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δ-9-四氢大麻酚（THC）和大麻二酚（CBD）。THC被认为是大麻精神病影响的原因，在健康人中产生广泛的拟精神病，认知和心理生理学影响，这些影响与精神分裂症有关。另一方面，CBD没有任何propsychotic影响，反而似乎减少了大麻的整体精神病影响。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重大局限性。CBD减弱了许多THC诱导的主观效应，这是否延伸到THC诱导的拟精神病或认知效应尚不清楚。目的：该提案的总体目标是证明CBD预处理将减少健康人中THC急性给药引起的广泛的拟精神病，认知和心理生理学影响。这项研究被设计为探索CBD在健康个体中的抗精神病潜力的第一个概念证明。这项研究的数据将作为CBD在精神分裂症患者中进行更全面和昂贵的临床试验的前奏。研究方法：将从社区招募20名精神和医学健康的人，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，安慰剂对照的研究。受试者将随机分配至（A）4个试验日或（B）6个试验日。所有20名受试者将完成（A）4个测试日，并接受CBD（5 mg）或安慰剂，然后静脉注射THC或安慰剂。随机分配至（B）6个测试日的10名受试者将参加2个额外的测试日，在此期间，他们将接受CBD（2.5 mg或7.5 mg），然后接受THC。受试者将在给药前后接受精神分裂症样症状检测（用阳性和阴性症状量表（PANSS）和临床医生管理的分离症状量表（CADSS）测量，认知障碍（在言语记忆、空间工作记忆和持续注意力方面），主观效应（在焦虑和欣快的情绪状态的视觉模拟量表上测量）、心理生理效应（P300事件相关电位）和内分泌效应（血清ACTH、皮质醇和催乳素水平）。此外，将在每个受试者中测量THC，其活性和非活性代谢物以及CBD的血液水平，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多巴胺能系统。有必要开发新的药物治疗精神分裂症驱动的新的假设。CBD靶向大麻素系统，可能具有抗精神病特性。因此，探索其抗精神病特性可能会导致精神分裂症的新的治疗选择。

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.