METHAMPHETAMINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Available Forms Sources

1) PHARMACEUTICAL PREPARATIONS

a) Methamphetamine hydrochloride is available in the US as 5 mg tablets (Desoxyn(R)) (Prod Info DESOXYN(R) oral tablets, 2007a).

2) ILLICIT USE

a) SLANG TERMS associated with methamphetamine: "speed," "chalk," "crystal," "crank," "glass," "go," "meth", and "ice" (Anon, 1995).

3) SYNTHETIC METHAMPHETAMINE ANALOGUE

a) Methiopropramine (1-(Thiophen-2-yl)-2-methylaminopropane) is a synthetic methamphetamine analogue with a thiophene ring instead of a benzene ring. It is widely used as a psychoactive substance in many countries. The recreational use of methiopropramine has resulted in death (Anne et al, 2015).

4) ADULTERANTS

a) Many illicitly sold drugs alleged to be methamphetamine are often found to contain caffeine, ephedrine, or phenylpropanolamine (Renfroe & Messinger, 1985). Local anesthetics (eg, benzocaine, lidocaine, procaine, tetracaine), quinine, phencyclidine, pseudoephedrine, and strychnine may also be misrepresented as methamphetamine.
b) Agents used to dilute ("cut") the amount of true drug in a given sample include detergents, talc, and sugars such as lactose, sucrose, mannitol, and sorbitol (Newburn, 1981; Jordan, 1981; Pharm Chem, 1984).
c) SMOKING: Methamphetamine has also been abused via smoking mixed with tobacco (Sekine & Nakahara, 1987).
d) "ICE"

1) ICE is a form of methamphetamine and so named for its clear crystalline appearance. It can be smoked, insufflated or injected, and produces an almost instantaneous "rush" similar to intravenous methamphetamine. Its effects reportedly last from 8 to 24 hours, and severe psychoses have been reported with use (Hall, 1989; Derlet & Heischober, 1990). It has also been referred to as "crystal" or "crank" (Catanzarite & Stein, 1995).
2) Use of "ice" is associated with neuropsychiatric toxicity. Auditory hallucinations, severe paranoia, and violent behavior have been reported (Anon, 1989).

e) METHAMPHETAMINE LABS

1) Clandestine laboratories for the manufacture of methamphetamine may use a variety of chemicals depending on the method of synthesis employed. These may include (Farst et al, 2007):

1) Acetone and paint thinner (paint supplies)
2) Ammonium hydroxide (household cleaners)
3) Anhydrous ammonia (farming supplies)
4) Camp fuel and kerosene (camping or fuel supplies)
5) Ephedrine (weight loss or stimulant supplements)
6) Ethanol
7) Ethyl ether
8) Hydrochloric acid (swimming pool supplies)
9) Hydrogen peroxide
10) Hypophosphorous acid
11) Iodine (farming and healthcare supplies)
12) Isopropanol
13) Metallic lithium (batteries)
14) Methanol (auto supplies, gas line treatment)
15) Mineral spirits
16) Muriatic acid (gardening and cleaning supplies)
17) Naphtha
18) Petroleum distillates
19) Pseudoephedrine (decongestant medications)
20) Red phosphorous (match striker plates)
21) Sodium hydroxide (lye and drain openers)
22) Sulfuric acid (household cleaner and drain opener)
23) Toluene

2) Exposure to these chemicals may occur in first responders (eg, police, firefighters, paramedics) or occupants of a household being used as a methamphetamine lab.
3) Young children have experienced severe dermal and mucosal injuries after exposure to caustic substances used in the production of methamphetamine in the home (Burge et al, 2009; Farst et al, 2007). A child died after ingesting sulfuric acid drain cleaner at a clandestine home methamphetamine laboratory (Burge et al, 2009).
4) The following adverse effects have been reported following exposures to chemical components of methamphetamine laboratories (Grant, 2007):

a) Ammonia; liquid, anhydrous

1) Inhalation - eye, nose, throat irritation, dyspnea, chest pain, acute lung injury.
2) Dermal - burns, vesiculation, frostbite.

b) Acids and bases

1) Inhalation - pneumonitis, acute lung injury
2) Dermal - caustic burns
3) Ingestion - nausea, vomiting, gastric perforation, esophageal damage with later strictures.

c) Solvents

1) Inhalation and ingestion - liver and kidney damage, respiratory irritation, CNS effects, aspiration, headache.

d) Iodine

1) Inhalation - Respiratory distress, mucus membrane irritation.
2) Ingestion - corrosive gastritis.

e) Phosphorus

1) Ingestion - gastrointestinal irritation, liver damage, oliguria.

f) Red phosphorus

1) Flammable.

g) Phosphine gas (potential)

1) Inhalation - ocular irritation, nausea, headache, fatal respiratory effects.

5) ROUTE OF EXPOSURE

a) As a drug of abuse, methamphetamine is most often injected, smoked, ingested, or insufflated. Rectal administration has also been described ("booty bumping", "keistering", "butt whacking") (Cantrell et al, 2006).

1) CASE REPORT: A man developed methamphetamine toxicity after inserting a methampethamine-soaked tampon transrectally (Gupta et al, 2009).

1) PHARMACEUTICAL PREPARATIONS

a) Methamphetamine is used to treat attention deficit disorder with hyperactivity in children older than 6 years of age. It is also used in the short term treatment of exogenous obesity in adults and children older than 12 years in whom alternative therapy has not been effective (Prod Info DESOXYN(R) oral tablets, 2007a).

2) ILLICIT USE

a) Because of its ease of manufacture and addictive properties, it is widely used as a drug of abuse.

Therapeutic Toxic Class

Specific Substances

1) amp (synonym)
2) chalk (synonym)
3) crank (synonym)
4) crystal (synonym)
5) crystal meth (synonym)
6) glass (synonym)
7) ice (synonym)
8) meth (synonym)
9) speed (synonym)
10) tweak (synonym)

1) d-Deoxyephedrine Hydrochloride (synonym)
2) d-Desoxyephedrine Hydrochloride (synonym)
3) Methamfetamine (synonym)
4) Methamphetamine HCl (synonym)
5) Methamphetamine hydrochloride (synonym)
6) Methedrene (synonym)
7) Methiopropramine
8) Methylamphetamine Hydrochloride (synonym)
9) Phenylmethylaminopropane Hydrochloride (synonym)
10) CAS Registry: 537-46-2 (synonym)

1.2.1) MOLECULAR FORMULA
1) C10-H15-N-CL-H (Methamphetamine hydrochloride) (RTECS, 2006)

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Methamphetamine is a drug that is abused for its stimulant and euphoric effects that is synthesized in clandestine labs. Other names for methamphetamine include speed or crank. "Ice" is smokable high purity methamphetamine hydrochloride. Although rare, methamphetamine can also be prescribed for the treatment of ADHD and obesity. Methiopropramine is a synthetic methamphetamine analogue that is widely used as a psychoactive substance in many countries. The recreational use of methiopropramine has resulted in death.
B) PHARMACOLOGY: Methamphetamine increases catecholamine release resulting in stimulation of adrenergic receptors in the CNS and periphery.
C) TOXICOLOGY: Well absorbed by many routes (ingestion, smoking, nasal insufflation, parenterally); high lipophilicity allows it to readily cross the blood-brain barrier. Overstimulation of adrenergic receptors causes tachycardia, hypertension, agitation. Increased norepinephrine causes alerting and anorectic effects and locomotor stimulation. Increases in serotonin and dopamine alter perception, induce euphoria, and often cause psychotic behavior.
D) EPIDEMIOLOGY: Methamphetamine is a common drug of abuse that displays unique features of acute and chronic toxicity.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Abdominal pain, loss of appetite, xerostomia, headache, insomnia, tremor, euphoria, dysphoria, and agitation may occur with methamphetamine therapy.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: In recreational doses or mild overdoses, patients may demonstrate sympathetic findings of diaphoresis, tachypnea, mydriasis, tremor, and nausea. Potential cardiovascular effects include hypertension and tachycardia. Neuropsychiatric signs and symptoms include euphoria, mild agitation, hyperreflexia, bruxism, and headache.
2) SEVERE TOXICITY: Life-threatening hyperthermia occurs as a direct result of increased muscular activity and neuromuscular excitation. In addition, acute intoxication can cause severe agitation, seizures, intracerebral hemorrhage, choreoathetoid movements, and paranoid psychosis. Muscle rigidity and psychomotor agitation can also lead to rhabdomyolysis and renal failure. Ventricular dysrhythmias, vasospasm, myocardial infarction, and aortic dissection are rare complications of severe overdose. Acute ischemic events occur from severe vasospasm (ie, acute lung injury, ischemic colitis). Death may result from hyperthermia in addition to other complications.
3) CHRONIC TOXICITY: Poor dentition, skin lesions and excoriations from formication, cachexia, and generally poor self-care are common findings with chronic abuse (months to years). Cardiovascular complications from long-term abuse include vasculitis, cardiomyopathy, pulmonary hypertension, and aortic and mitral valve regurgitation. Infectious complications (HIV, viral hepatitis, endocarditis, abscess, osteomyelitis) may develop with parenteral abuse.
4) BODY PACKERS/BODY STUFFERS: Please refer to the appropriate management if body packing or body stuffing is known or suspected.

0.2.20)

A) Methamphetamine hydrochloride crosses the placenta and is classified as FDA pregnancy category C. Withdrawal symptoms were observed in an infant born to a woman who used IV amphetamine. Infants have also been found to have low birth weights and prone to prematurity. Prenatal exposure to methamphetamine was also associated with behavioral problems in children at ages 3 and 5 years. Fetal distress and death have occurred.
B) Amphetamines have been measured in breast milk.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients may only need observation. Some may need benzodiazepines and intravenous fluids for symptomatic treatment.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive and liberal use of benzodiazepines are the mainstay of treatment. The goals of treatment are to control agitation and prevent or limit end organ toxicity. Orotracheal intubation for airway protection should be performed early in cases of severe psychomotor agitation, repeated seizure activity, or coma.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital decontamination is not recommended as the risk of aspiration (seizures) probably outweighs any potential benefit.
2) HOSPITAL: Consider activated charcoal if a patient presents promptly after an oral overdose and is not manifesting toxicity. Activated charcoal is generally not recommended in patients that are manifesting signs of toxicity, as the risk of aspiration probably outweighs any potential benefit. If the airway is protected with orotracheal intubation, charcoal may be considered if the ingestion is recent.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe poisoning (coma, seizures, severe agitation).

E) ANTIDOTE

1) There is no specific antidote for methamphetamine.

F) AGITATION/DELIRIUM

1) Liberal use of benzodiazepines is recommended until patient is under control.

