Evaluating Contributors to Relapse in Comorbid Major Depressive Disorder and Cannabis Use Disorder

在过去一年中使用过大麻的人中，近五分之一患有大麻使用障碍（CUD）， 近三分之一的CUD患者患有重度抑郁症（MDD）。共病 MDD/CUD与更高的成瘾治疗寻求率和更差的治疗结果相关 相对于单独的CUD。然而，对于CUD没有可用的药物治疗，并且很少有临床试验 针对MDD/CUD共病的治疗一直不成功。临床恶化的一种可能解释是 共病MDD/CUD的结局是CUD复发的两个主要因素，大麻戒断 症状和压力，可以通过添加MDD来增强。这是假设，由于重叠 在大麻戒断和MDD症状中， MDD单独相对于神经典型个体。大麻戒断和压力反应都受到 内源性大麻素（eCB）系统;已经在中枢（大脑）和 外周（血液中）。由于eCB系统与这些复发的主要因素有关， 它为成瘾药物治疗的发展提供了潜在的靶点。此外，eCB 与神经型个体相比，在MDD患者中观察到的失调表明eCB调节 相对于单独的CUD，在MDD/CUD共病患者中可能具有额外的效用。但目前 尚不清楚eCB系统在MDD/CUD共病患者中相对于单独的CUD是否存在独特的失调（目的 1）如果与单独的CUD相比，MDD/CUD共病患者的大麻戒断严重程度增加（目标2），或 如果合并MDD/CUD与相对于单独CUD的应激反应增强相关（目的3）。到 为了实现这些目标，将招募30名成年人（15名CUD，15名MDD/CUD）亲自完成4项 实验室检查一周以上。第一次访问将在大麻照常使用期间完成， 其余三次访视将在急性停药期间进行。将在三个时间点采集血样 在每次访视期间评估eCB张力，参与者将完成大麻戒断症状 在一周内的多个时间点进行评估。在研究参与的最后一天，受试者将 进行社会压力测试。压力和药物渴求的主观经历， 在暴露于应激之前和暴露于应激时，将收集应激（如血液皮质醇和心率）和血液eCB。 之后的四个时间点。拟议项目的成果将用于确定 eCB调节作为未来MDD/CUD共病的药物治疗策略 临床试验开发。在拟议项目的过程中，申请人（艾琳马丁）将收到 指导转化研究的关键方面，包括研究设计和实施，科学 通信和高级统计分析。这项培训将应用于未来的发展 一项独立的研究项目，调查患有精神病合并症的人的成瘾情况。

Nearly one-fifth of individuals that have used cannabis in the past year have Cannabis Use Disorder (CUD), and nearly one-third of individuals with CUD have comorbid Major Depressive Disorder (MDD). Comorbid MDD/CUD is associated with greater rates of addiction treatment-seeking and worse treatment outcomes relative to CUD alone. However, there is no available pharmacotherapy for CUD and the few clinical trials targeting comorbid MDD/CUD have been unsuccessful. One potential explanation for worsened clinical outcomes in comorbid MDD/CUD is that two major contributors to relapse in CUD, cannabis withdrawal symptoms and stress, may be enhanced by the addition of MDD. This is hypothesized due to the overlap across cannabis withdrawal and MDD symptoms and the enhanced stress response observed in people with MDD alone relative to neurotypical individuals. Both cannabis withdrawal and stress response are regulated by the endocannabinoid (eCB) system; evidence of this has been observed both centrally (in brain) and peripherally (in blood). Because the eCB system has been associated with these major contributors to relapse, it presents a potential target for the development of addiction pharmacotherapy. Furthermore, eCB dysregulation observed in people with MDD compared to neurotypical individuals suggests eCB modulation may have additional utility in people with comorbid MDD/CUD relative to CUD alone. However, it is currently unknown if the eCB system is uniquely dysregulated in comorbid MDD/CUD relative to CUD alone (Aim 1), if cannabis withdrawal severity is enhanced in comorbid MDD/CUD relative to CUD alone (Aim 2), or if comorbid MDD/CUD is associated with enhanced stress responding relative to CUD alone (Aim 3). To address these aims, thirty adults (15 CUD, 15 MDD/CUD) will be recruited to complete four in-person laboratory visits over one week. The first visit will be completed during cannabis use-as-usual and the remaining three visits will occur during acute withdrawal. Blood samples will be collected at three time points during each visit to assess eCB tone and participants will complete cannabis withdrawal symptom assessments at multiple time points over the week. On the final day of study participation, participants will be subjected to a social stress test. Subjective experiences of stress and drug craving, objective biomarkers of stress such as blood cortisol and heart rate, and blood eCBs will be collected prior to stress exposure and at four time points thereafter. Outcomes from the proposed project will be used to determine the relevance of eCB modulation as a pharmacotherapeutic strategy for comorbid MDD/CUD in the context of future clinical trial development. Over the course of the proposed project, the applicant (Erin Martin) will receive mentorship in key aspects of translational research including study design and implementation, scientific communication, and advanced statistical analysis. This training will be applied to the development of a future independent research program examining addiction in people with psychiatric comorbidities.