Background: “New psychoactive substances” (NPS), has been described as a “growing global epidemic”. The aim of our study was to document acute and chronic lesions that can be induced by NPS from autopsy cases for which complete toxicological analyses (including hair analysis) have been performed, in order to better define the role of NPS in the mechanisms of death. Material and methods: A retrospective study was performed at the Department of Forensic Medicine and Pathology, jointly with the Department of Pharmacology and Toxicology. All records for forensic autopsy case within a 6-year period, from January 2016 to January 2021, were reviewed for the diagnosis “death associated with NPS”. Results and discussion: Twelve young male adults complied with the inclusion criteria. Lifestyles were dominated by drug addiction and homosexual context which could be anchored in a practice of ChemSex or even of “slamming”. In regard to autopsy findings, previous pathological state was dominated by cardiovascular and hepatic lesions possibly of toxic etiology. Causes and manners of death were, on the whole, quite heterogeneous; however, an accident as a manner of death was the most frequently observed. In terms of histological findings, the most notable lesions were: (1) cardiovascular (sequelae of myocardial infarction probably secondary to a vasospasm, accelerated atherosclerosis); (2) hepatic (steatohepatitis); (3) neurological (peri mortem convulsions); (4) renal (granular cylinders that may indicate rhabdomyolysis); (5) pulmonary (chronic instertitial inflammation); all of them may have had a toxic origin. In regard to toxicological findings, our case series was mostly subject to chronic consumption of synthetic cathinones, in particular 3-MMC; their involvement in the fatal determinism was retained in 7 cases. Tissue distribution was highlighted as increased in brain, explaining at least partially psychoactive effects of these NPS. Average cardio-femoral ratio of 3.78 suggested a cardiac tropism. A lethal concentration of mexedrone, measured at 640 ng/mL, was described for the first time. Conclusion: We provide autopsy data on NPS consumption habits in Ile-de-France, namely men who have sex with men in ChemSex. Macroscopic and microscopic lesions observed were cardiovascular, hepatic, neurological, renal and pulmonary. From a toxicological point of view, we collect additional data on toxic, even lethal concentrations of NPS. Concerning 3-MMC, calculated cardio-femoral ratio is positive; moreover, it is to our knowledge the first study that demonstrates its pharmacokinetic tissue distribution.