G) TACHYCARDIA

1) May occur from a combination of agitation and catecholamine release. Treat with benzodiazepines and intravenous fluids. Beta blockers should generally be avoided in these patients, because of the risks of unopposed alpha stimulation.

H) SEIZURES

1) Seizures are rare and often self-limited but may be a result of CNS stimulation. Treatment includes intravenous benzodiazepines, propofol or barbiturates and paralysis with continuous EEG and neurology consult if necessary for status epilepticus.

I) HYPERTENSION

1) Should be treated with benzodiazepines initially to control agitation. Alpha adrenergic receptor antagonists, such as phentolamine, and vasodilators, such as nitroprusside and nitroglycerin, are second line agents to be considered for severe hypertension with end organ compromise. Beta-blockers should generally be avoided in these patients, because of the risks of unopposed alpha stimulation.

J) HYPERTHERMIA

1) Hyperthermia can result from psychomotor agitation and must be treated aggressively. Monitor rectal temperature, and sedate the patient aggressively with benzodiazepines. Placing the patient in an ice water bath is the most effective technique of rapid cooling. More practical methods include keeping the skin moist and encouraging evaporation with fans (may be less effective in a humid environment) or packing the patient in ice from head to toe, anteriorly and posteriorly. Other cooling measures such as cool packs in the axilla and groin are often ineffective in lowering core temperature rapidly. Consider intubation and neuromuscular paralysis for severe hyperthermia.

K) RHABDOMYOLYSIS

1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.

L) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion are not of value for methamphetamine.

M) PATIENT DISPOSITION

1) HOME CRITERIA: Children with any exposure, symptomatic adults or those with intentional overdose, should be evaluated in a health care facility.
2) OBSERVATION CRITERIA: Patients should be observed for at least 4 hours, as peak plasma concentrations and thus symptoms will likely develop within this time period. Symptomatic patients should be treated and observed until symptoms improve or resolve.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous stimulation and/or abnormal vital signs should be admitted. Patients with coma, seizures, dysrhythmias, delirium, any other life threatening result of toxicity or intubated patients should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Refer patients with chronic abuse for rehabilitation.

N) PITFALLS

1) It is essential to get the patient’s psychomotor agitation under control rapidly to prevent rhabdomyolysis, severe hyperthermia and other complications. Toxicity from being in an environment where methamphetamine is synthesized is rare. The greatest risk to children living in clandestine methamphetamine labs is abuse and neglect. These children are not "contaminated"; they need evaluation for abuse/neglect and discharge to a safe and secure environment. A variety of toxic substances are used in the clandestine manufacture of methamphetamine. Burns (chemical and thermal), exposure to strong acids or alkaline corrosives, or toxic by-products (e.g., phosgene) are possible in patients involved in this process.

O) PHARMACOKINETICS

1) Elimination is via multiple pathways with approximately 40% to 50% being renal. Half-life is 12 to 34 hours. The volume of distribution is 3 to 4 L/kg.

P) TOXICOKINETICS

1) Repeat doses can lead to drug accumulation and prolongation of apparent half-life and duration of effect.

Q) DIFFERENTIAL DIAGNOSIS

1) CNS infection, intracranial hemorrhage, manic or psychotic episode due to psychiatric illness, ethanol/benzodiazepine/barbiturate withdrawal, hypoglycemia, hypoxia, cocaine or other stimulant poisoning, or thyroid storm. Methamphetamine-induced rhabdomyolysis: Symptoms may be mistaken as heat stroke, neuroleptic malignant syndrome, serotonin syndrome, or malignant hyperthermia.

0.4.6)

A) ARTERIAL SPASM - Phentolamine (alpha blocker) or nitroprusside may be used.

1) If thrombosis is confirmed or suspected, heparin may be indicated. Vascular surgical consultation is warranted for such cases.

B) SEE the oral overview section as indicated.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

1) ADVERSE EFFECTS: Abdominal pain, loss of appetite, xerostomia, headache, insomnia, tremor, euphoria, dysphoria, and agitation may occur with methamphetamine therapy.

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPERTHERMIA: Severe hyperthermia may develop after methamphetamine use (Katsumata et al, 1993; Chan et al, 1994; Kolecki, 1998). It occurs as a direct result of increased muscular activity and neuromuscular excitation. Hyperthermia may result from hypothalamic dysfunction, metabolic and muscle hyperactivity, or prolonged seizures.

a) Severe hyperthermia (greater than 41 degrees C) is associated with a high fatality rate and requires aggressive sedation and cooling (Lan et al, 1998).

1) CASE REPORT: A rectal temperature of 45 degrees Celsius (113 degrees F) was reported in a young male after ingesting 1 gram ("body stuffing") of methamphetamine during a police altercation in which the individual fled the scene on foot and was chased, eventually requiring physical restraint. Following aggressive cooling therapy and supportive care, the patient made a complete recovery (Suchard & Saba, 1999).
2) In a retrospective review of 47 children (younger than 6 years) exposed to methamphetamine, mild elevations of temperature (mean 37.4; CI 36.9 to 37.9) were noted (Matteucci et al, 2007).

2) COTTON FEVER: Cotton fever is a self-limiting reaction seen in intravenous drug addicts who have injected solutions filtered through cotton balls. Signs include fever, malaise, chills, and abdominal and leg pain. The syndrome is self-limiting and responds to time and supportive care. Fever in a patient with a history of injection drug use should be presumed to be secondary to infection until proven otherwise (Harrison & Walls, 1990).
3) It is suggested that cotton fever may be caused by the injection of Gram-negative endotoxin (Gugelmann & Durrani, 2015).

a) CASE REPORT: A 37-year-old man with a remote spinal infarct, caused by IV drug abuse, presented within 10 minutes of developing dysphoria, shaking chills, and angor animi. Over the next 2 hours, his vital signs ranged from a BP of 66/41 mmHg to 169/133 mmHg (average mean arterial pressure 61 mmHg), heart rate of 84 beats/min to 144 beats/min, temperature peak of 38.2 degrees C, respiratory rate of 18 breaths/min to 26 breaths/min, with oxygen saturation of 98% to 100%. Laboratory results showed mild renal impairment (serum creatinine 1.57 mg/dL, BUN 20), elevated WBC (6 to 21 k/mcL; 94% neutrophils), reduced hemoglobin (12.3 g/dL from 14.2 g/dL), increased creatine kinase (peak of 488 Units/L), elevated AST/ALT (peak of 322/121 Units/L), and lactic acid peak of 2.2 mmol/L. Toxicology analysis revealed methamphetamine and metabolites in his urine. One of the 4 blood culture samples, believed to be a contaminant, grew Propionibacterium acnes. He was treated with IV fluids, broad-spectrum antibiotics, and norepinephrine. About 14 hours after presentation, he left against medical advice, but returned after the results of his blood cultures were released. At this time, he had normal labs and vital signs and was asymptomatic. He admitted to desiccating (for 5 hours in 500 F oven) and freezing (for 5 hours) 3-month-old water from a methamphetamine bong. After reconstituting it with water, he injected it into his left femoral vein immediately before developing his symptoms. (Gugelmann & Durrani, 2015).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPERTENSION: Systolic and diastolic hypertension are common and may be postural.
2) In a retrospective review of 47 children (younger than 6 years) exposed to methamphetamine, mild elevations of blood pressure (mean systolic BP 120 mmHg; CI 104 to 136; mean diastolic BP 70 mmHg; CI 51 to 88) were noted (Matteucci et al, 2007).

3.3.5)

A) WITH POISONING/EXPOSURE

1) TACHYCARDIA/BRADYCARDIA: Tachycardia is common (Lan et al, 1998); reflex bradycardia secondary to hypertension may be observed.
2) In a retrospective review of 47 children (younger than 6 years) exposed to methamphetamine, tachycardia was common (mean heart rate, 171 bpm; CI 154 to 187) (Matteucci et al, 2007).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS: Pupils are usually mydriatic and often sluggishly reactive to light following exposure (Chan et al, 1994).

Cardiovascular

3.5.2)

A) TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) Sinus tachycardia is common with methamphetamine use (Carlson et al, 2012; Eilert & Kliewer, 2011; Gupta et al, 2009; Prosser et al, 2006; Chan et al, 1994; Lan et al, 1998).
b) CASE SERIES/PEDIATRIC: In a 9-year retrospective chart review of inadvertent methamphetamine poisoning in children (range: 7 months to 8 years), tachycardia was reported in all cases (n=18). In general, children developed the same adrenergic symptoms as adults exposed to methamphetamines (Kolecki, 1998).
c) In a retrospective review of 47 children (younger than 6 years) exposed to methamphetamine, tachycardia was common (mean heart rate, 171 bpm; CI 154 to 187) (Matteucci et al, 2007).
d) MONOMORPHIC VENTRICULAR TACHYCARDIA: CASE REPORT: A 30-year-old man, who was using methamphetamine intermittently (over 10 times in the past year; 100 to 200 mg each time), presented with tachycardia, chest discomfort, dizziness, fatigue, nausea, and vomiting after smoking about 200 mg of methamphetamine. An ECG revealed ventricular tachycardia (VT) with monomorphic morphology and a heart rate of 224 beats/min. He received IV propafenone and was successfully cardioverted. He also received dopamine to maintain his blood pressure. Laboratory results revealed a peak myoglobin of 586.9 ng/mL (reference values 28 to 72 ng/mL), a peak creatine kinase-MB of 181.4 ng/mL (reference values less than 4.94 ng/mL), a troponin T level of 3846 ng/L (reference values: 0 to 14 ng/L), elevated liver enzymes, and elevated creatine 212 mcmol/L (reference values 53-140 mcmol/L). A contrast-enhanced cardiac MRI did not reveal an abnormal enhancement of the ventricles. In addition, no structural or functional abnormalities of the heart were observed in the cardiac MRI and an echocardiography, except for a minor mitral and tricuspid regurgitation (ejection fraction of 67%). Following supportive care, including glutathione and coenzyme Q10 therapies to improve his hepatic and cardiac function, he gradually recovered and his laboratory results revealed normal values a week later (Li et al, 2014).

