Agonist Replacement Therapy for Methamphetamine Dependence: Human Lab Studies

描述（由申请人提供）：甲基苯丙胺依赖是一个重大的公共卫生问题。临床试验的结果表明，激动剂替代疗法（例如，d-安非他明）可能对甲基安非他明依赖有效。本项目有三个具体目标。第一个具体目标是证明鼻内甲基苯丙胺在维持d-苯丙胺的人类中的安全性、耐受性和行为效应。为了实现这一目标，我们将进行一项实验，其中近期有非法兴奋剂使用史的非寻求治疗的志愿者将接受递增剂量的鼻内甲基苯丙胺，同时维持递增剂量的d-苯丙胺（实验1）。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，而主观效应问卷将用于表征行为效应。该实验的结果将指导后续研究中待测剂量的选择。第二个具体目标是证明，d-苯丙胺的维护减弱甲基苯丙胺的强化作用。为了实现这一目标，我们将确定鼻内甲基苯丙胺在d-苯丙胺维持过程中的增强作用，使用渐进比程序（实验1）。2）。减弱甲基苯丙胺强化作用的药物疗法可能对开始戒断有效。第三个具体的目的是证明，d-苯丙胺的维护减弱甲基苯丙胺的歧视性刺激作用。为了实现这一目标，志愿者将学习区分鼻内甲基苯丙胺（实验）。3）。甲基苯丙胺的区别作用可能涉及吸毒行为的复发，因为初始剂量（即，失效）可以用作发出更多药物可用性的信号的区别性刺激。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。拟议的研究将提供关于激动剂替代疗法对甲基苯丙胺依赖的疗效的重要额外临床信息。通过使用两种复杂的人类实验室程序，一种模拟禁欲开始（即，药物自我给药）和另一个用于模拟复发预防（即，药物歧视），拟议的研究将确定介导d-苯丙胺对甲基苯丙胺依赖的临床疗效的机制。然后，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性药物治疗有效的最佳条件（即，开始禁欲或防止复发）。最后，由于d-苯丙胺减少甲基苯丙胺的使用，这些临床研究结果可以作为参考，以确定人类实验室程序的预测有效性。通过“实验台旁”或“逆向工程”策略确定用于评估推定药物疗法疗效的程序是重要的，因为人体实验室研究可以比临床试验更快速有效地进行。

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.