Volume I:
First Thirty Minutes
- Section 1
  Acute Care Algorithm/ Treatment Plans/ Acronyms
- Section 2
  Universal Approach
  - CALS Universal Approach To Emergency Advanced Life Support
- Section 3
  Steps 1-6
- Section 4
  Preliminary Impression/Focused Clinical Pathways
Volume II:
Resuscitation Procedures
Volume III:
Definitive Care

Toxicology 13: Amphetamine Analog Intoxication Portal

(Methamphetamine and MDMA [Ecstasy])

Methamphetamine Intoxication
Methamphetamine, a commonly abused street drug, is a highly addictive central nervous system (CNS) stimulant. First synthesized in 1893, methamphetamine began to be used in the early 1900s for treatment of asthma and nasal congestion. During World War II, it was used by the Japanese, German, and American military to increase alertness and decrease fatigue. More recently it has been used for the treatment of narcolepsy, attention deficit disorder (ADD), and obesity.¹ Methamphetamine is easily and inexpensively produced from readily available, over-the-counter cold medicines such as ephedrine and pseudoephedrine. Clandestine methamphetamine laboratories are often constructed in private homes or garages and can be disassembled without difficulty. That means, the labs can be easily moved from place to place, making illegal production difficult to track. Ease of synthesis, availability, and huge profits have fostered rampant and dangerous abuse of illicit methamphetamine. The federal government and some states have passed legislation to reduce the availability of precursor agents; however, many can still be purchased in neighboring states and countries.

Similar to cocaine, methamphetamine produces euphoria² and is rapidly absorbed following oral, inhaled (smoked), intranasal (IN), IV, IM, rectal, or vaginal administration. The onset of action occurs within seconds if smoked or given IV, within 5 minutes after IN use, and within 20 minutes after oral ingestion.¹ Inhaled methamphetamine is replacing cocaine as the drug of choice as it delivers an equally intense and longer-lasting high. Street names for methamphetamine include chalk, crank, crystal, crystal meth, cristy, glass, go, ice, meth, and zip. Patients who smoke methamphetamine experience an immediate euphoria similar to crack cocaine. Heavy abusers may consume 15 to 1000 times the recommended therapeutic dose.³

Pharmacology
Methamphetamine is a sympathomimetic amine that belongs to a class of compounds, the phenethylamines, which possess a variety of stimulant, anorexiant, euphoric, and hallucinogenic effects. Methamphetamine lacks direct adrenergic effects, but instead is an indirect neurotransmitter. Methamphetamine acts in part by being incorporated into the cytoplasmic vesicles of the presynaptic adrenergic neurons where it displaces the normal neurotransmitters (ie, epinephrine, norepinephrine, dopamine, and serotonin) into the neuron cytoplasm and then into the synapse where these normal neurotransmitters activate the postsynaptic receptors. Methamphetamine also inactivates neurotransmitter reuptake systems. Thus, by these two mechanisms it causes a surge of adrenergic stimulation. The stimulated alpha- and beta-adrenergic receptors produce tachycardia, hypertension, vasospasm, and hyperthermia. The dopamine receptor stimulation affects drug-craving, drug-seeking, and psychiatric symptoms. The increased serotonergic activity contributes to mood alterations and unusual responses to thirst and hunger.¹

The elimination of methamphetamine is by both renal and hepatic mechanisms, but the enzymatic degradation results in a number of active metabolites, which may accumulate with repeated, frequent, or binge use.

Clinical Presentation of Overdose
Methamphetamine intoxication should be included in the diagnosis of any patient who is diaphoretic, tachycardic, hypertensive, severely agitated, and psychotic. Patients are frequently unwilling or unable to give an accurate history of which illicit substance or the amount of illicit substance they ingested. Methamphetamine can cause a wide range of cardiac, respiratory, neurologic, psychiatric, dental, traumatic, and ophthalmologic signs and symptoms. Patients may vary from being virtually asymptomatic to possessing life-threatening symptoms, including severe tachycardia, hypertension, agitation, hyperthermia, metabolic acidosis, seizures, or cardiac arrest. Patients in coma, shock, hyperthermia >102ºF (39ºC), metabolic acidosis, acute renal failure, or hyperkalemia >5.6 mEq/L are at a significantly increased risk of dying from their overdose.¹

For symptom frequency of patients presenting in the ED, see the following table.

