Leveraging partnerships to address substance use among American Indian and Alaska Native populations: A commentary on research within the NIDA Clinical Trials Network.

American Indian and Alaska Native (AI/AN) communities experience a disproportionate burden of substance use disorders (SUDs) alongside persistent barriers to culturally responsive care and research participation. Despite this need, AI/AN populations remain underrepresented in substance use research, in part due to historical and ongoing systemic inequities, including research practices that have not adequately respected Tribal sovereignty or incorporated Indigenous knowledge systems. This commentary synthesizes research conducted within the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) focused on AI/AN communities, identifies key lessons learned from this body of work, and offers recommendations for future research. First, we provide an overview of CTN-supported studies involving AI/AN populations, highlighting both the diversity of substance use patterns across communities and the feasibility of conducting rigorous, culturally responsive research. Second, we synthesize lessons learned from these studies and related literature, including the importance of long-term relationship building, the need for culturally responsive research frameworks, structural barriers to implementation, and workforce and infrastructure challenges. Third, we present recommendations for the field, emphasizing the central role of community-based participatory research (CBPR) and Tribal participatory research (TPR), the integration of Indigenous knowledge systems, and the importance of Tribal data sovereignty and community-led dissemination. Collectively, this commentary argues that sustainable progress in addressing SUDs among AI/AN populations requires a fundamental shift toward community-engaged, culturally responsive, and equity-focused research partnerships. The experiences of the CTN AI/AN Special Interest Group demonstrate that such approaches are not only feasible but essential for advancing both scientific knowledge and community health.