Molecular Aspects of Forensic Toxicology

Dear Colleagues,

The best evidence provided in the literature worldwide suggests the importance of harmonizing the investigation of molecular research in drug-related fatalities. Although death-scene findings could be highly suggestive of drug intoxication, external examination and toxicological screening tests alone are insufficient.In forensic toxicology, it is essential to understand the pivotal role of pharmacogenetics (the study of how genetic variations give rise to differences in drug response), considering that pharmacokinetics, pharmacodynamics, and the bioavailability of a drug are conditioned by a genetic substrate. In this scenario, pharmacogenetics may be helpful to solve toxicological puzzles, especially in cases of suicides, accidents, and death by unknown cause. The possible influence of pharmacogenetics on drug metabolism should also be considered when interpreting the post-mortem concentration of a substance in body fluids or organs. Currently, deaths from overdose continue to increase in prevalence due to the diffusion of novel illicit drugs. Moreover, a higher risk of overdose is associated with younger age, polydrug use, and heroin abuse. Post-mortem toxicology has a crucial role in determining the cause and manner of death when illicit drugs consumption or poisoning is suspected. Therefore, it has relevant public health and social functions. The toxicology laboratory can identify and measure drugs in biological samples assisting the forensic pathologist and the medical examiner in their work. The recommendations regarding the investigation, evaluation, and certification of deaths related to drugs misuse were recently updated by the National Association of Medical Examiners and an expert panel of medical toxicologists. The best evidence provided in the literature worldwide suggests the importance of harmonizing the investigation in drug-related fatalities. The application of pharmacogenetics and pharmacogenomics allows researchers to produce entirely new vantage points from which to examine the therapeutic landscape, allowing a priori determination of what the dosing and the expected patient response will be and producing a pre-determined estimate of whether nefarious effects ought to be observed as a result of such medical interventions. Recently, pharmacogenomics, as a tool of molecular autopsy, has been used for the assessment of genetic contribution to drug toxicity in post-mortem forensic toxicology. The findings, as well as other applications of clinical and scientific findings in forensicscience, might add to the understanding of disease mechanisms and optimization of treatment including drug therapy. In addition, the use of pharmacogenomics in forensic toxicology may add to the understanding of drug toxicity due to genetically linked impairment of drug metabolism; it may also provide findings that may be back-extrapolated for the benefits of optimizing antemortem drug therapy. Pharmacogenomics in forensic toxicology would, thus, provide a better interpretation of the obtained results, indirectly enabling the emergence of personalized medicine.The full use of post-mortem PGx is only possible by integrating forensic pathology, toxicology, and genetics. Pathophysiological condition(s) and the concentrations of all drugs and their relevant metabolites in the body at the time of death, combined with the genotype, could shed light on the prediction of individual responses.All the data collected in this manner should be considered alongside the fact that the effect of an individual’s pathophysiological phenotype on drug efficacy (the ability of a drug to produce the desired therapeutic effect) depends, to some degree, on the individual’s genetic constitution and several other factors. These additional factors include developmental stage, physiological and environmental factors, and associations with disease states or specific conditions, such as ion channelopathies (e.g., long QT syndrome), diabetes, obesity, and gut microbiology.The quality of forensic diagnosis is affected by the quality of toxicological analyses, technical equipment, personnel competence, and financial resources. Moreover, there are extreme regional and national differences in the post-mortem diagnosis of drug-related deaths. Such scenarios influence investigation results, leading to lower quality and contributing to epidemiological reports and public health and law enforcement measures. In this regard, high-quality and standardized methodologies are required in forensic diagnosis for the identification of drug-related deaths. When drug intoxication is suspected, a multidisciplinary approach to establish the cause and manner of death is mandatory.

The New Psychoactive Substances (NPSs) phenomenon represents an ever-changing global issue, with a number of new molecules entering the illicit market every year in response to international banning laws. While it has been confirmed that the most-represented class per analogue number and consumer is synthetic cannabinoid receptor agonists (SCRAs), newly emerging compounds active on opioid receptors have recently been reported, representing an unknown challenge for health specialists and toxicologists.

In conclusion, this Special Issue provides updated studies and reviews concerning the most recent aspects of drug abuse, their molecular mechanisms and pathophysiology, their toxicity, and their pharmacokinetic profiles. We aim to contribute to the general knowledge in this still-unclear field and highlight the importance of continuous investigation by the scientific community and health professionals.

Dr. Angelo Montana
Guest Editor

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• forensic toxicology
• molecular mechanism
• toxicological biomarkers
• post-mortem interval
• in vitro, in vivo, and in silico models
• new psychoactive substances (NPSs)
• new synthetic opioids
• liquid chromatography-high resolution mass spectrometry (LC-HRMS/MS)
• liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS)