This paper proposes a model of MDMA-induced neurotoxicity arising from a cascade of effects stemming from energy impairment and involving a highly reactive metabolite of serotonin (5-HT), tryptamine-4,5-dione (T-4,5-D). However, the model is not tested directly in this report, and the authors state that it would be very hard to detect T-4,5-D in vivo because of its high reactivity. In this report, the authors investigate the ability of T-4,5-D to alter or inhibits an element of mitochondrial respiration, as measured in rat brain mitochondrial preparations. T-4,5-D inhibited state 3 respiration in mitochondria in the presence of pyruvate, and it also inhibited state 3 respiration in the presence of alpha-ketoglutarate. However, other studies, including that of Yuan and colleagues (Yuan et al. 2002, located this month) appear to contradict models based on energy exhaustion. In addition, the serotonin precursor 5-HTP appears to be neuroprotective in studies MDMA neurotoxicity in rodents. These findings make it difficult to support the case for neurotoxic effects of a reactive 5-HT metabolite, regardless of findings reported here.