Clinical Effects of CNS Stimulant Drugs
Hypertension	33%
Agitation	22%
Coma	10%
Chest pain	9%
Hallucinations	7%
Confusion	6%
Delusion	5%
Weakness and lethargy	5%
Headache	4%
Abdominal pain	4%
Palpitations	3%
Seizures	3%
Paresthesia	2%

Reproduced with permission from The Toxicology Handbook for Clinicians, 2006.³

Other Clinical Manifestations

Vital Signs
Methamphetamine produces a dose-dependent change in vital signs with severely agitated patients frequently requiring sedation before vital signs can be obtained. This is especially evident in patients demonstrating severe intoxication as manifested by hypertensive crisis, severe hyperthermia, and/or refractory tachydysrhythmias.

Cardiovascular
In addition to the nearly universal hypertension and tachycardia observed in methamphetamine-intoxicated patients, cardiac ischemia, myocardial infarction, and cardiomyopathy are frequently observed in acute and chronic users. One study4 of methamphetamine-ingesting patients who presented to the ED with chest pain showed that 25% had evidence of an acute coronary syndrome. The severe hypertension and vasospasm predispose users to cerebrovascular accidents, aortic dissection, and intracranial hemorrhage, in addition to myocardial ischemia.

Sudden cardiovascular collapse is another serious association observed in severe methamphetamine intoxication. This is particularly observed in very agitated patients who require physical restraint for protection against injury to self and others. It is postulated that the cardiovascular collapse arises from a combination of neurotransmitter depletion, dehydration, and metabolic acidosis.⁵

Respiratory
Tachypnea, increases in minute ventilation, pulmonary hypertension, and noncardiogenic pulmonary edema may all be observed with severe intoxication. Other pulmonary complications include pneumothorax, pneumonia, pulmonary hemorrhage, and lung toxicity from pulmonary irritants manifested as dyspnea and wheezing.

Neurological
CNS ischemia, infarction, or hemorrhage may be manifested as focal neurologic deficits. Seizures are common in severe intoxication and usually occur within 24 hours of methamphetamine use. They are usually brief and self-limited.6 Tremor, hyperreflexia, choreoathetoid movements, and bruxism (tooth grinding) are common and are thought to arise from alteration in the dopaminergic neurotransmission.⁷ Altered level of consciousness (LOC) to the point of coma is also observed in some patients.

Psychiatric
Psychiatric symptoms are often the chief complaints of patients presenting for acute or emergency care after amphetamine ingestion. Agitated delirium (sometimes severe), paranoia, psychosis, delusions, hallucinations, suicidal ideation, severe anxiety, and abnormal behavior are all possible symptoms observed on initial presentation. Active psychosis can last from 10 days (64% of abusers) to 6 months (10% of abusers).³

Gastrointestinal
Methamphetamine can induce vomiting and diarrhea due to sympathetic stimulation. Bowel ischemia, especially associated with body packing and stuffing, may result in abdominal pain which is out of proportion to the findings on physical examination.

Genitourinary
The agitated delirium with increased muscular activity may lead to hyperthermia, rhabdomyolysis, dehydration, acidosis, and hyperkalemia, with the resulting acute renal failure.

Dermatologic
Multiple skin excoriations caused by user picking at his or her skin due to formication (an abnormal sensation that resembles that made by insects creeping in or on the skin) is common in protracted methamphetamine abuse. Drug preparation may cause thermal and chemical burns. Injection drug use may be associated with cellulitis, skin abscesses, and tract marks. Acutely, patients are frequently very diaphoretic.

Metabolic
The severe agitation may lead to life-threatening hyperthermia, severe acidosis, and hyperkalemia.

Obstetric
Methamphetamine use in pregnancy may result in placenta insufficiency, hemorrhage, preterm labor, abruption, and altered neonatal behavior patterns.⁸

HEENT
Common findings in chronic methamphetamine users include extensive tooth decay (meth-mouth) resulting from decreased saliva production, poor dental hygiene, and bruxism. Acutely, the patient frequently demonstrates minimally reactive mydriasis. Gingival hypertrophy, oropharyngeal burns from methamphetamine smoking, and mucosal injuries from insufflation (snorting) may also be observed.

