Repeated small doses of MDMA produce a lasting pro-convulsant effect that lowers the threshold for limbic seizures and increases metabolic hyperexcitability in mice, even before structural changes like mossy fiber sprouting appear. While clinical seizures after MDMA use are often attributed to acute effects such as hyponatremia and hyperthermia, additional mechanisms involving monoaminergic systems may also contribute. Chronic effects of MDMA on seizure threshold have been underexplored, and this review presents preliminary data showing that seizure susceptibility emerges early, without accompanying mossy fiber sprouting.
MDMA treatment activates caspase-3, an enzyme involved in cell death, in the amygdala and hippocampus of rodents, but not in the striatum or frontal cortex. This indicates that limbic brain structures are particularly sensitive to MDMA's potential to trigger apoptotic pathways, which may help explain memory loss and cognitive impairments observed in chronic MDMA users.