Novel psychoactive substances (NPS) are a new emerging and analytically challenging group of drugs which present significant challenges to postmortem forensic toxicology. Conventional targeted assays and immunoassays that are commonly used for drug detection usually do not detect emerging analogues due to the fact that they are continuously modified and tend to be pharmacologically different. The limited availability of certified reference materials and incomplete metabolic data and the short detection windows of many parent compounds further complicate the reliable identification. The ability to identify new or unknown compounds and metabolites has been enhanced by the use of high resolution mass spectrometry as well as suspect and non-targeted screening methods, but these must be confirmed with strict criteria and regular updates to library databases. It is just as difficult to interpret positive results. Because of post mortem redistribution, chemical instability, and matrix effects, in addition to the absence of known toxic and lethal concentration ranges, it is not possible to make a simple extrapolation between the measured level and the estimated antemortem exposure or toxicity. The use of a combination of drugs, which often occurs with NPS-related deaths, creates further pharmacodynamic and pharmacokinetic interactions that make attribution of cause difficult. Thus, results from a positive analysis should not be considered as evidence of lethal contribution, toxicological data should be interpreted in conjunction with autopsy findings, pathological observations, medical history and case circumstances. The review highlights the opportunities and challenges of new analytical innovations and interpretive principles that must be embraced in a flexible and multi-platform workflow and with an integrated approach to case assessment to ensure the correct medicolegal conclusion in an evolving NPS environment.

Adrija Saha, Dr.Munish Kumar Mishra, Ms.Vetolu P Tunyi,"Analytical Challenges and Interpretation of Novel Psychoactive Substances (NPS) in Postmortem Toxicology" International Journal of Advanced Multidisciplinary Research and Educational Development, V2(5): Page(606-624) September - October 2026. ISSN: 3107-6513. www.ijamred.com. Published by Scientific and Academic Research Publishing.