Methamphetamine: Acute intoxication

INTRODUCTION — Methamphetamine is a sympathomimetic amine that belongs to a class of compounds, the phenethylamines, with a variety of stimulant, anorexiant, euphoric, and hallucinogenic effects. Methamphetamine is used clinically for treatment of attention deficit disorder with hyperactivity (ADHD), short-term treatment of obesity, and as an off-label treatment for narcolepsy.

Methamphetamine may be synthesized via simple reactions using readily available chemicals and over-the-counter cold medicines, such as ephedrine and pseudoephedrine. Although some illicit methamphetamine is diverted pharmaceutical product, the majority of recreational methamphetamine is manufactured specifically for illicit use. Clandestine methamphetamine synthesis carries significant risk of explosion or toxic exposure and is responsible for exposing many children to profoundly toxic products [1].

The toxicology, diagnosis, and management of acute methamphetamine intoxication are reviewed here. The general management of acute drug overdose and the management of other stimulants, such as cocaine, are discussed separately. (See "General approach to drug poisoning in adults" and "Cocaine: Acute intoxication".)

EPIDEMIOLOGY — Recreational use of methamphetamine and other amphetamine-derived stimulants has reached epidemic proportions in the United States, Southern Asia, the Philippines, and Japan. After cannabis, it is the most widely used illicit drug worldwide [2]. Approximately 5 percent of the United States population has used methamphetamine in their lifetime, with an estimated 500,000 people using the drug in a given month [3-6].

PHARMACOLOGY AND CELLULAR TOXICOLOGY — Phenethylamines comprise a class of central nervous system (CNS) stimulants (figure 1). Various substitutions on the basic phenethylamine structure determine the degree of CNS penetration, likelihood of degradation by monoamine oxidase (MAO), receptor binding affinity, and the range of effects.

The prototypical phenylethylamine is alpha methyl phenylethylamine, which is contracted to give the common name amphetamine. Amphetamine possesses a methyl group at the alpha position of the carbon chain (figure 2). Methamphetamine has a second methyl group (figure 3), which increases lipophilicity and CNS activity. Methamphetamine exists in dextro- or levo- stereoisomers; the dextro- isomer exerts greater CNS stimulation.

●Methamphetamine-neurotransmitter interactions – The neurotransmitters norepinephrine, epinephrine, and serotonin are stored within cytoplasmic vesicles of presynaptic adrenergic neurons. These neurotransmitters are released into the synapse with nerve depolarization. Once in the synapse, the neurotransmitters bind to postsynaptic receptors and elicit neurochemical responses. Thereafter, they diffuse away from the postsynaptic receptor and are either quickly degraded or undergo cellular reuptake and re-placement into vesicles. Reuptake is mediated through adenosine triphosphate (ATP)-dependent or ion-dependent (Na+) neurotransmitter transporters, as well as by concentration gradient channels.

Methamphetamine lacks direct adrenergic effects, but is instead an indirect neurotransmitter. Methamphetamine is incorporated into cytoplasmic vesicles where it displaces epinephrine, norepinephrine, dopamine, and serotonin into the cytosol. As cytosolic concentrations rise, neurotransmitters diffuse out of the neuron and into the synapse where they activate postsynaptic receptors. Methamphetamine also inactivates neurotransmitter reuptake transporter systems.

The result of these two processes is a surge of adrenergic stimulation. The lone modulatory response to such stimulation is degradation by catechol o-methyl transferase (COMT), a slow, saturable degradation pathway.

Stimulated alpha- and beta-adrenergic receptors produce hypertension, tachycardia, hyperthermia, and vasospasm. Serotonergic activation contributes to alterations in mood as well as deranged responses to hunger and thirst. Dopamine receptor stimulation affects drug-craving and drug-seeking behavior, as well as psychiatric symptoms.

PHARMACOKINETICS AND METABOLISM — Methamphetamine is readily absorbed following administration via oral, pulmonary, nasal, intramuscular, intravenous, rectal, and vaginal routes. Body stuffing has been reported [7-9].

Methamphetamine is lipophilic, readily crosses the blood-brain barrier, and has a large volume of distribution (3 to 4 L/kg) [10]. Onset of action occurs within seconds after smoking or injection; effects may be observed within 5 minutes after intranasal use or within 20 minutes following oral ingestion [11]. Peak plasma concentrations are achieved approximately 30 minutes following intravenous or intramuscular administration and up to 2 to 3 hours after ingestion. Although methamphetamine has a plasma half-life of 12 to 34 hours, the duration of its effect commonly persists beyond 24 hours [12].

Elimination of methamphetamine occurs via several hepatic and renal pathways, including cytochrome CYP2D6. Polymorphisms of this cytochrome isoform have been implicated in cases of unanticipated toxicity [11]. Enzymatic degradation of methamphetamine results in active metabolites which may accumulate with repeated, frequent, or binge use. Renal elimination is pH dependent because methamphetamine has an alkaline pKa of 9 to 10.

CLINICAL FEATURES — Clinicians should consider the diagnosis of methamphetamine intoxication in any diaphoretic patient with hypertension, tachycardia, severe agitation, and psychosis. Acutely intoxicated patients may become extremely agitated and pose a danger to themselves, other patients, and medical staff.

History — Some patients are unable to provide any history because of severe agitation. If possible, clinicians should identify the route of exposure to methamphetamine and the frequency of use, which can help distinguish among short-term, binge, and chronic abuse. Ascertaining the potential amounts of methamphetamine ingested, as well as the use of other illicit substances and co-ingestants (eg, heroin, benzodiazepines), can guide therapeutic interventions.

Methamphetamine can cause a host of respiratory, cardiac, vascular, otolaryngologic, neurologic, integumentary, psychiatric, infectious, traumatic, and dental maladies. When possible, a thorough review of systems is in order.

