibiting their reuptake. The binding of noradrenergic, histaminergic, and muscarinic receptors contribute to the noradrenaline, histamine, GABA, and acetylcholine effects of the drug.  The result is a surge of activity upon post-synaptic receptors that play a role in mood, thermoregulation, and autonomic nervous system activity.[5][6]

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 increase in circulation of the neurotransmitters mentioned above, dopamine and serotonin. Blood pressure and heart rate elevations are secondary to the adrenergic effects of an increase in circulating norepinephrine acting on alpha, beta-1, and beta-2 receptors.[14][15]

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

Toxicokinetics

MDMA is absorbed via the GI tract with an onset of effect between 20 minutes and 1 hour after consumption. Peak concentrations occur 2 hours after oral ingestion, and it is broken down in the liver by the enzyme CYP2D6. MDMA has a half-life of about 8 hours, taking approximately 40 hours to clear 95% of the drug from the body. Thus, continued effects of the drug will continue to linger for several hours after ingestion.[6][17][18]

History and Physical

Presentation of MDMA toxicity is variable due to the common practice of co-ingestion with other illicit substances. Even self-reported mono-ingestion of Ecstasy/Molly is not reliable due to the varying composition of the synthesized drug. Patients may present tachycardic, hypertensive, hyperthermic, and agitated.  Even at minor recreational doses, adverse effects include increased muscle activity (such as bruxism, restless legs, and jaw clenching), hyperactivity, insomnia, difficulty concentrating, and feelings of restlessness.[14] The sympathomimetic properties in MDMA overdose can lead to severe toxicity manifesting as cardiovascular, neurologic, hepatic, and electrolyte disturbances. Significant elevations in both heart rate and blood pressure have led to reports of life-threatening cardiac dysrhythmias, myocardial infarction, aortic dissection, and intracranial hemorrhages.[8][19][20] Because MDMA undergoes hepatic metabolism via cytochrome P450, severe hepatoxicity can occur, leading to fulminant liver failure.[21]  CNS hyperactivity can lead to delirium and seizures.[22] Elevated levels of serotonin can result in serotonin syndrome, and patients may present with hyperpyrexia and myoclonus.[23] 

Because Ecstasy is a popular rave drug, the dangerous combination of intense physical activity (such as dancing) along with the heightened sympathomimetic effects of the drug lead to an increase in body temperature that resembles heat stroke and resulting in rhabdomyolysis.[24] Significant increases in fluid consumption by users in such a setting coupled with elevated vasopressin levels have potentially contributed to the development of cerebral edema, seizures, and death.[25][26]

Evaluation

• Obtain finger stick for blood sugar levels
• Chemistry for sodium levels and other electrolyte abnormalities such as hyper or hypokalemia
• Urine, potassium, BUN/Cr, CK levels, and myoglobin levels for the evaluation of rhabdomyolysis and renal injury
• LFTs for hepatoxicity
• Aspirin, alcohol, acetaminophen levels, and urine drug screening
• EKG
• Head CT, LP may be necessary for the undifferentiated altered and febrile patient.

Treatment / Management

Emphasis should be on maintaining the airway along with stabilization of breathing and circulation. Patients may present obtunded due to hyponatremia requiring endotracheal intubation. Though no formal contraindication to specific RSI agents exists, caution is necessary with ketamine which could potentiate the hyperadrenergic state of the already hypertensive and tachycardic patient. If rhabdomyolysis is a consideration, avoiding succinylcholine due to hyperkalemia should be considered in favor of rocuronium or vecuronium. Patients who present in severe toxicity within one hour of ingestion can receive activated charcoal PO or via an NG tube. Agitation should be controlled with benzodiazepines such as lorazepam or diazepam.  For the hyperthermic patient, evaporative cooling along with ice packs to the groin and axilla are beneficial.  More invasive measures may be necessary in extreme cases. If treatment fails, dantrolene is a consideration. Antipyretics, such as acetaminophen, have no role and can worsen an already compromised liver. 

Patients with MDMA toxicity can present with seizures and hyponatremia. Those with seizures should receive benzodiazepines. If hyponatremia is the cause, patients should be free water restricted and treated with hypertonic saline. Urine output should be closely monitored with a foley. Caution is necessary with the judicious administration of IV fluids.

