Kappa Opioid Antagonist for Cocaine Addiction

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Cocaine abuse/dependence remains a major social and public health problem and for a significant number of cocaine dependent individuals, current treatment interventions are ineffective. Finding a pharmacological treatment for cocaine abuse is an important yet elusive goal. The primary purpose of this project is to provide safety data on an orally active, slow onset, long-acting kappa antagonist, JDTic, being developed through the SPIRDAP mechanism for the treatment of cocaine dependence. Prior to the initiation of this research project, toxicity and pharmacokinetic studies will have been carried out in normal human volunteers with JDTic (Project 3 Kosten). The safety of JDTic in individuals with a history of high dose cocaine abuse must also be determined (Aim 1). In addition, because it is likely that individuals receiving a medication for the treatment of cocaine dependence will continue to take cocaine, particularly early in treatment, it is essential to determine whether this drug combination produces any adverse reactions (Aim 2). In this project, cocaine dependent volunteers who will remain on an inpatient unit for a total of 33 days will be recruited. Physiological and subjective effects will be measured during each cocaine administration test session to assess the effects of the combination. To assess the effects of JDTic in this population, an adverse event symptom questionnaire developed by Kosten, the Tiffany craving questionnaire, and psychological symptom questionnaires of depression will be administered at regular intervals each day. Physicals, EKGs and laboratory tests will be done before and after the study. In addition to providing safety data, this research might also yield information suggestive of the potential efficacy of JDTic. Animal data have shown that KOR antagonists, such as JDTic, attenuate: stress-induced reinstatement of cocaine responding; the potentiation of cocaine's ability to produce place preference, and immobility of rats subjected to a forced swim test. Thus, JDTic may attenuate two of the major factors (stress and depression) that lead to relapse in individuals attempting to abstain from cocaine use (Aim 3). If no significant adverse events are found in these safety studies, studies of the effects of JDTic on stress-induced craving in human research volunteers and as a relapse prevention medication in clinical trials in cocaine dependent treatment seekers are warranted.