I. Problem/Condition.

3,4-Methylenedioxymethamphetamine (MDMA) (i.e. ecstasy, Adam, X, XTC, E) is one of many methylated amphetamine derivatives, and is structurally similar to that of methamphetamine. It differs pharmacologically in that it has both stimulatory and mild psychedelic properties, noted to be equivalent to that of hallucinogenic mescaline, however, auditory and visual hallucinations are uncommon.

MDMA elicits its neurochemical effects in much the same manner as amphetamines and methamphetamines, by stimulating catecholamine release of norepinephrine and dopamine, and blocking presynaptic reuptake of these catecholamines. Additionally, the mescaline-like ring structure enhances both serotonergic and dopaminergic release, as well as inhibition of serotonin reuptake.

MDMA was classified as a Schedule I drug by the Drug Enforcement Administration (DEA) in 1985, as it had been linked to neurotoxicity and potential brain damage, and therefore data from clinical studies have been very limited.

It is noted to give users a sense of euphoria, empathy, and decreased inhibitions, lasting approximately 3–6 hours. Many users attempt to prolong and augment these effects by stacking doses or coingesting a variety of other “club drugs", most notably ketamine, gamma-hydroxybutyric acid (GHB), flunitrazepam (Rohypnol), psilocybin, and lysergic acid diethylamide (LSD). It is also taken in conjunction with marijuana and alcohol. Many users take MDMA while dancing for long hours at “raves” or dance clubs which may be confined or poorly ventilated, which can potentiate negative effects.

Unfortunately, for clinicians attempting to identify the agent ingested, what is being sold in the street as pure MDMA, often times had been adulterated with a wide variety of chemical and pharmaceutical substitutes: acetaminophen, ibuprofen, methamphetamine, caffeine, dextromethorphan, ephedrine, and cocaine are common. The typical amount of MDMA varies from 30–150 mg, or none at all.

Most pills are labeled with a variety of symbols or “trademarks,” to identify their brand. Ecstasydata.org has launched a website in which users can submit suspected MDMA samples for gas chromatography/mass spectrography (GC/MS). The data is then published online along with pill image and name, active contents, its sales location, and the date tested.

As the drugs purity is typically in question, the clinician must always consider other variants being sold as pure MDMA. One drug which has come to the attention of researchers and clinicians is paramethoxyamphetamine (PMA), which has been associated with a higher incidence of death than MDMA at relatively lower doses. In addition to stimulating the release of serotonin, it also acts as a monoamine oxidase inhibitor (MAOI), which can result in serotonin syndrome and can lead to refractory hyperthermia and death.

There are varying estimates of MDMA’s use among North Americans; however, its exact prevalence remains unknown and obtaining data on its use can be a daunting task. On occasion, it is pooled with data on stimulants, and in others, with hallucinogenics, although it lacks true hallucinogenic properties.

According to the 2004 National Survey on Drug Use and Health, more than 11 million individuals aged 12 years and older had tried MDMA. The 2009 report showed a significant increase in lifetime use among individuals aged 12 years or older, from 4.3% (10.2 million) in 2002 to 5.7% (14.2 million). Among persons aged 12–49 years, the average age at first use of MDMA was 20.2 years.

According to the Drug Abuse Warning Network (DAWN) the number of ecstasy-related emergency department (ED) visits increased by 74.8% between 2004–2008.

Among young adults aged 18–25 years, males were more likely to have used ecstasy during the past year than females. However, among youths aged 12–17 years, females were more likely to have used ecstasy during the past year than males. Among both youths (12–17 years) and young adults (18–25 years), Caucasians were more likely to have used ecstasy in the past year than Hispanics, African Americans, and American Indians/Alaska Natives.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Central nervous system

• central nervous system (CNS) stimulation

• altered mental status

• syncope

• seizure

• cerebral edema

• heat stroke

• intracranial hemorrhage

Cardiovascular

• hypertension

• cardiac arrhythmias / ventricular arrhythmias

• chest pain

• myocardial infarction / ischemia

• aortic dissection

• congestive heart failure

• cardiovascular collapse

Respiratory

• non-cardiogenic pulmonary edema

• acute respiratory distress syndrome

• spontaneous pneumomediastinum

• asthma / reactive airways disease

Renal

• acute renal failure

• pheochromocytoma

• rhabdomyolysis

• urinary retention

• hyperkalemia

Endocrine / Metabolic

• hyponatremia

• syndrome of inappropriate antidiuretic hormone (SIADH)

