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An overview of the latest technological advancements and knowledge in wastewater-based epidemiology (WBE) for monitoring illicit drug usage, using mass spectrometry-based analytical methods, is critically discussed with a particular focus on fentanyl-related substances. The higher potency of many such substances in comparison to other opioids, and thus the amount used, has posed significant challenges to their detection and reliable monitoring in wastewater matrices at the low nanogram per litre concentration level. Sample preparation approaches for multi-analyte qualitative screening and quantitative monitoring are discussed, with a particular emphasis on scalability for large national and international surveillance programmes. Following analytical measurement, this chapter also overviews the back-calculation process to determine community wastewater loadings and consumption, as well as some of the key constraints and limitations of the WBE methodology, especially regarding interpretation and ethics. Finally, examples of key WBE studies are discussed for fentanyl-related substances globally and in context with other opioids and illicit drugs. The use of WBE to measure the consumption of such substances represents a useful new and sustainable way to gather intelligence to guide interventions and actions to protect public health.

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