3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) is widely consumed recreationally. Currently little is known about its effects on the human metabolome. Mapping biochemical changes after drug exposure can complement traditional approaches by revealing potential biomarkers of organ toxicity or discovering new metabolomic features in a time- and dose-dependent manner. We aimed to analyze for the first time plasma samples from a randomized, double-blind, placebo-controlled crossover study in healthy adults to explore changes in endogenous plasma metabolites following a single intake of MDMA. Plasma samples from 15 subjects taken at four different time points were analyzed with the commercially available AbsoluteIDQ® kit (Biocrates). Time series analysis revealed a total of nine metabolites which showed a significant concentration change after MDMA administration compared with placebo. Paired t-tests of the single time points showed statistically significant concentration changes mainly of glycerophospholipids and the metabolic ratio of methionine-sulfoxide over methionine. Changes of this metabolic ratio may be indicative for changes in systemic oxidative stress levels, the increased amount of glycerophospholipids could be interpreted as an upregulation of energy production. Baseline samples within the experimental study design were crucial for evaluation of metabolomics data as inter-day individuality within subjects was high otherwise resulting in overestimations of the findings.