• thyroid storm

• metabolic acidosis

Gastrointestinal

• nausea and vomiting

• abdominal pain

• hepatic failure

• hepatitis

Psychological

• depression

• anxiety disorder

• psychosis

Toxicological

• serotonin syndrome

• amphetamine/methamphetamine derivative (PMA) toxicity

• cocaine toxicity

• MAOI overdose

• phencyclidine poisoning

• theophylline poisoning

• antihistamine poisoning

• hallucinogenic toxicity

• anticholinergic overdose

• neuroleptic malignant syndrome

B. Describe a diagnostic approach/method to the patient with this problem.

1. Historical information important in the diagnosis of this problem.

As with any ingestion, whenever possible, obtaining a detailed history is of the upmost importance. Type of drug, amount taken, last ingestion time, frequency of use, route, and coingestants can guide therapeutic interventions.

It is important to remember that MDMA is manufactured clandestinely and therefore the true composition and purity are difficult to establish. However, it is not recommended to delay care while identifying the offending agent or agents. Drug toxicology can be erroneous and delaying care while awaiting the results can have negative implications on patient outcomes.

The user can present with a wide variety of signs and symptoms from CNS stimulation following use, with most being mild and non-life threatening. During the acute phase minor reactions have been reported including: anxiety, nausea, euphoria, enhanced sensory perception, pupillary dilation, diaphoresis, bruxism, dry mouth, tachycardia, and hypertension.

REVIEW OF SYSTEMS

Constitutional

• loss of appetite

• fatigue

• increased thirst

• warmth

• diaphoresis

Central Nervous System

• euphoria

• enhanced sensory perception

• headache

• anxiety

• ataxia

Head, Ears, Eyes, Nose, Throat

• blurred vision

• dry mouth

• bruxism

• trismus

Cardiac

• tachycardia

• palpations

• chest pain

Pulmonary

• tachypnea

• shortness of breath

Gastrointestinal

• nausea / vomiting

• diarrhea / constipation

• muscle cramping

Genitourological

• urinary retention

• increased urination

Psychological

• anxiety

• paranoia

• depression

• insomnia

• difficulty concentrating

LIFE THREATENING COMPLICATIONS

The development of serious side effects of MDMA intoxication vary individually and there is no established correlation between the amount of MDMA taken and severity of side effects. Case reports have confirmed that some individuals have died after consuming only one dose of MDMA, while others have consumed relatively lethal doses and have survived.

A list is provided of the potential life-threatening complications which have been observed with MDMA toxicity and it should be kept in mind by the clinician assessing the patient:

• acute renal failure

• cerebral vascular accident (CVA)

• disseminated intravascular coagulation (DIC)

• hepatotoxicity / hepatic failure

• hyperthermia

• hyponatremia

• myocardial infarction

• panic disorders

• pneumomediastinum

• pneumothorax

• prolonged QTc interval

• rhabdomyolysis

• seizure

• serotonin syndrome

• SIADH

• tachyarrhythmia / ventricular arrhythmias

• sudden cardiac death

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

General

• may present in dance or “rave” type attire

• may present with flashing / glowing objects, “glow sticks,” pacifiers, face masks, energy drinks

• mentholated products

Head, eyes, ears, nose, throat

• pupil dilation

• bruxism

• trismus

• nystagmus

• dry mouth

Central nervous system

• altered mental status

• ataxia

• syncope

• seizures

• coma

Cardiovascular

• tachycardia

• hypertension

• arrhythmia

• hypotension (late)

Pulmonary

• tachypnea

• shortness of breath

• respiratory distress / failure

Psychiatric

• euphoria

• anxiety

• delirium

• psychosis

• paranoia

• hallucinations

Integumentary

• hyperthermia

• pallor

• diaphoresis

• piloerection

Gastrointestinal

• abdominal pain / cramping

• nausea / vomiting

• diarrhea

Musculoskeletal

• muscle rigidity

• muscle spasms

• tremors

• hyperflexia

• bruxism

• clonus / myoclonus

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Laboratory and radiological testing depends on the severity of the intoxicated patient and should be expanded based on the history and physical.

A complete metabolic panel along with a creatine phosphokinase (CPK) is indicated in all patients. Additional testing should be tailored to each patient.

