In April 2018, the National Institutes of Health (NIH) launched the Helping to End Addiction Long-termSMInitiative or HEAL InitiativeSM, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Through this initiative the National Institute on Drug Abuse, in partnership with other NIH Institutes, Centers, and Offices, requests applications for studies designed to develop and test multi-level interventions to prevent opioid misuse, opioid use disorder, and co-occurring conditionsby intervening on social determinants of health (SDOH).This initiative aims to build an evidence base for multi-level interventions that target malleable factors and conditions affecting the social context. Applications must seek to reduce health inequities in a U.S. population or population subgroup affected by the opioid crisis by studyingthe effects of a theory driven, multi-level intervention on the prevention of opioid misuse/opioid use disorder and co-occurring conditions. Such conditions could include mental health conditions and/or suicide, and may alsoinclude other substance use and substance use-related outcomes. The research project must examinethe mechanisms by which the interventions exert their effects, and conduct economic analyses to inform decisions about adoption of strategies. Investigators should study interventions that are sustainable and easily taken to scale if effective.