2011 |
Sevak, Rajkumar Jyotishchandra |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Human Methamphetamine Self-Administration in a Progressive-Ratio Paradigm @ University of California Los Angeles
DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse and dependence are major public health concerns;however, a widely accepted pharmacotherapy has not yet been identified (Elkashef, 2008). Efforts in this regard have been limited, in part, by the inadequate sensitivity of human laboratory methods for measuring abuse-related behavioral effects (e.g., reinforcing effects) of MA. Enhancing the sensitivity of the human laboratory procedures to reveal sizable reinforcing effects could facilitate the testing of pharmacological agents in modifying these effects. Only a handful of studies have measured the reinforcing effects of MA in the human laboratory, and the procedures used (e.g., choosing between drug and monetary rewards) have yielded only small to moderate effects. The modest reinforcing effects of MA found in these procedures limit the extent to which pharmacological modification can be examined. Notably, progressive-ratio procedure is an efficient method for assessing the reinforcing effects of abused drug. In this procedure, the response requirement (i.e., ratio) for obtaining each reinforcer progressively increases until subjects stop responding. The final ratio completed is the "break point," which reflects the maximum effort expended to receive the reinforcer. Progressive-ratio procedures have not yet been used to study human MA self-administration;and, although d-amphetamine self-administration has been examined using this procedure, the modest effects observed have limited its utility for evaluating pharmacotherapies for amphetamine abuse. Particular experimental design parameters likely contributed to the modest effects found in the d- amphetamine progressive-ratio studies. Notably, in these studies response requirements ranged from either 50 to 6,400 or 25 to 3,200 responses (i.e., mouse clicks) to earn capsules. This contributed to high responses for placebo and low responses for d-amphetamine, resulting in small to moderate magnitudes of the measured reinforcement. We propose to use different response requirements (i.e., 400 to 1,800 clicks) under a progressive-ratio schedule. We hypothesize that the higher "minimal" and lower "maximal" ratios would decrease responding for placebo and increase responding for MA, revealing an enhanced magnitude of the reinforcing effects of MA. Ten MA-dependent individuals will participate in this 11-day inpatient study. They will first sample IV doses of MA (0, 8, 16, and 24 mg), and in subsequent sessions, they will receive opportunities to work for the sampled dose on a progressive-ratio procedure. A battery of subjective-effect questionnaires and cardiovascular measures will be assessed to characterize the effects of MA. We expect that the proposed response requirements will result in low levels of placebo taking and a wide difference between the number of placebo and MA infusions earned, resulting in a large effect size of the MA reinforcement. The proposed research offers to provide a sensitive human laboratory procedure for assessing reinforcing effects of MA. The outcomes could help develop an efficient and economical human laboratory screen of medications for MA dependence. PUBLIC HEALTH RELEVANCE: The application offers to refine a human laboratory procedure, the progressive-ratio schedule, for assessing reinforcing effects of MA in MA-dependent individuals. A widely accepted medication for treating MA dependence is not yet available, and the cost associated with clinical trials is substantial. An efficient human laboratory procedure can, therefore, provide an economical approach for determining preliminary efficacy of medications for MA dependence.
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2012 |
Sevak, Rajkumar Jyotishchandra |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Safety and Initial Efficacy of Lisdexamfetamine For Methamphetamine Dependence @ University of California Los Angeles
DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence is a major public health concern; however, a widely accepted pharmacotherapy has not yet been identified. The results of several clinical trials indicate that d-amphetamine, a medication that shares neurochemical, behavioral and pharmacological effects with MA, reduces street use of stimulants and severity of withdrawal in amphetamine-dependent patients. Unfortunately, clinicians may not favor d-amphetamine, because of its high abuse potential. Indeed, d-amphetamine is reportedly abused, primarily by crushing the tablets in order to snort the drug. It is likely then, the potential for the clinical utility of d- amphetamine may be enhanced by the development of abuse-deterrent formulations, that are resistant to tampering to extract the active stimulant. One such product, lisdexamfetamine (LDX) is the first FDA-approved pro-drug stimulant, that is a therapeutically inactive molecule. After oral ingestion, however, it is converted to d-amphetamine, which is responsible for the drug's activity. A recent study of abuse liability showed that at doses of LDX and d- amphetamine that contain equivalent molar amounts of free amphetamine base, LDX produced significantly less drug liking than did d-amphetamine. This finding suggests that LDX has low stimulant properties, and little abuse potential, highlighting its suitability as a candidate medication for MA dependence. However, the safety of administering LDX with MA, and the ability of LDX to modify the abuse-related behavioral effects of MA have yet to be tested. We propose to conduct human laboratory evaluations of the safety and initial efficacy of LDX as a pharmacotherapy for MA dependence. The first specific aim is to evaluate the safety and tolerability of administering LDX in combination with intravenous MA in humans. MA-dependent individuals will receive ascending doses of intravenous (i.v.) MA while maintained on increasing doses of LDX (Exp. 1). Cardiovascular indices will be used to determine the safety of the LDX-MA combinations while subjective measures will be used to characterize the behavioral effects. The results of this experiment will guide the selection of the dose to be tested in Exp.2. The second specific aim is to determine whether LDX maintenance attenuates the reinforcing effects of MA. To accomplish this aim, we will assess MA self-administration, during LDX maintenance, in a progressive-ratio schedule of reinforcement (Exp. 2). The reinforcing effects of drugs, including MA, are central to their abuse potential. An effective pharmacotherapy for stimulant dependence should reduce MA self-administration. If successful, the findings from the proposed study will provide crucial scientific information on the safety and initial efficacy of LDX that could be useful for larger clinical trials evaluating efficacy of LDX for MA dependence. The results of this study will also help elucidate the optimal conditions (e.g., dose) under which LDX might be expected to be effective. PUBLIC HEALTH RELEVANCE: The proposal offers to provide important scientific and clinical information on the safety and initial efficacy of lisdexamfetamine (LDX) as a putative pharmacotherapy for methamphetamine (MA) dependence. The proposed human laboratory research will elucidate the optimal conditions (e.g., dose) under which LDX might be expected to be safe and effective. Because a widely accepted medication for treating MA dependence is not yet available, and the cost associated with clinical trials is substantial, human laboratory research can provide an economical and efficient approach for determining preliminary efficacy of LDX for MA dependence.
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