Methamphetamine and methylenedioxymethamphetamine neurotoxicity: possible mechanisms of cell destruction

Methamphetamine and MDMA as well as similar substituted phenethylamines are toxic to DA and/or 5-HT neurons. The duration and magnitude of these effects are dose dependent and are accompanied by different degrees of recovery. MDMA-induced 5-HT damage persists for up to 52 weeks in the rat, and methamphetamine-induced DA damage persists for up to 3 years in the rhesus monkey. Several possible mechanisms of amphetamine-analog toxicity have been reviewed. The excitatory feed-forward loop theory is best supported by the literature. This theory, however, is very wide ranging and difficult to prove or disprove. The hydroxy radical and DA mediation theories are both well supported by the data reviewed. It should be noted that these two hypotheses are closely related to each other. The DA mediation theory is based on the requirement of an intact DA system for methamphetamine and MDMA neurotoxicity to occur. The hydroxy radical theory is also based on the presence of DA and 5-HT; in addition, it suggests the formation of toxic hydroxy radicals from DA or 5-HT as the specific mechanism for the amphetamine-analog neurotoxicity. The hydroxy radical theory also accounts for the fact that amphetamine-analog neurotoxicity is selectively toxic to the DA and/or 5-HT systems of the brain; that is, the toxin is formed either in the synapse or within the neurons that release DA and/or 5-HT as a result of amphetamine analog treatment. The toxic drug metabolite theory, while not exhaustively studied, has little support from the literature at present. Similarly, the NMDA receptor mediation theory, in its most straightforward form, also has little support from the literature. The protective effects of the NMDA receptor antagonist MK-801 may be a modulatory effect resulting from changes in temperature regulation, rather than a direct effect of antagonizing a link in the toxic mechanism itself. It should be noted that the effects of the protective agent plus amphetamine-analog combinations on body temperature, when thoroughly investigated, may serve to separate agents which protect through a cooling mechanism from agents that protect by interfering with the toxic process itself.