Pharmacological Facilitation of Behavioral Modification for Cocaine Use Disorders

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(CUDS)的药物治疗。我们的初步调查与 氯胺酮是一种谷氨酸调节剂，具有强大的前额叶效应，建议使用亚麻醉剂 输液可能通过解决关键线索来促进行为改变- 相关漏洞。除了对活跃的可卡因使用者进行安全管理外，我们 有研究发现，亚麻药氯胺酮在输注后24小时显著增加 停止使用可卡因的动力减少60%，以类似的方式减少暗示诱导的渴望 数量，现在与以后的钱相比，现在可卡因的选择减少了67% 与主动控制相比。一项试点疗效试验也表明，单次输注 氯胺酮促进基于正念的复发预防(MBRP)并促进 禁欲(53%的氯胺酮与11%的咪达唑仑)。在这些有希望的基础上进行扩展 初步发现，这项试验旨在评估氯胺酮是否通过 促进接近一般临床的治疗模型中的行为修改 布景。我们将评估最多两种门诊亚麻醉剂量的效果 氯胺酮(2分钟内0.11毫克/公斤，50分钟内0.60毫克/公斤) 110名非抑郁者参与动机增强治疗的CUDS 其次是MBRP。我们预测，与对照组咪达唑仑相比，氯胺酮将 在这项为期7周的试验中，显著促进3周的研究结束禁欲。次要的 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；以及行为和生物介体的评价 氯胺酮疗效，如血清脑源性神经营养因子(BDNF)水平和 行为非反应性的衡量标准。如果成功，这个项目将做出贡献 对CUDS的治疗意义重大，目前尚无明显疗效 目前的药物治疗，并有潜力引领该领域的新方向 药物与行为治疗相结合的发展。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，以及重点澄清 氯胺酮处理CUD的机制。

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.