Introduction: Wastewater-based epidemiology (WBE) has emerged as a timely, non-invasive, and cost-effective indicator of illicit drug consumption. It is increasingly used by international organizations as a proxy measure for estimates of drug prevalence and related trends. Nevertheless, the literature exploring the limitations of WBE remains limited. This paper aims to shed further light on important shortcomings of WBE with recommendations on moving forward. Method: Utilizing case study and statistical analysis, the paper critically reviews methodological challenges associated with WBE results related to (i) levels, (ii) trends, and (iii) between-city comparisons of drug use. Data from raw influent wastewater samples from wastewater plants in the cities of Oslo, Bergen and Stavanger/Sandnes were analysed for amphetamine, methamphetamine, MDMA, and cocaine (benzoylecgonine) over a 3-year period. Normalized population loads were calculated and variation in daily loads analysed with plots and estimation of means, confidence intervals, and coefficient of variation. Linear regression models examined trends and between-city differences. Results: Plots and statistical analyses revealed extensive variation in daily loads, with min/max values of 6.1/453.9 mg/day per 1,000 inhabitants 15–64 years for amphetamine and correspondingly 9.4/675.9 mg for methamphetamine. Substantial differences in load levels and patterns across time and plants were also observed. A carefully designed sampling procedure and a relatively large number of daily samples are required to obtain estimates of sufficient precision for determining trends in space or time. Cross-referencing with alternative trend variables can improve the interpretation of WBE trend indicators. Finally, when using mean load levels for different wastewater-treatment plants to assess spatial variation in drug use, the representativeness of the catchment area should be evaluated before interpreting observed changes as city differences. Conclusion: Although WBE is a useful supplementary indicator of illicit drug consumption, important methodological issues and potential shortcomings should be taken into account when designing sampling procedures and interpreting the analytical results.

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