Synthetic cannabinoids have stolen the media spotlight recently, for good reason. They have clinical characteristics similar to homegrown THC, but these drugs are not identified by any common drug screen, and they are much more powerful than good old-fashioned marijuana. Synthetic cannabinoids consist of a number of THC-related compounds, including K2 and spice, which have been recently regulated as schedule 1 by the FDA.
But multiple similar compounds remain popular with the drug-abusing crowd. An amphetamine derivative, MDMA (AKA ecstasy), is still on the scene, though it has been somewhat replaced by newer products. It may still confront emergency clinicians, and the relevant clinical aspects are important to know.
‘Eve’ and ’Ecstasy.’ A Report of Five Deaths Associated with the Use of MDEA and MDMA
Dowling G, McDonough ET 3rd, Bost RO
A synthetic analog of methamphetamine arrived onto the drug-abusing market in 1987 under the name of ecstasy, and more recently, molly. It was first developed as an appetite suppressant in the early 1900s but was never marketed. It also had some psychotherapy use to facilitate therapeutic communications and to increase patients' self-esteem. MDMA became increasingly popular as a recreational drug in the 1980s, particularly among the young and college students. Experiencing MDMA was apparently a pleasurable way to spend your time, but unlike mescaline, it did not produce frank hallucinations.
MDMA was placed on a schedule 1 designation by the FDA in 1985, naming it as a drug with high potential for abuse without accepted medical use. A structurally related compound, MDE, never caught on as a drug of abuse. Though it was initially thought to be relatively safe, street use of MDMA has resulted in serious complications, including death.
This article is an early report of five deaths associated with MDMA use. It was concluded that MDMA contributed to death in three case by inducting a lethal arrhythmia. All cases were evaluated by the Dallas medical examiner for the presence of MDMA, and were confirmed with gas chromatography. A 22-year-old man, who had MDMA in his blood, died after being electrocuted while climbing a utility tower. A 25-year-old was also killed in an automobile crash, but he had significant coronary artery disease on autopsy.
MDMA, swallowed in a pill or capsule, causes euphoria and enhanced sociability, without strong hallucinogenic properties. The authors concluded 25 years ago that MDMA is dangerous, especially when used by someone with existing cardiac disease.
Few clinicians had ever heard of ecstasy in 1987. It has gained remarkable popularity by the drug-abusing set over the decades, and today it is in the clinical vocabulary of most emergency clinicians. The specific name for MDMA is 3,4-methylenedioxymethamphetamine. MDMA is a manmade chemical structurally similar to amphetamines and mescaline. Typical effects include overall stimulation, but also euphoria, wakefulness, sexual arousal, and loss of inhibition. No wonder it is a popular drug of abuse.
Ecstasy was particularly popular among young partygoers at music events called raves, as well as dance clubs and music festivals. MDMA was particularly popular because it was felt to be a safe and pleasurable high; but, in fact, it does share similar toxicities with amphetamines. Overall, severe reactions to MDMA are rare, but one does not always know what one is ingesting. The popularity of MDMA seems to be waning in favor of other street drugs, but it is still worth a refresher on this drug.
MDMA has physiological activity similar to amphetamines, causing increased release of catecholamines, such as norepinephrine and dopamine, and blocking their reuptake into presynaptic neurons. The drug also increases the release of serotonin and inhibits serotonin reuptake, probably its greatest chemical activity. MDMA causes more serotonin increase than methamphetamine. Serotonin regulates mood, sleep, pain, and appetite, and excess serotonin is the basis for the omnipresent, almost normal flora, SSRI mediations. MDMA damages brain serotonin neurons in animals, but that effect on humans is not proven.
MDMA is a feel-good drug, and it undergoes relatively fast absorption from the GI track and lasts about four to six hours. As with any other homemade drug, samples bought on the street have varying chemical composition. Similar to other methamphetamines, MDMA increases alertness, reduces fatigue, and increases physical and mental powers, as well as producing much sought-after euphoria. Associated adverse reactions include agitation, nausea, bruxism, ataxia, diaphoresis, tachycardia, and hypertension. Classically, patients under the drug's effects will manifest hypertension, tachycardia, and occasionally hyperthermia.
Drug-related hyperthermia is of particular interest. The drug facilitates prolonged physical exertion, particularly dancing, which is commonly the aim of rave parties, but patients also often use the drug in crowded, hot rooms. Hyperthermia can be severe and life-threatening. Another rather curious manifestation of MDMA use is hyponatremia. Marked alterations in serum sodium can lead to significant neurologic manifestations including coma, seizures, cerebral edema, and cerebral herniation. Users also believe they can prolong the action of MDMA by drinking large amounts of water.
The clinical manifestations of MDMA are quite similar to many street drugs, including cocaine and other amphetamines. MDMA will not turn a drug screen positive for amphetamines, and most stat toxicology tests only analyze for amphetamines, not methamphetamine, so they will be negative. The ED analysis for MDMA is helpful, but generally not clinically useful because treatment is based on the patient's clinical status.