Differential Diagnosis
The differential diagnosis of methamphetamine intoxication includes many toxicological and nontoxicological etiologies. Essential in the diagnosis of methamphetamine intoxication is the recognition of the sympathomimetic toxidrome, a syndrome characterized by signs of adrenergic excess, including tachycardia, hypertension, hyperthermia, agitation, minimally-reactive mydriasis, and diaphoresis. A positive qualitative urine drug screen is supportive but is neither diagnostic if positive or excludes methamphetamine intoxication if negative.¹

Toxicological conditions that mimic methamphetamine intoxication include:

Adrenergic substances like cocaine and phencyclidine (PCP) have clinical presentations similar to methamphetamine, but the duration of action of methamphetamine is much longer at about 20 hours as opposed to the duration of action of 30 minutes for cocaine and < 8 hours for PCP.¹
The serotonin syndrome and monoamine oxidase inhibitor poisoning clinical manifestations include agitation, tachycardia, and diaphoresis but can be clinically distinguished by the presence of lower extremity tremor and clonus, which are not typical for methamphetamine toxicity.¹
Patients with the anticholinergic toxidrome have an unusual mumbling speech and tend to pick at objects, while methamphetamine produces an agitated delirium requiring restraints.¹

Nontoxicological conditions that mimic methamphetamine intoxication include:

Thyrotoxicosis that differs from methamphetamine intoxication due to the presence of exophthalmos, goiter, and pretibial edema.
Pheochromocytoma usually produces intermittent hypertension, diaphoresis, diarrhea, and vomiting.
Heat stroke can best be differentiated by the history of a hot environment, especially associated with prolonged exercise, in a patient on antipsychotic or cardiovascular medications who is at high risk due to debility, age, or autonomic dysfunction.¹

Laboratory Evaluation
The evaluation of a methamphetamine-intoxicated patient should consider many of the following tests¹:

Finger-stick glucose, to rule out hypoglycemia as the cause of the altered mental state
Salicylate and acetaminophen levels to rule out co-ingestions
Pregnancy test in females of childbearing age
Toxicology screens are usually obtained but may give false positive and false negative results. The result should not be solely relied upon to determine the proper treatment of the patient. Medications that may give a falsely positive methamphetamine test result include bupropion, doxepin, labetalol, methylphenidate, overdose of ranitidine, many other commonly used drugs, as well as amphetamine-containing medications like Dexedrine, Adderall, and others.⁹Urine screens may be negative due to insufficient time elapsing from ingestion to urine test for the drug to be excreted in the urine. The time frame for detection of methamphetamine in urine is usually within 2 to 4 days from the last ingestion.
Basic serum electrolytes—including potassium, sodium, chloride, and bicarbonate levels—are needed to check the specific levels and for anion gap values.
ABGs help evaluate for metabolic acidosis and the potential need for bicarbonate IV.
Serum lactate helps to rule out lactic acidosis.
Creatinine phosphokinase (CPK) and possibly myoglobin level is needed to evaluate for the occurrence of rhabdomyolysis.
BUN and creatinine is needed to evaluate renal function and the potential of acute renal failure.
Serum phosphate levels are evaluated in cases where rhabdomyolysis is suspected due the risk of severe hyperphosphatemia resulting from the damage to muscle cells.
Evaluate serum calcium levels due to the risk of severe hypocalcemia occurring in patients with rhabdomyolysis. The hypocalcemia is due to the deposition of calcium salts in damaged muscle and the decreased bone response to parathyroid hormone (PTH).¹⁰
Liver function studies, including ALT and AST.
Order coagulation studies, including PT-INR, PTT, platelet count, and D-dimer to assess for disseminated intravascular coagulation (DIC).¹¹
If the patient has chest pain or co-ingestion is a concern, obtain a troponin level and a 12-lead ECG. Look for ST depression or elevation to rule out myocardial ischemia or infarction in chest pain patients as well as for clues to possible co-ingestions, such as tricyclic antidepressant toxicity, which may cause a prolongation of the QRS or QTc interval.
In patients with altered mental status or who report a severe headache, conduct a head CT. This is especially important if the patient has had a seizure or has any neurologic abnormality.
Chest x-ray, CT of chest or abdomen, and echocardiography may be indicated in selective patients where the risk of an aortic dissection or rupture, cardiomyopathy, or pneumothorax are suspected.¹
Pelvic ultrasound may be necessary in pregnancy where there is suspicion of a placental abruption.
Determine the need for other testing depending on presentation. Methamphetamine users who inject the drug and may re-use or share needles, syringes, and other injection equipment have a high rate of transmission of HIV and hepatitis B and C.

