This letter is in response to the comments by Byron and Cassel on our study entitled ‘Binge ethanol administration enhances the MDMA-induced long-term neurotoxicity in rat brain’. Byron and Cassel have published several studies in which they analyzed some of the behavioral and neurochemical effects induced by the concurrent administration of ethanol and MDMA to rats. As most of the results differed from those reported in our paper, they speculated in their comments about the possible reasons for this discrepancy. Nevertheless, doses of ethanol and MDMA, experimental design, ambient temperature, and strain are so different that what is really difficult is to find some common point between the studies carried out by the two groups. In contrast to the studies by Cassel’s group, in our study, the hyperthermia induced by MDMA was similar in rats exposed and not exposed to ethanol; in other words, ethanol did not prevent the rise in rectal temperature induced by MDMA. From our point of view, the key factor is that the last exposure to ethanol was carried out approximately 24 h before MDMA injection—that is, ethanol was not injected simultaneously with MDMA as in the studies by Cassel et al. We chose this experimental protocol precisely in order to avoid the possible interferences of the hypothermia induced by ethanol with the long-term neurotoxicity caused by MDMA. Numerous studies have shown that the prevention of MDMA-induced hyperthermia attenuates or abolishes the long-term neurotoxicity by the drug (Colado et al. 1999; O’Shea et al. 2006). Had ethanol been given together with MDMA, the result would have probably been quite different as the rats developed a significant hypothermia at least at the end of the first day of ethanol vapor exposure (Fig. 4; Izco et al. 2007). It is interesting to note that, in a similar protocol to ours, Cassel’s group also described a lack of effect of the 4-day ethanol preexposure (1.5 g/kg, i.p.) on MDMA-induced (6.6 mg/kg, i.p.) hyperthermia 24 h after the last ethanol dose (Hamida et al. 2006). Another crucial difference between our study and that of Cassel’s group is that in our study, MDMA was given at a high ambient temperature, which is often the environment in which MDMA is consumed recreationally. At a high ambient temperature, not only was the body temperature response to MDMA different to that observed at standard temperature, but rats preexposed to ethanol also showed a body temperature significantly higher than that of salinetreated rats. This could be related to alterations of the compensatory physiological responses that mediate temperature control and are triggered in response to a thermal challenge (Myers 1981). In the study where no enhancement of MDMA neurotoxicity by ethanol is observed (Cassel et al. 2005), the authors claimed that the dose of ethanol used (1.5 g/kg, i.p.) typically results in blood ethanol levels of 175 mg/dl. This appears to be below the level necessary to cause neurodegeneration (reflected by silver staining) in areas such as the hippocampus and the cortex of adults (250– 400 mg/dl; Obernier et al. 2002; Hamelink et al. 2005; Crews et al. 2006) and neonatal rats (379–432 mg/dl; West et al. 1986; Miki et al. 2000). In addition, the blood ethanol level and dose used by Cassel et al. (2005) were below those reported to produce oxidative stress in rat brains (Dahchour et al. 2005). An increase in the production of hydroxyl radicals is important in mediating the neurotoxic Psychopharmacology (2007) 190:581–582 DOI 10.1007/s00213-007-0700-8