Body stuffers and body packers — In body stuffers (individuals who ingest methamphetamine to avoid arrest) and body packers (individuals who internally conceal large volumes of drug for transport), special attention should be paid to the heart rate and temperature. According to at least two case series, methamphetamine body stuffers who present with a heart rate above 120 beats per minute or a temperature over 38°C are at greater risk of severe outcomes (including: seizures, altered mental status requiring intubation, creatine kinase >50,000 U/L, increased troponin, liver transaminase increase >1000 U/L, and death). The number of packets ingested, their size, the wrapping used, the time from ingestion, and abdominal complaints (eg, constipation, obstipation, distention, and vomiting) do not correlate as closely with severe morbidity [13]. (See "Internal concealment of drugs of abuse (body packing)".)

Examination findings associated with intoxication and complications — Patients with methamphetamine intoxication range from the virtually asymptomatic to those in sympathomimetic crisis with seizures, metabolic acidosis, and imminent cardiovascular collapse. Agitation, tachycardia, and psychosis are among the most frequent findings identified on presentation to the emergency department [14,15]. Life-threatening intoxication is characterized by hypertension, tachycardia, severely agitated delirium, hyperthermia, metabolic acidosis, and seizures. Prognostic factors for mortality include coma, shock, body temperature >39°C, acute renal failure, metabolic acidosis, and hyperkalemia (K 5.6 to 8.5 mmol/L) [16].

●General appearance – Chronic methamphetamine abusers may appear malnourished, agitated, and disheveled [17]. Hypervigilance and akathisia may be present in mildly intoxicated patients, while patients with severe acute intoxication may exhibit abrupt changes in behavior, becoming extraordinarily violent. Change in sleeping patterns, severe mood swings and unpredictable behavior are common. Excoriations on the skin and "track marks" (linear eschars over a vein) suggest prolonged and intravenous use, respectively. Profound diaphoresis is common in moderate to severe acute intoxication. Look carefully for stigmata of trauma, which is common among methamphetamine abusers [18,19].

●Vital signs – The severity of patient agitation sometimes prevents measurement of vital signs. Methamphetamine produces dose-dependent variations of pulse, blood pressure, and temperature. At low doses (10 to 25 mg), elevations in heart rate and blood pressure may be insignificant [20]. At the higher doses generally seen in acute intoxication (30 to 40 mg), sympathomimetic stimulation may produce dramatic increases in heart rate, blood pressure, and respiratory rate [20]. Elevated temperature is common in moderate to severe intoxication while hypertensive crisis, hyperthermia, and refractory tachydysrhythmias are associated with severe intoxication.

●Cardiovascular – Tachycardia and hypertension are nearly universal among intoxicated patients irrespective of severity. Cardiac ischemia, myocardial infarction, and cardiomyopathy have been identified in acute and chronic users. Retrospective, observational studies of methamphetamine-exposed patients report that a substantial minority show signs of acute coronary syndrome [21,22].

Severe methamphetamine intoxication is associated with sudden cardiovascular collapse, particularly in agitated patients who are physically restrained to prevent injury to themselves and others, including law enforcement and clinicians. Severe agitation often presages cardiac arrest, which can occur with frightening rapidity, and has been observed after only a few minutes' struggle. The causes, prevention, and management of restraint-related cardiovascular collapse is discussed separately. (See "Restraint-related cardiac arrest: Pathogenesis, strategies for prevention, and management for hospital clinicians".)

Valvular dysfunction may be related to the serotonergic effects of methamphetamine, while aortic dissection and rupture are more likely due to its vasospastic and hypertensive effects. Injection drug use increases the risk of infectious sequelae, such as bacterial endocarditis.

●Head, eyes, ears, nose and throat (HEENT) – Common HEENT examination findings include minimally reactive mydriasis, mucosal injuries from insufflation (snorting), oropharyngeal burns in methamphetamine smokers, and gingival hypertrophy. Those involved in methamphetamine production are at risk for burn and inhalation injuries [23,24].

Extensive tooth decay ("meth mouth") is common in chronic methamphetamine abuse due to bruxism, decreased saliva production, and poor dental hygiene (picture 1).

●Pulmonary – Increases in minute ventilation, respiratory rate, and tidal volume are often associated with severe intoxication. Illicit methamphetamine may contain pulmonary irritants that are directly toxic to the lung. Methamphetamine has been implicated in acute pulmonary edema [25], pulmonary hypertension [26,27], and, if smoked, thermal injury. Other pulmonary complications include pneumothorax, pneumomediastinum, pneumonia, acute lung injury, and pulmonary hemorrhage. Similar injuries have been seen after inhalation of heroin and smoked cocaine (crack) [28]. (See "Pulmonary complications of cocaine use".)

●Gastrointestinal – Methamphetamine can induce vomiting and diarrhea due to sympathomimetic stimulatory effects. Severe abdominal pain out of proportion to physical examination findings suggests methamphetamine-associated bowel ischemia [29], particularly in the setting of body packing and stuffing. Rectal exposure to methamphetamine occurs in cases of transport for distribution (ie, body packing) and rectal administration ("booty bumping") [8]. (See "Internal concealment of drugs of abuse (body packing)".)

●Gynecologic/obstetric – Vaginal exposure to methamphetamine arises from body stuffing, body packing, or vaginal administration of the drug [9]. Among pregnant abusers, placental insufficiency, hemorrhage, and abruption are reported [30].

●Extremities – The extremities are a likely site of injury from burns or trauma, and stigmata of repeated intravenous injection (track marks) may be present.

