Abstract Background Most chromatographic-based procedures have defined analytical scopes. This allows for laboratories to include the most relevant analytes in test panels and for care providers to know exactly what is included and excluded in ordered tests. Analytical scopes can be developed based on drug trend data, consensus body recommendations, or mandatory guidelines. However, it is reasonable to conclude that strictly adhering to these scopes, or not having robust processes in place that permit for rapid scope changes, will result in the underreporting of drug use in a population or miss a relevant drug finding for a single patient. For example, SAMHSA’s minimum mandatory guidelines for urine workplace drug testing does not include fentanyl. While true the number of fentanyl positive cases that are missed in this population is speculative, a factual case in point is made by evaluating laboratory results for a major novel psychoactive substance (NPS) drug class - designer benzodiazepines (DB). We performed a retrospective review to study the frequency that designer benzodiazepines would have been missed in reporting without further intervention by laboratory staff. Methods Blood samples were screened by ELISA and LC-TOF/MS. Confirmation testing using two different LC-MS/MS panels was conducted on samples that screened presumptive positive for benzodiazepines. Analytical results were retrieved from the laboratory’s data management system using the following criteria: a) date range: Feb 2023 to Feb 2024, b) blood matrix, c) DUID testing cases where benzodiazepine screening was performed by ELISA and by LC-TOF/MS, and d) at least one DB was reported regardless of the presence of other drugs. Results Nine parent DB or their metabolites were identified in the 46 cases in this study: 8-aminoclonazolam (n=3), alpha-hydroxyetizolam (n=2), bromazolam (n=35), clonazolam (n=2), deschloroetizolam (n=1), etizolam (n=1), flubromazolam (n=7), flualprazolam (n=1), and pyrazolam (n=1). Benzodiazepine screening by ELISA and LC-TOF/MS was positive for 45 and 46 cases, respectively. In the 45 cases that screened positive by ELISA, 41 did not confirm positive for any classical benzodiazepine (CBZ) which included alprazolam, diazepam, lorazepam, clonazepam, temazepam, oxazepam, and the nordiazepam metabolite. Only 4 cases tested positive for both a DB and CBZ (alprazolam or clonazepam) simultaneously. Conclusions While it is understood that defined analytical scopes are a laboratory necessity, care providers, law enforcement, public policy decision makers, and communities at large need to understand the limitations and regulations surrounding analytical test procedures. For some testing, a laboratory is obligated to follow mandatory guidelines, but from a clinical or medicolegal perspective, the risk is two-fold. The first is that the causative drug producing any untoward effects goes unrecognized. The second is that symptoms displayed are attributed to the presence of other drugs. This work stresses the importance of sincere collaboration between laboratories and entities that are responsible for analytical scope development and providing funding to ensure the appropriateness of real-time drug surveillance and reporting efforts.