An enduring threat: NPS benzodiazepines in forensic and clinical toxicology from 2021 to 2025.

The proliferation and sustained detection of novel psychoactive benzodiazepines in forensic and clinical toxicology, combined with their potential for adverse events, poses an enduring threat to public health and safety with complex characteristics and challenges unique from other subclasses of novel psychoactive substances (NPS). This study aimed to systematically review the published effects, observations, and toxicological data from postmortem and human performance studies [including clinical, driving under the influence of drugs (DUID), and drug-facilitated crimes (DFC)] involving NPS benzodiazepines from 2021 to 2025. The challenges this class of compounds presents to clinicians, toxicologists, and medical professionals were also addressed, including both analytical and interpretative challenges. Literature reviews were performed in PubMed, Google Scholar, Google Search, toxicology journals, and conference abstract proceedings using search terms such as "NPS benzodiazepines," "designer benzodiazepines," and compound specific searches; authoritative websites such as NPS Discovery, National Forensic Laboratory Information System, and the European Union Drug Agency were also consulted. A total of 259 NPS benzodiazepine-related studies were identified including 29 postmortem, 15 DUID, 27 clinical, and 5 DFC studies detailed in this review. NPS benzodiazepines were widely pervasive in both postmortem and human performance cases with overlapping toxic and recreational concentrations; often involving polysubstance use with other central nervous system depressants and stimulants. Unique clinical presentations, observed effects, and autopsy findings were also reported for NPS benzodiazepines. This review provides an updated, consolidated resource to support toxicologists and clinicians in interpretation, emerging risk assessment, and evolving challenges associated with NPS benzodiazepines across postmortem and human performance settings.