3,4-Methylenedioxymethamphetamine (ecstasy, MDMA) and related amphetamines are CNS stimulants that have euphoric, memory-enhancing and neurotoxic properties. When applied in pharmacological doses to cultured rat hippocampal neurons, ecstasy reduced the conductance of a 50-pS barium-sensitive resting K+ channel and increased neuronal excitability. Ecstasy enhanced synaptic strength by irreversibly increasing the amplitude of excitatory autaptic currents and the frequency of spontaneous excitatory postsynaptic currents. Ecstasy did not alter the amplitude of inhibitory autaptic currents or the frequency of spontaneous inhibitory postsynaptic currents but reversibly prolonged the decay phase of inhibitory autaptic currents and spontaneous inhibitory postsynaptic currents. These results suggest that K+ channel blockade and the effects on synaptic transmission may contribute to the pharmacological effects of ecstasy and other amphetamines.