Treatment

General Approach
The diagnosis of methamphetamine intoxication should be considered in any diaphoretic patient with tachycardia, hypertension, severe agitation, and psychosis. Minimizing stimuli, such as reducing bright lights and noise, may be helpful. Even in patients who are relatively calm at presentation, sudden violent agitation may develop at any time. Acute control of agitation may be essential to initial management in these patients.

Most cases of methamphetamine toxicity can be managed supportively in the ED. Address the basics: airway, breathing, circulation, disability, DONT (Dextrose, Oxygen, Narcan, Thiamine). Take the patient’s vital signs, including rectal temperature. Address hyperpyrexia immediately.

In severe overdoses, immediately begin airway control, oxygenation and ventilation support, and appropriate monitoring. Termination of methamphetamine-induced seizure activity and arrhythmias are of immediate importance. Other serious abnormalities such as severe hypertension, hypotension, and hyperthermia in addition to metabolic and electrolyte abnormalities need to be addressed rapidly.

Sedation for Control of Agitation
Extreme agitation in acutely intoxicated methamphetamine users may pose a significant danger to staff, other patients, as well as patients themselves. Thus, immediate control of severe agitation is essential.

Benzodiazepines IV are usually the drugs of choice for initial management.

Lorazepam 2 to 4 mg IV. PEDS: Give 0.05 to 0.1 mg/kg over 1 to 2 minutes and repeat if needed.
Or, diazepam 5 to 10 mg IV may be given acutely and repeated every 8 to 10 minutes. PEDS: Give 0.1 to 0.2 mg/kg IV every 15 to 20 minutes.¹
In less agitated patients, lower doses of a benzodiazepine (lorazepam 1 to 2 mg or diazepam 2 to 5 mg) may be adequate and may be repeated as needed.

In some situations, the use of benzodiazepines may not be sufficient to control the patient’s agitation, and an antipsychotic agent may be added as adjunct therapy.

Haloperidol (Haldol) 5 to 10 mg IV.^12,13PEDS: A dose for children < 3 years has not been established. For children 3 to 12 years, give 0.05 to 0.15 mg/kg/day divided twice or 3 times daily. For children > 12 years, give the adult dose.
Droperidol is faster acting and more sedating than haloperidol but is more likely to cause hypotension. Administer in small IV boluses and titrate to effect. In adults, give 2.5 mg IV initial bolus for mildly agitated patients and 5 to 10 mg IV initial bolus for more severely agitated patients.^12,13 PEDS: For children < 12 years, no dose has been established. For children > 12 years, give the adult dose. Additional doses may be given every 5 to 10 minutes.
Ziprasidone (Geodon) 5 to 10 mg IV.^12,13

Although IV administration of benzodiazepines and antipsychotics is preferred in the treatment of severely agitated patients with methamphetamine intoxication, IM administration of these medications may be necessary when IV access is not available.

Physical restraints are not desirable and should be avoided if possible. As patients struggle against the restraints, they increase their risks of hyperthermia, lactic acidosis, sudden cardiac collapse, and death.¹

Airway Management
Patients with severe methamphetamine intoxication may require paralysis and endotracheal intubation by RSI to protect their airways and to manage their refractory agitation, muscle rigidity, hyperthermia, and metabolic acidosis. (Vol III—AIR1 Rapid Sequence Intubation) The use of succinylcholine is relatively contraindicated because of the risk of rhabdomyolysis and the adverse effects of the hyperkalemia on the heart conduction. Therefore, nondepolarizing agents like vecuronium or rocuronium should be used to perform RSI.¹

