Methamphetamine Toxicity

Updated: Oct 29, 2020
  • Author: John R Richards, MD, FAAEM; Chief Editor: Jeter (Jay) Pritchard Taylor, III, MD  more...
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Overview

Practice Essentials

Methamphetamine is a highly addictive psychostimulant drug that is chemically related to amphetamine. Methamphetamine can produce euphoria and stimulant effects like those from other stimulants such as cocaine. In addition, methamphetamine is easily synthesized from inexpensive and readily obtainable chemicals. Those qualities have led to the widespread and rampant abuse of this dangerous drug. [1]

Methamphetamine use has increased rapidly throughout the world, with more than 30 million users worldwide. East and Southeast Asia and North America remain the two main subregions for methamphetamine trafficking worldwide. In North America, the availability of methamphetamine was reported to have increased between 2013 and 2016, and, in 2016, the drug was reported to be the second greatest drug threat in the United States, after heroin. [2] In the US, the National Institute on Drug Abuse reported that although lifetime methamphetamine use by those 12 years of age and older remained stable at 5.4% of the population, use in the past year increased from 0.5% to 0.7% of the population between 2016 and 2018. [3]  

Methamphetamine is available in powder and crystalline forms. It may be taken orally or intravenously, or be snorted or smoked. The smokable form of methamphetamine (“ice”) produces an immediate euphoria similar to that of crack cocaine, but the effects may last much longer. [4, 5]

Inadvertent absorption of methamphetamine may occur in “body packers”, who swallow packages of the drug for transportation purposes, or “body stuffers”, who insert bags of methamphetamine rectally or vaginally in an attempt to elude drug enforcement. There are also users who indulge in "parachuting", in which the drug is loosely wrapped to delay absorption and prolong effect. These persons, and body stuffers, are at high risk for toxicity as the drug wrapping may be compromised and allow complete drug absorption. [6]

North American methamphetamine abusers are predominantly white men in their 30s and 40s. [7, 8] However, 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. [9]

Most cases of methamphetamine toxicity can be managed supportively. In severe overdoses, termination of methamphetamine-induced seizure activity and arrhythmias are of immediate importance. Correction of hypertension, hypotension, hyperthermia, metabolic and electrolyte abnormalities, and control of severe psychiatric agitation are indicated. See Treatment and Medication.

For patient education information, see What is Methamphetamine? and Addiction Treatment & Recovery - Methamphetamine.

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Background

The medical history of amphetamine-like compounds extends back over a century, beginning with the identification of ephedrine as the active ingredient in extracts from the Ephedra sinica shrub, which had long been used in traditional Chinese and Indian medicine. [4, 5, 10] A Japanese pharmacologist first synthesized methamphetamine from ephedrine 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 the recent Iraq and Afghanistan conflicts to increase wakefulness and attention. [4, 11]

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, 5] The Controlled Substance Act of 1970 stringently regulated the manufacture of amphetamine.

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Pathophysiology

Methamphetamine is structurally similar to amphetamine and to the neurotransmitter dopamine. Amphetamines stimulate the central nervous system (CNS), which results in clinical effects that include the following [4, 12] :

  • Inducing euphoria
  • Intensifying emotions
  • Altering self-esteem
  • Increasing alertness, aggression, and sexual appetite.

In the CNS, amphetamines block presynaptic reuptake of catecholamines (ie, dopamine, norepinephrine), causing hyperstimulation at selected postsynaptic neuron receptors. Indirect sympathomimetic effects result from blockade of presynaptic vesicular storage and by reduction in cytoplasmic destruction of catecholamines by inhibition of mitochondrial monoamine oxidase. [13, 14]

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. [15]

Long-term exposure to methamphetamine results in significant down-regulation of both presynaptic and postsynaptic aspects of the dopamine system in the striatum. Dysregulation of the dopamine system has been proposed as a mechanism of addiction. [16]  Oxidative stress and neuroinflammation appear to play a role in the psychosis and cognitive deficits induced by repeated low doses of methamphetamine. [17]

In humans, the half-life of methamphetamine ranges from 10-20 hours, depending on the urine pH, history of recent use, and dosage. [13] Metabolism occurs faster in acidic urine. Methamphetamine has greater CNS effects compared with D-amphetamine of equal milligram quantity. 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. [18, 19] Peak plasma levels are observed approximately 30 minutes after intravenous or intramuscular routes and 2-3 hours after ingestion. [14] 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 urinary excretion of metabolites.

