Drug-related fatalities in the EU are predominantly associated with opioids. MDMA (Ecstasy) consumption results in fewer lethal intoxications despite its widespread use. This study investigates MDMA-related fatalities, focusing on enantiomer ratios of MDMA and its metabolite MDA to explore the role of metabolism in fatal outcomes. MDMA induces euphoria, increased empathy, and physiological effects such as tachycardia, hypertension, and hyperthermia. Metabolism mainly involves CYP1A2 and CYP2D6, with polymorphism of the latter influencing metabolism rates. Our institute observed several MDMA-related fatalities, which prompted an investigation into the potential role of inefficient drug metabolism in these cases. A novel quantitative chiral analysis method was developed and validated for MDMA, MDA, amphetamine and methamphetamine enantiomers in human blood. Analysis of post mortem blood samples from eleven MDMA-related fatalities exhibited a wide range of concentrations and enantiomer ratios. Variability in R/S MDMA ratios, however, could be linked to the time period of metabolism. Hair analysis revealed high MDMA concentrations in all segments, irrespective of prior drug abuse anamnesis. Therefore, hair analysis may not be suitable for the assessment of past drug use in ecstasy-related fatalities. The results indicated that elevated levels of the MDMA enantiomer are correlated with longer survival times in cases of intoxication. However, there was no clear evidence for slowed MDMA metabolism as a cause of lethal intoxications. While challenges remain due to the diversity of cases, this study contributes valuable insights into ecstasy intoxications, aiding future interpretation of post mortem analysis.