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

在过去的一年里，近五分之一的吸食大麻的人患有大麻使用障碍(CUD)， 近三分之一的CUD患者患有严重抑郁障碍(MDD)。并存 MDD/CUD与更高的成瘾治疗率和更差的治疗结果相关 仅相对于CUD。然而，目前尚无有效的药物治疗慢性阻塞性肺疾病，临床试验寥寥无几。 以MDD/CUD共病为靶点未获成功。临床恶化的一个潜在解释 MDD/CUD并存的结果是导致CUD复发的两个主要因素，即大麻戒断 症状和压力，可以通过添加MDD来增强。由于重叠，这是假设的 在大麻戒断和MDD症状和增强的应激反应中观察到 相对于神经典型个体，MDD单独存在。大麻戒断和应激反应都是由 内源性大麻素(ECB)系统；这方面的证据已经在中枢(大脑)和 在外围(在血液中)。由于欧洲央行系统一直与这些复发的主要贡献者有关， 这为成瘾药物治疗的发展提供了一个潜在的靶点。此外，欧洲央行 与神经典型个体相比，MDD患者的调节失调提示ECB的调节 对于患有MDD/CUD的患者，相对于单独患有CUD的患者，可能有额外的效用。不过，目前 尚不清楚欧洲央行系统是否与仅有CUD(AIM)相比，在MDD/CUD并存方面存在独特的失调 1)，如果共患MDD/CUD的大麻戒断程度比单独CUD更严重(目标2)，或 如果MDD/CUD并存与相对于单独CUD的应激反应增强相关(目标3)。至 为了实现这些目标，将招募30名成年人(15名CUD，15名MDD/CUD)来完成四个面对面的培训 实验室探视超过一周。第一次访问将在大麻正常使用期间完成， 其余三次探视将在急性撤退期间进行。血液样本将在三个时间点采集 在每次访问期间评估欧洲央行的语气和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。在参加研究的最后一天，参与者将 接受社会压力测试。应激和药物渴求的主观体验、客观生物标记物 在压力暴露前和在压力暴露时，将收集血液皮质醇和心率以及血液ECB。 之后的四个时间点。拟议项目的结果将被用来确定相关性 ECB调制作为未来MDD/CUD共病药物治疗策略的研究 临床试验开发。在提议的项目过程中，申请人(Erin Martin)将收到 指导翻译研究的关键方面，包括研究设计和实施、科学 通信和高级统计分析。这一培训将应用于未来的发展 独立研究项目，检查患有精神疾病的人的成瘾情况。

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.