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。临床试验结果表明，激动剂替代疗法（如d-安非他明）可能对甲基苯丙胺依赖有效。目前的项目有三个具体目标。第一个具体目标是证明在d-安非他明的维持下，人类鼻内甲基苯丙胺的安全性、耐受性和行为影响。为了实现这一目标，我们将进行一项实验，在该实验中，近期有非法兴奋剂使用史的非寻求治疗的志愿者将接受鼻内甲基苯丙胺的递增剂量，同时保持d-安非他明的递增剂量（实验1）。心血管指数将用于确定d-安非他明-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。本实验的结果将指导后续研究中试验剂量的选择。第二个具体目标是证明d-安非他明维持会减弱甲基苯丙胺的强化作用。为了实现这一目标，我们将使用渐进比例程序确定d-安非他明维持期间鼻内甲基苯丙胺的强化作用（实验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。第三个具体目标是证明d-安非他明维持减弱甲基苯丙胺的区别刺激效应。为了实现这一目标，志愿者将学习辨别鼻内甲基苯丙胺（实验3）。甲基苯丙胺的区别性作用可能与吸毒行为的复发有关，因为初始剂量（即失效）可能起到区别性刺激的作用，表明可以获得更多的毒品。减轻甲基苯丙胺的鉴别刺激作用的药物治疗可能对预防复发有效。拟议的研究将为甲基苯丙胺依赖激动剂替代疗法的疗效提供重要的额外临床信息。通过使用两种复杂的人类实验室程序，一种模拟戒断开始（即药物自我给药），另一种模拟复发预防（即药物歧视），拟议的研究将确定调解d-安非他明对甲基苯丙胺依赖的临床疗效的机制。因此，通过推断，拟议的研究将确定d-安非他明作为甲基苯丙胺依赖药物治疗有效的最佳条件（即开始戒断或防止复发）。最后，由于d-安非他明减少了甲基苯丙胺的使用，这些临床发现可以作为确定人类实验室程序预测有效性的参考。通过“从旁边到实验台”或“逆向工程”策略确定评估假定药物治疗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和有效地进行。公共卫生相关性：甲基苯丙胺依赖是一个重大的公共卫生问题。提出的研究将提供重要的临床信息关于激动剂替代治疗甲基苯丙胺依赖的疗效。拟议的研究还将确定d-安非他明作为甲基苯丙胺依赖药物治疗有效的最佳条件（即开始戒断或防止复发）。最后，拟议的研究将确定适当的人类实验室程序测试药物治疗甲基苯丙胺依赖。确定适当的人体实验室程序以评估药物治疗对甲基苯丙胺依赖的疗效是重要的，因为实验室研究可以比临床试验更迅速和有效地进行。

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.