Methamphetamine is a CNS stimulant, and its chronic abuse continues to be a significant problem in the US and worldwide. Powerfully addictive, it has devastating effects on health and other aspects of life. It is a schedule II drug, which can be prescribed only for ADHD, extreme obesity, and narcolepsy. Amphetamine is more often prescribed for these conditions because of its approximately 2-fold lower reinforcing potential.
Although amphetamine is less potent than methamphetamine, it can also be neurotoxic when taken at high doses and has the same molecular mechanisms of action as methamphetamine. The mechanisms underlying neurotoxicity are complex, and they ultimately lead to severe dysfunction of dopaminergic and serotonergic neurotransmission. Short of abstinence, there is no treatment for the neurologic complications associated with chronic methamphetamine use.
Understanding the relationship between the molecular mechanisms underlying the neurotoxicity of methamphetamine and related clinical manifestations is imperative to provide more effective treatments for methamphetamine users.
Methamphetamine is an indirectly acting sympathomimetic amine. It releases dopamine (DA), serotonin, noradrenaline, and adrenaline from nerve terminals, thus increasing their neurotransmission. As a result of its high lipophilicity, methamphetamine easily crosses the blood-brain barrier.
Because its chemical structure is similar to that of monoamines, methamphetamine is recognized as a substrate by DA, serotonin, and the noradrenaline plasma membrane transporter in the brain and transported into neurons and neuronal terminals. Methamphetamine also crosses the neuronal membranes via passive diffusion. Once in the terminals, methamphetamine acts on the monoamine storage vesicles and depletes them of neurotransmitters. In addition, methamphetamine inhibits monoamine metabolism via inhibition of monoamine oxidase. Consequently, intracellular levels of cytoplasmic DA and other monoamines are increased. DA quickly antoxidizes in the cytoplasm and generates reactive oxygen species, leading to degeneration of dopaminergic terminals in most species. Methamphetamine also inhibits and triggers a reversal of the monoamine transporters, which results in a massive release of monoamines into the synaptic cleft.
The net result of the actions of methamphetamine is overstimulation of the monoaminergic pathways in the central and peripheral nervous systems. Higher doses trigger an increase in glutamate in the striatum, which results in excitotoxicity. Methamphetamine interacts with presynaptic DA receptors by competitive antagonism and has minimal effect as an agonist at postsynaptic DA receptors but activates them indirectly via released DA. In addition to damaging dopaminergic and serotonergic terminals, methamphetamine damages neurons in some brain areas (Figure 1).
Medical use of methamphetamine
Both methamphetamine and amphetamine have active optic isoforms: d-enantiomer and l-enantiomer. The l-isomer contributes more to the peripheral effects, and the d-isomer contributes more to the CNS effects. d-Methamphetamine has 3 to 4 times higher central stimulant effects than l-methamphetamine. Effectiveness and adverse effects are determined not only by the dose but also by the enantiomeric composition of the drug.
Amphetamines are prescribed for ADHD, narcolepsy, and severe obesity. Their therapeutic doses range from 5 to 60 mg daily (usually in divided doses). The d-enantiomer has stronger CNS effects, but it is metabolized quicker than the l-enantiomer, which is longer lasting. Better clinical response was seen in children with ADHD who were treated with drugs that contain both enantiomers.1 The initial strong central effect comes from the d-enantiomer, while elongation of the effect is provided by the l-enantiomer. This allows less frequent dosing than a medication containing d-amphetamine only. The maximum therapeutic dose of d-amphetamine and d-methamphetamine is 60 mg daily. However, adverse effects such as insomnia, loss of appetite, and anxiety have occurred with therapeutic doses of amphetamine.2
Dr. Moszczynska is Associate Professor, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI. She reports no conflicts of interest concerning the subject matter of this article.
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