• Complete metabolic panel: to monitor for hyponatremia, hyperkalemia, acute renal failure, acute liver failure and metabolic acidosis

• Blood glucose: to rule out hypoglycemia

• Acetaminophen and salicylate levels: to rule out common coingestants

• Urine toxicology screen: used to support diagnosis and to determine use of other drugs of abuse

• Electrocardiography (EKG): to rule out conduction impairment (prolonged QRS, QTc), ventricular arrhythmias, tachyarrhythmias

• Liver function test: to monitor for acute hepatitis or liver failure

• Lactate: if concern for acidosis

• Clotting times: (prothrombin time [PT], activated partial thromboplastin time [aPTT], platelets) if DIC is suspected

• Complete blood count (CBC): if concern for infection

• CPK and urine myoglobin: if rhabdomyolysis is suspected

• Pregnancy test: for women of childbearing age

• Lumbar puncture: if concern for infection or patient remains altered

• Computed tomography (CT) of head: if concern for an intracranial process

• Chest film - posterior/anterior (PA): if concern for pneumomediastinum or pneumothorax

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

N/A

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Urine drug testing for MDMA can be erroneous and therefore supportive care should not be delayed while awaiting the results. However, it may support the clinical diagnosis and also provide information on common drugs of abuse which may have been taken concurrently.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Methylenedioxymethamphetamine (MDMA) Toxicity.

Acutely intoxicated patients are at risk for developing a wide range of medical complications from minor symptoms, which require minimal intervention, to potentially life-threatening side effects, which require intubation, sedation, and monitoring within an intensive care unit (ICU) setting.

Following the acronym ABC (Airway, Breathing, Circulation), along with establishing good intravenous access, is essential. Clinical intervention is managed on an individual basis and is typically supportive in nature.

Some life-threatening complications are discussed below in detail.

LIFE THREATENING COMPLICATIONS

Hyponatremia

Hyponatremia associated with MDMA use can be multi-factorial. Many users are aware of the risks of developing hyperthermia, and compensate by drinking copious amounts of water leading to delusional hyponatremia.

MDMA has shown to increase plasma anti-diuretic hormone (ADH) levels, which can result in SIADH. This can be exacerbated in individuals already taking selective serotonin reuptake inhibitor (SSRI) or other psychotropic medications.

Serious neurological complications resulting from hyponatremia include altered mental status, seizures, cerebral edema, and death.

Serotonin syndrome

MDMA has structural similarity to serotonin, which accounts for increased serotonin release and inhibition of serotonin reuptake. Clinicians should be concerned for serotonin syndrome particularly in individuals already taking SSRI, MAOI, or other psychotropic medications.

Severe symptoms of serotonin syndrome consist of the triad of cognitive-behavioral, neuromuscular and autonomic derangements. This results in hyperthermia, agitation, seizures, hyperflexia and altered mental status, leading to refractory hyperthermia, multisystem organ failure, and death.

Hyperthermia

In most cases hyperthermia is associated with excessive activity without adequate fluid replacement. Additional factors can be from dancing for long hours without breaks in poorly ventilated areas. Clinicians should always consider serotonin syndrome as a possible cause.

Hyperthermia can lead to seizures, multisystem organ failure, rhabdomyolysis, DIC, and death.

Sudden cardiac death

Sudden cardiac death has been postulated to occur secondary to sympathomimetic stimulation, resulting in lethal dysrhythmias. Individuals with undiagnosed cardiac disease and conduction abnormalities are at greater risk. MDMA has been associated with prolonged QTc intervals.

Patients with evidence of end-organ damage, focal neurological deficits, arrhythmias, delirium, or uncontrolled agitation should be admitted for observation. Consultation with a toxicologist and/or the local poison control center may be indicated. Substance abuse referrals should also be made prior to discharge.

MANAGEMENT

Activated charcoal

• It is recommended to give activated charcoal if the ingestion occurred within the previous hour: 1–2 g/kg PO up to 100 g

Anxiety and agitation

• Diazepam: 5–10 mg IV every 15 minutes (titrated to effect)

• Lorazepam: 2–6 mg IV every 15 minutes (titrated to effect)

Hypertension and tachycardia

• Treating agitation with benzodiazepines is the first line treatment.

• Nitroprusside: 0.1–0.5 mcg/kg/minute IV, increase by 0.5 mcg/kg/minute (titrated to blood pressure [BP])

• Phentolamine: (class IIb) 1–5 mg IV over 5 minutes (titrated to BP)

• Hydralazine: 10–20 mg IV push slow, may repeat every 4–6 hours

• A beta blocker may be used only if an alpha adrenergic antagonist is concomitantly administered. Use of a beta blocker without alpha blockade may result in paradoxical increase in BP as it may cause unopposed alpha-receptor stimulation.