●Dermatologic – Drug preparation may cause thermal or chemical burns, most commonly to the hands and face [23,24]. Injection drug use may produce cellulitis, abscesses, and track marks (picture 2). Protracted methamphetamine abuse is associated with formication ("crank bugs," a feeling that ants are crawling on the skin), and many methamphetamine abusers suffer multiple small skin excoriations from unremitting picking (picture 3). Jaundice may be due to hepatitis, while poor nutrition and vitamin deficiencies may cause skin changes (cracking, angular cheilitis, aphthous ulcers) or abdominal bleeding and bruising.

●Neurologic – Choreiform movement disorders are a relatively common finding in acute methamphetamine intoxication, and arise from derangements in dopaminergic neurotransmission [31]. Focal neurologic deficits may represent central nervous system ischemia, infarction, or hemorrhage. Seizures are associated with severe intoxication, typically within 24 hours of methamphetamine use. They are usually self-limited and brief [32,33].

●Psychiatric – Acute methamphetamine use can induce agitated delirium and paranoia. Binge or chronic methamphetamine use is strongly associated with a variety of psychiatric symptoms, including paranoia and psychosis, but delusions, homicidal and suicidal ideation, mood disturbance, anxiety, and hallucinations also occur [34]. Suicidality, homicidality, psychosis, and abnormal behavior and movements are commonly seen in binge as well as chronic users. Psychiatric symptoms are often the chief complaint of patients presenting to the emergency or acute care setting.  

DIFFERENTIAL DIAGNOSIS — Establishing the diagnosis of methamphetamine intoxication requires recognition of the sympathomimetic toxidrome, a condition characterized by signs of adrenergic excess, including: hypertension, tachycardia, hyperthermia, diaphoresis, minimally-reactive mydriasis, and agitation. The diagnosis of methamphetamine intoxication in patients with these findings is supported by a positive result on the amphetamine portion of a qualitative urine drug screen ("tox screen"), although a positive drug screen is not sufficient to make the diagnosis without supporting clinical evidence. Causes of an acute hyperadrenergic state are listed in the following table (table 1). (See 'Laboratory evaluation' below and "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose".)

The differential diagnosis for patients with clinical findings consistent with the sympathomimetic toxidrome is broad and includes toxicologic and non-toxicologic etiologies. Toxicologic conditions mimicking methamphetamine intoxication include intoxication or poisoning with any of the following drugs (table 2): adrenergic substances (eg, cocaine, phencyclidine [PCP], synthetic cathinones and other synthetic phenethylamines), theophylline, aspirin, monoamine oxidase inhibitors, serotonin syndrome, and anticholinergic poisoning. (See "Cocaine: Acute intoxication" and "Phencyclidine (PCP) intoxication in adults" and "Acute amphetamine and synthetic cathinone ("bath salt") intoxication" and "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation" and "Serotonin syndrome (serotonin toxicity)" and "Anticholinergic poisoning" and "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects" and "Theophylline poisoning".)

The prolonged duration of action of methamphetamine (approximately 20 hours) helps differentiate it from cocaine (duration of action 30 minutes) and PCP. The duration of action for PCP is less than 8 hours and patients more often manifest nystagmus and rapid, involuntary eye movements. Distinguishing methamphetamine from agents such as synthetic cathinones or other phenethylamines in real time may not be possible, as their pharmacokinetics may be unknown and they may produce false positive results on qualitative screens for amphetamines. The clinically distinct features of theophylline intoxication (tachycardia, unremitting vomiting, and widened pulse pressure) are confirmed by measurement of the serum theophylline concentration. Aspirin intoxication produces tinnitus and hyperpnea even in resting patients, as well as metabolic acidosis, hyperthermia, and elevated serum aspirin concentrations.

Monoamine oxidase inhibitor poisoning has a clinical appearance nearly identical to serotonin syndrome, and both share clinical features with methamphetamine toxicity. While the clinical manifestations of serotonin syndrome include agitation, tachycardia, and diaphoresis, they also include lower extremity tremor and clonus, which distinguish the condition from methamphetamine intoxication [35]. Patients with anticholinergic poisoning have anhidrosis, whereas methamphetamine intoxicated individuals are profusely diaphoretic. Furthermore, patients with the anticholinergic toxidrome typically pick feebly at objects (sometimes imaginary) and have a peculiar mumbling speech; methamphetamine often produces wildly agitated delirium that often requires a combination of physical and chemical restraint.

Leading nontoxicologic mimics of methamphetamine intoxication include heat stroke, thyrotoxicosis, and pheochromocytoma. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults" and "Exertional heat illness in adolescents and adults: Epidemiology, thermoregulation, risk factors, and diagnosis" and "Diagnosis of hyperthyroidism" and "Clinical presentation and diagnosis of pheochromocytoma".)

Diagnosis of heat stroke should have corroborating history, such as a hot environment, prolonged exercise or exertion, or decreased ability to regulate temperature. Associated medication (such as diuretics, antipsychotics, and some cardiovascular medications) or conditions (such as advanced age, intoxication, debility, and autonomic dysfunction) predispose certain patients to heat stroke. The degree of agitation in heat stroke is significantly less than that seen in methamphetamine intoxication.

While thyrotoxicosis may have several features consistent with methamphetamine intoxication, presence of goiter, thyroid artery bruit, exophthalmos, and pretibial edema are seen only in thyrotoxicosis. The associated agitation is unlikely to be as severe as that caused by methamphetamine intoxication. Pheochromocytoma usually produces intermittent hypertension, diaphoresis, vomiting, and diarrhea; duration of episodes is variable and may be associated with an inciting stimulus.