B) CHEST PAIN

1) WITH POISONING/EXPOSURE

C) CARDIOMYOPATHY

1) WITH POISONING/EXPOSURE

a) SUMMARY: Acute and chronic cardiomyopathy from methamphetamine abuse is probably related to direct amphetamine toxicity and indirectly by amphetamine-induced hypertension, necrosis, and ischemia.
b) CASE REPORTS

1) A 42-year-old woman with a history of hypertension developed transient left ventricular dysfunction due to stress-induced cardiomyopathy (also known as Takotsubo syndrome) after snorting a week's worth of methamphetamine over a 3-day period. Initially, she experienced palpitations and mild intermittent precordial discomfort 3 days before presentation. On admission, she had chest pain, dyspnea, nausea and vomiting (for 5 hours), a blood pressure of 197/110 mmHg, and a heart rate of 85 beats/min. An ECG showed anterior ST-segment elevation. Initial laboratory results revealed normal troponin I concentration, which subsequently peaked at 4.32 on the second day of hospitalization. Two hours after presentation, a coronary angiography showed no luminal obstruction. Left ventriculography showed anteroapical akinesis and mild mitral regurgitation with an angiogram typical for the Takotsubo syndrome. At this time, the ejection fraction was 20%. She developed hypotension and a cold, pulseless right foot; there was no thrombus in the femoral artery and it was felt she had poor perfusion in the setting of severe left ventricular dysfunction, a low cardiac output, and peripheral arterial spasm. Following supportive therapy (including dobutamine and dopamine), her symptoms improved over the next 3 days. Serial ECG revealed normalization of the ST segment and the development of deep, symmetrical T-wave inversions in the anterolateral leads with QTc prolongation. Subsequent echocardiography revealed a significant improvement in left ventricular function (Srikanth et al, 2008).
2) RECTAL BODY STUFFING: A 28-year-old man with schizoaffective disorder presented to the ED after a witnessed seizure. His vital signs showed a blood pressure of 60/40 mmHg, temperature of 104 degrees F, a pulse of 144 beats/min, and altered mental status. Despite supportive care, his condition deteriorated and he developed cardiomyopathy (ejection fraction at 15% to 20%), elevated liver enzymes, and renal dysfunction with profound rhabdomyolysis. A CT scan revealed the presence of a rectal tube. During rectal examination, methamphetamine paraphernalia including a pipe, remnants and intact packets of methamphetamine powder were removed. Following further supportive care, including volume resuscitation, vasopressors, empiric n-acetylcysteine for liver injury, and hemodialysis, his condition improved and he was discharged after 10 days of hospitalization (Baalachandran et al, 2015).
3) A 14-year-old girl presented with agitation, delirium, hyperthermia, tachycardia, hypertension, and tachypnea after abusing methamphetamine. Initially, her troponin was 7.2 ng/mL, which rose to 23.8 ng/mL on day 4. At this time, she was diagnosed with congestive heart failure and pulmonary edema. An echocardiogram revealed a new cardiomyopathy with a shortening fraction of 7%. Following supportive care, her condition improved and she was extubated on day 15 (Prosser et al, 2006).
4) ICE: Dilated cardiomyopathy, which resolved within 5 days, occurred in a 28-year-old woman admitted after smoking crystalline methamphetamine ("ICE") (Nestor et al, 1989). A retrospective case series at a single center suggested that dilated cardiomyopathy may develop secondary to chronic methamphetamine use, but generalizability to other patient populations may be limited (Wijetunga et al, 2003).
5) A 34-year-old woman with an extensive history of marijuana and crystalline methamphetamine use, who smoked up to 3.5 g/day of "ICE" up to one week before admission, presented with progressive dyspnea. Pulmonary edema, atrial tachycardia, and left ventricular enlargement were present on admission, along with an ejection fraction of 24%. Tachycardia and exertional dyspnea resolved and she was discharged 12 days after admission. She was asymptomatic after discharge despite demonstration by echocardiography of residual global left ventricular hypokinesis (Hong et al, 1991).

c) POLYMORPHISMS IN CYP2D6: One prospective case-control pilot study evaluated polymorphisms in CYP2D6 and the risk of developing methamphetamine-induced cardiomyopathy. Days of use in a month, age, gender, or ethnicity did not significantly differ between case patients (n=19) and control subjects (n=37). All participants had urinary drug screens positive for amphetamines. Case patients had evidence of heart failure by beta natriuretic peptide (BNP) greater than 300 pg/mL and symptoms of heart failure. Control subjects had no evidence of heart failure defined by a BNP less than 300 pg/mL or symptoms of heart failure. It was determined that poor metabolizers/lower activity scores were less likely to develop heart failure than those who are extensive metabolizers or higher activity score. However, this did not reach statistical significance. Extensive metabolizers had the highest odds of developing a dilated cardiomyopathy (odds ratio [OR]: 2.33, 95% CI: 0.54 to 10.13) after adjusting for higher days of use. Echocardiographic findings in all cases revealed reduced ejection fractions with a mean of 18.6% (range: 10% to 35%). A dilated cardiomyopathy was observed in 70% of these patients. None of the control subjects had cardiomyopathies (mean ejection fraction: 56.75%; range: 45% to 70%). In extensive metabolizers, the odds ratio of having a dilated cardiomyopathy was 1.62 (95% CI: 0.47 to 5.5). Overall, extensive metabolizers had the highest odds of developing a dilated cardiomyopathy after adjusting for age and gender (Sutter et al, 2013).
d) In a retrospective review, 2356 adults (mean age: 31.8 years) with methamphetamine exposure were identified. Minor effects, moderate effects, major effects, and death occurred in 584, 450, 208, and 28 patients, respectively. ECG and total troponin results were available for 627 and 228 patients, respectively. Based on these results, myocardial ischemia was reported in 82 patients. Ten of these patients also used cocaine. Episodes of ventricular tachycardia were reported in 14 patients (Hawley et al, 2013).

D) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) Myocardial infarction, ischemia, and ventricular dysfunction may occur. In addition, exertional angina may occur after acute or chronic methamphetamine use (Carson et al, 1987; Furst et al, 1990; Hong et al, 1991).

1) CASE REPORT: A 31-year-old man, with no symptoms suggestive of an ischemic cardiac event, experienced a non-Q-wave anterior wall myocardial infarction after injecting 4 doses of amphetamine and methamphetamine ("crank") over a 48-hour period. An initial ECG revealed inverted T waves in leads II, III, aVF, and V1 through V5. A second ECG showed a new left bundle branch block. Transthoracic echocardiography showed reduced anterior wall motion with an estimated shortening fraction of 25% (Waksman et al, 2001).
2) CASE REPORT: A 23-year-old man presented to the ED with a 12-hour history of abdominal pain and general malaise. Although he denied chest pain on presentation, he revealed that he was having difficulty taking full breaths due to pain in his chest. The patient was hypotensive and bradycardic. An ECG showed ST elevation in leads V1 through V4 and complete heart block, and cardiac markers revealed an elevated troponin I concentration (362.1 ng/mL), indicating a myocardial infarction. Catheterization of the left side of his heart demonstrated severe systolic left ventricular dysfunction with an ejection fraction of 15% to 20%, but coronary arteries were normal, suggesting vasospastic etiology. A pacemaker was inserted and, 7 days later, a repeat echocardiogram revealed an ejection fraction of 35% to 40% and a follow-up ECG showed resolution of the ST elevation. A urine tox screen was positive for amphetamines and the patient admitted to inhalation of methamphetamine less than 24 hours prior to presentation (Watts & McCollester, 2006).

E) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypertension is common following methamphetamine use and may result in end organ damage (Prosser et al, 2006; Chan et al, 1994).
b) In a retrospective review of 47 children (younger than 6 years) exposed to methamphetamine, mild elevations of blood pressure (mean systolic BP 120 mmHg; CI 104 to 136; mean diastolic BP 70 mmHg; CI 51 to 88) were noted (Matteucci et al, 2007).

F) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension and cardiovascular collapse may result from severe methamphetamine toxicity (Li et al, 2014; Eilert & Kliewer, 2011; Chan et al, 1994).
b) Hypotension in the setting of methamphetamine poisoning is associated with a high fatality rate (Lan et al, 1998).

G) DISSECTION OF AORTA

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: Three cases of fatal aortic dissection associated with chronic methamphetamine use have been reported (Davis & Swalwell, 1994).

H) THROMBOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 35-year-old man with a history of methamphetamine abuse, presented with a 2-week history of dyspnea and chest pain. Physical examination showed jugular venous distension, bilateral lung crackles, and pedal edema consistent with acute heart failure. No ischemic changes were observed during an ECG. IV heparin was initiated after a CT chest angiogram showed a left-sided pulmonary embolism. Severe global hypokinesis of both ventricles, with left ventricular ejection fraction of 23%, and multiple large masses in the left and right ventricles were observed during a transthoracic echocardiogram. These masses were confirmed by a cardiac magnetic resonance imaging as being multiple thrombi in both ventricles. Heparin treatment was replaced by warfarin and diuretics, beta-blockers, and angiotensin-converting enzyme inhibitors were added to treat left ventricular dysfunction and heart failure. At a 3-month follow-up visit, an echocardiogram showed some reduction in ventricular thrombus burden. At this time, he was started on fondaparinux and ticagrelor, and his condition gradually improved with no further embolic events (Janardhanan & Kannan, 2016).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) ICE: The use of smoked crystal methamphetamine 24 to 36 hours prior to admission was associated with acute pulmonary edema in a 28-year-old woman (Nestor et al, 1989).
b) POSTMORTEM FINDING

1) Autopsy finding of a body packer with acute poisoning from 20 grams of methamphetamine revealed extreme pulmonary congestion and edema as well as moderate hepatic edema and several petechiae (Takekawa et al, 2007).
2) Autopsy finding of a body packer with acute poisoning from 360 grams of methamphetamine revealed pulmonary edema. There were 25 packages (each about 10 to 16 grams; total: 360 g) of methamphetamine in the gastrointestinal tract. Radiological findings revealed bilateral pulmonary edema in both lungs with ascending pneumomediastinum in the anterior mediastinum and a unilateral left pneumothorax without pleural effusion (Bin Abdul Rashid et al, 2013).
3) METHIOPROPRAMINE: In one case report, the recreational use of methiopropramine (a synthetic methamphetamine analogue) resulted in death. Autopsy finding 3 days after death revealed nonspecific pulmonary edema, but no signs of hyperthermia or any other significant disease processes. A methiopropramine peripheral blood concentration of 38 mg/L was detected. Methiopropramine was also found in urine (Anne et al, 2015).

B) PULMONARY HYPERTENSION

1) WITH POISONING/EXPOSURE

a) Pulmonary hypertension has been associated with methamphetamine use (Schaiberger et al, 1993; Albertson et al, 1995). It has been suggested that contaminants were a major factor in the development of disease (Albertson et al, 1995).
b) Methamphetamine use is associated with an increased risk of developing pulmonary hypertension (PH). In a retrospective study, rate of stimulant use was determined in 97 patients with idiopathic PH (28.9%), compared with 106 patients with PH with know risk factors (3.8%) and 137 patients with chronic thromboembolic PH (4.3%). After adjustment for age differences, the patients with idiopathic PH were 10.14 (95% CI 3.39 to 30.3) times more likely to have used stimulants (primarily methamphetamine) than patients with PH and known risk factors, and 7.63 (95% CI 2.99 to 19.5) times more likely to have used stimulants than patients with chronic thromboembolic PH (Chin et al, 2006). Rothman et al (2007) suggested that 2 critical factors may increase the risk of idiopathic pulmonary arterial hypertension: the preferential interaction of methamphetamine with serotonin transporters in vivo and high doses of methamphetamine typically self-administered (Rothman & Baumann, 2007).