Hypertension Management
If adequate sedation does not control the patient’s severe hypertension, give IV antihypertensive drugs. Avoid the use of beta blockers, including labetalol, in any hyperadrenergic condition due to the potential of their leading to an unopposed alpha-adrenergic vasoconstriction with the development of worsening of the hypertension.¹ Even though labetalol acts as a mixed alpha/beta antagonist, it acts primarily as a beta blocking agent and thus is safer not to use in settings of sympathomimetic poisoning.¹¹

Drugs of choice in this setting include:

Nitroprusside IV starting at 0.25 to 0.5 µg/kg/min and titrating to effect. Maximum dose is 8 to 10 µg/kg/min. Cyanide accumulation is a risk if doses greater than 2 µg/kg/minute are used.¹⁴
Phentolamine, an alpha-adenergic blocker, given at doses of 5 to 10 mg IV every 5 to 15 minutes as needed.¹⁴

Hyperthermia Management
Treatment of severe hyperthermia, with temperatures > 40ºC (104ºF), requires aggressive management. Adequate sedation, neuromuscular paralysis followed by endotracheal intubation and ventilation, and adequate fluid resuscitation are needed to control the methamphetamine-induced hyperthermia. Active cooling of the patient with cooling blankets and other cooling devices are necessary to prevent the development of life-threatening hyperthermia. Antipyretics have no role in the treatment of methamphetamine-induced hyperthermia since the rise in patient’s temperature is due to increased muscular activity and not due to an alteration of the hypothalamic temperature control mechanism.¹

Rhabdomyolysis
Evaluate for rhabdomyolysis by testing the CK level. Patients demonstrating rhabdomyolysis need treatment with bicarbonate IV (see below) and aggressive IV fluids. Start with isotonic saline and give enough IV fluids to maintain a urinary output of 200 to 300 mL/hour.¹⁰ Carefully monitor for development of fluid overload.

Management of Fluid Needs and Metabolic Acidosis
The fluid needs of the methamphetamine-toxic patient are difficult to assess since the usual signs of hypovolemia, such as hypotension and tachycardia, are either misleading or hard to interpret. Excess fluid resuscitation may lead to pulmonary edema. Nevertheless, if the patient is clinically dehydrated, normal saline IV fluid resuscitation is necessary, but the patient must be carefully monitored for fluid overload.

If the patient has severe lactic acidosis (pH <7.10) or demonstrates rhabdomyolysis, give bicarbonate IV. In lactic acidosis, bring the arterial pH up to at least 7.15. If rhabdomyolysis is present, alkalinizing the urine to a pH >6.5 helps to reduce the renal toxicity of the myoglobin and hemoglobin.10 Give the bicarbonate as an isotonic solution by mixing 3 ampules of bicarbonate in D₅W and administer at the rate of 200 mL/hour.¹ (This can be easily prepared by withdrawing 150 mL from 1 L of D₅W, then adding 3 amps of sodium bicarbonate.)

Gastrointestinal (GI) Decontamination
Activated charcoal (AC) is rarely indicated since the most common route of methamphetamine administration is IN, inhalation, or injection. Use of AC may be beneficial to minimize systemic absorption, if oral ingestion is recent, especially < 2 hours.¹⁵ If AC is given, the standard dose is 1 g/kg to a maximum of 50 g given PO or NG.¹PEDS: Administer as in adults (12.5 to 25 g usual dose). The need for protecting the airway before administration in patients with absent gag reflex or a depressed LOC must be considered.

In cases of a single large recent ingestion, as occurs in body packing or stuffing, or a slow release mechanism as occurs when the drug is swallowed wrapped in paper or plastic to slow down absorption, GI decontamination with an agent like polyethylene may be helpful.¹ It is suggested that this be done only after consultation with a toxicologist.