When methamphetamine is used with ethanol, increased psychological and cardiac effects are observed. [20] This is presumed to be the result of pharmacodynamic rather than pharmacokinetic interactions. Similarly, the increased toxicity of concomitant opioids and amphetamines ("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. [5] A distinguishing clinical feature is the longer pharmacokinetic and pharmacodynamic half-life of methamphetamine, which may be as much as 10 times longer than that of 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. [21]

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Etiology

Most of the methamphetamine abused in the United States is produced in so-called superlabs, many of which are located in Mexico. [22]  However, methamphetamine is relatively easy and inexpensive to synthesize, and small-scale illicit production occurs in home kitchens, workshops, recreational vehicles, and rural cabins. [5, 23] Instructions for synthesis can be found on the Internet and the precursors are not difficult to obtain.

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 federal government and some states have enacted laws decreasing the availability of necessary precursor chemicals such as ephedrine, but many of these agents can still be obtained in other countries.

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. The manufacture of "ice", the smokable form of methamphetamine, from standard quality methamphetamine HCl is essentially a purification process.

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. [24, 25]  Street methamphetamine may be mixed with other drugs, including cocaine and phencyclidine.

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Epidemiology

Frequency

United States

According to the 2018 National Survey on Drug Use and Health (NSDUH), approximately 1.9 million people had used methamphetamine in the past year. Approximate numbers of users by age group and percentages of that age group were as follows [26] :

  • 12-17 years: 43,000 (0.2%)
  • 18-25 years: 273,000 (0.8%)
  • 26 years or older: 1.6 million (0.7%)

Estimates of past-year methamphetamine use in 2018 were similar to the estimates in 2015 to 2017.

The 2018 Annual Report of the American Association of Poison Control Centers' National Poison Data System reported 3,971 single case exposures with 1360 moderate and 306 major outcomes and 183 fatalities. [27]

International

The United Nations Office on Drugs and Crime estimates that worldwide in 2018 there were 27 million past-year users of amphetamine-type stimulants, which includes methamphetamine. Past-year use was particularly high in North America, Australia, and New Zealand. Methamphetamine is a feature of amphetamine-type stimulant markets worldwide, but is particularly dominant in East and Southeast Asian Oceania, and North America  In East and Southeast Asia, the market for both tablet and crystalline methamphetamine is large and growing. [2]

The European Monitoring Centre for Drugs and Drug Addiction reports that methamphetamine use has generally been low and was historically concentrated in the Czech Republic and Slovakia. In 2018, treatment program entrants reporting primary methamphetamine use were concentrated in Czechia, Germany, Slovakia, Poland, and Turkey. [28]  

An Australian study that used liquid chromatography–mass spectrometry to analyze wastewater (an increasingly popular method for monitoring trends of illicit drug use) reported that from 2009-2015, methamphetamine consumption increased fivefold. In the study, which involved wastewater from wastewater treatment plants in South East Queensland, methamphetamine residues were consistently detected in both urban and rural catchments. [29]

Race-, Sex-, and Age-related Demographics

Demographic variations include the following [7, 8] :

  • In North America, methamphetamine use is predominantly by whites
  • Males are more likely to abuse methamphetamine than females
  • Peak methamphetamine use is observed in the 20- to 40-year-old range
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Prognosis

Acute methamphetamine overdose may result in sympathetic overdrive, intracranial hemorrhage, [30]  cardiovascular collapse, rhabdomyolysis, ventricular tachyarrhythmia, and death. Injuries from blunt and penetrating trauma are common. [4, 12, 31, 32]

Long-term methamphetamine use may result in the following [33] :

In a study of 590 patients between 18 and 50 years old with cardiomyopathy or heart failure who were seen at a single medical center from 2008-2012, the 223 patients with a history of methamphetamine use were more likely to have a moderately or severely reduced ejection fraction ≤40%). In addition, male patients were more likely to have worse left ventricular systolic dysfunction. [34]

Methamphetamine abuse has severe adverse effects on oral health, colloquially termed "meth mouth". As a result of its sympathomimetic effects, methamphetamine results in significantly reduced saliva production and pH, and increased bruxism. Consequently, long-term abusers are at increased risk for caries, dental erosion, periodontal lesions, and temporomandibular joint pain. [35]

Use of methamphetamine during pregnancy has been associated with intrauterine growth restriction and preterm birth. Neonates have an increased incidence of poor cardiorespiratory adaptation, cardiac defects, and floppy muscle tone. [36]  Prenatal exposure may have a long-term impact on cognitive skills that becomes more pronounced with age. [37]

Complications of methamphetamine use include the following:

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