Amphetamines

Amphetamines have been commonly prescribed for obesity since the first introduction of amphetamine (Benzedrine) as a dietary aid in 1937 and continuing to the present day. By 1948, 92 percent of physicians surveyed were prescribing amphetamines for weight loss. In 1959, phentermine was approved for weight loss by the U.S. Food and Drug Administration. As shown in the accompanying figure, phentermine differs from amphetamine itself only in the addition of a methyl group. The primary effect of this change is to slow its breakdown and therefore prolong its half-life within the body, so that phentermine can be taken once a day, whereas amphetamine itself is only active for around four hours. Phentermine is also closely related to methamphetamine, which has a methyl group attached to the amine nitrogen. Methamphetamine has a faster onset of action, leading to intense euphoria, whereas phentermine has a much slower onset and is only a mild euphoriant.

Amphetamines have long been prescribed as an aid in dieting and weight loss, but with a potential cost to the health of users.

Drugs in the amphetamine class are sympathomimetics, because they mimic the action of the sympathetic nervous system. Amphetamines activate sympathetic nerve terminals release norepinephrine in three ways. First, they block the reuptake of norepinephrine and dopamine by the nerve terminal, thereby prolonging the action of norepinephrine within the active zone of the nerve synapse. Second, they directly provoke the release of norepinephrine and dopamine from nerve terminals. Third, the amphetamines slightly inhibit the activity of monoamine oxidase, which breaks down norepinephrine and dopamine. These three actions synergize to stimulate norepinephrine secreting nerve terminals. The nonamphetamine obesity drug sibutramine shares the first action with amphetamine—blocking reuptake—but lacks any effects on release and breakdown. Thus, sibutramine has a milder stimulant action than amphetamines.

Increased norepinephrine and dopamine within the brain—specifically within the appetite centers of the hypothalamus—leads to suppression of appetite and reduced food intake. The effect on food intake tends to fade over time, so that maximum weight loss with amphetamine is achieved within 12 weeks. This is one reason why the use of amphetamines for weight loss is not recommended for more than 12 weeks. The additional [Page 31]weight loss relative to placebo ranges between 5–20 lb. As would be expected, weight regain occurs rapidly upon discontinuation of amphetamines.

Amphetamines are not only active in the brain, but also throughout the body. Activation of the sympathetic system slows the digestive tract leading to a sensation described as “butterflies in the stomach.” Undoubtedly, these systemic effects contribute to weight loss during amphetamine treatment.

The sympathomimetic action of amphetamines can lead to a number of physiological side effects, especially on the cardiovascular system. According to the Hazardous Substances Databank, the primary hazards of phentermine are:

Cardiotoxicity causing tachycardia, arrhythmias, hypertension and cardiovascular collapse; high risk of dependency and abuse; palpitation; chest pain; and hypertension are common. Cardiovascular collapse can occur in severe poisoning. Myocardial ischemia, infarction and ventricular dysfunction are described.

All of these effects are predictable based on the known functions of the sympathetic nervous system. Furthermore, sympathoinhibitory drugs such as beta-blockers are commonly used in cardiology and have been shown to reduce cardiovascular mortality.

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