Cardiac Effects
Methamphetamine may produce cardiac ischemia or infarction. Thus, chest pain associated with methamphetamine use should be evaluated as a possible acute coronary syndrome with the obtaining of ECGs and cardiac enzymes. Management is similar to chest pain management associated with cocaine ingestion. The use of aspirin, NTG, and supplemental O₂ are all indicated. Benzodiazepines IV are appropriate for blood pressure and agitation control. The use of beta blockers, including labetalol, is not recommended.¹

Sudden Cardiovascular Collapse and Cardiac Arrest
Despite appropriate management, sudden cardiovascular collapse may occur in severe methamphetamine-intoxicated patients. No accurate factors can predict which patients may suddenly deteriorate and arrest. However, patients placed in physical restraints are at greatest risk of sudden cardiac arrest due to a combination of dehydration, depletion of adrenergic neurotransmitters, and metabolic acidosis.¹

The complex mix of factors present with the cardiovascular collapse and cardiac arrest makes the resuscitation very difficult. The treatment of these conditions includes therapies directed at¹:

Large volumes of normal saline IV for fluid resuscitation probably need to be administered to restore circulation. While there are no specific guidelines for fluid administration, a useful starting point is a bolus of 2 L normal saline. (PEDS: 20 mL/kg IV)
Severe metabolic acidosis needs to be corrected with sodium bicarbonate. Give 1 to 3 ampules of bicarbonate IV as a starting dose.
Administer vasoactive amines to overcome neurotransmitter depletion. Direct-acting vasopressors like norepinephrine and epinephrine are preferred for the management of shock from methamphetamine intoxication, since it is postulated that these direct-acting vasopressor amines are more effective in reestablishing vascular tone than the indirect vasopressors like dopamine. Treatment goals with the use of the vasopressors include a systolic BP > 90 mm Hg and a urinary output of at least 1 mL/kg/hour.
Severe hyperkalemia may be associated with cardiac arrest. If the patient’s ECG suggests severe hyperkalemia, treat aggressively with calcium IV plus insulin and dextrose.

Seizures
Methamphetamine-induced seizures may be isolated events. They may also be associated with hyperthermia, coma, muscle hyperactivity, metabolic acidosis, shock, renal failure, and secondary rhabdomyolysis.

Treat methamphetamine-induced seizures as seizures of unknown etiology. (Vol III—NEU1 Status Epilepticus)
For refractory seizures, consider propofol 2.5 mg/kg followed by 0.2 mg/kg/min IV drip. (Vol III—NEU1 Status Epilepticus)

Use midazolam to terminate refractory status epilepticus. For adults, give 0.01 to 0.05 mg/kg IV (usually 0.5 to 4 mg, up to 10 mg) over several minutes; may repeat every 10 to 15 minutes until patient achieves adequate response. Midazolam may be administered IM if vascular access cannot be achieved. PEDS: For infants < 32 weeks, give 0.05 to 0.2 mg/kg IV over 2 to 3 minutes followed by 1 to 2 µg/kg/min IV; titrate dose upward every 5 minutes until seizure is controlled. Clinicians should wait 2 to 3 minutes to fully evaluate sedative effects before initiating procedure or repeating dose.

All patients with methamphetamine-induced seizures are at high risk for intracranial bleed. Perform a head CT as soon as possible.

Pediatric Consideration
The exposure of children to methamphetamine is increasing. This exposure may be intentional (as seen in adolescents) or unintentional (as observed in neonates, infants, and children). The most common symptoms observed in young children include tachycardia, agitation, crying, vomiting, abdominal pain, hyperthermia, mydriasis, seizures, ataxia, and roving eyes.¹⁶ When methamphetamine intoxication is suspected in a child, routine laboratory evaluation and aggressive management of the agitation, hypertension, and hyperthermia is indicated. (See above evaluation and management information.)

Treatment Summary of Amphetamine Toxicity

Agitation Benzodiazepines

Seizures Benzodiazepines
Barbiturates

Hyperthermia Control agitation
External cooling with mist and fans

Hypertension Control agitation
Vasodilator (nitroprusside)
α-antagonist (phentolamine)
Avoid ß-blockers (unopposed α effects)

Psychosis Benzodiazepines
Consider neuroleptics if normal vital signs

Rhabdomyolysis Control agitation
External cooling
IV fluids to maintain urine output of 1 to 2 mL/kg/min

Reproduced with permission from The Toxicology Handbook for Clinicians, 2006.³

Poisoning from heavy metals (eg, lead, mercury, or solvents used in the synthesis process) that contaminate methamphetamine and exposures to carcinogenic materials has been reported with illegally manufactured methamphetamine. Be aware of these possibilities.
Specific treatments for contaminant-caused heavy metal toxicity in some methamphetamine preparations may be needed. Consult the Poison Center (1-800-222-1222) or a local medical toxicologist to obtain additional information and patient care recommendations. Also see Vol III—TOX2, Essential Antidotes.

