Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence

普瑞巴林和噻加宾大麻依赖性人体实验室筛查

• 批准号: 9506724
• 负责人: Joshua Anthony Lile
• 金额: $ 44.68万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9506724
• 关键词: Abstinence; Acute; Admission activity; Adult; Adverse effects; Attenuated; Award; Basic Science; Behavior; Behavior Therapy; Calcium Channel; Cannabis; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Cost Savings; Data; Dependence; Development; Dose; Double-Blind Method; Drug Addiction; Drug Kinetics; Drug usage; Effectiveness; Environment; Exclusion; Goals; Human; Hybrids; Illicit Drugs; Incentives; Independent Scientist Award; Information Sciences; Intervention; Laboratories; Ligands; Maintenance; Marijuana Dependence; Measures; Methods; Modeling; Monitor; Motivation; Outpatients; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Placebos; Principal Investigator; Procedures; Process; Psychological reinforcement; Public Health; Randomized; Relapse; Research; Resources; Role; Schedule; Self Administration; Statistical Data Interpretation; Statistical Models; Study Subject; Techniques; Technology; Testing; Therapeutic Effect; Time; Translating; Treatment Efficacy; United States; career development; cost effectiveness; drug maintenance; experience; gabapentin; gamma-Aminobutyric Acid; illicit drug use; improved; inhibitor/antagonist; innovation; marijuana use; marijuana use disorder; marijuana user; next generation; novel; pregabalin; primary outcome; public health relevance; reinforcer; response; reuptake; screening; secondary outcome; success; therapy development; tiagabine; treatment response

DESCRIPTION (provided by applicant): Cannabis use disorders are a significant public health concern and the absence of effective medications is a critical barrier to overcome. This application is founded on promising results from our laboratory suggesting that drugs that act at a2d-1 subunit containing voltage-dependent calcium channels (VDCCs) and/or elevate g- aminobutyric acid (i.e., GABA) will be effective medications for cannabis-use disorders. Our laboratory results are supported by a recent pilot clinical trial showing that gabapentin, which is a VDCC ligand and elevates GABA, reduced cannabis use in dependent, treatment-seeking adults. The goal of the present proposal is to build upon these promising laboratory and clinical findings by determining the ability of outpatient maintenance on pregabalin, a "next generation" VDCC ligand, and tiagabine, a GABA reuptake inhibitor, to attenuate the reinforcing effects of cannabis. Pregabalin will be tested because, although their mechanism of action is the same, the pharmacokinetic profile of pregabalin is improved compared to gabapentin, and clinical results suggest that this translates into greater pharmacotherapeutic effectiveness. Tiagabine will be tested because its effects overlap with gabapentin and pregabalin, GABA elevation is a possible mechanism for gabapentin's effects on cannabis use, and our recent data demonstrated that tiagabine produced a profile of effects that was comparable to gabapentin when tested in combination with D9-THC. Outpatient maintenance dosing will be tested because it more closely resembles the clinical treatment situation. Cannabis self-administration using a concurrent progressive-ratio drug-money choice procedure will be the primary outcome because drug seeking and drug taking behaviors, and the choice to use drugs to the exclusion of other behaviors, are defining characteristics of drug dependence, and drug self-administration procedures are predictive of therapeutic efficacy. Cannabis use in the natural environment will also be monitored during drug maintenance as a secondary outcome to optimize resource management and quicken the pace of intervention development. Our preliminary data with the proposed procedures support the feasibility of the project, the assembled research team is highly qualified and the environment will significantly contribute to the success of the research. The proposed project is innovative because it employs a novel hybrid procedure to study the impact of medication maintenance on direct cannabis effects in the laboratory as well as cannabis use in the natural environment, the effects of pregabalin and tiagabine on cannabis self-administration have not been tested previously, and a novel, real-time medication maintenance compliance technology will be implemented. Positive findings will exert an immediate and sustained impact by rapidly advancing currently available medications for the treatment of cannabis-use disorders, promoting novel pharmacological targets for further medications development and providing valuable basic science information about the mechanisms underlying cannabis reinforcement.

描述（由申请人提供）：大麻使用障碍是一个重大的公共健康问题，缺乏有效的药物是克服的关键障碍。该应用是基于我们实验室的有希望的结果，这表明在含有电压依赖性钙通道（VDCC）的A2D-1亚基的药物和/或升高G-氨基丁酸（即GABA）将是用于大麻使用灾难的有效药物。我们的实验室结果得到了最近的试点临床试验的支持，表明加巴喷丁是 VDCC配体并提高了GABA，减少了依赖，寻求治疗的成年人的大麻使用。本提案的目的是通过确定对Pregabalin的门诊维持的能力来建立这些有前途的实验室和临床发现，即“下一代” VDCC配体和GABA再摄取抑制剂Tiagabine衰减罐头cannabis的增强作用。将测试前伽巴林，因为尽管它们的作用机理相同，但与加巴喷丁相比，前gabalin的药代动力学特征得到了改善，并且临床结果表明这转化为更大的药物治疗效果。 Tiagabine将进行测试，因为其作用与Gabapentin和Pregabalin重叠，Gaba升高是Gabapentin对大麻使用作用的可能机制，而我们的最新数据表明，与D9-Thc结合测试时，Tiagabine产生的作用与Gabapentin相当。将测试门诊维持剂量，因为它更像临床治疗情况。大麻使用同时进行的进行性比率药物选择程序的自我管理将是主要结果，因为寻求药物和吸毒行为，以及选择使用药物排除其他行为的选择，是药物依赖性的确定特征，药物自我管理程序可以预测治疗效果。在药物维持期间，在自然环境中使用大麻的使用也将作为次要结果，以优化资源管理并加快干预发展的步伐。我们的初步数据和拟议的程序支持该项目的可行性，组装的研究团队具有很高的资格，环境将有助于研究的成功。拟议的项目具有创新性，因为它采用了一种新型的混合程序来研究药物维护对实验室直接大麻效应的影响，以及在自然环境中的大麻使用，前Gababalin和Tiagabine对大麻自我管理的影响，以前尚未测试过小说，以及一种小说，实时的，实时的依从性技术。积极的发现将通过快速推进目前可用的大麻疾病治疗药物，促进新的药理学靶标，以进一步开发药物，并提供有关大麻加固基础机制的有价值的基础科学信息，从而产生直接和持续的影响。