eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Methamphetamine

Author: Robert W Derlet, MD, Professor of Emergency Medicine, University of California at Davis School of Medicine; Chief Emeritus, Emergency Department, University of California at Davis Health System
Coauthor(s): Timothy E Albertson, MD, MPH, PhD, Professor of Pharmacology and Toxicology, Division Chief and Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Vice-Chair, Department of Internal Medicine, University of California, Davis, School of Medicine; Professor of Anesthesiology, Associate Dean, Academic Clinical Programs, University of California, Davis Health System; Professor of Emergency Medicine and Clinical Toxicology, Davis Medical Center; Chief of Pulmonary and Critical Care, Veterans Affairs, Northern California Health Care System; Medical Director of Poison Control System, University of California at San Francisco, School of Pharmacy.; John R Richards, MD, FAAEM, Professor of Emergency Medicine, University of California at Davis School of Medicine
Contributor Information and Disclosures

Updated: Dec 4, 2009

Introduction

Background

Over the past 25 years, methamphetamine use has increased rapidly throughout the world. In the United States, all regions have experienced a significant increase in the number of persons using the drug as well as medical complications seen in emergency departments (EDs).¹ Methamphetamine and related compounds can produce euphoria and stimulant effects and share many of the same toxic clinical effects seen with other stimulants such as cocaine. The ease of synthesis from inexpensive and readily obtainable chemicals has led to the widespread and rampant abuse of this dangerous drug.
 
The euphoria produced by methamphetamine is similar to that produced by cocaine. Methamphetamine may be taken orally, intravenously, snorted, or smoked. Patients who inhale the smokable form of methamphetamine (ie, ice) experience an immediate euphoria similar to that of crack cocaine, but the effects may last much longer.^2,3,4 North American methamphetamine abusers are predominantly Caucasian males in their 30s and 40s.^5,6 Recently, epidemic abuse has been described in adolescents; they cite availability, low cost, and a longer duration of action than cocaine as reasons for their drug preference.⁷
 
The medical history of amphetamine-like compounds extends back nearly 100 years.⁴ A Japanese pharmacologist first synthesized methamphetamine in 1919. A more detailed analysis of the pharmacology of amphetamine derived from the basic phenylethylamine structure was reported in 1930. In the 1930s, amphetamine was introduced in the form of inhalers for rhinitis and asthma treatment. The stimulant, euphoric, and anorectic effects of amphetamine were quickly recognized, leading to its abuse. In 1937, a report that amphetamine enhanced intellectual performance and wakefulness further contributed to its popularity. Amphetamines were used extensively by Allied and Axis armed forces during World War II and during Operation Desert Storm to increase wakefulness and attention.^8,3

In the late 1950s, initial federal controls were enacted; however, in spite of additional regulation and increased enforcement, amphetamines continued to be used by students, athletes, shift workers, long haul drivers, and for weight loss.⁴ The Controlled Substance Act of 1970 stringently regulated the manufacture of amphetamine. Despite attempts to decrease production, illicit methamphetamine use continues to increase.^3,9

Pathophysiology

Amphetamines stimulate the central nervous system (CNS), which results in several clinical effects such as inducing euphoria, intensifying emotions, altering self-esteem, and increasing alertness, aggression, and sexual appetite.^3,10 In the CNS, presynaptic reuptake of catecholamines (ie, dopamine, norepinephrine) is blocked, causing hyperstimulation at selected postsynaptic neuron receptors. Indirect sympathomimetic effects of amphetamines are also caused by blocking presynaptic vesicular storage and by reducing cytoplasmic destruction of catecholamines by inhibiting mitochondrial monoamine oxidase.^11,12

Indirectly, these hyperstimulated neurons can stimulate various other noncatecholaminergic central and peripheral nervous pathways. Changes in mood, excitation, motor movements, sensory perception, and appetite appear to be mediated more directly by CNS dopaminergic alterations. It has been postulated that serotonin alterations also contribute to mood changes, psychotic behavior, and aggressiveness.
 