LABORATORY EVALUATION

●General testing – Routine laboratory evaluation of the poisoned patient should include the following:

•Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

•Acetaminophen and salicylate levels, to rule out these common co-ingestions

•Electrocardiogram (ECG), to rule out conduction system impairment by drugs that prolong the QRS or QTc intervals

•Pregnancy test in women of childbearing age

●Specific testing – Reliance upon qualitative toxicologic screens can be disastrous if care is delayed while awaiting test results. Although urine drug tests may support the diagnosis of acute methamphetamine intoxication, the results of such a "tox screen" have little clinical utility. (See "Testing for drugs of abuse (DOAs)".)

The amphetamine portion of the "tox screen" is susceptible to both false positive and false negative results and must be interpreted in clinical context [36]. Drugs of abuse, such as benzphetamine and bupropion (a synthetic cathinone), may give positive results [37,38]. In addition, medications such as selegiline (following its metabolism to l-methamphetamine) and nonprescription nasal inhalers containing the active ingredient l-methamphetamine (l-desoxyephedrine) may yield positive results for amphetamine. Conversely, urine drug assays, which are dependent upon renal clearance, may fail to detect methamphetamine if insufficient time has elapsed for drug to be excreted in the urine [39].

Because of these concerns, clinicians should never withhold immediate treatment for an acutely intoxicated individual while awaiting urine toxicology results.

Many patients who are admitted users of methamphetamine but are clinically well with normal vital signs do not need any lab testing. However, methamphetamine users with moderate to severe intoxication can develop a number of dangerous manifestations and complications. These may include hypovolemia, metabolic acidosis, hyperthermia, disseminated intravascular coagulation (DIC), rhabdomyolysis, tachydysrhythmia, hypertension, and seizures. When any such effects or complications are seen we recommend the following tests also be obtained:

•Basic serum electrolytes (ie, sodium, chloride, potassium, bicarbonate)

•Serum lactate

•Creatine phosphokinase (CPK)

•Aminotransferases (ie, ALT, AST)

•Clotting times (ie, prothrombin time, activated partial thromboplastin time)

•Renal function studies (ie, creatine, BUN)

•Urinalysis

Rhabdomyolysis can cause acute renal failure and hyperkalemia in methamphetamine abusers [16,40].

An arterial blood gas can confirm the presence and severity of metabolic acidosis (usually lactic acidosis) in a patient with a low serum bicarbonate and an elevated anion gap but is often unnecessary. Additional studies, including echocardiography, chest and abdominal computed tomography, and chest radiography, are obtained as needed to investigate other potential complications of methamphetamine abuse, such as cardiomyopathy, aortic dissection and rupture, pneumothorax, and stroke.

MANAGEMENT

General approach and warning about agitation — Clinicians should consider the diagnosis of methamphetamine intoxication in any diaphoretic patient with hypertension, tachycardia, severe agitation, and psychosis. In addition, patients with acute methamphetamine intoxication may, without provocation, abruptly develop severe agitation and manifest extreme violence. A summary table to facilitate emergency management is provided (table 3).

Control of agitation and hyperthermia comprise the core of the acute management of methamphetamine intoxication. Some patients also require pharmacologic therapy for control of hypertension. Patients who appear hypovolemic may need fluid resuscitation. (See 'Hypertension' below.)

The intensity of therapy depends upon the severity of illness, but cases of abrupt decompensation among conservatively treated patients highlight the need for immediate, aggressive intervention [16,41]. Interventions frequently must be initiated prior to confirmatory laboratory data or, in violent patients, even before vital signs are obtained.

Sedation — Acutely intoxicated patients may become extremely agitated and pose a danger to themselves, other patients, and medical staff. Control of violent behavior is of critical importance. We treat severely intoxicated patients immediately with intravenous (IV) benzodiazepines (midazolam 2.5 to 5 mg IV or lorazepam 2 to 4 mg IV or diazepam 10 to 20 mg IV). The initial dose of midazolam or lorazepam may be given intramuscularly (IM) if required. IV doses can be repeated every 8 to 10 minutes based upon patient response; high cumulative doses may be needed. As different patients may respond differently to particular benzodiazepines or doses, clinicians may need to add a second benzodiazepine quickly if two or more doses of the first drug selected have little effect. In animal models, benzodiazepines blunt the hyperadrenergic effects of methamphetamine, an outcome associated with increased survival.

Second-generation (eg, ziprasidone 10 mg IM) or first-generation neuroleptics (eg, haloperidol 5 to 10 mg given IM or IV) may be used as adjunctive therapy when high doses of benzodiazepines (for example, more than 20 mg of lorazepam in 30 minutes) do not adequately control agitation or delirium. However, these medications are not free of risk. Although some studies report that these antipsychotic medications are safe and effective in this setting [42-45], neuroleptics may interfere with heat dissipation, lower the seizure threshold, and prolong the QTc interval [46]. Since prolongation of the QT interval is a class effect, these agents should not be administered to patients whose QT interval is prolonged or before an electrocardiogram (ECG) is obtained. In addition, for patients with undifferentiated agitation in whom the diagnosis of neuroleptic malignant syndrome has not been excluded, neuroleptics are contraindicated. Limited research suggests that haloperidol may be harmful in methamphetamine intoxication. In rats given high-dose methamphetamine, haloperidol was toxic to gamma-aminobutyric acid (GABA)-ergic cells [47].(See "Neuroleptic malignant syndrome".)

Although intravenous administration of sedatives is strongly preferred in severely intoxicated patients, IM injection may be used if IV access is unavailable. IM injection may provide sufficient sedation to allow definitive care, including placement of intravenous catheters.

A less aggressive regimen can be used in patients who are mildly or moderately intoxicated. This includes a quiet environment with minimal sedation in mild intoxications plus, in moderate intoxication, a benzodiazepine. Lorazepam 1 to 2 mg or diazepam 10 to 20 mg may be adequate to sedate these patients, but doses should be repeated or increased as needed.

