Herbert D. Kleber - US grants

We propose a placebo controlled, double-blind randomized experiment evaluating lithium carbonate, desipramine, methylphenidate and placebo as treatments for cocaine abuse in 80 chronic users. The study is designed to: 1) determine the relative general efficacy of the four pharmacologic treatments, in combination with psychotherapy, in alleviating or halting cocaine abuse; 2) evaluate the psychological characteristics (symptoms, personality, social functioning and diagnosis) of chronic cocaine abusers pre and post treatment; 3) explore the possible presence of a "central" withdrawal state via neuroendocrine evaluation (Prolactin, Growth Hormone) of chronic cocaine abusers pre and post treatment. The study will also examine the relationships between treatment success or failure and psychological characteristics in order to explore a possible approach to treatment based on a potential specific effficacy for each pharmacologic treatment in clinically distinct sub-populations.

This longitudinal study of intravenous drug users (IVDU) in New Haven, Connecticut will critically evaluate the effectiveness of methadone maintenance programs (MMP) in limiting the spread of the AIDS virus (HTLV III/LAV) among IVDU by retrospective and prospective comparisons of four groups of IVDU over 2-6 years. This long follow-up will allow description of the clinical course of HTLV III/LAV infection in very closely followed IVDU as well as expansion of the data base needed for an evaluation of factors predictive of clinical outcome. Preliminary studies show that 10% of a group of 283 New Haven IVDU were already infected with HTLV III/LAV in 1982-83. Therefore, this area may serve as a useful location to test the hypothesis that the rate of acquisition of HTLV III/LAV infection over time is less for a group on MMP than for IVDU not on drug treatment. The proposed study will re-evaluate up to 175 of the subjects for whom HTLV III/LAV antibody status in 1982-83 is known. Sixty-five of this 1982-83 cohort are currently on MMP and will be invited to participate in the study. The 110 subjects from the 1982-83 serum collection not currently on drug treatment in New Haven will be traced and invited to participate. Two other groups will be enrolled in 1986 and followed: 100 subjects who have been on MMP continuously since 1982 and 100 IVDU actively injecting drugs since 1982-83 invited to participate from consecutive admissions to the MMP. In addition, ongoing control seroprevalence data for those actively using injection drugs will be available from the State of Connecticut surveillance of all MMP admissions at selected drug treatment centers statewide (including New Haven after all new MMP entrants are enrolled in 1986). Evaluation of all subjects will include comprehensive medical evaluation, testing for HTLV III/LAV antibody with "western" blot confirmation, interview collection of behavioral data including drug injection, sexual and contraceptive practices, and cytomegalovirus and hepatitis B serologies. Seropositive subjects will have additional tests of immunologic function, HTLV III/LAV cultures and Epstein-Barr virus serologies. Comparison of the rate of increase in HTLV III/LAV antibody prevalence among those continuing in MMP to the rate of increase seen in active intravenous drug users over the same time will most directly test the hypothesis. Multivariate analysis with logistic regression modelling will provide a preliminary evaluation of predictors of outcome.

We propose a placebo controlled, double-blind randomized experiment evaluating lithium carbonate, desipramine, methylphenidate and placebo as treatments for cocaine abuse in 80 chronic users. The study is designed to: 1) determine the relative general efficacy of the four pharmacologic treatments, in combination with psychotherapy, in alleviating or halting cocaine abuse; 2) evaluate the psychological characteristics (symptoms, personality, social functioning and diagnosis) of chronic cocaine abusers pre and post treatment; 3) explore the possible presence of a "central" withdrawal state via neuroendocrine evaluation (Prolactin, Growth Hormone) of chronic cocaine abusers pre and post treatment. The study will also examine the relationships between treatment success or failure and psychological characteristics in order to explore a possible approach to treatment based on a potential specific effficacy for each pharmacologic treatment in clinically distinct sub-populations.

detoxification; human therapy evaluation; general anesthesia; drug addiction; drug abuse chemotherapy; drug withdrawal; heroin; drug /alcohol abstinence; clonidine; buprenorphine; naltrexone; patient oriented research; human subject; clinical research;

DESCRIPTION: (Provided by Applicant) 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.