Project Summary Many individuals with substance use disorders (SUDs) also experience significant psychological distress or meet the criteria for common mood and anxiety disorders with potentially significant implications for SUD outcomes and SUD treatment effects. Examining these implications is important for identifying optimal treatments for patients with comorbid conditions. Past research on the impact of such comorbidities has produced mixed results, mainly due to small sample sizes or reliance on observational studies. In this proposal, a large-scale study of the impact of 1) mood and anxiety disorder as well as 2) psychological distress comorbidity on SUD outcomes and SUD treatment effects is proposed using data from over 5,000 patients from 20 randomized controlled trials (RCTs) of pharmacological and psychosocial treatments of SUDs sponsored by the National Institute on Drug Abuse. Our aims include the use of modern individual participant meta-analytic methods to combine the individual level data and to examine whether and to what extent SUD outcomes and SUD treatment effects vary among patients with and without comorbidity. Outcomes will include retention in treatment to the end of the trial, continued use of drugs ascertained by urine toxicology and self- report, and social outcomes (including occupational outcomes and criminal justice involvement). In Aim 1, data from RCTs will be combined to examine the impact of psychiatric comorbidity (i.e., mood and anxiety disorders as well as psychological distress, jointly and separately) on the SUD outcomes, irrespective of treatment arm, using mixed effect regression models. The RCT samples will be balanced with regards to socio-demographic and clinical factors that may vary across studies using propensity score methods. Aim 2 will use a similar methodology to examine the moderating effect of comorbidity on SUD treatment effects by examining interaction terms of SUD treatment by comorbidity in mixed regression models. In Aim 3, we will examine whether concomitant medication treatment of mood and anxiety disorders will change the impact of these disorders on the SUD outcomes and SUD treatment effects. In Aim 4, we will reweight the RCT samples to resemble target samples of individuals with SUDs receiving treatment in the general population to address exclusion (and possible under-representation) of patients with severe psychiatric conditions from SUD RCTs. The results from reweighted samples will be compared with the results of the original unweighted samples. The project significantly advances research on the impact of these comorbidities on SUD outcomes and SUD treatment effects using individual participant data from an unprecedentedly large group of rigorously conducted trials that have used a core set of standardized assessments and consistent outcome measures.