This is a competitive renewal of a NIDA-funded P50 Center that serves as a Medication Development Center of Excellence (MDCE). Our MDCE complements Penn's longstanding research program to develop effective addiction treatments. Our MDCE is integrated within the umbrella of the PennA/A Center for the Study of Addiction, allowing us to focus on pharmacotherapy for cocaine alcohol dependence (CAD). Yet, the MDCE benefits greatly from Center integration because it permits access to infrastructure resources not provided by a P50 Center. The MDCE has priority access to important resources: 1) Clinical Translational Research Center - an inpatient/outpatient facility for human laboratory trials; 2) Center bio-statistician; 3) web-based Data Management Unit; and, 4) a specialty drug screen laboratory. Our theme is testing innovative medication combinations for managing hard-to-treat CAD patients. This group responds poorly to existing treatments and is notoriously treatment nonadherent. Our MDCE proposes to continue testing new medications singly and in combination with an emphasis on novel medications not yet approved by the FDA, plus improved treatment adherence procedures. The CORE will coordinate and integrate a Neuro Core Pilot Program and three Components. Core functions also identify candidate medications, conduct safety studies of medication combinations and their interactions with cocaine and/or alcohol, and provide a mentoring structure for new investigators. The Neuro Core Pilot Program emphasizes a multidimensional neuroimaging-behavioral-genetic model that identifies individual predictors of response to the medications to be studied in MDCE Components. The Components reflect developing prototypes, which contain descriptions of projects planned over the next 5 years. Projects are arranged to allow for novel medications to be studied from safety through efficacy, singly and in combination, to make more informed selections for clinical trials from among the group of candidates now available. Component 1 proposes to evaluate promising novel compounds in 9-week placebo-controlled trials. Component 2 proposes human lab studies to evaluate the mechanisms by which those compounds may decrease cocaine use, also providing more safety data for these compounds. Component 3 will test the efficacy of specific medication combinations for CAD. By starting with a large number of candidate medications and sequentially testing as described, we hope to more rapidly identify effective medications that justify the next level of development: Multi-site trials.