Our study reveals a paradoxical phenomenon in the global burden of DUDs. Despite an 8% reduction in ASIR, total mortality rate more than doubled. This disparity was most extreme in high-SDI regions, where North America recorded an 11.2-fold rise in drug-related deaths. This finding suggests that while preventive measures may have reduced new cases, critical gaps remain in harm reduction and treatment interventions, leading to escalating mortality (6, 12, 15). The global decline in incidence likely reflects partial success of prevention strategies, including enhanced prescription drug regulations and educational interventions in some regions. However, the concurrent rise in mortality and DALYs indicates systemic failures in emergency care, harm reduction, and treatment retention for existing cases. This divergence underscores that prevention alone cannot address the multifaceted health risks of DUDs, necessitating comprehensive approaches integrating prevention, intervention, and long-term management (16).

In the past decades, the global architecture of drug policy underwent marked heterogeneity. High-income jurisdictions progressively supplanted punitive paradigms with harm-reduction frameworks rooted in public-health principles (17). Yet implementation remains uneven: Western Europe exhibits robust coverage, whereas Central and Eastern Europe and the Western Balkans report persistent legal and socio-cultural barriers that attenuate programme reach (18) (19). Conversely, North America experienced pharmaceutical deregulation during the same interval, precipitating unprecedented increases in prescription-opioid availability (20). This regulatory trajectory aligns with the region’s concomitant rise in age-standardised DALYs and incidence rates attributable to opioid use disorders, the highest globally recorded. In East Asia, stringent prohibitionist regimes—most notably China’s 2008 Anti-Drug Law—have coincided with declining ASR of drug-use disorders (21). Collectively, these divergent policy regimes and their differential enforcement offer a compelling explanation for the pronounced regional disparities in drug-related health burdens observed over the study period.

Notably, our study provides comprehensive epidemiological evidence establishing opioids as a predominant contributor to the global burden of DUDs. The marked rise in opioid-attributable DALYs reflects two concurrent phenomena: 1) the extensive proliferation of opioids in both medical and illicit markets, and 2) a public health crisis in high-income nations driven by overprescription, aggressive pharmaceutical marketing, and regulatory failures (22, 23). These findings suggest that despite greater healthcare resources, high-income countries face significant challenges in opioid stewardship, with inadequate distribution systems and regulatory oversight potentially exacerbating socioeconomic burdens. This evidence complements existing research on postoperative opioid risks (24) and reinforces the critical importance of robust regulatory frameworks in preventing opioid misuse, as previously emphasized by Hall and Degenhardt (25). Furthermore, our results challenge the efficacy of single-substance intervention strategies, particularly given the 108% increase in cocaine-related mortality observed in parallel with rising opioid burdens. The frequent co-use of cocaine and opioids—with their potential synergistic toxicity—presents unique clinical and public health challenges (26), underscoring the need for integrated approaches to address polysubstance use disorders (27).

DUDs are strongly associated with socioeconomic determinants including economic inequality, unemployment, low education, and weak social support systems (26, 28), with these disparities further compounded by sociocultural factors such as ethnicity, gender, and migrant status (29, 30). Empirical evidence consistently shows that regions experiencing greater economic distress exhibit elevated DUDs prevalence, with these burdens extending beyond health outcomes to impact social stability and national security (31). Particularly concerning are institutional settings such as prisons, where systemic deficiencies and social marginalization contribute to disproportionately high rates of DUDs and comorbid mental health conditions (32). Addressing these challenges requires both a deeper understanding of the complex socioeconomic-health relationships and methodological advancements in research approaches. Recent developments in disparity analysis frameworks and cost-effectiveness threshold methodologies offer improved tools for evaluating public health interventions (33, 34). Furthermore, multinational comparative studies have enhanced our capacity to quantify and address regional health inequalities (Mokdad, 2018), providing critical evidence to inform more targeted and effective policy responses to the DUDs epidemic (28).

Despite significant advances in burden assessment and intervention strategies for DUDs, several key limitations persist in current research. First, DALYs are limited by inconsistent data quality and reporting, especially in low- and middle-income countries (LMICs) where underreporting and bias are common (35). This, combined with scarce primary data, leads to reliance on models that may reduce estimate accuracy (36, 37). Second, research often focuses on single substances, ignoring polysubstance interactions and cumulative effects (38). Third, few multinational studies limit the understanding of cross-cultural DUDs variations. Additionally, underestimating mortality linked to some substances (e.g., cannabis) can result in burden miscalculations (39). Lastly, while descriptive analyses are common, rigorous evaluations of prevention and treatment interventions are lacking, hindering evidence-based policy and program development (40).