CANNABIDIOL AS A NOVEL THERAPEUTIC AGENT FOR PATIENTS AT ULTRA HIGH-RISK OF PSYCHOSIS: AN EXPERIMENTAL MEDICINE APPROACH

在世界范围内，越来越多的人关注在坦率的精神病发作之前进行干预，以防止与这种疾病相关的大部分残疾。然而，目前还没有安全、有效和耐受性良好的治疗方法来治疗患有精神病(UHR)的高危人群。此外，由于一些UHR患者永远不会发展为坦率的精神病，开发不仅安全而且耐受性良好的药物至关重要。UHR个人通常经历焦虑和精神病症状，与他们发展为坦率的精神病时相比，这些症状是短暂的和/或不那么严重的。大麻二酚(CBD)是从大麻提取物中发现的一种天然可用化学物质，由于在动物模型和人类中显示出抗焦虑和抗精神病的性质，并且在人类研究中也得到了很好的耐受性，因此成为一种有前途的候选药物。然而，它是否在治疗焦虑和精神症状方面可能有有益的效果，这些症状通常出现在UHR个人中，从未得到测试。我们建议通过一种实验方法来研究CBD是否可用于UHR患者的治疗，我们采用一种实验方法，在治疗三周后的急性和短期内测试CBD对焦虑和精神症状及其潜在神经基础的影响。符合标准诊断标准且从未接受过任何抗精神病药物治疗的UHR患者将被随机分配到CBD治疗组或安慰剂治疗组。在研究的第一天，CBD治疗组的UHR患者将被要求口服一颗600毫克的CBD胶囊，而安慰剂治疗组的患者将服用相同的安慰剂胶囊。在服药前和服药后第1天，使用标准评定量表测量焦虑和精神病性症状。同一天，他们还将接受脑扫描，并在扫描仪外完成两项心理任务。研究人员以前曾使用过这些任务，旨在暂时引发焦虑和偏执的感觉。在其中一项任务中，他们将被要求准备并发表一篇简短的演讲。他们将被告知，这将被心理学家拍摄和分析，从而引发焦虑。第二项任务将包括在繁忙的伦敦地铁列车上进行虚拟现实之旅，这将在真实世界的3D环境中重现场景、声音和沉浸感。这项任务已被证明会在UHR个体中诱发短暂的偏执。只有那些在研究第一天对实验的所有方面都耐受的UHR患者才会被要求继续服用相同的药物，每天一次，持续三周。否则，他们将被从研究中撤回。在研究的最后一天(第21天)，所有的实验程序，包括临床测量、脑扫描和离线症状诱导任务，将像第一天一样重复。通过比较两个实验期间安慰剂组和CBD组的焦虑和精神病症状以及脑活动指标，我们将能够确定CBD在急性治疗和短期治疗后是否对症状有有益影响，并建立这些影响的神经机制。参与这项研究的医生和研究人员以及参与UHR的个人都将对参与者将接受的治疗视而不见。在整个研究过程中，将通过定期重复常规血液检查、心电图、临床访谈和体检来监测参与者的安全性。这项研究将在获得道德和其他监管批准后，按照监管指南进行。这项研究将有助于提供有关CBD作为一种安全、有效和耐受性良好的治疗方法的潜力的重要早期信息，这将指导未来的临床试验。

Worldwide, there is increasing focus on intervening before the onset of frank psychosis in order to prevent much of the disability associated with the disorder. However, safe, effective and well-tolerated treatments for individuals who are at high-risk of developing psychosis (UHR) are currently unavailable. Further, as some of the UHR individuals will never go on to develop frank psychosis, it is critical to develop medications that are not only safe but also tolerated well. UHR individuals commonly experience anxiety and psychotic symptoms that are short-lasting and/ or less severe compared to when they develop frank psychosis. Cannabidiol (CBD), a naturally available chemical found in the extract of cannabis, has emerged as a promising candidate as it displays anti-anxiety and anti-psychotic like properties in animal models and in man and has also been tolerated very well in human studies. However, whether it may have beneficial effects in treating anxiety and psychotic symptoms that are commonly present in UHR individuals has never been tested. We propose to investigate whether CBD may be useful as a treatment in UHR individuals by employing an experimental approach where we test the effects of CBD on anxiety and psychotic symptoms and their underlying neural substrate both acutely and in the short-term following three weeks of treatment. UHR individuals who satisfy standard diagnostic criteria and have never received any antipsychotic treatment will be randomly allocated to a CBD treatment group or a placebo treatment group. On day 1 of the study, UHR individuals in the CBD treatment group will be asked to take one 600 mg capsule of CBD orally, while those in the placebo treatment group will take an identical placebo capsule. Anxiety and psychotic symptoms will be measured using standard rating scales both before and after drug administration on day 1. On the same day they will also undergo brain scanning and complete two psychological tasks outside the scanner. These tasks have been used by researchers before, and are meant to temporarily trigger feelings of anxiety and paranoia. In one of the tasks they will be asked to prepare and deliver a short speech. They will be told that this will be filmed and analysed by psychologists, to trigger anxiety. The second task will involve a virtual-reality journey on a busy London tube train, which will recreate the sights, sounds, and sense of immersion in a real-world 3D environment. This task has been shown to induce brief-lasting paranoia in UHR individuals. Only those UHR individuals who tolerate all aspects of the experiment on day 1 of the study will be asked to continue on the same drug, once a day, for 3 weeks. Otherwise, they will be withdrawn from the study. On the final day (day 21) of the study, all the experimental procedures, including clinical measures, brain scanning and off-line symptom-induction tasks, will be repeated as on day 1. By comparing the anxiety and psychotic symptoms with and without the symptom-induction tasks and the brain activity measures between the placebo and CBD treatment groups across the two experimental sessions, we will be able to establish whether CBD has a beneficial effect on symptoms both acutely and following short-term treatment and also establish the neural mechanisms underlying these effects. Both doctors and researchers involved in carrying out the study and the UHR individuals who participate will be blind to the treatment that the participants will be receiving. Safety of the participants will be monitored throughout the study by repeating routine blood investigations, ECG, clinical interviews and physical examination at regular intervals. The study will be carried out following regulatory guidelines after obtaining ethical and other regulatory approvals. This study will help provide important early information regarding the potential of CBD as a safe, effective and well-tolerated treatment that will guide future clinical trials.