• Labetalol: 20 mg IV push over 2 minutes, may repeat 20–80 mg IV every 10 minutes (up to 300 mg total dose) until desired BP is reached or start continuous infusion at 2 mg/minute (range 1–3 mg/minute) (titrated to BP)

• Esmolol: 500 mcg/kg IV push over 1 minute, followed by infusion 50–100 mcg/kg/minute (titrated to effect)

Seizures

• Diazepam: 5–10 mg IV push initially, may repeat every 5–10 minutes as needed; consider a second agent if seizures persist or recur after total dose of 30 mg diazepam administered

• Lorazepam: 2–4 mg IV push initially, may repeat every 10 minutes as needed

• Phenobarbital: 15–20 mg/kg at 25–50 mg/minute until cessation of seizure activity

• Intubation may be required in severe cases.

Rhabdomyolysis

• Monitoring of CPK, renal function, and potassium frequently

• IV hydration with 0.9% saline

• Monitor intake and output with a goal of at least 2–3 mL/kg

• Sodium bicarbonate to alkalize urine

• Nephrology consult

Hyperthermia

• IV hydration with 0.9% saline

• Treat agitation with benzodiazepines

• Cooling blanket

• Evaporative cooling

• Frequent monitoring of temperature

• Antipyretics are of no benefit.

• For severe cases intubation and sedation with a non-depolarizing neuromuscular blocker is indicated.

• Avoid succinylcholine as it may lead to life-threatening hyperkalemia.

• Administration of dantrolene 1–2 mg/kg IV up to 10 mg/kg IV has been shown to be beneficial.

Myocardial infarction

• EKG

• Cardiac enzymes

• Aspirin

• Heparin

• Morphine

• Nitrates

• Oxygen

• Cardiology consult

• Refrain from utilizing beta blockers.

CVA

• Non-contrast CT of the head

• Frequent neurological checks

• Neurology consult

Cardiac arrhythmias

• Many arrhythmias are self-limiting.

• Cardiac monitoring

• Advanced Cardiac Life Support (ACLS) protocol if indicated

• Cardiology consult

Hyponatremia secondary to SIADH and/or execessive water intake

• Typically corrects without intervention

• Frequent monitoring of serum sodium levels, to eliminate rapid correction leading to osmotic demyelination syndrome

• Fluid restriction may be indicated.

• Administration of 3% sodium chloride may be indicated in severe cases at the rate of 0.5–1 mEq/hr.

• Mannitol and diuretics are not shown to be beneficial.

Serotonin syndrome from massive serotonin release

• Benzodiazepines

• Cyproheptadine (a 5-HT2 antagonist): 4–12 mg PO; limited research, but has shown to be effective in case reports

Other considerations

• Hepatotoxicity / liver failure have been reported.

• DIC

• Neuropsychiatric issues have been seen with recurrent use.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

• Failure to diagnose and treat hyponatremia.

• Failure to diagnose and treat hepatic failure.

• Failure to diagnose and treat DIC.

• Failure to diagnose and treat rhabdomyolysis.

• Failure to diagnose and treat hyperthermia.

• Failure to diagnose and treat myocardial infarction.

• Failure to consult a board certified toxicologist or the local poison control center.

IV. What's the Evidence?

"Results from the 2004 National Survey on Drug Use and Health: Summary of National Findings". NSDUH Series H-28: DHHS Publication No. SMA 05-4062 Findings, 2005. [http://www.oas.samhsa.gov/nsduh/2k5nsduh/2k5Results.pdf.

"Results from the 2009 National Survey on Drug Use and Health Volume I: Summary of National Findings". NSDUH Series H-38A: DHHS Publication No. SMA 10-4856 Findings, 2010. [http://www.oas.samhsa.gov/NSDUH/2k9NSDUH/MH/2k9MHResults.htm.

"The Drug Abuse Warning Network (DAWN) Report: Emergency Department Visits Involving Ecstasy.". [http://www.oas.samhsa.gov/2k11/DAWN027/EcstasyHTML.pdf.

"Results from the 2002 National Survey on Drug Use and Health: Summary of National Findings". NSDUH Series H-22: DHHS Publication No. SMA 03-3836 Findings, 2003. [http://www.oas.samhsa.gov/2k3/ecstasy/ecstasy.pdf.