C) MEDIASTINAL EMPHYSEMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 22-year-old man presented with acute psychosis after an 11-day binge of smoking and injecting methamphetamine. Crepitus over the anterior neck and Hamman's crunch were noted during the physical exam. Chest film and computerized tomography revealed pneumomediastinum with extensive subcutaneous emphysema and pneumorrhachis (air in the epidural space). Following supportive care for 48 hours, his symptoms resolved (James et al, 2007).

D) RESPIRATORY DISTRESS

1) WITH POISONING/EXPOSURE

a) CHILDREN: Respiratory distress has been reported in children after methamphetamine ingestion (Grant, 2007).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) CNS manifestations can include agitation, confusion, delirium, hallucinations, dizziness, dyskinesias, hyperactivity, muscle fasciculations and rigidity, rigors, tics, tremors, seizures, and coma (Bin Abdul Rashid et al, 2013; Eilert & Kliewer, 2011; Grant, 2007; Matteucci et al, 2007; Prosser et al, 2006; Nagorka & Bergeson, 1998; Kolecki, 1998; Nagorka & Bergeson, 1998; Schaffer & Pauli, 1980).
b) Methamphetamine has a greater CNS penetration and efficacy than amphetamine (Derlet & Heischober, 1990).
c) CHILDREN: Irritability, agitation, inconsolable crying, hyperactivity, ataxia, constant movement, flailing movements of head, neck and extremities, and involuntary side-to-side head turning have been reported in children after methamphetamine ingestion (Grant, 2007).
d) In a retrospective review of 47 children (younger than 6 years) exposed to methamphetamine, agitation was the most common symptom (82%) reported. Patients experienced symptoms for an average of 22 hours (CI, 16.3 to 27.2). Treatment with benzodiazepines was effective in reducing the agitation (Matteucci et al, 2007).
e) One study examined the link between adolescent methamphetamine exposures and suicidal ideation and suicide attempts from California Poison Control System from 2000 to 2009. Charts of 293 patients (age range, 11 to 18 years) were reviewed and classified based on severity. Suicidal ideation and suicide attempts were observed in 31% and 21% of patients, respectively. Agitation was the most commonly observed symptoms, occurring in 31% of patients (Auten et al, 2012).
f) CASE REPORT/PEDIATRIC: Extreme agitation and rapid eye movement were observed in a 13-month-old girl exposed to methamphetamine. The patient was initially thought to have been exposed to a scorpion and inadvertently received antivenom (Nagorka & Bergeson, 1998).

1) Several children in the southwestern US have inadvertently received antivenom for presumed scorpion envenomation following methamphetamine exposure. Based on the similarity of symptoms, the authors recommended toxicological drug screening with all suspected scorpion stings in young children (Kolecki, 1998; Nagorka & Bergeson, 1998).

g) CASE REPORT: Agitation, delirium, and disorientation developed in a 14-year-old girl after methamphetamine abuse (Prosser et al, 2006).

B) CEREBROVASCULAR DISEASE

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) CEREBROVASCULAR EVENTS: Hemorrhagic or vasospastic cerebrovascular events, cerebral vasculitis, and ischemic cerebrovascular disease have been reported following the use of methamphetamine.
2) RELATIVE RISK: Abuse of methamphetamine, cocaine, and related drugs can increase the risk for cerebrovascular incidents in young adults (Chaudhuri & Salahudeen, 1999). In a retrospective review of 214 consecutive young patients admitted for ischemic or hemorrhagic stroke, the estimated relative risk for stroke among drug users compared with that among nonusers was 6.5 (Kaku & Lowenstein, 1990).
3) In a small study of 10 young adults with a diagnosis of drug-related (ie, amphetamine/methamphetamine, cocaine, and ecstasy) intracerebral hemorrhage (ICH), intracranial aneurysms were found in 6 patients and arteriovenous malformations in 3 other patients; only one patient had a normal cerebral angiogram. Three other patients who were part of the study died prior to cerebral angiography. At autopsy, one patient had a middle cerebral artery aneurysm. The authors concluded that contrary to previous opinion, drug-related ICH is frequently related to an underlying vascular malformation and arteriography is recommended for any young patient with a nontraumatic ICH with suspected amphetamine use (McEvoy et al, 2000).
4) In a retrospective review, hospital records of 30 patients (mean age, 43 years) with methamphetamine-associated cerebrovascular complications were reviewed. Risk factors associated with neurovascular diagnoses included previous stroke (n=3), hypertension (n=13), hyperlipidemia (n=2), diabetes mellitus (n=4), tobacco (n=16), and alcohol use (n=5). Ten patients had ischemic stroke, mostly in the anterior circulation. Radiologic imaging of the majority of these patients revealed arterial stenoses in the vascular distribution of the stroke. Nine patients had aneurysmal subarachnoid hemorrhage, mostly located in the anterior circulation. Eleven patients had intracerebral hemorrhage. Four patients died despite supportive therapy. Overall, it was suggested that methamphetamine causes ischemic stroke by accelerating atherosclerosis and not by an inflammatory etiology (Ho et al, 2009).
5) In a retrospective review, hospital records of 374 patients with aneurysmal subarachnoid hemorrhage (SAH) were reviewed and 28 (7%) of them were identified as methamphetamine users. Overall, methamphetamine users had significantly worse presentations and poorer outcomes when compared with age-matched controls (n=28) (Beadell et al, 2012).

b) CASE REPORTS

1) Three cases of ischemic stroke were described after methamphetamine nasal inhalation. Stroke onset was delayed 12 hours in 2 patients and 2 weeks in 1 patient after the last use. In one patient it occurred presumably after first-time use (Rothrock et al, 1988).
2) Four cases of fatal ruptured Berry aneurysm associated with chronic methamphetamine abuse have been reported (Davis & Swalwell, 1994).
3) DELAYED ISCHEMIC STROKE AND CHRONIC CEREBRAL VASCULITIS: A 19-year-old woman developed right occipital infarction 3 months after the use of methamphetamine injection. She had no history of risk factors such as hypertension, vasculitis, or coagulation abnormalities. Signs and symptoms included right-sided headache, left superior quadrant hemianopia, and left hypesthesia. Magnetic resonance angiography showed segmental narrowing of the right posterior cerebral artery suggestive of vasculitis (Ohta et al, 2005).
4) CASE SERIES: Four cases of methamphetamine-related stroke occurred in drug users ranging in age from 29 to 45 years. Three patients presented with hypertension (Perez et al, 1999).

a) One patient had a documented cerebellar and brainstem hemorrhage with obstructive hydrocephalus who died within 24 hours of admission following documented brain death. Two of the remaining patients had permanent neurological deficits, and only one patient was asymptomatic 2 weeks after presentation (Perez et al, 1999).

5) CASE REPORT: A 31-year-old man experienced headache and nausea and vomiting approximately 10 to 15 minutes after smoking and insufflating 0.25 to 0.50 grams of methamphetamine. Subsequent symptoms included slurred speech and left-sided hemiparesis. The patient was found dead approximately 9.5 hours later. An autopsy revealed a bilateral subarachnoid and an intracerebral hemorrhage involving the right cerebral hemisphere. No evidence of vasculitis, infarction, intraventricular hemorrhage, or ruptured aneurysm were present. Postmortem toxicologic analysis revealed a blood methamphetamine concentration of 300 ng/mL (McGee et al, 2004).
6) CASE REPORTS: Two patients developed dissection of the carotid artery and a middle cerebral artery stroke following the use of methamphetamine (McIntosh et al, 2006).

a) The first patient, a 36-year-old woman, presented to the ED 30 minutes after the onset of speech difficulty and right-sided weakness. After presentation, the patient indicated that she had smoked methamphetamine the preceding 2 nights. Physical examination indicated global aphasia, left gaze preference, and right hemiplegia. An MRI of the brain showed a small left frontal infarct. Carotid evaluation revealed and intimal flap, with an intramural thrombus. Intravenous administration of tissue plasminogen activator (tPA) 80 minutes after symptom onset significantly improved her aphasia and hemiplegia. She was subsequently discharged 5 days later, recovering with only mild expressive aphasia (McIntosh et al, 2006).
b) The second patient, a 29-year-old woman, presented with speech difficulty and right-sided weakness 4 days after methamphetamine use. Her social history indicated chronic methamphetamine use over the last 10 years. Physical examination showed global aphasia and right hemiparesis. An MRI revealed a large left middle cerebral artery infarct, and a cerebral angiography showed severe stenosis with a clot underneath a large intimal flap. Following stent-assisted angioplasty to treat the dissection, the patient was discharged home, subsequently recovering with moderate expressive aphasia and mild weakness of the right hand (McIntosh et al, 2006).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures may develop in patients with severe methamphetamine overdose (Chan et al, 1994). Seizures in the setting of methamphetamine poisoning are associated with a high mortality rate (Lan et al, 1998).
b) In a retrospective review of 47 children (younger than 6 years) exposed to methamphetamine, seizures and agitation developed in 9% and 82% of patients, respectively. Patients experienced symptoms for an average of 22 hours (CI, 16.3 to 27.2). Treatment with benzodiazepines was effective in reducing the agitation (Matteucci et al, 2007).
c) RECTAL BODY STUFFING: A 28-year-old man with schizoaffective disorder presented to the ED after a witnessed seizure. His vital signs showed a blood pressure of 60/40 mmHg, temperature of 104 degrees F, a pulse of 144 beats/min, and altered mental status. Despite supportive care, his condition deteriorated and he developed cardiomyopathy (ejection fraction at 15% to 20%), elevated liver enzymes, and renal dysfunction with profound rhabdomyolysis. A CT scan revealed the presence of a rectal tube. During rectal examination, methamphetamine paraphernalia including a pipe, remnants and intact packets of methamphetamine powder were removed. Following further supportive care, including volume resuscitation, vasopressors, empiric n-acetylcysteine for liver injury, and hemodialysis, his condition improved and he was discharged after 10 days of hospitalization (Baalachandran et al, 2015).