Physical restraints should be avoided if possible. Patients who struggle against physical restraints undergo isometric muscle contractions that can be associated with lactic acidosis, hyperthermia, sudden cardiac collapse, and death. Chemical sedation must always accompany physical restraints, and physical restraints should be removed as rapidly as possible. (See "Restraint-related cardiac arrest: Pathogenesis, strategies for prevention, and management for hospital clinicians".)

Airway management — Severely intoxicated hyperthermic patients may require paralysis and endotracheal intubation. Additional indications for endotracheal intubation include refractory agitation; skeletal, cervical, or facial muscle rigidity; and worsening, severe metabolic acidosis. (See 'Hyperthermia' below.)

Succinylcholine is relatively contraindicated because of the risk of rhabdomyolysis from severe methamphetamine intoxication, which can cause an acute rise in serum potassium that can impair cardiac conduction. Instead, nondepolarizing agents, such as rocuronium and vecuronium, are preferable when performing rapid sequence intubation. (See "Rapid sequence intubation in adults for emergency medicine and critical care".)

Patients with severe metabolic acidosis may deteriorate during or soon after tracheal intubation due to the accompanying reduction in minute ventilation (and associated decrease in CO2 elimination). In patients with severe methamphetamine intoxication in whom severe metabolic acidosis (pH <7.1) is known or strongly suspected, some toxicologists give 50 to 150 mEq (one to three 50 mEq [50 mL] vials or prefilled syringes) of sodium bicarbonate prior to intubation to help prevent such complications. However, there is no high quality evidence to support this approach. When administered, bicarbonate should be reserved for severe metabolic acidosis, and then only to raise the serum pH above 7.1 while the cause of the acidosis is determined and definitive measures are taken to treat it. The efficacy of bicarbonate therapy in lactic acidosis is unproven in the absence of severe acidemia and may cause potential harm. (See "Bicarbonate therapy in lactic acidosis".)

Patients paralyzed as part of their airway management who have seized or are at risk for seizures should receive continuous bedside electroencephalography.

Hypertension — In rare instances, patients with acute methamphetamine intoxication may develop severe hypertension refractory to aggressive treatment with sedatives. However, hypertension attributable solely to methamphetamine intoxication that is not well controlled with adequate sedative therapy is so uncommon that the clinician should reassess the patient and investigate potential alternative causes (eg, aortic dissection, hemorrhagic stroke, thyroid storm). Patients with persistent severe hypertension due to methamphetamine alone may require treatment with intravenous antihypertensive drugs, although generally antihypertensive medications should be avoided in patients with methamphetamine intoxication. Suitable antihypertensive medications for these patients include nitroprusside, nitroglycerin, and phentolamine.

We suggest avoiding medications with beta-blocking activity when treating hypertension during the acute phase of methamphetamine intoxication. Poisoning with sympathomimetic agents such as methamphetamine can produce a hyperadrenergic state associated with an increase in both alpha- and beta-adrenergic tone. We believe that the optimal therapy for patients experiencing cardiovascular complications from acute sympathomimetic poisoning begins with reduction in central nervous system (CNS) catecholamine release, rather than peripheral antagonism of released catecholamines, and that benzodiazepines have a proven role in this regard. Benzodiazepine dosing is described in the section discussing sedation above; the role of beta blockers in the treatment of sympathomimetic overdose is discussed in greater detail separately. (See 'Sedation' above and "Cocaine: Acute intoxication", section on 'Use of beta adrenergic antagonists (beta blockers)'.)

Tachycardia — Although tachycardia is common among patients intoxicated with methamphetamine, heart rates are usually in a range that is well tolerated in the short-term [48]. However, heart rates above 180 beats per minute may be associated with decreased cardiac output, and individuals with underlying coronary artery disease may develop myocardial ischemia at such rates. In these individuals, benzodiazepine therapy often reduces CNS catecholamine release sufficiently to produce an adequate reduction in heart rate.

Should additional rate control be needed, we suggest treatment with a calcium channel blocking drug (eg, diltiazem) using standard doses. We suggest avoiding beta-blockers. Even beta-blockers with some degree of alpha-adrenergic blocking activity, or beta blockers used concurrently with alpha-blockers, increase the risk of vasoconstriction from unopposed alpha-adrenergic activity. (See 'Hypertension' above.)

Hyperthermia — Control of hyperthermia (temperature ≥41.1°C) involves eliminating excessive muscle activity and aggressive cooling. While benzodiazepines alone offer benefit to moderately ill patients, severely intoxicated hyperthermic patients may require paralysis with nondepolarizing agents, such as rocuronium and vecuronium, followed by tracheal intubation and mechanical ventilation. (See 'Airway management' above.)

Aggressive sedation, neuromuscular paralysis, and fluid resuscitation are used to control methamphetamine-induced hyperthermia; these measures can be supplemented with external cooling blankets or evaporative cooling techniques. Paralyzed patients at risk for seizures should receive continuous bedside electroencephalography. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults".)

Antipyretics have no role in the management of acute methamphetamine intoxication. Increased body temperature in this setting arises from muscular activity, not an alteration in the hypothalamic temperature set point.

Lipid emulsion therapy has been used in a case of acute methamphetamine toxicity with apparently beneficial effects on hyperthermia and heart and respiratory rates [49]. We suggest consultation with a medical toxicologist or poison control center to determine whether lipid emulsion therapy is appropriate. (See "Calcium channel blocker poisoning", section on 'Lipid emulsion therapy'.)