MDMA (Ecstasy) Intoxication
MDMA (3.4-methylenedioxymethamphetamine) is a synthetic compound with structural and pharmacologic similarities to amphetamine and other amphetamine analogs. Originally developed as an appetite suppressant in 1914, MDMA was found during the 1970s to possess psychotherapeutic uses.¹¹ Its abuse potential quickly led to it being restricted from its medical uses but it has become a common drug of abuse, especially among young party-goers at raves and circuit parties due to its ability to elicit feelings of euphoria, wakefulness, intimacy, disinhibition, and sexual arousal.¹¹ MDMA shares the toxicity of other amphetamine analogs as well as possesses some unique toxicities.¹¹

Clinical Features
As a sympathomimetic amphetamine, MDMA causes release of endogenous catecholamines (especially norepinephrine and dopamine) and blocks their reuptake into presynaptic vesicles resulting in the typical amphetamine toxicities of hypertension, tachycardia, agitation, and hyperthermia. In addition, MDMA causes increased serotonin release and inhibits serotonin reuptake, which results in additional serotonergic toxic effects (serotonin syndrome) and syndrome of inappropriate antidiuretic hormone secretion (SIADH).¹¹

The serotonin syndrome is characterized by abnormal neuromuscular activity (manifested as spontaneous clonus, hyperreflexia, hypertonia, and tremor), altered mental status, and autonomic dysfunction.¹¹Patients who combine drugs that increase 5-HT1A receptor activity (like lithium, meperidine, or tryptophan), monoamine oxidase inhibitors (MAOIs), or selective serotonin reuptake inhibitors (SSRI) with the ingestion of MDMA are at special increased risk of developing a severe form of serotonin syndrome, which may be life threatening.¹¹

The MDMA-induced SIADH appears to play a central role of another manifestation of MDMA ingestion, ie, hyponatremia.¹⁷ In many cases, the hyponatremia is also made worse by the patient’s consumption of excess fluid resulting in free water intoxication. Severe serum sodium levels < 115 mEq/L are not uncommon and may be associated with persistent seizures.

Laboratory Evaluation
Routine laboratory evaluation of patients with presumed MDMA intoxication is similar to patients with methamphetamine intoxication. Since hyponatremia is common with MDMA intoxication, a serum osmolality may be helpful in patients with hyponatremia.

Management
The general management of MDMA intoxication is similar to the emergency management of methamphetamine. This includes the appropriate management of the ABCs. Tachycardia in the absence of severe hypertension rarely needs specific treatment unless a PSVT is present needing treatment with adenosine or a calcium channel blocker. If hypertension needs treatment, beta blocking agents should be avoided and nitroprusside or phentolamine used for blood pressure control.

Hyperthermia may be more severe than with methamphetamine intoxication. Treatment starts with the routine cooling techniques. In more severe cases, paralysis and mechanical ventilation will be required to help decrease the additional heat production from agitation and muscle contraction. Sedation with the use of benzodiazepines is beneficial but in severe hyperthermia, the use of cyproheptadine, a serotonin antagonist, may be appropriate.¹⁸

Hyponatremia may be very severe, Na+ < 115 mEq/L, and result in resistant seizures. Much of the hyponatremia is due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). If the patient has only mild hyponatremia and is not hypovolemic, management consists of fluid restriction, which generally results in resolution of the hyponatremia within 12 to 24 hours.¹⁹ If severe hyponatremia is present or persistent seizures are occurring, the use of hypertonic saline is suggested (3% or 513 mEq/L).¹⁷

Use of 3% saline for severe hyponatremia: Give 100 mL hypertonic saline IV over 10 minutes. Follow by another 100 mL IV over 50 minutes. Monitor serum sodium levels frequently to avoid too rapid correction of hyponatremia, which can induce the devastating osmotic demyelization syndrome.²⁰

Seizures associated with MDMA intoxication are usually the result of an altered balance of excitatory and inhibitory neurotransmitters rather than the usual cause of electrical instability observed in other forms of seizures.¹¹ The usual initial treatment is with IV benzodiazepines. Phenytoin is not likely to be helpful in controlling the seizures due to the above-mentioned mechanism of the seizure.¹¹ Severe hyponatremia needs to be watched for and treated if present.