D) ALTERED MENTAL STATUS

1) WITH POISONING/EXPOSURE

a) Patients may be confused, agitated, combative, or hallucinating (Bin Abdul Rashid et al, 2013; Chan et al, 1994). CNS depression and coma may develop in severe poisoning (Chan et al, 1994).
b) Methamphetamine can induce spontaneous recurrences of paranoid hallucinatory states known as flashbacks. One study found an increase in peripheral noradrenergic activity in patients during flashbacks compared with non-flashback-experiencing users (Yui et al, 1997).
c) CASE SERIES/PEDIATRIC: Agitation was reported in 50% (n=9) of pediatric patients inadvertently exposed to methamphetamine. Inconsolable crying and irritability were reported in 25% of patients (Kolecki, 1998).
d) One study determined that postmortem concentrations of striatal dopamine in methamphetamine users can be reduced to concentrations similar to those seen in patients with Parkinson disease in the caudate, but not in the putamen subdivision of the striatum. This reduction of the neurotransmitter in the striatal subdivision could explain the presence of cognitive problems in methamphetamine users (Moszczynska et al, 2004).

E) CHOREOATHETOSIS

1) WITH POISONING/EXPOSURE

a) Choreoathetoid movements are common with methamphetamine smoking (Personal Communication, 1989).

F) COMA

1) WITH POISONING/EXPOSURE

a) Coma in the setting of methamphetamine overdose is associated with a high mortality rate (Lan et al, 1998).
b) CASE REPORT: A 23-year-old man with severe hyperthermia and rhabdomyolysis remained comatose for 26 hours following intentional ingestion of 1 gram of methamphetamine during a police altercation. Aggressive cooling and rehydration measures along with urinary alkalinization resulted in complete recovery (Suchard & Saba, 1999).

G) CHRONIC POISONING

1) In a comparison study of subjects with a known history of methamphetamine dependence and healthy controls, magnetic resonance spectroscopy (MRI and localized H(1) MRS) revealed that concentrations of N-acetylaspartate (NA), a neuronal marker, were significantly reduced in the basal ganglia by 6%, and in frontal white matter by 5% of methamphetamine users as compared with controls. The authors suggested that reduced NA indicated a decrease in neuronal density, which has been observed in some neurological diseases (eg, dementia, epilepsy, brain tumors, cerebral infarction, and HIV brain diseases) (Ernst et al, 2000).

Gastrointestinal

3.8.2)

A) NAUSEA, VOMITING AND DIARRHEA

1) WITH POISONING/EXPOSURE

a) Nausea, vomiting (Li et al, 2014), diarrhea, and abdominal cramps are common following exposure.
b) CASE SERIES/PEDIATRICS: Vomiting was reported in 25% of pediatric patients inadvertently exposed to methamphetamines (Kolecki, 1998).

B) ISCHEMIA

1) WITH POISONING/EXPOSURE

a) Ischemic colitis has been reported in several patients following methamphetamine abuse (Holubar et al, 2009; Herr & Cavarati, 1991; Johnson & Berenson, 1991).
b) CASE REPORTS: Ischemic colitis was reported in a normotensive adult who had apparently abused methamphetamine (Herr & Cavarati, 1991), and was reported in another adult who had used methamphetamine for months. Symptoms resolved within 10 days of drug cessation (Johnson & Berenson, 1991).

C) PARALYTIC ILEUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 19-year-old man presented to an acute care clinic with a right-sided chest pain and sinus tachycardia (HR 138 beats/min). His chest pain resolved after he was transferred to an ED, but he complained of focal right lower quadrant abdominal pain and anorexia. Laboratory results revealed a white blood cell count of 22 x 10(9) cells/L with 85% neutrophils, arterial pH of 7.44, PaCO2 of 27 mmHg, serum bicarbonate of 16 mmol/L, and base deficit of 6 mmol/L. Amphetamine was detected in his urine drug screen which later was determined to be methamphetamine. Both an abdominal x-ray and a CT scan revealed the presence of air throughout the small intestine, appendix, and colon. After the diagnosis of methamphetamine-induced ileus was made, he was treated with supportive care and observed for 48 hours. He was discharged after consultation with the psychiatric service for drug abuse (Carlson et al, 2012).

D) DENTAL CARIES

1) WITH POISONING/EXPOSURE

a) Chronic methamphetamine abusers may develop dental caries and teeth erosion ("meth mouth" with tooth loss and fracture), as a result of increase in brain monoamines. These effects may be caused by poor oral hygiene and drinking sugar-containing carbonated soft drinks, as well as xerostomia, bruxism, and jaw clenching (Rusyniak, 2013).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) Hepatic injury is common in patients who develop hyperthermia associated with methamphetamine abuse. Vasospasm may also contribute to hepatic injury.
b) CASE REPORT: Elevated liver enzymes developed in a man after smoking about 200 mg of methamphetamine (Li et al, 2014).
c) CASE REPORT: Severe hepatitis developed in a 14-year-old girl with multiorgan system dysfunction from severe methamphetamine overdose (Prosser et al, 2006).
d) AUTOPSY FINDING: Autopsy finding of a body packer with acute poisoning from 20 grams of methamphetamine revealed extreme pulmonary congestion and edema as well as moderate hepatic edema and several petechiae (Takekawa et al, 2007).
e) RECTAL BODY STUFFING: A 28-year-old man with schizoaffective disorder presented to the ED after a witnessed seizure. His vital signs showed a blood pressure of 60/40 mmHg, temperature of 104 degrees F, a pulse of 144 beats/min, and altered mental status. Despite supportive care, his condition deteriorated and he developed cardiomyopathy (ejection fraction at 15% to 20%), elevated liver enzymes, and renal dysfunction with profound rhabdomyolysis. A CT scan revealed the presence of a rectal tube. During rectal examination, methamphetamine paraphernalia including a pipe, remnants and intact packets of methamphetamine powder were removed. Following further supportive care, including volume resuscitation, vasopressors, empiric n-acetylcysteine for liver injury, and hemodialysis, his condition improved and he was discharged after 10 days of hospitalization (Baalachandran et al, 2015).

Genitourinary

3.10.2)

A) RENAL IMPAIRMENT

1) WITH POISONING/EXPOSURE

a) RECTAL BODY STUFFING: A 28-year-old man with schizoaffective disorder presented to the ED after a witnessed seizure. His vital signs showed a blood pressure of 60/40 mmHg, temperature of 104 degrees F, a pulse of 144 beats/min, and altered mental status. Despite supportive care, his condition deteriorated and he developed cardiomyopathy (ejection fraction at 15% to 20%), elevated liver enzymes, and renal dysfunction with profound rhabdomyolysis. A CT scan revealed the presence of a rectal tube. During rectal examination, methamphetamine paraphernalia including a pipe, remnants and intact packets of methamphetamine powder were removed. Following further supportive care, including volume resuscitation, vasopressors, empiric n-acetylcysteine for liver injury, and hemodialysis, his condition improved and he was discharged after 10 days of hospitalization (Baalachandran et al, 2015).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Renal failure reflected by decreased urine output and/or increased serum creatinine concentration may develop secondary to dehydration or rhabdomyolysis in patients with severe methamphetamine poisoning (Eilert & Kliewer, 2011; Chan et al, 1994). Oliguric renal failure in the setting of methamphetamine overdose is also associated with a high mortality (Lan et al, 1998).
b) CASE REPORT: Acute renal failure developed in a 14-year-old girl after methamphetamine abuse. On hospital day 6, she underwent continuous venovenous hemodialysis for worsening renal function and volume overload (Prosser et al, 2006).

C) SERUM CREATININE RAISED

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Elevated creatinine level (1.3 mg/dL) was observed in a 30-year-old man who experienced tachycardia, agitation, and altered mental status after inserting a methamphetamine-soaked tampon transrectally. Following a bowel movement productive of the tampon, his mental status resolved (Gupta et al, 2009).

Acid-Base

3.11.2)

A) METABOLIC ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis occurs with severe methamphetamine poisoning (Lan et al, 1998), and has been reported in adults after smoking crystal methamphetamine (Eilert & Kliewer, 2011; Burchell et al, 2000).

Hematologic

3.13.2)

A) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH POISONING/EXPOSURE

a) Disseminated intravascular coagulation has been reported following methamphetamine exposure (Gray et al, 2007).
b) CASE REPORT: Disseminated intravascular coagulation with thrombocytopenia developed in a 14-year-old girl after methamphetamine abuse (Prosser et al, 2006).

Dermatologic

3.14.2)

A) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) The skin is usually flushed and diaphoretic following amphetamine exposure.

B) VITAMIN DEFICIENCY

1) CHRONIC TOXICITY

a) Poor dietary habits may lead to vitamin deficiency, which can result in dermatologic signs such as cheilosis or purpura. Intravenous methamphetamine use can produce skin lesions, such as "tracks", abscesses, ulcers, cellulitis, or necrotizing angitis.

C) LOCAL INFECTION OF WOUND

1) WITH POISONING/EXPOSURE

a) In a review of 461 parenteral methamphetamine exposures, 21 cases of skin abscess and 7 cases of cellulitis were reported. All patients with abscesses required incision and drainage, of which 9 required an operative procedure (Richards et al, 1999).

Musculoskeletal

3.15.2)

A) SPASMODIC MOVEMENT

1) WITH POISONING/EXPOSURE

a) Muscle rigidity and fasciculations may occur.

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis may develop in patients with severe agitation, muscular hyperactivity, hyperthermia, or seizures (Eilert & Kliewer, 2011; Gupta et al, 2009; Prosser et al, 2006; Chan et al, 1994; Lan et al, 1998; Suchard & Saba, 1999).
b) RECTAL BODY STUFFING: A 28-year-old man with schizoaffective disorder presented to the ED after a witnessed seizure. His vital signs showed a blood pressure of 60/40 mmHg, temperature of 104 degrees F, a pulse of 144 beats/min, and altered mental status. Despite supportive care, his condition deteriorated and he developed cardiomyopathy (ejection fraction at 15% to 20%), elevated liver enzymes, and renal dysfunction with profound rhabdomyolysis. A CT scan revealed the presence of a rectal tube. During rectal examination, methamphetamine paraphernalia including a pipe, remnants and intact packets of methamphetamine powder were removed. Following further supportive care, including volume resuscitation, vasopressors, empiric n-acetylcysteine for liver injury, and hemodialysis, his condition improved and he was discharged after 10 days of hospitalization (Baalachandran et al, 2015).
c) CASE SERIES: In a retrospective review of ED admissions with a discharge diagnosis of rhabdomyolysis, not related to blunt trauma, extensive burns, or soft tissue infections, an association between methamphetamine use and the occurrence of rhabdomyolysis was observed. It was suggested that a combination of drug behavior (ie, neglecting to eat or drink fluids properly during "binges"), and the action of methamphetamine (ie, elevates serum norepinephrine and dopamine resulting in an increase in adenosine triphosphate (ATP) demand) may explain the higher incidence of rhabdomyolysis observed in this population (Richards et al, 1999).
d) In a retrospective review of 47 children (younger than 6 years) exposed to methamphetamine, creatine kinase was measured in 3 (one with seizures and two with agitation) patients; all 3 patients had elevated creatine kinase concentrations (mean 1984 International Units (IU)/L; range, 212 to 4942 IU/L; normal value, less than 198 IU/L) (Matteucci et al, 2007).
e) CASE REPORT: Rhabdomyolysis (myoglobin: greater than 10,000 ng/mL; CK: 2300 Units/L) developed in a 21-year-old man after methamphetamine use. The patient's hospital course was complicated by hemodynamic instability, oliguria, mixed refractory acidosis, and hyperkalemia (potassium 8.1 mEq/L). Despite supportive care, including dialysis, he died the next day. It is suggested that rhabdomyolysis may be caused by multiple factors: a direct toxic effect of the drug on skeletal myocytes; repetitive muscular activity due to the stimulating effects of the drug; decreased perfusion as a result of severe vasoconstriction; inappropriate thermoregulation leading to hyperthermia (Eilert & Kliewer, 2011).