Fluid resuscitation — The role of fluid resuscitation in patients with severe methamphetamine intoxication is not defined. One problem is the limited utility of some traditional markers for hypovolemia in this setting. Tachycardia is almost universal and many patients are hypertensive. Thus, both heart rate and blood pressure may prove unhelpful when assessing volume status. In addition, there is potential for harm from aggressive fluid resuscitation in patients who are acutely hypertensive and may have myocardial dysfunction, possibly leading to pulmonary edema [50,51]. If a patient with methamphetamine toxicity is thought to be hypovolemic, resuscitation using isotonic saline is appropriate. Patients receiving fluid resuscitation should be monitored for fluid overload.

If severe lactic acidosis (pH <7.10) or rhabdomyolysis is present, we suggest aggressive intravenous fluid resuscitation to maintain a urine output of at least 1 to 2 mL/kg per hour. Sodium bicarbonate may be used to raise the arterial pH above 7.15 in lactic acidosis and to alkalinize the urine. In animal models, urine alkalization protects against the development of acute renal failure in rhabdomyolysis, but well-controlled human data is lacking. The bicarbonate solution should be isotonic (eg, three 50 mEq [50 mL] vials or prefilled syringes of sodium bicarbonate in 5 percent dextrose with water) and administered at a rate of 200 mL/hour. These issues are discussed in detail elsewhere. (See "Bicarbonate therapy in lactic acidosis" and "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on 'Prevention'.)

Sudden cardiac arrest — Despite appropriate and expeditious management, some patients with severe methamphetamine intoxication will sustain sudden cardiovascular collapse. No predisposing factors rigorously predict collapse, but the clinician should anticipate clinical deterioration and cardiac arrest in any wildly agitated patient, particularly those requiring physical restraints to maintain patient safety [52]. (See "Restraint-related cardiac arrest: Pathogenesis, strategies for prevention, and management for hospital clinicians".)

Patients placed in physical restraints can suffer sudden cardiac arrest due to a combination of dehydration, depletion of adrenergic neurotransmitters, and metabolic acidosis. Contributing factors to metabolic acidosis may include excessive muscular activity and increased ATP hydrolysis from methamphetamine-induced increases in metabolism. The multifactorial nature of cardiovascular collapse makes successful resuscitation notoriously difficult, even when arrest is witnessed [52]. In addition to airway control with endotracheal intubation, therapy is directed toward:

●Administration of vasoactive amines to overcome neurotransmitter depletion

●Correction of metabolic acidosis with sodium bicarbonate

●Fluid resuscitation with large volumes of normal saline

A direct-acting vasopressor, such as norepinephrine, is preferred for management of shock associated with methamphetamine intoxication. Continuous norepinephrine administration should be titrated to a systolic blood pressure greater than 90 mmHg and a urine output greater than 1 mL/kg per hour. The use of direct-acting vasopressor amines, such as norepinephrine and epinephrine, is postulated to be more effective at reestablishing effective vascular tone than indirect vasopressors, such as dopamine, which require neuronal uptake and conversion to norepinephrine.

Treatment of metabolic acidosis consists of fluid resuscitation, as described above, and administration of sodium bicarbonate, 50 to 150 mEq (one to three 50 mEq [50 mL] vials or prefilled syringes) administered intravenously. Intravenous fluids should be administered until circulation is restored. Specific guidelines for fluid administration in methamphetamine-associated cardiovascular collapse are lacking, but a useful starting point is a bolus of 2 L of normal saline (or 20 mL/kg in a child) administered over 30 minutes, followed by repeat boluses as needed.

Hyperkalemic cardiac arrest may occur in acute methamphetamine intoxication; patients with a suggestive ECG may benefit from standard treatment with calcium and insulin with dextrose. (See "Treatment and prevention of hyperkalemia in adults".)

Gastrointestinal decontamination — Activated charcoal is rarely indicated due to the route of methamphetamine administration (eg, intranasal, inhalation, injection). If methamphetamine has been ingested, the greatest benefit of activated charcoal occurs if administered within 1 to 2 hours of ingestion [53]. Activated charcoal should not be given to a patient with a declining mental status, severe agitation requiring sedation, or at risk of seizure. If given, the standard dose is 1 g/kg (maximum of 50 g).

In the case of a single large recent ingestion, body packing or stuffing, or a slow-release mechanism (ie, "parachuting," in which the drug is folded into plastic or paper before swallowing allowing for gradual absorption), gastrointestinal (GI) decontamination with whole bowel irrigation using agents, such as polyethylene glycol, may be useful [7,54]. We suggest such treatment be done in consultation with a medical toxicologist or poison control center since individuals who have GI exposure to methamphetamine (eg, body stuffers) and abdominal pain may deserve immediate laparotomy to prevent bowel ischemia from local vasoconstriction. Gastric lavage in that setting is unlikely to be of benefit, and is discouraged.

Enhanced elimination — Urine acidification, formerly used to promote the elimination of methamphetamine, is no longer recommended. The administration of acidic intravenous fluids may exacerbate life-threatening metabolic acidosis.

Seizure — Seizures caused by acute methamphetamine intoxication are usually brief and self-limited, and do not require medical therapy [32,33]. Prolonged seizures are treated initially with benzodiazepines (eg, lorazepam, diazepam) and should prompt a search for causes other than isolated methamphetamine intoxication (eg, hypoglycemia, intracranial hemorrhage, ischemic stroke, pre-existing seizure disorder). In the case of seizures that are not brief or self-limited, and for which a clear cause cannot be established (eg, severe hypoglycemia), many toxicologists recommend obtaining a head CT to assess for intracranial hemorrhage. Phenytoin should be avoided. (See "Initial management of the critically ill adult with an unknown overdose", section on '"D": Disability and neurological stabilization' and "General approach to drug poisoning in adults", section on 'Supportive care'.)

