Background: 3, 4-methylenedioxymethamphetamine (MDMA) is a chemical derivative of amphetamine that can induce learning and memory impairment. Due to the effect of neurotrophins on memory and learning, the impact of MDMA was evaluated on the brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and tropomyosin-related kinase B (Trk-β ) expression in the hippocampus. Methods: In this study, 20 adult male Wistar rats (200-250 g) received saline (1 mL) or 10 mg/kg of MDMA intraperitoneally as single or multiple injection for 2 consecutive days per week for 2 months. Expression of BDNF, Trk-β , and NT4 were assessed using Western blotting and RT PCR methods. Results: Our results revealed that the expression of BDNF, Trk-β , and NT4 proteins and genes significantly decreased in MDMA groups compared to the sham group (p<0. 05). Furthermore, the acute group showed the lowest expression of these proteins. Conclusion: The results of the present study suggest that ecstasy administration may downregulate the expression of BDNF, Trk-β , and NT-4 in hippocampus, which is more extensive in case of acute treatment. It seems that in the chronic group, hippocampus was able to compensate the ecstasy-induced neurotoxicity.