MDMA (ecstasy) use continues to be popular as a drug of abuse, especially among adolescents and young adults attending parties due to its ability to elicit the feelings of intimacy, wakefulness, disinhibition, and euphoria.

References

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Derlet R, Albertson, T. Methamphetamine Toxicity. Last updated July 12, 2006. www.emedicine.com/EMERG/topic859.htm . Accessed October 16, 2007.

Harris CR. The Toxicology Handbook for Clinicians. Philadelphia, Pa: Mosby Elsevier, 2006.

Turnipseed SD, Richards JR, Kirk JD, Diercks DB, Amsterdam EA. Frequency of acute coronary syndrome in patients presenting to the emergency department with chest pain after methamphetamine use. J Emerg Med. 2003;24:369-373.

Lai MW, Klein-Schwartz W, Rodgers GC, et al. 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database. Clin Toxicol (Phila). 2006;44:803-932.

Olson KR, Kearney TE, Dyer JE, Benowitz NL, Blanc PD. Seizures associated with poisoning and drug overdose. Am J Emerg Med. 1993;11:565-568.

Sperling LS, Horowitz JL. Methamphetamine-induced choreoathetosis and rhabdomyolysis. Ann Intern Med. 1994;121:986.

Oro AS, Dixon SD. Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates. J Pediatr. 1987;111:571-578.

Hendrickson RG, Martin TG, et al. Methamphetamine. Emergency Medicine reports. 27:18; August 21, 2006.

Rose BD. Clinical features and prevention of heme pigment-induced acute tubular necrosis UpToDate. Version 16.1, 2008. www.uptodate.com Accessed May 21, 2008.

Hoffman RJ. MDMA (ecstasy) intoxication. UpToDate. Version 16.1, 2008. http://www.uptodate.com/contents/mdma-ecstasy-intoxication?source=search_resul&selectedTitle=1%7E150 Accessed May 21, 2008.

Richards JR, Derlet RW, Duncan DR. Methamphetamine toxicity: treatment with a benzodiazepine versus a butyrophenone. Eur J Emerg Med. 1997;4:130-135.

Martel, M, Sterzinger, A, Miner, J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. Acad Emerg Med. 2005;12:1167-1172.

Kaplan NM, Rose BD. Drug treatment of hypertensive emergencies. UpToDate. Version 16.1, 2008. http://www.uptodate.com/contents/drug-treatment-of-hypertensive-emergencies?source=search_result&selectedTitle=1%7E150 Accessed May 21, 2008.

Chyka PA, Seger D, Krenzelok EP, Vale JA. American Academy of Clinical Toxicology: European Association of Poisons Centers and Clinical Toxicologists. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005;43:61-87.

Kolecki P. Inadvertent methamphetamine poisoning in pediatric patients. Pediatr Emerg Care. 1998;14:385-387.

Hartung TK, Schofield E, Short AI, et al. Hyponatraemic states following 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') ingestion. QJM. 2002;95:431-437.

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Slovis CM. Electrolyte emergencies. Presented at American College of Emergency Physicians Scientific Assembly, Washington DC, October 2005.

Edition 13-October 2011

Treatment Summary of Amphetamine Toxicity
Agitation	Benzodiazepines
Seizures	Benzodiazepines Barbiturates
Hyperthermia	Control agitation External cooling with mist and fans
Hypertension	Control agitation Vasodilator (nitroprusside) α-antagonist (phentolamine) Avoid ß-blockers (unopposed α effects)
Psychosis	Benzodiazepines Consider neuroleptics if normal vital signs
Rhabdomyolysis	Control agitation External cooling IV fluids to maintain urine output of 1 to 2 mL/kg/min