Setting <p>Advocates of a public health approach to psychoactive substances need actionable evidence. In several countries, multidisciplinary groups have used multi-criteria decision analysis (MCDA) to generate harm scores and rankings for commonly used psychoactive substances; however, these did not fully&#xa0;reflect substances’ prevalence of use. Public health policy decisions around psychoactive substances should be informed by population-level outcomes, which are driven by use prevalence.</p> Intervention <p>Led by a policy practitioner, a multidisciplinary group from across Canada conducted a MCDA of harms caused by 16 commonly used psychoactive substances. To make the analysis more relevant to public health policy, we adapted it to account for not only the severity of harms associated with a substance, but also prevalence of use. This adaptation was applied across harm criteria.</p> Outcomes <p>Adapting MCDA this way allowed for the generation of harm scores that represent total population-level harm caused by each substance rather than individual-level harm. As a result, they provide clear evidence of the relative population-level harm caused by different substances. This evidence can inform prioritization of public health efforts and be used by policy practitioners advocating for a public health approach to substances.</p> Implications <p>Adapting MCDA to reflect population-level outcomes is a practical innovation for public health policy and practice. Prevalence-adjusted MCDA produces evidence that is well aligned with how public health policy decisions are made and evaluated, and may be applicable to other public health issues characterized by multiple data sources and competing policy objectives.</p>