Cannabidiol Modulation of ???-9-THC???s Psychotomimetic Effects in Healthy Humans

描述（由申请人提供）：大麻含有多种化合物，包括德尔塔-9-四氢大麻酚（THC）和大麻二酚（CBD）。四氢大麻酚被认为是大麻对精神病的影响的原因，它在健康人身上产生与精神分裂症有关的广泛的拟精神、认知和心理生理影响。另一方面，CBD没有任何促精神病作用，反而似乎减少了大麻的整体精神病作用。虽然临床前数据支持CBD在许多精神病动物模型中的抗精神病潜力，但人类研究的证据存在显着局限性。CBD减弱了一些四氢大麻酚诱导的主观效应，这是否延伸到四氢大麻酚诱导的拟精神或认知效应尚不清楚。目的：本提案的总体目标是证明CBD预处理将减少健康人类急性给药四氢大麻酚引起的广泛的拟精神、认知和心理生理效应。本研究旨在作为探索CBD在健康个体中的抗精神病潜力的第一个概念证明。这项研究的数据将为更全面、更昂贵的CBD在精神分裂症患者中的临床试验拉开序幕。方法：将从社区招募20名精神和医学上健康的个体，他们曾接触过大麻，但从未达到大麻使用障碍的标准，参加这项随机、双盲、安慰剂对照研究。受试者将被随机分配到(A) 4个测试日或(B) 6个测试日。所有20名受试者将完成(A) 4天的测试，并接受CBD （5mg）或安慰剂，然后静脉注射四氢大麻酚或安慰剂。随机分配到(B) 6天的10名受试者将参加2个额外的测试天，在此期间他们将接受CBD (2.5mg或7.5mg)，然后是THC。受试者将在给药前后测试精神分裂症样症状(用阳性和阴性综合征量表（PANSS）和临床医生管理的分离症状量表（CADSS）测量，认知障碍（言语记忆、空间工作记忆和持续注意力），主观影响（用焦虑和兴奋的情绪状态的视觉模拟量表测量），心理生理影响（P300事件相关电位）和内分泌影响(血清ACTH，皮质醇和催乳素水平)。此外，将测量每位受试者血液中THC、其活性和非活性代谢物以及CBD的水平，以探索药代动力学相互作用。意义：目前大多数精神分裂症的药物治疗主要涉及多巴胺能和血清素能系统。在新的假设的驱动下，有必要开发新的精神分裂症药物疗法。CBD针对大麻素系统，可能具有抗精神病特性。因此，对其抗精神病特性的探索可能会为精神分裂症带来新的治疗选择。

DESCRIPTION (provided by applicant): Cannabis contains a number of compounds including delta-9-Tetrahydrocannabinol (THC) and cannabidiol (CBD). THC, believed to be responsible for the psychotic effects of cannabis, produces a wide range of psychotomimetic, cognitive and psychophysiological effects in healthy humans that are relevant to schizophrenia. CBD, on the other hand, does not have any propsychotic effects and instead appears to reduce the overall psychotic effects of cannabis. While preclinical data support the antipsychotic potential of CBD in a number of animal models of psychosis, there are significant limitations to evidence from human studies. CBD attenuates a number of THC-induced subjective effects, whether this extends to THC-induced psychotomimetic or cognitive effects is unclear. Aims: The overarching aim of this proposal is to demonstrate that pretreatment with CBD will reduce a wide range of psychotomimetic, cognitive and psychophysiological effects induced by the acute administration of THC in healthy humans. This study is designed as a first proof of concept to explore the antipsychotic potential of CBD in healthy individuals. The data from this study will serve as a prelude to more comprehensive and expensive clinical trials of CBD in patients with schizophrenia. Methods: 20 psychiatrically and medically healthy individuals, who have been exposed to cannabis but have never met criteria for a cannabis use disorder, will be recruited from the community to participate in this randomized, double-blinded, placebo-controlled study. Subjects will be randomized to (A) four test days or (B) six test days. All 20 subjects will complete (A) 4 test days and receive either CBD (5mg) or placebo followed by THC or placebo intravenously. 10 subjects randomized to (B) six test days will participate in 2 extra test days during which they will receive CBD (2.5mg or 7.5mg) followed by THC. Subjects will be tested before and after drug administration for schizophrenia-like symptoms (measured on the positive and negative syndrome scale (PANSS) and clinician administered dissociative symptoms scale (CADSS), cognitive impairments (in verbal memory, spatial working memory and sustained attention), subjective effects (measured on a visual analog scale of mood states for anxiety and euphoria), psychophysiological effects (P300 event related potential) and endocrine effects (serum ACTH, cortisol and prolactin levels). In addition, blood levels of THC, its active and inactive metabolites, and CBD will be measured in each subject to explore pharmacokinetic interactions. Significance: Most pharmacological treatments currently available for schizophrenia involve primarily the dopaminergic and serotonergic systems. There is a need to develop new pharmacotherapies for schizophrenia driven by novel hypotheses. CBD targets the cannabinoid system and may have antipsychotic properties. Thus, exploration of its antipsychotic properties may lead to newer therapeutic options for schizophrenia. PUBLIC HEALTH RELEVANCE: There is a need to develop new medications for the treatment of schizophrenia based on new hypotheses. Cannabidiol (CBD), which produces effects through the brain cannabinoid system, appears to have antipsychotic potential. The aim of this proposal is to test the antipsychotic effects of CBD in humans in a controlled laboratory study.