Reproductive

3.20.1)

3.20.2)

A) PLACENTAL BARRIER

1) Methamphetamine crosses the placenta (Bost et al, 1989; Garriott & Spruill, 1973).

B) ANIMAL STUDIES

1) Experiments using the ovine model demonstrate that methamphetamine does cross the placenta and is distributed in fetal tissue (Burchfield et al, 1991).

3.20.3)

A) PREGNANCY CATEGORY

1) Methamphetamine hydrochloride is classified as FDA pregnancy category C (Prod Info DESOXYN(R) oral tablets, 2007).

B) NEONATAL WITHDRAWAL

1) Infants born to mothers dependent on methamphetamine may experience withdrawal, manifestations can include dysphoria, agitation, and lassitude (Prod Info DESOXYN(R) oral tablets, 2007). It can be unclear whether there is actual withdrawal versus intoxication. About 4% of infants identified as suffering from neonatal methamphetamine withdrawal receive treatment (Smith et al, 2003).

C) PREMATURE BIRTH

1) Infants who have been exposed to methamphetamine tend to have low birth weights and are prone to prematurity (Prod Info DESOXYN(R) oral tablets, 2007; Oro & Dixon, 1987; Little et al, 1988).

D) SMALL FOR GESTATIONAL AGE

1) In a study of 1618 mother-infant pairs, infants exposed to methamphetamine (determined by maternal history and/or meconium analysis) were 3.5 times more likely to be small for gestational age (SGA defined as <10th percentile for birth weight) than unexposed infants. The incidence of SGA for methamphetamine exposed infants was 19% compared with 8.5% in unexposed infants. Gestational age at birth was also lower in methamphetamine exposed compared with unexposed infants (mean 38.7 +/- 2.4 weeks compared with 39.2 +/- 1.9 weeks). In addition, 12.5% of methamphetamine exposed infants were born before 37 weeks gestation compared with 6.5% of unexposed infants (Smith LM et al, 2006).

E) BEHAVIORAL PROBLEMS

1) A prospective, longitudinal study in 166 children who were prenatally exposed to methamphetamine (MA) and matched on race, birth weight, public health insurance, and education to 164 unexposed children (comparison group) found that prenatal exposure was associated with increased emotional reactivity and anxious/depressed problems at ages 3 and 5 years as well as ADHD issues at 5 years, with heavy exposure linked to attention problems and withdrawn behavior at both ages. Limitations of this study include cohort study findings that may not generalize to all populations who use MA during pregnancy, reporting bias from caregivers, and potential recall problems of early pregnancy drug use (LaGasse et al, 2012).

F) MATERNAL DEATH

1) CASE REPORT - Two cases of maternal death have been associated with "crystal," also known as "ice" methamphetamine. In both cases, the women were multiparous and presented in their third trimester having acutely abused "crystal." One woman died of amniotic fluid embolism due to methamphetamine abuse, and the other died of eclampsia and HELLP syndrome that may have been related to amphetamine abuse (Catanzarite & Stein, 1995).

3.20.4)

A) BREAST MILK

1) Amphetamines are excreted in human milk. Mothers taking methamphetamine should refrain from nursing (Prod Info DESOXYN(R) oral tablets, 2007).
2) METHYLAMPHETAMINE/AMPHETAMINE - Two case reports described methylamphetamine and amphetamine exposure in 4- and 2-month-old nursing infants following recreational use of methylamphetamine by the 2 mothers ages 29 and 26 years, respectively, who were recruited from the intervention arm of the randomized, controlled HIT trial. The women self-injected a single methylamphetamine dose of unknown purity and quantity. Four hours following drug use, urine samples were collected. A 5- to 10-mL breast milk sample was collected just prior to drug use and then in 2 to 6 hour intervals for 24 hours following methylamphetamine use. Methylamphetamine and amphetamine were estimated using high-performance liquid chromatography. The primary compound detected in the urine and breast milk of both subjects was methylamphetamine with a small quantity of amphetamine present. The approximate methylamphetamine and amphetamine half-lives were 13.6 and 43 hours, respectively, in subject 1, and 7.4 and 14 hours, respectively, in subject 2. The average concentration (Cavg) of methylamphetamine in the breast milk was 111 and 281 mcg/L for subjects 1 and 2, respectively, resulting in an absolute infant dose of 16.7 and 42.2 mcg/kg/day. The Cavg of amphetamine in the breast milk was 4 and 15 mcg/L for subjects 1 and 2, respectively, resulting in an absolute infant dose of 0.8 and 2.5 mcg/kg/day (Bartu et al, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Methamphetamine plasma concentrations are not clinically useful or readily available. Screening urine toxicology immunoassays may indicate exposure, however, there are many substances that cause a false positive result.
C) No specific lab work is needed in most patients but may be helpful in ruling out other causes of altered mental status if the diagnosis of methamphetamine toxicity is uncertain. Laboratory or radiological studies should be performed if warranted by the patient's clinical presentation.
D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity. Obtain cardiac enzymes if patient has chest pain.
E) Consider a head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the patient has altered mental status. Consider CT angiogram, if aortic pathology is suspected.
F) CPK should be obtained if rhabdomyolysis is suspected in the patient who has severe psychomotor agitation, seizure activity, or hyperthermia.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor serum electrolytes, glucose, renal function, and hepatic enzymes in symptomatic patients. Monitor CPK in patients with prolonged agitation or seizures.
2) Additional laboratory studies may include a CBC and coagulation profile as indicated in symptomatic patients.

4.1.3)

A) Screening urine toxicology immunoassays may indicate exposure, however, there are many substances that cause a false positive result.
B) Collect urine from any child that may have been exposed to methamphetamine in the past 72 hours. Place specimen cup in a biohazard bag and seal with security tape. Complete the chain of evidence form and release to the appropriate law enforcement personnel (Mecham & Melini, 2002).
C) In a study of 104 children who were removed from clandestine methamphetamine laboratories, 48 children (a mean and median age of 5 years; range, less than 1 year to 13 years) had positive urine test for methamphetamine soon after removal. No child had positive test results 6.5 hours after removal (Grant et al, 2010).

4.1.4)

A) OTHER

1) CARDIAC MONITORING

a) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity. Obtain cardiac enzymes if patient has chest pain. Consider CT angiogram if aortic pathology is suspected.

2) FORENSIC EVALUATION

a) For children removed from suspected clandestine methamphetamine laboratories the following procedure is recommended to document exposure and aid prosecution:

1) Collect urine from any child that may have been exposed to methamphetamine in the past 72 hours. Place specimen cup in a biohazard bag and seal with security tape. Complete the chain of evidence form and release to the appropriate law enforcement personnel (Mecham & Melini, 2002).
2) Hair analysis may provide documentation of methamphetamine or other drug exposure for several months or longer. The condition of the hair (wet, dry, dirty, permed or dyed) does not affect results.
3) To obtain hair samples, a new disposable scissors should be used to cut a very small amount of hair (100 mg total, about the width of a pencil) from about 10 places. Obtain the hair as close to the scalp as possible (Mecham & Melini, 2002).
4) Place the specimen in an evidence envelope or plastic bag and seal with security tape. Complete the chain of evidence form and release to the appropriate law enforcement personnel.

3) HAIR

a) To obtain hair samples, a new disposable scissors with alcohol should be used to cut a very small amount of hair (100 mg from wet, dry, clean, dirty, dyed, or permed hair) from about 10 places. Obtain the hair as close to the scalp as possible (Mecham & Melini, 2002).

Radiographic Studies

1) Severe headache following the use of amphetamines may be a symptom of intracerebral hemorrhage (McEvoy et al, 2000). Consider head CT and lumbar puncture to rule out intracranial mass, bleeding or infection.

Methods

1) A SEMIQUANTITATIVE EMIT(R) HOMOGENEOUS ENZYME IMMUNOASSAY is available for measurement of the class of commonly abused amphetamines in urine. The detection limit (sensitivity) is 0.3 mcg/mL for amphetamine or methamphetamine.

a) The assay also detects other phenylethylamines at higher levels, and confirmatory testing is recommended (Prod Info EMIT(R) d.a.u.(TM) Amphetamine Assay, 1984). CDC proficiency testing shows the method to be at least as accurate as GC and TLC.
b) A confirmatory test is available to eliminate interference from OTC cold medications containing ephedrine, pseudoephedrine, or phenylpropanolamine.