In humans, the half-life of methamphetamine ranges from 10-20 hours, depending on the urine pH, history of recent use, and dosage.¹¹ Metabolism occurs faster in acidic urine. Methamphetamine has greater CNS effects compared with D-amphetamine of equal milligram quantity. Methamphetamine has more effective absorption into critical behavior-controlling neurons in the CNS and has a prolonged half-life. The majority of methamphetamine is metabolized to amphetamine, which provides further CNS stimulation. Methamphetamine is absorbed readily from the gut, airway, nasopharynx, muscle, placenta, and vagina.^13,14 Peak plasma levels are observed approximately 30 minutes after intravenous or intramuscular routes and 2-3 hours after ingestion.¹² Rapid tissue redistribution occurs with steady-state cerebrospinal fluid levels at 80% of plasma levels. Hepatic conjugation pathways with glucuronide and glycine addition result in inactivation and urine excretion of metabolites.
 
When methamphetamine is used with ethanol, increased psychological and cardiac effects are observed.¹⁵ This is presumed to be the result of pharmacodynamic rather than pharmacokinetic interactions. Similarly, the increased toxicity of concomitant opioids and amphetamines (ie, speedballing), appear to result from pharmacodynamic interactions. The euphoric effects produced by methamphetamine, cocaine, and various designer amphetamines are similar and may be difficult to clinically differentiate.⁴ A distinguishing clinical feature is the longer pharmacokinetic and pharmacodynamic half-life of methamphetamine, which may be as much as 10 times longer than cocaine. Because of the variability in quality and concentration of illicitly purchased methamphetamines, the clinical observation of toxic effects is more relevant than estimated total ingested dose.¹⁶

Frequency

United States

Methamphetamine use is widespread, predominantly in Midwest, Southwest, Northwest, and Western States.⁹

International

Methamphetamine use is widespread, predominantly in North America, Eastern Europe, and Southeast Asia.¹⁷

Mortality/Morbidity

Acute methamphetamine overdose may result in sympathetic overdrive, cardiovascular collapse, rhabdomyolysis, ventricular tachyarrhythmia, and death. Injuries from blunt and penetrating trauma are common.^18,19

Chronic methamphetamine use may result in atherosclerosis, hypertension, myocardial infarction, congestive heart failure, soft tissue infection, periodontal disease, sepsis, changes in cognitive CNS function, and personality disorders.

Race

In North America, methamphetamine use is predominantly by Caucasians.^9,5,6

Sex

Males are more likely to abuse methamphetamine than females.^9,5,6

Age

Peak methamphetamine use is observed in the 20- to 40-year-old range.^9,5

Clinical

History

Signs and symptoms of methamphetamine use:

• Cardiovascular:^{20,21,22,23,24,25}
  • Chest pain, aortic dissection, myocardial ischemia/infarction
  • Palpitations, tachyarrhythmia
  • Dyspnea and edema
  • Hypertension 
• Central nervous system:^26,27,28
  • Agitation, violent behavior, self-harm
  • Coma
  • New-onset seizure
  • Emotional lability, confusion, psychosis, paranoia, hypersexuality, and hallucinations
  • Headache
• Respiratory:^29,30,31
  • Dyspnea
  • Wheezing
  • Pneumothorax
• Skin:³²
  • Delusional parasitosis
  • Abscess, cellulitis
• Gastrointestinal:^13,33
  • Abdominal pain
  • Obstruction
• Dental: Caries, peridental abscess^34,35

