The overall aim of this K-05 proposal is to support and expand the applicant's work in developing and improving pharmacotherapy and psychotherapy for substance abuse as well as mentoring scientists embarking on such a career. The applicant has had a productive career in both areas, developing such programs first at Yale and currently at Columbia. During his eight years at Columbia the applicant has, in addition to these activities, served as Executive Vice President and Medical Director of CASA, a policy research center he and Joseph Califano founded in 1992. Receiving the K05 award would provide financial support for the candidate so that he could relinquish his CASA position with its administrative duties and policy research, and devote himself full time to biomedical research and training at the medical school. The applicant's current research has two major themes: 1) treating opioid withdrawal, 2) developing and improving medications and behavioral approaches for treating cocaine, heroin and marijuana dependence. Current funding for these areas is in hand for the first three years of this award. The applicant will direct a study comparing Anesthesia Rapid Opioid Detox (AROD) to Buprenorphine Rapid Opioid Detox to Clonidine Assisted Opioid Detox. The popularity of AROD has not been matched by evaluation of the technique, side effects and long term follow-up. This is the first controlled study to do so. In addition, the applicant will be PI at the Columbia site of a NIDA multi-site phase III trial of lofexidine, an alpha-adrenergic agonist with possible better efficacy than clonidine, and his Center will run an outpatient trial of a new Depot Naltrexone. Also focused on antagonist therapy is a Stage II Trial where he is Co-Investigator, testing a newly developed manualized psychotherapy for naltrexone-maintained individuals, which will also be the 1st study to test the usefulness of the new Depot Naltrexone in a clinical study. The Medication Development Research Center, where he is PI, focuses on targeting subgroups of addicts as well as development and/or utilization of models to improve testing potential medications. It includes human laboratory research on heroin, PET imaging, a large scale medication trial for cocaine, and testing potential medications for marijuana withdrawal and craving. In addition, the applicant plans to expand his time mentoring young scientists, including fellows on his training grant as well as young faculty. Additional time would also be spent in increasing collaborative research with other investigators at Columbia and developing new medication development projects.