TRAINING, DEGREES, AND TITLES
Sofuoglu, M., Singha, A., Kosten, T. R., McCance-Katz, F. E., Petrakis, I., & Oliveto, A. (2003). Effects of naltrexone and isradipine, alone or in combination, on cocaine responses in humans. Pharmacol Biochem Behav, 75(4), 801-808.
Oliveto, A., Sevarino, K., McCance-Katz, E., Benios, T., Poling, J., & Feingold, A. (2003). Clonidine and yohimbine in opioid-dependent humans responding under a naloxone novel-response discrimination procedure. Behav Pharmacol, 14(2), 97-109.
Oliveto, A., McCance-Katz, F. E., Singha, A., Petrakis, I., Hameedi, F., & Kosten, T. R. (2001). Effects of cocaine prior to and during bupropion maintenance in cocaine-abusing volunteers. Drug Alcohol Depend, 63(2), 155-167.
Oliveto, A. H., Feingold, A., Schottenfeld, R., Jatlow, P., & Kosten, T. R. (1999). Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone. Arch Gen Psychiatry, 56(9), 812-820.
CURRENT RESEARCH PROJECTS
N.I.D.A. (P50): “Stimulant Pharmacotherapy: Nonadrenergic Targets”
Project 3: “Efficacy of Carvedilol in Recently Abstinent Psychostimulant Dependent Patients”
Cocaine (COC) and methamphetamine (MTH) dependence have profound adverse medical, social and societal consequences. Medications development for these disorders is complicated by the fact that characteristics of COC and MTH addicts differ; the pharmacology of COC and MTH is similar, but not identical; and several agents demonstrating preliminary efficacy in COC users do not appear to be effective in MTH users. Because methodological issues may also be a factor in differential outcome, of importance is to examine medications in both COC and MTH dependent individuals in the same context. Thus, given that recent evidence suggests agents that decrease adrenergic activity may be effective in treating drug dependence, this proposal will examine the efficacy of the alpha1- and beta-adrenergic antagonist carvedilol in delaying time to relapse in recently abstinent COC- and MTH-dependent individuals. This 12-wk, randomized, double blind, placebo-controlled clinical trial will provide treatment for 60 COC-dependent and 60 MTH-dependent (18-65 yrs) individuals over a five-year period. Participants first will reside at a residential facility (Recovery Centers of Arkansas) to initiate initial drug abstinence and be inducted on the study medication. They will be randomized by sex, severity of dependence, depressive/anxiety symptom severity and race to receive either placebo (N=30COC; N=30MTH), or carvedilol (50 mg/day; N=30COC; N=30MTH). Then participants transfer to the Outpatient Treatment Research Program and continue to receive study medication for weeks 3-12. During the outpatient portion of the trial, subjects participate in weekly individual cognitive behavioral therapy. During the trial, participants are given monetary incentives for complying with study requirements. At the end of 12 weeks, patients will be tapered off the study medication and referred to an appropriate treatment program. Efficacy will be determined by length of time in treatment, alleviation of withdrawal symptoms, length of time to lapse/relapse by self-report and urine toxicology, and psychosocial functioning. Prognostic relevance of factors such as sex, withdrawal symptoms, mood, genetic polymorphisms at the, e.g., alpha 1 receptor subtypes, and cognitive measures will be explored.
This project will examine whether carvedilol prevents relapse relative to placebo in cocaine and/or methamphetamine dependent individuals. Findings of this study will not only shed light on whether carvedilol may improve upon treatment for psychostimulant dependence but also inform future medication development strategies for improving treatment for drug dependence disorders.
N.I.D.A. (R01): “Monoamine Antagonist Therapies for MA Abuse.”