Physical

• Cardiovascular:
  • Tachycardia and hypertension is frequently observed.³⁶
  • Atrial and ventricular arrhythmias may occur.³⁶
  • Chest pain from cardiac ischemia and infarction following methamphetamine use has been reported. Patients are at risk because of accelerated atherosclerosis from chronic use. Acute aortic dissection or aneurysm has been associated with methamphetamine abuse.^24,21
  • Hypotension may be observed with methamphetamine overdose with profound depletion of catecholamines.³⁷
  • Acute and chronic cardiomyopathy results directly from methamphetamine cardiac toxicity and indirectly from chronic hypertension and ischemia. Intravenous use may result in endocarditis. Patients may present with dyspnea, edema, and other signs of acute congestive heart failure (CHF) exacerbation.^38,22
• Central nervous system:
  • New-onset seizures may occur from direct CNS methamphetamine toxicity.²⁸
  • Acute and chronic methamphetamine exposure has been associated with a jerking, choreoathetoid movement disorder. These repetitive movements, hyperactivity, and inability to focus thought have been referred to as "tweaking."²⁷
  • Headache and cerebrovascular accidents with focal neurologic deficits may be caused by hemorrhage or vasospasm, cerebral edema, and cerebral vasculitis.²⁵
  • Acute psychosis, agitation, violence, and paranoia frequently results from alteration in CNS dopamine, serotonin, and glutamate pathways.³⁹
  • Coma may result from depletion of catecholamine stores and/or concomitant ingestion of sedatives such as ethanol or narcotics.³⁷
• Respiratory:
  • Barotrauma, including pneumomediastinum, pneumothorax, and pneumopericardium may result from forceful inhalation.²⁹
  • Acute noncardiogenic pulmonary edema and pulmonary hypertension may result from acute and chronic use, as well as from adulterants introduced during intravenous use such as talc or cornstarch.^29,30,31
  • Wheezing from reactive airway disease may be induced by methamphetamine.²⁹
• Gastrointestinal:
  • Hepatocellular damage has been reported with methamphetamine after acute and chronic abuse. Direct effects such as hypotension, hepatotoxic contaminants, hepatic vasoconstriction, lipid peroxidation, occult viral causes, necrotizing angiitis have been postulated.⁴⁰
  • Severe abdominal pain may result from acute mesenteric vasoconstriction. Methamphetamine has also been associated with the formation of ulcers and ischemic colitis.³³
  • Necrotizing angiitis with arterial aneurysms and sacculations have been observed in the liver, pancreas, and small bowel of methamphetamine drug abusers.²⁵

• Renal:
  • Renal failure associated with amphetamines has been related to hypoxemia, rhabdomyolysis, necrotizing angiitis, acute interstitial nephritis, and cardiovascular shock with subsequent acute tubular necrosis.⁴¹
• Skin:
  • Delusions of parasitosis and chronic skin-picking may result in neurotic excoriations and prurigo nodularis ("speed bumps").⁴
  • Methamphetamine injectors frequently present with abscess and cellulitis, which is frequently blamed on a "spider bite."³²
  • Lab workers involved with illicit methamphetamine production may present with extensive thermal and/or chemical burns.⁴²
• Dental:
  • Severe caries, especially of the maxillary teeth, is commonly seen in chronic methamphetamine users ("meth mouth") and results from maxillary artery vasoconstriction, xerostomia, and poor hygiene.^34,35
• Pregnancy:
  • Methamphetamine use during pregnancy can be fatal to the mother and fetus.^43,44 Methamphetamine has been shown to cause placental vasoconstriction and interfere with placental monoamine transporters resulting in spontaneous abortion.⁴⁵
  • Methamphetamine is present in the breastmilk of postnatal women abusers. A case of infant death from methamphetamine-toxic breastmilk ingestion has been reported.⁴⁶

Causes

• Illicit production of methamphetamine^4,9,47  
  • Methamphetamine is relatively easy and inexpensive to synthesize, and illicit production occurs in home kitchens, workshops, recreational vehicles, and rural cabins. Instructions for synthesis can be found on the Internet and the precursors are not difficult to obtain.
  • Methamphetamine is a derivative of phenylethylamine. The substances differ structurally in that a methyl group attaches to the terminal nitrogen to form methamphetamine.
  • The federal government and some states have enacted laws decreasing the availability of necessary precursor chemicals such as ephedrine. Many of these agents can still be obtained in other countries.
  • A common method of synthesis begins with ephedrine, which is reduced to methamphetamine using hydriodic acid and red phosphorus.
  • Alternative approaches include using a different acid, a different catalyst, or a substituted ephedrine (eg, chloroephedrine, methylephedrine).
  • The methamphetamine produced by ephedrine reduction is a lipid-soluble pure base form, which is fairly volatile and can evaporate if left exposed to room air temperature. This product is converted to the water-soluble form, methamphetamine hydrochloride (HCl) salt.
  • Illicitly synthesized methamphetamine is frequently contaminated by nonstimulant organic or inorganic impurities. Poisoning from heavy metals, such as lead and mercury, or from carcinogenic solvents used in the synthesis process, has been reported.^48,49
  • Street methamphetamine may be mixed with other drugs, including cocaine and phencyclidine.
  • Making ice, the smokable form of methamphetamine, from standard quality methamphetamine HCl is essentially a purification process.

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