Neuro-psychiatric — Brief interventions by health care providers in the emergency setting may encourage patients to stop abusing methamphetamine. Therefore, education regarding the adverse health consequences of methamphetamine use and encouragement to stop should be provided to patients capable of understanding. Patients with a history of chronic methamphetamine abuse showed improved verbal memory, behavior, problem solving, and quality of life after six months of abstinence [55]. (See "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis" and "Stimulant use disorder: Treatment overview".)  

PEDIATRIC CONSIDERATIONS

Pediatric exposure — Pediatric exposure to methamphetamine may be intentional (typically seen in adolescents), or unintentional (in neonates, infants, or children). Presentation and management of methamphetamine-related illness in adolescents is largely similar to that of adults, but with an increased need for attention to social ramifications.

In children and infants, inadvertent exposure to methamphetamine is increasing [56]. Although sympathomimetic and neuropsychiatric manifestations of methamphetamine exposure should be similar in a pediatric patient, inadvertent exposure may be difficult to diagnose. Caregivers may not be forthcoming about access to this illicit substance, and the most frequent signs and symptoms noted in pediatric patients exposed to methamphetamine are nonspecific.

Agitation, tachycardia, and crying are the most common symptoms of exposure in young children, followed by vomiting with or without abdominal pain, hyperthermia, ataxia, mydriasis, seizures, and roving eye movements [56,57].

Evaluation often includes an extensive workup to exclude other neurologic or abdominal pathologies. Methamphetamine poisoning has been mistaken for scorpion envenomation (Centruroides sculpturatus), with administration of antivenom [56]. Additionally, caustic ingestion or injury in the pediatric patient should prompt consideration for methamphetamine exposure; such presentations may be more common among children living in methamphetamine-production sites ("meth labs") [58]. Once methamphetamine exposure is suspected, we recommend that routine laboratory work and an electrocardiogram (ECG) be performed to evaluate for possible rhabdomyolysis and methamphetamine-induced ischemia. In a study of 91 children exposed to methamphetamine, analysis of hair samples using liquid chromatography and tandem mass spectrometry provided substantially greater sensitivity for the detection of methamphetamine than analysis of oral fluid or urine [59].

Symptoms may persist up to 24 hours, and ongoing management may require frequent vital signs, telemetry monitoring, sedation, aggressive cooling measures, control of hypertension with benzodiazepines and (if necessary) rapidly-acting antihypertensive agents, and intravenous fluid hydration to maintain urine output of 1 to 2 mL/kg per hour to prevent myoglobinuric renal failure (see "Heat stroke in children", section on 'Rapid cooling' and "Initial management of hypertensive emergencies and urgencies in children"). Hospitalization should continue until appropriate social and child protection services are enlisted.

Asymptomatic children taken from clandestine production sites may also have been exposed to methamphetamine and other chemicals (eg, ephedrine) used to synthesize methamphetamine [60]. In one series, 48 of the 104 infants and children included tested positive for methamphetamine; 85 percent of children younger than nine years had positive toxicology screens.

Special attention should be given to children living at methamphetamine-manufacturing sites (ie, meth labs), whose numbers have increased substantially [61]. They are often discovered after an in-home fire or explosion. Any child brought from such an environment requires initial decontamination to prevent exposing health care workers to toxic chemicals. These children are particularly vulnerable to child abuse, neglect, serious injury, exposure to toxic chemicals, and malnutrition [62]. The hypersexuality and drug-seeking behaviors of adult methamphetamine users may lead to sexual abuse of such children, or they may be prostituted for money or drugs [63].

Pregnancy and lactation — In utero exposure to methamphetamine is associated with low birth weight and decreased head circumference, among several abnormalities, and may produce withdrawal symptoms in the perinatal period. There is an increased risk of perinatal complication, such as placental hemorrhage, in methamphetamine-exposed mothers. Amphetamines, including methamphetamine, are excreted into breast milk. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Amphetamines, including methamphetamine'.)

PITFALLS IN MANAGEMENT

●Failure to aggressively treat agitation – Uncontrolled agitation results in hyperthermia, acidosis, rhabdomyolysis, and sudden cardiovascular collapse. Control of agitation and chemical sedation is a clinical priority.

●Failure to aggressively treat hyperthermia – Hyperthermia is strongly associated with mortality and morbidity if not rapidly corrected.

●Failure to recognize rhabdomyolysis – A frequent complication of methamphetamine intoxication, rhabdomyolysis contributes to renal failure and hyperkalemia.

●Failure to consider associated illness – Methamphetamine-intoxicated patients are frequently the victims of traumatic injury. In addition, methamphetamine users may suffer from a range of complications, including: intracranial hemorrhage, myocardial infarction, aortic dissection, pulmonary edema or hemorrhage, endocarditis, injection site abscess, and placental abruption.

●Failure to note risk of contamination – Methamphetamine synthetic labs are often contaminated with toxic chemicals. Patients who work in or have contact with such labs may need decontamination to prevent poisoning patients and staff.

●Failure to appreciate the risk of violence – Methamphetamine-intoxicated patients can demonstrate a striking degree of violence. The use of physical and chemical restraints, personnel, and police is often required to ensure the safety of care providers and other patients.

