What is the pathophysiology of 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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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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