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Objective: The aim of the present study was to investigate the neuroprotective effects ofMelissa officinalis, a major antioxidant plant, against neuron toxicity in hippocampal primaryculture induced by 3,4-methylenedioxymethamphetamine (MDMA) or ecstasy, oneof the most abused drugs, which causes neurotoxicity.Materials and Methods: 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-tetrazolium bromide (MTT)assay was used to assess mitochondrial activity, reflecting cell survival. Caspase-3 activity assayand Hoechst / propiedium iodide (PI) staining were done to show apoptotic cell death.Results: A high dose of ecstasy caused profound mitochondrial dysfunction, around 40%less than the control value, and increased apoptotic neuronal death to around 35% morethan the control value in hippocampal neuronal culture. Co-treatment with Melissa officinalissignificantly reversed these damages to around 15% and 20% respectively ofthe MDMA alone group, and provided protection against MDMA-induced mitochondrialdysfunction and apoptosis in neurons.Conclusion: Melissa officinalis has revealed neuroprotective effects against apoptosisinduced by MDMA in the primary neurons of hippocampal culture, which could be due toits free radical scavenging properties and monoamine oxidase (MAO) inhibitory effects.