Methamphetamine use has increased in the US and worldwide in the past years resulting in greater frequency and severity of related medical problems. Yet, no medicines with a medically-acceptable balance of effectiveness and side effects have been discovered. While the brain chemical transmitter dopamine plays a major role in the pleasurable reinforcing and psychomotor stimulant effects of amphetamines, the transmitters norepinephrine and serotonin also contribute substantially to these effects. Recent evidence suggests that the functional links that exist between norepinephrine and serotonin systems may be profoundly important in methamphetamine effects and dependence. However, these neurotransmitter systems have not been tested as extensively as targets of pharmacologic interventions. This application proposes interrelated human studies to determine whether medicines that block norepinephrine action, serotonin action, or both can favorably alter the central nervous system (CNS) effects, cardiovascular effects, and/or pharmacokinetics of methamphetamine. The proposed medicines to be tested in humans are prazosin, cyproheptadine, and quetiapine. Methamphetamine-abusing volunteers will undergo six sessions spaced 2-3 days apart. A single oral dose of one of the treatment medicines (placebo, low dose, high dose) will be given in a randomized, double-blind design before methamphetamine or methamphetamine placebo administration in each session. The volunteers will receive only one of the treatment medicines during each six-session study. Methamphetamine will be given intravenously (iv) in a dosing regimen that is well-tolerated by humans but that results in easily measurable effects by itself. In Specific Aim 1, we will determine whether medications that block (1b-adrenergic receptors (prazosin), 5-HT2A receptors (cyproheptadine), or both (quetiapine) alter the self-reported/performance effects of methamphetamine. In Specific Aim 2, we will determine whether acute pretreatment with these medications alters the cardiovascular effects of methamphetamine relative to methamphetamine alone. In Specific Aim 3, we will determine whether these medications alter the concentration-effect (pharmacodynamics) relationships of methamphetamine. Before and after administering the treatment medicines (or placebo) and methamphetamine (or placebo), self-report (ARCI, POMS, VAS), cognitive performance (DSST, Stroop), and cardiac effect (e.g., cardiac output and arrhythmia) measures will be obtained. Blood samples will be obtained to determine the effect of the medicines on methamphetamine serum concentrations. These measures will provide a broad pharmacologic effect profile and help to understand how beneficial effects of these medicines are hindered by adverse side effects. These novel datasets could provide essential information on how to use existing medicines and design better medicines to treat what is currently an untreatable addiction. These studies have immediate relevance to public health because they will identify medications and characteristics of ideal medicines that have the potential to effectively treat the serious psychiatric and medical effects of methamphetamine abuse. The studies will define the most effective balance of beneficial effects and side effects of the treatment medications. These studies will also identify characteristics of methamphetamine pharmacology that can be targeted for future treatment medications development
These studies have immediate relevance to public health because they will identify medications and characteristics of ideal medicines that have the potential to effectively treat the serious psychiatric and medical effects of methamphetamine abuse. The studies will define the most effective balance of beneficial effects and side effects of the treatment medications. These studies will also identify characteristics of methamphetamine pharmacology that can be targeted for future treatment medications development.
N.I.D.A. (R01): “Opioid Antagonist Discrimination: A Model of Withdrawal.”
N.I.D.A. (R01): “Disulfiram for Cocaine Abuse in Methadone-Maintained Patients.”
This competitive renewal examines further the influence of dopamine beta-hydroxylase (DBH) enzyme activity on the efficacy of the novel pharmacotherapy, disulfiram, for treating cocaine dependence in opioid- and cocaine-dependent patients maintained on methadone. Cocaine use remains epidemic among most opioid maintenance programs and pharmacological therapeutic strategies specifically aimed at cocaine s dopaminergic actions have shown little efficacy in unselected populations. In our previous trial, we have shown that DBH activity influences response to disulfiram at lower doses (0, 62.5, 125, or 250 mg/day), such that, disulfiram at 62.5 and 125 mg/day increases and disulfiram at 250 mg/day decreases, respectively, cocaine use relative to placebo in cocaine-dependent, methadone-stabilized patients with low DBH activity. Disulfiram produced no differential effects on cocaine use in those with normal DBH activity. Thus, our aim is to examine the influence of DBH activity on the efficacy of disulfiram at higher doses for treating 160 methadone-maintained cocaine abusers in a 14-wk, double blind, randomized clinical trial. Because DpH activity is under strong genetic control, participants will be stratified on genotype at the dopamine beta- hydroxylase (DBH) locus to ensure equal proportions of subjects across treatment groups. Methadone induction, genotyping, and assessment of baseline cocaine use will occur during weeks 1-2. Then participants will continue on methadone, be stratified by genotype, etc., and be randomly assigned to receive one of the following doses of disulfiram for the next 12 weeks 0, 250, 375, 500 mg/day. At the end the study, participants will no longer receive disulfiram and either transfer to a regular methadone program or undergo detoxification from methadone over a 4- to 6-wk period. In order to enhance outcome, all participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision. The primary outcome will be the influence of genotype at the DBH locus and/or DBpH enzyme activity on reduction cocaine use, as assessed by thrice-weekly urinalyses. Secondary outcomes will include retention, reductions in other illicit drug and alcohol use, disulfiram side-effects profile, and improvements in psychosocial functioning. The prognostic relevance of other factors (e.g., sex, discounting behavior) will also be examined.
Dr. Alison Oliveto’s interests include examining the behavioral pharmacology and abuse liability of psychoactive drugs, the development of efficacious pharmacotherapies for psychostimulant or opioid dependence, the combination of pharmacological and behavioral interventions, and the pharmacogenetics of treatment response.