Methamphetamine

Mechanism of Action

Methamphetamine is an indirect monoamine agonist that increases intracellular and extracellular levels of the monoamine neurotransmitters, dopamine, serotonin, and norepinephrine. Methamphetamine gains entry into neurons either as a substrate at plasmalemmal neurotransmitter transporters or via diffusion across the plasmalemmal membrane as a result of its high lipophilicity. Once inside the presynaptic nerve terminal, methamphetamine inhibits neurotransmitter uptake at the vesicular monoamine transporter-2 located on synaptic vesicles and promotes neurotransmitter release from the vesicles, the result of which is to increase cytosolic neurotransmitter levels. In addition, methamphetamine inhibits monoamine oxidase, preventing a major route of intracellular metabolism of cytosolic neurotransmitter. The increased concentrations of cytosolic monoamines are available for reverse transport by the perisynaptic plasmalemmal neurotransmitter transporter. As neurotransmitter is transported from the cytosol to the extracellular space by the plasmalemmal transporter, methamphetamine is transported from the extracellular space into the cytosol. The outcome is that neurotransmitter concentration increases in the extracellular space. Finally, methamphetamine inhibits neurotransmitter uptake by the plasmalemmal monoamine transporters, contributing to the increased extracellular neurotransmitter concentrations.

Clinical Use of Methamphetamine

Methamphetamine is available on the market as a controlled substance, manufactured under the brand name Desoxyn (Ovation Pharmaceuticals, Deerfield, IL). Methamphetamine has the same schedule II designation as other psychostimulant medications, such as amphetamine and methylphenidate, indicating both its therapeutic uses and high potential for misuse. According to the package insert and labeling, methamphetamine can be used for the treatment of attention-deficit/hyperactivity disorder in children over the age of 6, short-term weight loss in obese individuals, and narcolepsy. The parameters for US Food and Drug Administration (FDA) approval in treating exogenous obesity include only short-term (i.e., a few weeks) usage in the context of a weight reduction plan including a structured diet with exercise, and only for patients in whom obesity has been refractory to other medications. In addition, methamphetamine use in obesity is discouraged if the patient is younger than age 12. Of interest, methamphetamine is not listed as a recommended therapy for the treatment of attention-deficit/hyperactivity disorder according to the current treatment guidelines from the American Academy of Pediatrics and the American Academy of Child and Adolescent Psychiatry. Not surprisingly, it is rare for practicing physicians to prescribe methamphetamine for this indication.

The dosage recommendation by the package insert for attention-deficit/hyperactivity disorder starts with 5 mg given in the morning, and proceeds with weekly 5-mg increases until optimal clinical response has been achieved. The usual dosing for childhood attention-deficit/hyperactivity disorder is 20–25 mg given as a once- or twice-daily dose. The recommended dosage in short-term obesity treatment is 5 mg taken 30 minutes before meals. Desoxyn is available only in 5-mg tablets, and no generic manufacturer currently exists. Abbott Pharmaceuticals produced Desoxyn since its introduction in 1942 and sold its rights to Ovation Pharmaceuticals in 2002, although Abbott maintains the facilities that manufacture the product. In addition, Abbott produced a sustained-release form of methamphetamine named Desoxyn Gradumet, utilizing a plastic matrix for gradual release of the methamphetamine. This product was available in 5-, 10-, and 15-mg doses. Manufacturing of the Desoxyn Gradumet was discontinued in 1999 due to “manufacturing difficulties.”

No clinical trials are available by PubMed search for the use of methamphetamine in attention-deficit/hyperactivity disorder or obesity. However, methamphetamine and amphetamine are major metabolites of l -deprenyl (selegiline). l -Deprenyl is commonly prescribed for Parkinson disease and has been evaluated in clinical trials for the treatment of attention-deficit/hyperactivity disorder. Results suggest that selegiline may be an efficacious medication for children with this disorder, particularly children presenting with the inattentive subtype. Although methamphetamine has not received official FDA approval for use in narcolepsy, this appears to be the main use for which it is prescribed in North America. Methamphetamine is used along with other stimulants and l -deprenyl to treat the excessive sleepiness symptom of narcolepsy. The last trial evaluating methamphetamine in the treatment of narcolepsy was reported in 1993 and found that daytime sleepiness was treated successfully in adults with doses of 40–60 mg/day.

Although methamphetamine may have proven efficacy and safety in the treatment of childhood attention-deficit/hyperactivity disorder and obesity, the risks of misuse and diversion along with its current negative stigma among health care workers and the public as an abused drug make it unlikely that many physicians will endorse its clinical use for these indications.