Evaluation of the neurotoxic potential of N,N-dimethylamphetamine: an illicit analog of methamphetamine.

The purpose of this study was to evaluate the neurotoxic potential of N,N-dimethylamphetamine (N,N-DMA), a controlled substance analog that has recently appeared on the illicit drug market, and compare it to that of methamphetamine, a structurally related drug with known dopaminergic and serotonergic neurotoxic activity. Like methamphetamine, N,N-DMA induced degeneration of nerve terminals in the mouse striatum, but did not produce cell loss in the pars compacta of the substantia nigra. The dopamine-depleting effects of N,N-DMA were approximately one-eighth of those of methamphetamine. Assessment of N,N-DMA's effects on serotonergic neurons showed that it did not produce a long-lasting depletion of serotonin in either the mouse or rat brain. By contrast, equivalent doses of methamphetamine depleted serotonin in the rat brain by 82%. These results indicate that N,N-DMA, the N-methylated analog of methamphetamine, is considerably less potent than its parent compound both as a dopaminergic and serotonergic neurotoxin, and raise the question of whether or not it may be possible to dissociate the neurotoxic effects of methamphetamine from its reinforcing actions by means of N-methylation. Safety of N,N-DMA in humans remains to be investigated.