Topiramate, a substituted fructo-pyranose derivative, is a promising agent for the treatment of cocaine dependence, presumably because by reducing its rewarding affects associated with abuse liability. We propose two experiments using state-of-the-art human abuse liability assessment techniques to examine the subjective, behavioral, and physiological effects of cocaine both alone and in combination with topiramate. All studies will be double-blind and placebo-controlled using balanced (for sequence and position) cross-over designs in male and female non treatment-seeking cocaine abusers (total N = 42). The first experiment, a proof-of-concept systematic extension of our own preliminary study, will test the hypothesis that sub-acute topiramate significantly reduces acute cocaine-mediated changes in subjective mood and other abuse liability assessments. As a secondary objective of this experiment, we will characterize the cocaine's effects on cognition and physiological response in non-fatigued subjects during drug-taking, and determine if, and by how much, these effects are altered by topiramate. This placebo-controlled, double-blind, 3 x 3 counterbalanced, Latin Square, cross-over study will examine the effects of low- and high-dose combinations of both cocaine (0.325 mg/kg and 0.650 mg/kg i.v. I and topiramate (100 mg and 200 mg orally) in 18 non-treatment-seeking, cocaine-dependent men and women. The second experiment will test the hypothesis that the most effective topiramate dose from experiment #1, when administered chronically, also will reduce acute cocaine-mediated subjective mood. We also will characterize the effects of chronic topiramate treatment on acute cocaine-induced cognitive and physiological changes. This placebo-controlled, double-blind study will use 24 non-treatment-seeking, cocaine-dependent male and female subjects in a nested 2 x 3 factorial, counterbalanced, cross-over design to examine the pharmacological interaction between the optimal topiramate dose and low- and high-dose cocaine. In summary, experiment # I provides a proof-of-concept analysis of topiramate's ability to reduce cocaine's abuse potential. Experiment # 2 more directly addresses issues of potential clinical effectiveness and tolerability with which to guide efficacy trials. The results of these human laboratory studies should provide a solid basis for planning clinical trials examining the safety and effectiveness of topiramate for the treatment of cocaine-dependent individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA012191-07
Application #
7032683
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Oversby, Steven
Project Start
1999-09-30
Project End
2007-08-31
Budget Start
2005-03-11
Budget End
2005-08-31
Support Year
7
Fiscal Year
2004
Total Cost
$397,076
Indirect Cost
Name
University of Virginia
Department
Psychiatry
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Johnson, Bankole A; Messing, Robert O; Charness, Michael E et al. (2011) Should the reorganization of addiction-related research across all the National Institutes of Health be structural?--The devil is truly in the details. Alcohol Clin Exp Res 35:572-80
Johnson, Bankole A (2006) Pills for speedballing or cocaine dependence. Lancet 367:1714-6
Johnson, Bankole A; Roache, John D; Ait-Daoud, Nassima et al. (2005) Effects of isradipine on cocaine-induced changes in cognitive performance in recently abstinent cocaine-dependent individuals. Int J Neuropsychopharmacol 8:549-56
Roache, John D; Johnson, Bankole A; Ait-Daoud, Nassima et al. (2005) Effects of repeated-dose isradipine on the abuse liability of cocaine. Exp Clin Psychopharmacol 13:319-26
Johnson, Bankole A; Wells, Lynda T; Roache, John D et al. (2005) Isradipine decreases the hemodynamic response of cocaine and methamphetamine results from two human laboratory studies: results from two human laboratory studies. Am J Hypertens 18:813-22
Johnson, Bankole A; Javors, Martin A; Lam, Yui-Wing Francis et al. (2005) Kinetic and cardiovascular comparison of immediate-release isradipine and sustained-release isradipine among non-treatment-seeking, cocaine-dependent individuals. Prog Neuropsychopharmacol Biol Psychiatry 29:15-20
Johnson, Bankole A; Roache, John D; Ait-Daoud, Nassima et al. (2004) Effects of isradipine on cocaine-induced subjective mood. J Clin Psychopharmacol 24:180-91
Johnson, Bankole A (2004) Topiramate-induced neuromodulation of cortico-mesolimbic dopamine function: a new vista for the treatment of comorbid alcohol and nicotine dependence? Addict Behav 29:1465-79
Johnson, B A; Devous Sr, M D; Ruiz, P et al. (2001) Treatment advances for cocaine-induced ischemic stroke: focus on dihydropyridine-class calcium channel antagonists. Am J Psychiatry 158:1191-8