The purpose of this Funding Opportunity Announcement is to support the discovery and development of medications to prevent and treat opioid and/or psychostimulant use disorders and overdose. The UG3/UH3 Phase Innovation Awards Cooperative Agreement involves 2 phases. The UG3 is to support a project with specific milestones to be accomplished by the end of the 2-year period. The UH3 is to provide funding for 3 years to a project that successfully completed the milestones set in the UG3. UG3 projects that have met their milestones will be administratively considered by NIDA and prioritized for transition to the UH3 phase. Investigators responding to this FOA must address both UG3 and UH3 phases. Application may include preclinical or clinical research studies that will have high impact and quickly yield the necessary results to advance closer to FDA approval medications that are safe and effective to prevent and treat OUDs and overdose. The compounds to be evaluated can be small molecules or biologics. They can be tested in pre-clinical models and/or for the clinical manifestations of OUDs such as withdrawal, craving, relapse, or overdose. Applications may focus on the development of new chemical entities, new formulations of marketed medications available for other indications, or combinations of medications that hold promise for the treatment of OUDs and overdose. Through this FOA, NIDA seeks to fast-track the discovery and development of medications to prevent and treat OUDs or opioid overdose and to advance them in the FDA's drug development approval pipeline.