The effects of glucose metabolism on fenfluramine and MDMA neurotoxicity were investigated in rats using 2-deoxy-D-glucose, a compound that interferes with cellular glucose metabolism, thereby reducing glucose availability. Rats received 4 doses of 10 mg/kg fenfluramine or MDMA every 2 h or saline, either alone or in combination with 6 doses of 330 mg/kg 2-DG every 2 h, with 2-DG given 30 min before fenfluramine or MDMA. Because 2-DG lowered body temperature in fenfluramine-treated rats and attenuated hyperthermia in MDMA-treated rats, the researchers performed a second study wherein rats receiving all treatments were maintained in a warm environment (28 deg. C versus 22 deg C.) Rats were killed 2 wks after drug treatment, and concentration of serotonin (5-HT) and its metabolite 5-HIAA were measured in cortex, striatum, hypothalamus and hippocampus using HPLC. Serotonin transporter (SERT) density was assessed via binding assay with radiolabeled paroxetine (selective serotonin uptake inhibitor). 2-DG, given alone, did not reduce brain 5-HT, 5-HIAA or SERT density. Contrary to the authors' hypothesis, 2-DG did not potentiate reductions in 5-HT, 5-HIAA or SERT seen after neurotoxic fenfluramine or MDMA regimen; instead, it seemed to attenuate 5-HT reductions in striatum and hippocampus. When rats were placed in a warm environment, 2-DG no longer attenuated MDMA-induced reduction in 5-HT, 5-HIAA or SERT, but it still failed to potentiate MDMA neurotoxicity. Contrary to the authors' original hypothesis, reducing glucose availability via interrupting glucose metabolism did not potentiate the neurotoxic effects of either substituted amphetamine, despite findings of increased methamphetamine neurotoxicity when given after 2-DG. Because glucose metabolism may be linked to thermoregulation, it is still possible that some alterations in body temperature might be involved. These findings do not support models of MDMA neurotoxicity based on energy exhaustion, but do not lend support to any specific alternative model.