The continuous emergence of New Psychoactive Substances enter-ing the illegal markets poses always new challenges to forensic and clinical toxicology laboratories facing the lack of analytical methods capable of determining the newer parent compounds and eventual metabolites. More than 50 new molecules have been reported by the European Monitoring Centre for Drugs and Drug Addiction only in 2021, further expanding the panel of target analytes. However, the implementation of new detection methodologies may not be viable due to time constraints and inadequate resources. To this concern, the updatable analytical screening methods constitute a powerful tool for pharmacotoxicological laboratories investigating both non biological seizure materials and conventional and non conventional matrices coming from intoxications and fatalities of drugs consumers.