Pharmacological Facilitation of Behavioral Modification for Cocaine Use Disorders

可卡因使用障碍行为矫正的药理学促进

• 批准号: 9922890
• 负责人: Elias Dakwar
• 金额: $ 69.57万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922890
• 关键词: Abstinence; Address; Adverse effects; Affinity; Anesthetics; Behavior Therapy; Behavioral; Biological; Brain-Derived Neurotrophic Factor; Clinical; Clinical Trials; Cocaine; Cocaine Users; Cues; Data; Dependence; Development; Disease; Dose; Drug usage; Evaluation; Failure; Foundations; Future; Glutamates; Goals; Hour; Human; Individual; Infusion procedures; Inpatients; Intervention; Investigation; Ketamine; Laboratories; Laboratory Animals; Laboratory Study; Lead; Mediator of activation protein; Methods; Midazolam; Mindfulness Training; Modeling; Motivation; N-Methyl-D-Aspartate Receptors; Outcome; Outpatients; Participant; Pathogenesis; Patient Self-Report; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Protocols documentation; Public Health; Randomized; Research; Risk; Self Administration; Series; Serum; Stress; Testing; Toxic effect; Toxicology; Translating; Urine; Work; active control; base; behavior measurement; clinical efficacy; cocaine use; conditioning; craving; design; disorder later incidence prevention; drug craving; drug reward; effective therapy; efficacy trial; follow-up; improved; innovation; mindfulness; motivational enhancement therapy; neurotransmission; non-drug; novel; novel therapeutics; pilot trial; pre-clinical; programs; therapy development; treatment arm; treatment response; volunteer; week trial

Project Summary Alterations in glutamate neurotransmission are recognized as an important target of pharmacotherapy for cocaine use disorders (CUDs). Our preliminary investigations with ketamine, a glutamate modulator with potent prefrontal effects, suggest sub-anesthetic infusions may work to facilitate behavioral modification by addressing critical CUD- related vulnerabilities. Alongside being safely administered to active cocaine users, we have found that sub-anesthetic ketamine, 24 hours post-infusion, significantly increases motivation to stop cocaine use by 60%, decreases cue-induced craving by a similar magnitude, and reduces the choice for cocaine now vs. money later by 67% when compared to an active control. A pilot efficacy trial also indicates that a single infusion of ketamine facilitates mindfulness-based relapse prevention (MBRP) and promotes abstinence (53% ketamine vs. 11% midazolam). Expanding on these promising but preliminary findings, this trial aims to evaluate whether ketamine promotes abstinence by facilitating behavioral modification in a treatment model approximating a general clinical setting. We will evaluate the effect of up to two outpatient sub-anesthetic doses of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on CUDs in 110 non-depressed individuals engaged in motivation enhancement therapy followed by MBRP. We predict that, compared to the control midazolam, ketamine will significantly promote 3 weeks of end-of-study abstinence in this 7-week trial. Secondary aims pertain to the effects of ketamine on other drug use outcomes, such as reduction in number of cocaine use days; and the evaluation of behavioral and biological mediators of ketamine efficacy, such as serum brain-derived neurotrophic factor (BDNF) levels and measures of behavioral non-reactivity. If successful, this project stands to contribute significantly to the treatment of CUDs, for which there are no clearly effective pharmacotherapies at present, and has the potential to lead the field in new directions of combined medication-behavioral treatment development. Future studies might test other medications using the design introduced in this proposal, as well as focus on clarifying the mechanisms by which ketamine addresses CUDs.

项目摘要 谷氨酸神经传递的改变被认为是 可卡因使用障碍的药物治疗（CUD）。我们与 氯胺酮是具有有效前额叶作用的谷氨酸调节剂 输注可能通过解决关键的CUD- 相关漏洞。除了安全地管理给活跃的可卡因用户外，我们还 已经发现输入后24小时的亚手提感觉氯胺酮显着增加 阻止可卡因使用的动机减少了60％，减少了提示引起的渴望 幅度，现在可以将可卡因的选择减少到稍后的67％ 与主动对照相比。试点功效试验还表明 氯胺酮促进基于正念的基于正念的复发预防（MBRP）并促进 禁欲（53％氯胺酮和11％米唑仑）。扩展这些有希望的但是 初步发现，该试验旨在评估氯胺酮是否通过 在近似一般临床的治疗模型中促进行为修改 环境。我们将评估多达两种门诊亚警觉剂量的影响 氯胺酮（在2分钟内0.11 mg/kg，然后在50分钟内为0.60 mg/kg） 110名不抑郁的人进行动机增强疗法的CUD 其次是MBRP。我们预测，与对照咪达唑仑相比，氯胺酮将 在这项为期7周的试验中，显着促进了3周的戒酒结束。次要 目的与氯胺酮对其他药物使用结果的影响有关，例如减少 可卡因使用天数；以及行为和生物学介体的评估 氯胺酮疗效，例如血清脑衍生的神经营养因子（BDNF）水平和 行为无反应性的度量。如果成功，该项目将有助于 对CUD的治疗显着，这没有明显有效的 目前的药物治疗，有可能沿新方向领导领域 联合用药 - 行为治疗的开发。未来的研究可能会测试其他 使用本提案中介绍的设计的药物，并专注于澄清 氯胺酮解决CUD的机制。