Atypical postmortem redistribution in chronic methadone consumers.

Available literature demonstrates that methadone is prone to moderate postmortem redistribution, but subject to high interindividual variability in the central to peripheral blood concentration ratios (C/P). In this case series, 10 cases of chronic methadone users displaying C/P < 1 (range 0.26-0.82) are described. Femoral, cardiac and ante-mortem blood concentrations of methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) are reported for all cases, as well as sex, age, case history, results of the pathological investigation, other toxicological findings and cause and manner of death. EDDP blood concentrations, similar in both central and peripheral blood, as well as antemortem blood concentration results in Case 4, demonstrate that this atypical C/P < 1 finding is attributable to postmortem changes and not analytical or pre-analytical artifacts. Case 4 is a particularly instructive example, with femoral blood concentration (966 ng/mL) approximately twice as high as cardiac blood (499 ng/mL) and ante-mortem blood (418 ng/mL, collected 38 min prior to death)-clearly demonstrating that cardiac blood methadone concentration is more representative of the antemortem blood concentration in this case. In Case 4 and four others, toxicological interpretation based on femoral blood concentration alone would have been misleading. Based on these results and evidence from the literature, it is hypothesized that methadone bioaccumulates in the tissues of chronic users and redistributes from thigh tissues into femoral blood, increasing the concentration postmortem. This case series highlights how femoral blood is not always preserved from postmortem changes and that the analysis of multiple blood sources is necessary to avoid a misleading toxicological interpretation-particularly for cases of chronic methadone users.

Postmortem redistribution of cannabinoids: Statistical analysis of a novel dataset and meta-analysis.

The assessment of human postmortem concentrations of Δ9-THC (THC) and its metabolites, 11-nor-9-carboxy-THC (THCCOOH) and 11-hydroxy-THC (11-OH-THC), is routinely performed in forensic toxicology laboratories. However, the literature on cannabinoids postmortem redistribution (PMR) is scarce and highlights their complex postmortem changes. This study aims to investigate the postmortem behavior of THC and its metabolites in order to provide practitioners with potential indicators of PMR. To do so, antemortem and postmortem cases positive for cannabinoids were compiled in a database. Its analysis shows significantly higher THC concentrations in postmortem blood than in antemortem blood. Antemortem and postmortem blood also present significantly different profiles for their THC to THCCOOH ratios. Whereas antemortem blood generally shows THCCOOH concentrations higher or equal to THC, several postmortem cases show the opposite, with THC concentrations higher than THCCOOH. While occurrence of postmortem redistribution (PMR) is difficult to measure directly, an evaluation was performed using the central to peripheral (C/P) blood concentrations ratio as a proxy. With a C/P significantly lower than 1.0 for THC and significantly higher than 1.0 for THCCOOH, the PMR hypothesis is supported for both compounds, with redistribution towards peripheral blood for THC and towards central blood for THCCOOH. On the other hand, 11-OH-THC does not show a C/P significantly different than 1.0, suggesting the absence of PMR. Influence of body mass index, conservation state and postmortem interval on C/P was statistically analyzed and no significant impact was observed. To compare and contrast C/P observed in the database with those published in the literature, a meta-analysis was performed using a median of median (MM) model. THC PMR towards peripheral blood is supported by a global estimate of 0.81 (CI95%: 0.51 to 1.2). Redistribution towards femoral blood appears to be stronger than towards iliac blood; indeed, the median estimate of C/P decreases to 0.64 (CI95%: 0.40 to 1.1) when studies with iliac blood were removed from the meta-analysis. THCCOOH PMR towards central blood is supported by a C/P median estimate of 1.3 (CI95%: 0.97 to 1.6). THC PMR can be suspected when these indicators are observed (i) high THC blood concentration (>50 ng/mL), (ii) THC C/P lower than 1.0 (iii) blood THC/THCCOOH concentration ratios greater than 1.0 and (iv) non-detectability of THCCOOH in urine. In postmortem samples, many factors may contribute to the overestimation of THC concentration, therefore a careful interpretation is required, relying on both central and peripheral blood samples.

A comprehensive analytical process, from NPS threat identification to systematic screening: Method validation and one-year prevalence study.

Several New Psychoactive Substances (NPS) enter the illicit drug market each year. This constant evolution of compounds to screen is challenging to law enforcement and drug chemists, and even more so to forensic toxicologists, who need to detect such compounds which might be at low concentrations in complex biological matrices. While some technological solutions are better suited than others to address such a challenge (e.g., high resolution mass spectrometry), laboratories with limited instrumental and financial resources are faced with a complex task: systematically screening for a rapidly evolving NPS panel using an accredited method run on standard equipment (e.g., liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)). This work presents a solution to this challenge: a complete workflow from the detection of a regional NPS threat to its implementation in a method accredited under the ISO 17025:2017 norm. Initial LC-MS/MS method included 55 NPS and metabolites (31 Novel Synthetic Opioids (NSO), 22 NSO metabolites and 2 designer benzodiazepines). Following their identification as relevant territorial threats, flualprazolam, then isotonitazene, were added to the contingent. By relying on development aiming for maximal integration to the current analysis workflow, systematic NPS screening using this method was easily implemented. Between March 2019 and March 2020, the 5 079 forensic cases analyzed in the province of Québec (Canada) revealed a NPS positivity rate of 3.4%. While 94% involved designer benzodiazepines, 5% involved NSO. This process, combining high efficiency, simple detection technology, ISO accreditation and rapid response to new threats resulted in a four-fold increase in NPS detection.

Challenges Related to Three Cases of Fatal Intoxication to Multiple Novel Synthetic Opioids.

In the last two decades, a large increase in opioid overdose death rates has been recorded in North America. This phenomenon, related to the misuse of prescription opioids, has been dubbed an "opioids crisis". Recent years have seen the entrance of novel synthetic opioids (NSO) on the market, compounding the fatal intoxications issue. This brings several challenges for forensic toxicology laboratories: an increased number of cases, a large number of novel structurally similar compounds to include in screening analytical methods, the low concentration of drugs in biological fluids, and the challenging interpretation in the absence of sufficient literature. Three cases of fatal intoxication highlighting those challenges are presented, complete with post-mortem concentrations in cardiac blood, femoral blood and urine. Toxicological screening and quantitative analyses were performed on the biological specimens. In the first and second cases, furanylfentanyl, U-47700 and 4-anilino-N-phenethylpiperidine (4-ANPP) were detected at similar concentrations in cardiac blood. In the third case, a total of seventeen different NSO were detected. All intoxications showed a combination of NSO and other drugs. These three cases appear to be the harbinger of an increased NSO prevalence in the province of Québec, Canada.