Treating MDMA toxicity includes the basic airway, breathing, and circulation evaluations and standard interventions. Most patients will be hypertensive, but treating hypertension is controversial. Of course, hypertension can induce intracranial hemorrhage, myocardial infarction, or aortic dissection. It is generally stated that beta blockers, which will decrease heart rate, can cause unopposed alpha-adrenergic stimulation because of beta blockade, leading to severe hypertension. It is generally advised that the hypertension associated with MDMA use not be treated with beta blockers. Most symptoms, including hypertension, are often controlled with aggressive benzodiazepine therapy, but if hypertension is severe, nitroprusside or the alpha blocker phentolamine (2-5 mg IV) has been suggested. No double-blind studies have elucidated the role of any intervention for MDMA toxicity.
It takes about an hour for the drug to be absorbed, and the ability of gastric decontamination to limit toxicity is miniscule. Gastric emptying and charcoal are best eschewed because of lack of benefits and potential complications.
The best and safest initial treatment of psychomotor agitation, regardless of cause, is benzodiazepines. One has to use enough benzodiazepines, and regular sedative doses are of little value. There is no maximum dose of benzodiazepines, but lorazepam in doses of 2-4 mg IV, repeated every five to 10 minutes, or diazepam 5-10 mg IV likewise repeated for clinical effect, are probably the safest and best intervention in all cases of excited delirium. Haloperidol has some theoretical downsides, such as interference with heat loss, prolongation of QTC, and reduction of the seizure threshold. Many clinicians nonetheless successfully use a combination of haloperidol and benzodiazepine as initial treatment for any patient with severe psychomotor agitation.
Tipoff to MDMA Use
Core body temperature, though often not an initial intervention, should be obtained because this drug commonly produces hyperthermia. Of course, a bedside glucose test should also be performed rapidly. Most patients also get a standard blood test such as a CBC and an electrolyte and renal panel.
Hyponatremia may be a tipoff to this drug's use, and it may be severe enough to cause or exacerbate neurological symptoms, such as confusion and seizures. The approach to hyponatremia is somewhat controversial, and mild hyponatremia need not be treated because it usually resolves in 12 to 24 hours. Those patients with severe hyponatremia, usually less than 115 mEq/L, may require initial treatment with hypertonic (3%) saline. Not commonly used in the ED, 1 ml/kg of 3% saline, given as an IV bolus, should raise the serum concentration by 2-3 mEq/L. This can be repeated if neurologic symptoms persist. The use of hypertonic saline can also be helpful by reducing the degree of cerebral edema. Fluids should be used sparingly, particularly in the presence of hyponatremia.
Benzodiazepines are certainly indicated if seizures occur after the glucose and sodium have been checked. Phenytoin therapy has no benefit. Another treatment initiated in the ED would be an ice bath or other aggressive cooling measures; this type of measure cannot wait until the patient reaches the ICU.
Disseminated intravascular coagulation and rhabdomyolysis are also toxicities of MDMA. Bruxism, or teeth clenching, is a very common response after MDMA use, and many users can be spotted on the dance floor using a pacifier or munching on a lollipop.
A great number of MDMA users do not come to the ED. The decline in popularity may be one reason, but another is that moderate doses allow users to enjoy the effects of the drug and not present to the hospital.
MDMA Induced Hyperthermia: Report of a Fatality and Review of Current Therapy
Dar KJ, McBrien MD
Intensive Care Medicine
This 20-year-old article describes a 17-year-old young man who died from MDMA use. It details a common fatal scenario where excessive MDMA was consumed at a dance party. The patient was delirious, combative, and profusely diaphoretic, and he required restraint upon ED arrival. His axillary temperature was 41°C, blood pressure was 120/70 mm Hg, and his pulse rate was 178 bpm. He had dilated pupils and severe muscular rigidity. He was initially treated with dantrolene and external cooling. He deteriorated over the next six hours, and demonstrated hyperthermia, anuria, hypotension, pulmonary edema, coagulopathy, metabolic acidosis, and cardiogenic shock. The authors concluded that his death was expected once multisystem failure was noted. The benefit of dantrolene is unknown.
This fatal scenario is a well-described consequence of many adrenergic overdoses, especially cocaine. Whether fatality can be prevented once multisystem failure has intervened is unknown but likely impossible. The cause of MDMA multisystem failure is thought to be excessive serotonin release, and the scenario is similar to serotonin syndrome. Cyproheptadine has been shown to ameliorate serotonin excess, but whether it will be effective in such cases is unknown. The only agreed upon current approach is aggressive cooling, such as ice water immersion, ice packing, aggressive sedation with benzodiazepines, and neuromuscular blockade (not done in this case).
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