Interest and limits of using pharmacogenetics in MDMA-related fatalities: A case report

Abstract

Interpreting postmortem concentrations of 3,4-Methylenedioxymethamphetamine (MDMA) remains challenging due to the wide range of reported results and the potential idiosyncratic nature of MDMA toxicity. Consequently, forensic pathologists often rely on a body of evidence to establish conclusions regarding the cause and the manner of death in death involving MDMA. Given these issues, implementing pharmacogenetics' (PGx)' testing may be beneficial. Here, this report discusses an MDMA-related fatality and explores the benefits and limitations of implementing pharmacogenetics (PGx) analysis in such cases. A 34-year-old white European male was found dead at home, lying naked on his bed in a state of marked rigor mortis. MDMA and methylenedioxyamphetamine were quantified using liquid chromatography coupled to tandem mass spectrometry at respectively 3800 and 170 µg/L in femoral blood. PGx analysis was performed on a peripheral blood sample collected in EDTA tube. Deep analysis of cytochrome P450 (CYP) 2D6, 1A2, 2B6, 2C19, 3A4 and catechol-O-methyltransferase (COMT) genes (including copy number variations analysis) was performed by Next Generation Sequencing (NGS) on an Illumina MiSeq® sequencer using the Pharmacogenomics community panel (SOPHIA genetics® x RNPGx). The data obtained was analyzed using Sophia DDM® software. PGx analysis revealed three variants in CYP2C19 (rs75087398, rs12248560 and rs11188072) resulting in a CYP2C19 * 1/* 17 genotype, predictive of a rapid metabolism phenotype, implying greater MDMA elimination. Additionally, two variants were found in the COMT gene (rs4633TT, rs4680AA). In the literature, carriers of rs4680AA or rs4680GA genotypes exhibit lower enzyme activity compared to those homozygous for the G allele. Low COMT activity level has been associated with increased MDMA cardiovascular effects and biological changes, including an increased risk of hyponatremia which is particularly relevant here regarding the potential mechanism of death. Despite these findings, there are currently too few available studies to draw any definitive conclusions, indicating a need for further research in this area to fully understand all the implications. Moreover, focusing solely on metabolic enzymes may not fully explain all the variability in MDMA toxicity. A holistic genetic approach is necessary, incorporating both metabolic enzymes and pharmacological targets, including serotonin, dopamine, and norepinephrine transporters and receptors.

Keywords: 3; 4-Methylenedioxymethamphetamine; MDMA; Pharmacogenetics; Phenoconversion; Toxicogenetics.