Project Summary Stimulant use disorders, including cocaine and methamphetamine use disorders, impact the lives of millions of Americans and are associated with significant health and social consequences. There are currently no FDA- approved medications for treatment of stimulant use disorders. Most of the randomized controlled trials (RCTs) to find effective medications have been of short duration, typically lasting 8-12 weeks, and had small sample sizes. Attaining sustained abstinence from stimulants may require longer treatment and detecting these effects may require larger samples. However, available trials can provide information on short-term outcomes of treatment that are achieved earlier and less stringent than abstinence and, thus, help identify candidate medications for future long-term and larger trials. Drug craving is probably the most promising of such short- term outcomes. Stimulant use disorders are characterized by periods of heavy use followed by short periods of abstinence with withdrawal symptoms. These symptoms last a few days and are followed by increasing drug craving which often leads to relapse. Drug craving is a central phenomenon in these recurring cycles of drug use. Nevertheless, little research has specifically focused on craving as an outcome of stimulant use disorder or on reduction of craving as a mediator of abstinence or reduction in drug use. In the proposed project, we plan to examine craving as an outcome of stimulant use disorder as well as a mediator for other outcomes. More specifically, in Aim 1, we will compare the effect of 9 medications (in 11 RCTs) on stimulant drug craving. In Aim 2, we will assess the association of change in craving during trial with change in other outcomes and the potential mediating role of craving in the effect of treatments on these outcomes. In Aim 3 we will explore the variations in the effects of medications and in the association of craving with other outcomes in subgroups of patients. We propose to use individual participant data from 1,845 patients in 11 RCTs conducted in the context of NIDA’s Clinical Trials Network (CTN) and related trials to accomplish these study Aims. The project has the potential to significantly contribute to a better understanding of the role of craving in continued stimulant use disorder and the potential effect of medications on stimulant use disorders as mediated by their anti-craving qualities. Medications with anti-craving properties are currently used in treatment of nicotine and alcohol use disorders and have shown promising results in treatment of stimulant use disorders. The project also represents an efficient use of NIDA’s RCT data to answer new questions that were not addressed in the original studies. The findings would help identify candidate medications for future adequately powered trials based on the short-term anti-craving effects of candidate medications and contribute significantly to the ongoing efforts to find effective medic...