Agonist Replacement Therapy for Methamphetamine Dependence: Human Lab Studies

描述(申请人提供)：甲基苯丙胺依赖是一个重大的公共卫生问题。临床试验结果表明，激动剂替代疗法(例如，d-苯丙胺)可能对甲基苯丙胺依赖有效。本项目有三个具体目标。第一个具体目标是证明鼻腔注射甲基苯丙胺对人体的安全性、耐受性和对行为的影响。为了实现这一目标，我们将进行一项实验，在这项实验中，最近有非法兴奋剂使用史的不寻求治疗的志愿者将获得递增剂量的鼻内甲基苯丙胺，同时维持增加剂量的D-苯丙胺(实验。1)。心血管指数将用于确定d-苯丙胺-甲基苯丙胺组合的安全性和耐受性，而主观效果问卷将用于表征行为影响。本实验的结果将指导后续研究中要测试的剂量的选择。第二个具体目的是证明d-苯丙胺的维持减弱了甲基苯丙胺的增强作用。为了实现这一目标，我们将使用累进比率程序(Exp.2)。减弱甲基苯丙胺强化作用的药物疗法可能对开始戒毒有效。第三个具体目的是证明维持d-苯丙胺可以减弱甲基苯丙胺的辨别刺激效应。为了实现这一目标，志愿者将学习辨别鼻腔内的甲基苯丙胺(实验。3)。甲基苯丙胺的区别性作用可能与复吸吸毒行为有关，因为最初的剂量(即一次失误)可能起到区别性刺激的作用，表明有更多的药物可用。减弱甲基苯丙胺的辨别刺激效应的药物疗法可能对预防复发有效。这项拟议的研究将为激动剂替代疗法治疗甲基苯丙胺依赖的疗效提供重要的补充临床信息。通过使用两个复杂的人体实验室程序，一个模拟戒断开始(即药物自我给药)，另一个模拟复发预防(即药物歧视)，拟议的研究将确定调节d-苯丙胺对甲基苯丙胺依赖临床疗效的机制。因此，通过推断，拟议的研究将确定d-苯丙胺作为甲基苯丙胺依赖的药物疗法(即开始戒除或防止复发)的最佳条件。最后，由于d-苯丙胺减少了甲基苯丙胺的使用，这些临床研究结果可以作为确定人类实验室程序预测有效性的参考。确定通过“旁观式”或“反向工程”策略评估假定药物疗法的有效性的程序很重要，因为人体实验室研究可以比临床试验更快、更有效地进行。公共卫生相关性：对甲基苯丙胺的依赖是一个重大的公共卫生问题。这项拟议的研究将为激动剂替代疗法治疗甲基苯丙胺依赖的疗效提供重要的临床信息。拟议的研究还将确定d-苯丙胺作为甲基苯丙胺依赖的药物疗法(即开始戒除或防止复发)的最佳条件。最后，拟议的研究将确定适当的人体实验室程序，以测试甲基苯丙胺依赖的药物疗法。确定适当的人体实验室程序以评估甲基苯丙胺依赖药物疗法的疗效是重要的，因为实验室研究可以比临床试验更快、更有效地进行。

DESCRIPTION (provided by applicant): Methamphetamine dependence is a significant public-health concern. The results of clinical trials suggest that agonist replacement therapies (e.g., d-amphetamine) may be effective for methamphetamine dependence. The present project has three specific aims. The first specific aim is to demonstrate the safety, tolerability and behavioral effects of intranasal methamphetamine in humans maintained on d-amphetamine. To accomplish this aim, we will conduct one experiment in which non-treatment seeking volunteers with recent histories of illicit stimulant use will receive ascending doses of intranasal methamphetamine while maintained on increasing doses of d-amphetamine (Exp. 1). Cardiovascular indices will be used to determine the safety and tolerability of the d-amphetamine-methamphetamine combinations while subjective-effect questionnaires will be used to characterize the behavioral effects. The results of this experiment will guide the selection of doses to be tested in subsequent studies. The second specific aim is to demonstrate that d-amphetamine maintenance attenuates the reinforcing effects of methamphetamine. To accomplish this aim, we will determine the reinforcing effects of intranasal methamphetamine during d-amphetamine maintenance using a progressive-ratio procedure (Exp. 2). Pharmacotherapies that attenuate the reinforcing effects of methamphetamine may be effective for initiating abstinence. The third specific aim is to demonstrate that d-amphetamine maintenance attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim, volunteers will learn to discriminate intranasal methamphetamine (Exp. 3). The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e., a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide important additional clinical information regarding the efficacy of agonist replacement therapies for methamphetamine dependence. By using two sophisticated human laboratory procedures, one to model abstinence initiation (i.e., drug self-administration) and the other to model relapse prevention (i.e., drug discrimination), the proposed research will determine the mechanisms that mediate the clinical efficacy of d-amphetamine for methamphetamine dependence. By inference, then, the proposed research will identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e., initiate abstinence or prevent relapse). Finally, because d-amphetamine reduces methamphetamine use, these clinical findings can be used as a reference to determine the predictive validity of human laboratory procedures. Identifying procedures for assessing the efficacy of putative pharmacotherapies via a "beside-to-bench" or "reverse engineering" strategy is important because human laboratory studies can be conducted more rapidly and efficiently than clinical trials. PUBLIC HEALTH RELEVANCE: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the efficacy of agonist replacement therapy for methamphetamine dependence. The proposed research will also identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e., initiate abstinence or prevent relapse). Finally, the proposed research will determine appropriate human laboratory procedures for testing pharmacotherapies for methamphetamine dependence. Identifying appropriate human laboratory procedures for assessing the efficacy of pharmacotherapies for methamphetamine dependence is important because laboratory studies can be conducted more rapidly and efficiently than clinical trials.