The undifferentiated tachycardic, hypertensive, hyperthermic, and altered patient necessitates a broad approach to treatment and evaluation since this constellation of findings are not specific to MDMA toxicity. Hence, patients may require a head CT, LP, and coverage with broad-spectrum antibiotics.[27]

Differential Diagnosis

• Anticholinergic toxicity
• Cholinergic toxicity
• Neuroleptic malignant syndrome
• Malignant hyperthermia
• Serotonin syndrome
• MAOI inhibitor toxicity
• Meningitis/encephalitis
• Heatstroke/exhaustion
• Rhabdomyolysis
• Amphetamine toxicity
• Cocaine toxicity

Prognosis

The two most frequently reported causes of death include hyperthermia and hyponatremia. While toxicity can be severe, a literature review reveals deaths related to MDMA toxicity to be rare. Confounding factors in some reports are that other drugs were co-ingested, thus making it difficult to find MDMA as the sole cause of death. One study found that in the 10 years to 2006, ecstasy-related deaths numbered approximately 50 per year though they were not purely ecstasy-related. When it was the sole drug implicated, this number dropped to 10 per year. A retrospective case review of ED admissions related to ecstasy revealed a death rate of 0 to 2%.[28]  It is worth noting that these conclusions were level III evidence-based. 

Though deaths are rare, the potential for long-term side effects has been demonstrated through animal and radiological studies. Serotonin plays a role in emotion, memory, and high-order cognitive processes. Previous animal studies revealed a loss of serotonin axon terminal markers. These losses were found to be extremely long-lasting in MDMA-treated monkeys. PET scans in baboons showed significant decreases in radioactivity levels in various areas of the brain. 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 of PET scans in volunteers with a history of MDMA abuse yielded similar findings, however, with additional alterations to the amygdala and areas of the neocortex. Deficits in short-term memory,  visual memory, and verbal memory and reasoning seem to be associated. Cerebrovascular systems may also be affected, manifesting down the line as a decline in cognitive potential akin to dementia.[29][30]

Complications

• Neurologic complications include delirium, seizures.[22]
• Cardiovascular complications include cardiac dysrhythmias, myocardial infarction, aortic dissection, and intracranial hemorrhages.[8][19][20]
• GI complications include severe hepatotoxicity, which can lead to fulminant liver failure.[21]
• Renal complications include rhabdomyolysis and acute renal failure.[24]
• Endocrine complications include SIADH resulting in life-threatening hyponatremia. Patients can also present with hyperpyrexia mimicking heat stroke.[24][25][26]
• Minor complications include increased muscle activity (such as bruxism, restless legs, and jaw clenching), hyperactivity, insomnia, difficulty concentrating, and feelings of restlessness.[14]

Deterrence and Patient Education

Patient education is crucial in getting patients to understand both the short- and long-term risks of using MDMA. Many users incorrectly perceive MDMA to be a safe drug with few adverse effects. The truth is that tolerance develops rapidly, and those who respond by ingesting larger doses are at risk for complications that include sympathetic hyperactivity, potentially resulting in hyperthermia, arrhythmias, and hemodynamic instability.

Patients must also understand the long-term psychiatric implications that accompany regular use. There are reports of depression, paranoia, anxiety, and insomnia lasting years following cessation of MDMA use. Additionally, research shows correlations between impaired concentration and memory and using MDMA.[31]

Enhancing Healthcare Team Outcomes

MDMA toxicity can be life-threatening and involve multiple organ system dysfunctions necessitating the need for an interprofessional approach. Thus, providers need to be aware of the potential toxicities that may arise and be ready to treat aggressively as treatment is mainly supportive. This requires an interprofessional team approach to managing such toxicity, including education, interventions, monitoring, and follow-up from all disciplines, including clinicians, toxicology specialists, mid-level practitioners, nurses, pharmacists, and mental health professionals. By coordinating activity and sharing information, the patient is more likely to achieve successful short- and long-term outcomes. [Level 5]

Ultimately, the primary remedy to the problem is prevention. Peters and Kok performed a literature review to identify reasons for ecstasy use and found reasons varied widely from curiosity to achieve the same level of intoxication as friends, availability/pricing, enhance mood and social interaction, and social influence.[32] The myth that molly is safer because it is pure MDMA also does not aid in preventing its use. Further education among youth and young adolescents to the toxic potential of MDMA is essential to blunting its continued use.