2) Also available is a qualitative EMIT urine assay, which detects as little as 0.7 mcg/ml of amphetamine; this method correlated well with GLC, TLC, HPLC, and RIA in clinical studies.
3) Amphetamine immunoassays have limited ability to detect MDMA. High concentrations of MDMA (3,4-methylenedioxymethamphetamine) in the urine are needed to elicit a response on amphetamine immunoassays. For common monoclonal amphetamine immunoassays (eg, EMIT, FPIA, RIA) the sensitivity for MDMA is approximately 50% less than for amphetamines and methamphetamines (Moeller et al, 2008).
4) FALSE POSITIVE RESULTS

a) Bupropion and its metabolites may cause false-positive results for amphetamines in certain urine toxicology screens (EMIT U AMP method on the Dade-Behring aca(R)- discrete clinical analyzer, Syva Emit II monoclonal immunoassay) (Casey et al, 2011; Weintraub & Linder, 2000; Nixon et al, 1995).
b) THE EMIT MONOCLONAL AMPHETAMINE ASSAY: The Syva EMIT monoclonal amphetamine assay has produced FALSE POSITIVE results in patients taking: brompheniramine, chlorpromazine, fenfluramine, fluspirilene, isometheptene, isoxsuprine, labetalol, mephentermine, methylenedioxyethylamphetamine, nylidrin, phenylpropanolamine, phenethylamine, phenmetrazine, phentermine, pipothiazine, propylhexedrine, pseudoephedrine, ranitidine, ritodrine and tyramine (Crane et al, 1993; Olsen et al, 1992; Grinstead, 1989; Nice & Maturen, 1989). A confirmatory test should be done for positive samples done by this method.
c) Bupropion and its metabolites may cause false-positive results for amphetamines in certain urine toxicology screens (EMIT U AMP method on the Dade-Behring aca(R)- discrete clinical analyzer, Syva Emit II monoclonal immunoassay)(Weintraub & Linder, 2000; Nixon et al, 1995).
d) Ingestion of famprofazone, an analgesic and antipyretic agent available in Europe and known to metabolize to amphetamine and methamphetamine, has resulted in urine specimens testing positive for the presence of amphetamine and methamphetamine (Tseng et al, 2007).
e) The EMIT polyclonal amphetamine assay has NOT been associated with false positives in patients taking chlorpromazine, fluspirilene, or pipothiazine (Crane et al, 1993).

5) FALSE NEGATIVE RESULTS

a) Mefenamic acid interferes with the ability to detect amphetamines using the EMIT(TM) polyclonal assay (Crane et al, 1993).
b) Cross-reactivity of methamphetamine and chlorpromazine metabolites, including nor-2-chlropromazine sulfoxide, was responsible for the false negative results in detecting the presence of methamphetamine and amphetamine when using the Triage(R) Drug of Abuse panel (Hikiji et al, 2009).

6) VARIOUS METHODS

a) The monoclonal test showed less cross-sensitivity than the polyclonal EMIT test when evaluated in 500 patients (Poklis et al, 1990).
b) The Abuscreen ONLINE assay was associated with fewer false positive results for amphetamines than the Syva EMIT assay in one study (Baker et al, 1995).
c) Other methods that have been described for the detection of amphetamine and methamphetamine include fluorescence polarization immunoassay and radioimmunoassay (Poklis & Moore, 1995; Ward et al, 1994).

1) A specific, sensitive and reliable gas chromatography-mass spectrometry (GC/MS) technique for the detection of sympathomimetic amines has been described which includes: amphetamines, phentermine, mephenorex, benzphetamine, and clobenzorex (Waksman et al, 2001; Franceschini et al, 1991). It has also been used to differentiate amphetamine and methamphetamine from 7 common sympathomimetic amines and MDA and MDMA (Thurman et al, 1992).
2) FALSE POSITIVE RESULTS - Exposure to prescription diet drugs that are metabolized to amphetamine and/or methamphetamine can result in a positive urine test for amphetamine. In one patient taking clobenzorex, GC/MS urine testing was positive for amphetamine (Wallace et al, 2000).
3) Gas chromatography-mass spectrometry (GC/MS) technique has been used to analyze methamphetamine samples removed from 3 body packers (Takekawa et al, 2007).

1) PHENYL-2-PROPANONE (P2P) is used in the illicit synthesis of amphetamine and methamphetamine. It can be identified by either nuclear magnetic resonance or gas chromatography in combination with vapor-phase Fourier transform infrared spectroscopy and electron impact mass spectroscopy detection (Allen et al, 1992).
2) TEST COMPARISONS - Several references have evaluated the various amphetamine tests for effectiveness and cross-reactivity (Smith & Kidwell, 1991; Przekop et al, 1991; Thurman et al, 1992; Poklis et al, 1991; Cody, 1990).

1) Sectional hair analysis using stable-isotope dilution GC/MS correlated well with most histories of drug use/misuse (Nakahara, 1995; DuPont & Baumgartner, 1995; Nakahara et al, 1990). A GC/MS method also detected methamphetamine in hair samples using hepatafluorobutyric anhydride (HFBA) as the derivatizing reagent (Saito et al, 2000).
2) Immunoassay and HPLC methods for detecting amphetamines in hair have also been described (Nakahara, 1995; DuPont & Baumgartner, 1995).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous stimulation and/or abnormal vital signs should be admitted. Patients with coma, seizures, dysrhythmias, delirium, any other life threatening result of toxicity or intubated patients should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Children with any exposure, symptomatic adults or those with intentional overdose, should be evaluated in a health care facility.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Refer patients with chronic abuse for rehabilitation.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients should be observed for at least 4 hours, as peak plasma concentrations and thus symptoms will likely develop within this time period. Symptomatic patients should be treated and observed until symptoms improve or resolve.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital decontamination is not recommended as the risk of aspiration (seizures) probably outweighs any potential benefit.

6.5.2)

A) Consider activated charcoal if a patient presents promptly after an oral overdose and is not manifesting toxicity. Activated charcoal is generally not recommended in patients that are manifesting signs of toxicity, as the risk of aspiration probably outweighs any potential benefit. If the airway is protected with orotracheal intubation, charcoal may be considered if the ingestion is recent.
B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

3) In a controlled animal study, CD-1 mice given 1 gram/kilogram activated charcoal or an equivalent volume of water following 100 milligrams/kilogram methamphetamine (LD for fasting mice) were found to have delayed onset of toxicity and delayed early mortality following charcoal administration; overall mortality was not affected (McKinney et al, 1994).

C) BODY PACKERS/BODY STUFFERS - Please refer to the appropriate management if body packing or body stuffing is known/suspected.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Methamphetamine plasma concentrations are not clinically useful or readily available. Screening urine toxicology immunoassays may indicate exposure, however, there are many substances that cause a false positive result.
3) No specific lab work is needed in most patients but may be helpful in ruling out other causes of altered mental status if the diagnosis of methamphetamine toxicity is uncertain. Laboratory or radiological studies should be performed if warranted by the patient's clinical presentation.
4) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity. Obtain cardiac enzymes if patient has chest pain.
5) Consider a head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection. Consider CT angiogram if aortic pathology is suspected.
6) CPK should be obtained if rhabdomyolysis is suspected in the patient who has severe psychomotor agitation, seizure activity, or hyperthermia.

B) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

7) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

C) HYPERTENSIVE EPISODE

1) Hypertension is generally transient and frequently does not require pharmacologic treatment unless severe. AVOID beta blockers for the potential unopposed alpha effects.
2) Sedation with intravenous benzodiazepines (diazepam 5 to 10 milligrams IV repeated every 5 to 10 minutes as needed in adults) is often effective in treating hypertension. Phentolamine should probably be the next line agent after benzodiazepines to treat severe hypertension. Nitroprusside and nitroglycerin may also be used.
3) PHENTOLAMINE/INDICATIONS

a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).

4) PHENTOLAMINE/ADULT DOSE

a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).

5) PHENTOLAMINE/PEDIATRIC DOSE

a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).

6) PHENTOLAMINE/ADVERSE EFFECTS

a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).

7) CAUTION

a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).

8) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

9) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

10) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

11) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

12) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

13) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

14) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

15) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

D) DELIRIUM

1) If the patient is agitated, sedate with a benzodiazepine (diazepam 5 to 10 milligrams IV, 0.1 to 0.3 milligram/kilogram in children). Repeat every 5 to 10 minutes as needed. Extremely large doses of diazepam (hundreds of milligrams) may be required to obtain adequate sedation. Titrate dose to clinical response. Control of agitation is an important treatment in amphetamine overdose since agitation often leads to hyperthermia, a common cause of mortality in amphetamine overdose.
2) Benzodiazepines are the drugs of choice, and if given aggressively there is rarely a need to use additional agents. Benzodiazepines safety profile in undifferentiated agitation is also very favorable. Below are descriptions of alternative therapies (droperidol and haloperidol) that have some evidence for their use. Their use is somewhat controversial as they lower seizure threshold and may predispose to dysrhythmias.
3) Extreme agitation and hallucinations may respond to intravenous droperidol (up to 0.1 milligram/kilogram) (Derlet & Duncan, 1996; Richards et al, 1997; Gary & Saidi, 1978).

a) CAUTION - DROPERIDOL: Based on cases of QT prolongation and/or torsades de pointes in patients receiving droperidol at doses at or below recommended dosing, it should be reserved for use in patients who fail to show an acceptable response to other agents ((Anon, 2001)).
b) A baseline ECG (repeat as indicated) and continuous cardiac monitoring for 3 hours are recommended for all patients receiving droperidol.

4) In a prospective study of droperidol vs lorazepam for the sedation of agitated methamphetamine toxic patients both agents were able to control agitation in patients. Droperidol provided more rapid and deeper sedation (Derlet & Duncan, 1996; Richards et al, 1997). It has been observed that the use of lorazepam may require more repeat dosing as compared to droperidol(Richards et al, 1997).
5) HALOPERIDOL has been advocated by some authors (Catravas et al, 1975; Derlet & Heischober, 1990). Since haloperidol lowers the seizure threshold and is associated with neuroleptic malignant syndrome most authors consider benzodiazepines to be the agent of choice.

a) A retrospective chart review was conducted, involving 18 pediatric patients, ranging in age from 4 months to 7.25 years, with methamphetamine poisoning and who presented with tachycardia and agitation. All patients received benzodiazepines and 12 patients also received haloperidol intravenously. There were no reports of adverse effects associated with the administration of these medications (Ruha & Yarema, 2006).

E) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Hyperthermia is a common cause of mortality in amphetamine overdose and should be treated aggressively with deep sedation and rapid reduction in body temperature. Temperature should be monitored by rectal probe in extreme cases. Placing the patient in an ice water bath is the most effective technique of rapid cooling. More practical methods include keeping the skin moist and encouraging evaporation with fans (may be less effective in a humid environment) or packing the patient in ice from head to toe, anteriorly and posteriorly. Other cooling measures such as cool packs in the axilla and groin are often ineffective in lowering core temperature rapidly. Consider intubation and neuromuscular paralysis for severe hyperthermia.
2) Core temperature above 40 degrees may be life threatening and indicates the need for aggressive sedation and cooling.
3) Administer intravenous benzodiazepines (Diazepam: Adults: 5 to 10 milligrams IV repeat every 5 to 10 minutes as needed, Children: 0.1 to 0.3 milligrams/kilogram IV repeat every 5 to 10 minutes as required to achieve sedation. Lorazepam: Adults 2 to 4 milligrams IV repeat every 5 to 10 minutes as needed; Children: 0.05 to 0.1 milligram/kilogram IV repeat every 5 to 10 minutes as needed).
4) Large doses may be required. Monitor respiratory adequacy and airway. Be prepared to intubate and ventilate if needed.
5) Monitor temperature every 30 minutes until below 38 degrees centigrade.
6) Dantrolene may be useful adjunctive therapy in patients with hyperthermia after methamphetamine use (Eilert & Kliewer, 2011).

F) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

G) VENTRICULAR ARRHYTHMIA

1) In agitated patients, dysrhythmias may improve after sedation with benzodiazepines.
2) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

3) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

4) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

H) TACHYARRHYTHMIA

1) Sedation with benzodiazepines to control agitation is sufficient in the vast majority of cases. Administer oxygen and intravenous fluids and correct hyperthermia as clinically indicated. If severe tachycardia persists and is associated with hemodynamic compromise or myocardial ischemia, additional therapy may be required, but this is unusual. Small incremental doses of labetalol may be useful because of the combined alpha and beta blocking effects. A short acting agent such as esmolol may also be considered, however esmolol carries the risk of inducing hypertension due to unopposed alpha agonist effects of amphetamines in this setting, an alpha blocking agent such as phentolamine may be needed if esmolol is used.

I) HYPOTENSIVE EPISODE

1) A late clinical effect; should be treated with fluids. Vasopressors should be reserved for refractory cases. Warning: there is an increase in sympathetic tone which masks hypovolemia and postural hypotension.
2) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

3) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

4) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

J) DRUG-INDUCED CHOREA

1) Diazepam intravenously (Briscoe et al, 1988) and chlorpromazine (Bonthala & West, 1983).
2) Symptoms resolved or were markedly lessened within 12 to 18 hours in treated patients and resolved spontaneously in 38 to 48 hours in untreated patients (Singh et al, 1983; Nausieda et al, 1981).

K) PSYCHOTIC DISORDER

1) HALOPERIDOL VS QUETIAPINE

a) In a double-blind, randomized, controlled trial, 80 patients with methamphetamine-induced psychosis were randomly assigned to receive either quetiapine (n=36; dose at least 100 mg/day orally once a day for 4 weeks) or haloperidol (n=44; dose at least 2 mg/day orally once a day for 4 weeks). Overall, 32 patients in the quetiapine group and 37 patients in the haloperidol group completed the protocol and had a "cure" or had no psychotic symptoms. No significant differences in antipsychotic effects and adverse effects were observed between the 2 groups (p=0.32) (Verachai et al, 2014).

L) DRUG DEPENDENCE

1) FLUMAZENIL, HYDROXYZINE AND GABAPENTIN

a) In a 12-week, open-label, single-group study, 50 methamphetamine-dependent patients (18 to 65 years of age), who used methamphetamine within 7 days of study entry, received flumazenil, hydroxyzine, and gabapentin for 4 weeks and then they were followed for an additional 8 weeks. Initially, patients received 50 mg of hydroxyzine 1 hour before flumazenil; then flumazenil was given in incremental doses of 0.1 to 0.3 mg over 30 minutes. On the first day, gabapentin 300 mg/day was administered, then increased in increments of 300 mg/day up to 1500 mg/day. Patients were also administered a fourth and a fifth infusion of flumazenil as boosters, 3 weeks after the first treatment to reduce craving. Thirty-six patients completed the program. There was a significant reduction (p less than 0.001) in frequency of methamphetamine use (84 days vs 90 days before treatment; p less than 0.001). A 47% reduction in use was noted for the entire group after considering the missing data as days of methamphetamine use. There was a 65% reduction in use for the 36 patients who completed the 8-week evaluation phase (p less than 0.001). Overall, this treatment program was associated with significant reductions in frequency of thoughts about methamphetamine use, level of discomfort/disturbance from thoughts about use, short-term or long-term desire/intensity of cravings, intensity of cravings when in the presence of environmental cues to use, and time preoccupied by thoughts of methamphetamine use. The following adverse effects were observed during the study: fatigue (29; 58%), drowsiness (28; 56%), increased appetite (13; 26%), injection site burning (7; 14%) and bruising (4; 8%), and weight gain (4; 8%). There are no controlled trial evaluating the efficacy of this therapy (Urschel et al, 2007).

2) ARIPIPRAZOLE

a) In a double-blind, randomized, placebo-controlled trial, methamphetamine dependent patients (n=37) with a history of psychosis, were randomly assigned to receive either aripiprazole (5 to 10 mg daily; n=19) or placebo (n=18) for 8 weeks. All patients were evaluated on days 7, 14, 28, 42, and 56 after enrollment. When compared with placebo, aripiprazole therapy was more effective in retaining more patients in treatment (an average of 48.7 days versus 37.1 days), decreasing methamphetamine cravings, and improving psychotic and anxiety symptoms; however, no significant effect was observed in abstinence (Sulaiman et al, 2013).

Enhanced Elimination

1) Techniques to enhance elimination are generally not useful for methamphetamine exposure.

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) OBESITY

1) One 5-milligram tablet orally one-half hour before each meal. Treatment should not exceed a few weeks in duration (Prod Info DESOXYN(R) oral tablets, 2007).

7.2.2)

A) ATTENTION DEFICIT DISORDER WITH HYPERACTIVITY

1) For children 6 years or older, the initial dose is 5 milligrams once or twice a day. The daily dose may be increased by 5 mg/day at weekly intervals until optimal clinical response is observed. The usual effective dose is 20 to 25 mg/day which may be give in two divided doses (Prod Info DESOXYN(R) oral tablets, 2007).

B) OBESITY

1) Not recommended as an anorectic agent in children under 12 years of age (Prod Info DESOXYN(R) oral tablets, 2007).

Minimum Lethal Exposure

Maximum Tolerated Exposure

1) Response is variable and tolerance develops in chronic abusers who may use as much as 5 to 15,000 mg/day (Kramer et al, 1967). Symptomatology is clearly recognizable and occurs within one hour of ingestion.
2) Clinical observation of toxic effects is more relevant than attempting to determine the amount ingested. Hyperthermia above 40 degrees C may be life threatening and indicates the need for aggressive sedation and cooling.
3) CASE REPORT: A 30-year-old man, who was using methamphetamine intermittently (over 10 times in the past year; 100 to 200 mg each time), developed monomorphic ventricular tachycardia (VT) after smoking about 200 mg of methamphetamine. A contrast-enhanced cardiac MRI did not reveal an abnormal enhancement of the ventricles. No structural or functional abnormalities of the heart were observed in echocardiography and cardiac MRI. He recovered following supportive care (Li et al, 2014).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) Methamphetamine blood concentration in fatal cases: 0.23 to 40 mcg/mL (Logan et al, 1998); 1.4 to 13 mcg/mL (Molina & Jejurikar, 1999); 3.2 to 34 mcg/mL; severe cases 2.2 to 7 mcg/mL (Takekawa et al, 2007).
2) The plasma methamphetamine concentration of a body packer with acute poisoning from 20 grams of methamphetamine was 8.6 mcg/mL (17 hours before death). Because of postmortem methamphetamine redistribution, the following extremely high concentrations of methamphetamine (MA) and its metabolite amphetamine (AP) were obtained 30 hours after death (Takekawa et al, 2007):
3)

SAMPLE	MA (mcg/mL or mcg/g)	AP (mcg/mL or mcg/g)
Cardiac blood	63.5	1.2
Myocardium	87.2	1.4
Brain	162.4	3
Lung	236.7	4.5
Liver	149.9	3.4
Pancreas	241.1	2.5
Spleen	244.2	2.5
Gastric wall	1145	5
Gastric contents	8490	16.9
Kidney	210.5	3.8
Urine	4518	72.6

a) Another body packer with severe acute poisoning from 18 grams of methamphetamine had a plasma concentration of 7.8 mcg/mL (Takekawa et al, 2007).

4) Postmortem methamphetamine and amphetamine blood concentrations of a body packer were 52 mcg/mL and 1.3 mcg/mL, respectively. An autopsy revealed 25 packages (each about 10 to 16 grams; total: 360 g) of methamphetamine in the gastrointestinal tract (Bin Abdul Rashid et al, 2013).
5) Postmortem methamphetamine concentrations of a body packer were: Cardiac blood (24.8 mcg/mL); urine (191 mcg/mL); liver (116 mcg/mL); gastric contents (1045 mcg/mL). An autopsy revealed 158 packages of methamphetamine (390 g) in his alimentary tract. Some packages were found empty and ruptured (Li et al, 2009).
6) A 14-year-old girl with a methamphetamine concentration of 220 ng/dL (on day 2) developed multisystem organ failure necessitating extensive supportive care. Her condition improved gradually and she was extubated on hospital day 15 (Prosser et al, 2006)
7) Blood and urine concentrations remained at toxic concentrations (greater than 1.91 mg/L) for 11 hours in a 33-year-old man following an alcohol and methamphetamine ingestion. The authors suggested that the long half-life of methamphetamine led to probable vascular fatigue resulting in hemorrhage, neurological dysfunction, and death. Postmortem exam was refused by family (Molina & Jejurikar, 1999a).
8) Postmortem blood methamphetamine concentration in a 31-year-old man, who died from an intracerebral hemorrhage after smoking and insufflating between 0.25 and 0.50 grams of methamphetamine, was 300 ng/mL (McGee et al, 2004).
9) INTRAVAGINAL ABSORPTION: A 23-year-old woman was found unconscious and unresponsive in a county jail. She died after several unsuccessful cardiopulmonary resuscitation attempts. Autopsy revealed multiple small loosely wrapped plastic packages containing methamphetamine in the patient's vagina. Postmortem methamphetamine concentrations in her subclavian blood, vitreous fluid, and urine were 42.6 mg/L, 20.1 mg/L, and 771 mg/L, respectively. Concentrations of amphetamine (the active metabolite of methamphetamine) in subclavian blood, vitreous fluid, and urine were 1.3 mg/L, 0.5 mg/L, and 20.4 mg/L, respectively (Jones et al, 2014).
10) METHIOPROPRAMINE: In one case report, the recreational use of methiopropramine (a synthetic methamphetamine analogue) resulted in death. Autopsy finding 3 days after death revealed nonspecific pulmonary edema, but no signs of hyperthermia or any other significant disease processes. A methiopropramine peripheral blood concentration of 38 mg/L was detected. Methiopropramine was also found in urine (Anne et al, 2015).

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 15 mg/kg (RTECS, 2006)

B) LD50- (SUBCUTANEOUS)MOUSE:

1) 7560 mcg/kg (RTECS, 2006)

C) LD50- (SUBCUTANEOUS)RAT:

1) 10930 mcg/kg (RTECS, 2006)

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Molecular Weight

Animal Toxicology

References

General Bibliography

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METHAMPHETAMINE

Classification | Detailed evidence-based information

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