ACUTE WITHDRAWAL — Persistent methamphetamine abuse leads to derangements in neurochemistry, the consequences of which include compulsive and uncontrolled drug intake and addiction [64]. Particularly after heavy or prolonged use, abrupt discontinuation of methamphetamine can cause a withdrawal syndrome. Symptoms may develop within hours, typically peak within 1 to 2 days, and most often decrease within two weeks. During the acute withdrawal phase ("the crash"), signs and symptoms may include: dysphoria, anhedonia, fatigue, increased sleep, vivid dreams, insomnia, agitation, anxiety, drug craving, and increased appetite [65]

A subacute withdrawal phase may persist for up to three weeks with insomnia, hypersomnia, appetite changes, depression, and possibly suicidal thoughts. Studies have yet to identify a proven medication regimen for the treatment of methamphetamine withdrawal, but treatments have included benzodiazepines, antidepressants, antipsychotics, riluzole (a tetrodotoxin-sensitive sodium channel blocker used in amyotrophic lateral sclerosis) [66], naltrexone [67], and behavioral therapy.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stimulant use disorder and withdrawal" and "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use".)

SUMMARY AND RECOMMENDATIONS

●Emergency management – Methamphetamine intoxication is potentially life-threatening. A summary table to facilitate emergency management is provided (table 3).

●Pharmacology and metabolism – Methamphetamine is a sympathomimetic with a variety of stimulant, anorexiant, euphoric, and hallucinogenic effects. Methamphetamine is readily absorbed following administration via oral, pulmonary, nasal, intramuscular, intravenous, rectal, and vaginal routes. The pharmacology and kinetics of methamphetamine are discussed in the text. (See 'Pharmacology and cellular toxicology' above and 'Pharmacokinetics and metabolism' above.)

●Clinical features – Clinicians should consider the diagnosis of methamphetamine intoxication in any diaphoretic patient with hypertension, tachycardia, severe agitation, and psychosis. Patients with methamphetamine intoxication range from the virtually asymptomatic to those in sympathomimetic crisis with imminent cardiovascular collapse. (See 'Clinical features' above.)

Methamphetamine can cause a host of respiratory, cardiac, vascular, otolaryngologic, neurologic, integumentary, psychiatric, infectious, traumatic, and dental maladies. Agitation, tachycardia, hypertension, and psychosis are among the most frequent findings.

In severe intoxication, prognostic factors for mortality include coma, shock, body temperature >39°C, acute renal failure, metabolic acidosis, and hyperkalemia (serum potassium 5.6 to 8.5 mmol/L). Clinicians should anticipate clinical deterioration and cardiac arrest in any wildly agitated patient, particularly those requiring physical restraints to maintain safety.

Patients with acute methamphetamine intoxication may, without provocation, abruptly develop severe agitation and manifest extreme violence, placing themselves, their caretakers, and other patients at risk of major injury. (See 'General approach and warning about agitation' above and 'Sedation' above.)

●Differential diagnosis – The differential diagnosis includes multiple poisonings and medical conditions with characteristics of the sympathomimetic toxidrome, a condition characterized by signs of adrenergic excess (table 2 and table 1 and table 4). (See 'Differential diagnosis' above.)

●Laboratory testing – Reliance upon qualitative toxicologic screens can be disastrous if care is delayed while awaiting test results. Urine drug test results may support the diagnosis of acute methamphetamine intoxication, but have little clinical utility. (See 'Laboratory evaluation' above.)

●Management – The intensity of therapy depends upon the severity of illness. Patients can decompensate abruptly, highlighting the need for immediate, aggressive intervention, even in the absence of confirmatory laboratory data. Control of agitation and hyperthermia comprise the core of management. Common management pitfalls are described above. A summary table to facilitate emergency management is provided (table 3). (See 'Management' above and 'Pitfalls in management' above.)

•Severe agitation – Control of violent behavior is of critical importance. We suggest that severely intoxicated patients be treated immediately with parenteral benzodiazepines (Grade 2B). Reasonable initial doses include lorazepam 2 to 4 mg intravenously (IV) or diazepam 5 to 10 mg IV. These doses can be repeated every 8 to 10 minutes based on patient response; very large doses may be needed. IV administration is strongly preferred; intramuscular (IM) injection may be used initially when IV access is unavailable. (See 'Sedation' above.)

Neuroleptic medications (eg, ziprasidone 10 mg IM, droperidol 2.5 to 5 mg IM, haloperidol 10 mg given IM or IV) may be used as adjunctive therapy when high doses of benzodiazepines do not adequately control agitation. However, these medications may interfere with heat dissipation and lower the seizure threshold, and they can prolong the QT interval. Neuroleptic medications should not be given if the QT interval is prolonged. (See 'Sedation' above.)

•Severe hypertension – Severe hypertension, particularly if refractory to aggressive treatment with sedatives, may require treatment with vasodilators (eg, nitroprusside, nitroglycerin) or alpha-adrenergic antagonists (eg, phentolamine). We avoid beta-adrenergic antagonists (beta-blockers), including labetalol. (See 'Hypertension' above.)

•Tachycardia – Sinus tachycardia usually does not require specific treatment and may respond to benzodiazepines given for agitation and hypertension. If specific treatment is needed, we administer a calcium channel blocker (eg, diltiazem). We avoid beta-blockers, including esmolol and labetalol. (See 'Tachycardia' above.)

•Hyperthermia – Control of hyperthermia (T ≥41.1°C) involves eliminating excessive muscle activity. While benzodiazepines alone offer benefit to moderately ill patients, severely intoxicated hyperthermic patients may require paralysis with nondepolarizing agents, such as rocuronium and vecuronium, followed by tracheal intubation and mechanical ventilation. Succinylcholine is contraindicated because of the risk of rhabdomyolysis and hyperkalemic arrhythmias. (See 'Hyperthermia' above.)

●Pediatric considerations – In children and infants, inadvertent exposure to methamphetamine is increasing and may be difficult to diagnose. Agitation, tachycardia, and crying are the most common symptoms of exposure in young children, followed by vomiting with or without abdominal pain, hyperthermia, ataxia, mydriasis, seizures, and roving eye movements.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steven A Seifert, MD, FAACT, FACMT, who contributed to an earlier version of this topic review.