Neurotoxic amphetamine analogues: effects in monkeys and implications for humans

A wealth of evidence has accrued over the last 20 years indicating that certain amphetamine analogues have the potential to damage central monoaminergic neurons. For example, amphetamine has been shown to be toxic to dopamine neurons, MDMA to serotonin neurons, and methamphetamine to both (Table 1). In rodents, the toxic effects of amphetamines appear to be limited to axon terminals, and regenerative sprouting tends to be the rule. By contrast, in primates, nerve cell bodies appear to be affected, and the deleterious effects of amphetamine derivatives tend to be longer lasting, and possibly permanent (Fig. 2). Although findings in animals are compelling, observations in humans are less clear. In particular, it remains to be determined whether amphetamine analogues damage central monoaminergic neurons in humans and, if they do, whether functional consequences ensue. Also, the mechanism by which amphetamines damage monoaminergic neurons remains to be defined. Further insight into these basic and clinical aspects of amphetamine neurotoxicity should enhance our understanding of central monoaminergic systems in normal brain function, and their role in the pathophysiology of neuropsychiatric disorders.