The role of the endocannabinoid system and cannabis use in the expression of psychosis

精神疾病是死亡的主要原因，在英格兰每年造成120亿英镑的财政负担。迫切需要了解哪些人可以通过简单的有针对性的干预措施得到帮助。精神病结局的最可改变的风险因素是大麻使用，这是世界上使用最多的非法物质。此外，使用大麻的精神病患者更有可能参与攻击和暴力事件，有时需要根据《精神卫生法》拘留在精神病重症监护室（PICU）以控制风险。我以前的工作表明，重度大麻使用者的精神病患者比非大麻使用者的症状更严重，这可能反映了不同的生物机制。大麻的主要精神成分δ-9-四氢大麻酚（THC）通过与内源性大麻素系统（ECS）相互作用而发挥其作用。ECS是我们大脑中最广泛的受体系统。它可以对内部和外部刺激做出反应，包括调节大脑发育，记忆形成，压力，疼痛，能量代谢和免疫系统。这些反应由按需产生的内源性大麻素（eCB）介导，例如大麻素（AEA）。因此，eCB的血液水平已被用作ECS中活性的生物标志物。越来越多的研究表明，精神病患者的ECS中断，但其功能是否在使用大麻的精神病患者中特别中断尚未得到解决。事实上，人们认为AEA水平在精神病的急性期很低，随后增加以调节恢复过程。然而，没有研究测量了整个精神病发作最急性期的eCB水平。此外，从未研究过eCB水平与暴力和攻击结果的关系。最后，没有研究调查了整个ECS的遗传学，其中包括几个生物成分。我最近提供了在人群水平上ECS中大量遗传变异的初步研究结果，这可能使一些人患精神障碍的风险更高。这种遗传风险可以概括为内源性大麻素多基因风险评分（ECS-PRS）。拟议的研究将首先测试在两个大型非临床样本中，具有高ECS-PRS和使用大麻的个体是否更有可能出现亚临床精神病经历和攻击/暴力倾向。其次，它将利用两个网站收集数据，向患有急性精神病发作的个人和生活在社区中的精神病患者提供访问。我的目标是收集血液样本，以生成个体ECS-PRS并测量eCB血液水平。这些数据将使我能够解决三个目标。首先，在人口层面上，ECS-PRS和大麻的使用与精神病理学以及暴力和侵略行为是否有关系。第二，新招募的临床样本中的eCB血液水平在精神病表现的不同阶段以及使用和不使用大麻的患者之间是否存在差异。最后，做ECS-PRS和大麻的使用解释了ECB水平的正常化的差异在整个sample.The大麻的共同使用和目前的社会态度合法化使得它是必要的检查ECS和精神病理结果的神经生物学之间的关系。目前的研究建议可以告知公众，科学和临床社区。此外，该项目将有可能确定精神病恶化的血液生物标志物，这可能导致更好地管理PICU中的暴力行为，并防止在医院拘留及其令人痛苦的后果。

Psychotic illnesses are a major cause of mortality and cause a financial burden of £12 billion per annum in England. There is a pressing need to understand which individuals can be helped by simple targeted interventions. The most modifiable risk factor of psychotic outcomes is cannabis use, the most illicit substance used worldwide. Further, individuals with psychosis using cannabis are more likely to be involved in aggression and violence incidents, at times requiring detention in a psychiatric intensive care unit (PICU) under the Mental Health Act to contain the risks.My previous work has shown that patients with psychosis who are heavy cannabis users have more severe symptoms than those who are non-cannabis users, which may potentially reflect different biological mechanisms. The main psychotropic element of cannabis, delta-9-tetrahydrocannabinol (THC), elicits its effects through interacting with the endocannabinoid system (ECS). The ECS is the most widespread receptor system in our brain. It serves to respond to internal and external stimuli, which includes regulating brain development, memory formation, stress, pain, energy metabolism, and the immune system. These responses are mediated by endocannabinoids (eCBs) produced on demand, such as anandamide (AEA).Blood levels of eCBs have been therefore used as biological markers of the activity in the ECS. A growing body of studies indicates a disruption in the ECS in patients with psychosis, but whether its functioning is particularly disrupted in individuals with psychosis using cannabis is yet to be resolved. In fact, it is thought that AEA levels are low in the acute phase of psychosis and subsequently increase to regulate the recovery process. However, no study has measured eCB levels throughout the most acute phase of a psychotic episode. Moreover, eCB levels have never been examined in relation to violence and aggression outcomes. Finally, no study has investigated the genetics of the entire ECS, which includes several biological components. I recently provided preliminary findings on a substantial genetic variation in the ECS at a population level, that may make some individuals at a higher risk of developing a psychotic disorder. This genetic risk can be summarised into an endocannabinoid polygenic risk score (ECS-PRS).The proposed study will first test whether, in the two large non-clinical samples, individuals with high ECS-PRS and using cannabis are more likely to present with subclinical psychotic experiences and propensity to aggression/violence.Second, it will utilise two sites for data collection, providing access to individuals with an acute psychotic episode and individuals with psychosis living in the community. I aim to collect blood samples to generate an individual ECS-PRS and measure eCB blood levels. These data would allow me to address three objectives. Firstly, do ECS-PRS and cannabis use have a relationship with psychopathology and violence and aggression at a population level. Second, do eCB blood levels in the newly recruited clinical sample differ throughout the different phases of the psychosis presentation and between patients using and not using cannabis. Finally, do ECS-PRS and cannabis use explains differences in the normalization of eCB levels across the sample.The common use of cannabis and current social attitudes toward legalization makes it is imperative examining the relationship between the neurobiology of the ECS and psychopathological outcomes. The present research proposal may inform the public, scientific and clinical community. In addition, this project will potentially identify blood biomarkers of psychosis exacerbations, which could lead to better management of violence in PICU and prevent detention in the hospital and its distressing consequences.