Acute exposure to cannabis comes with neurocognitive impairment, leading to increased risk of human error and injury. Evidence however indicates that such acute effects are less prominent in chronic users, suggesting cannabis tolerance. Models of cannabis tolerance stress the importance of neurobiological or behavioral adaptations following repeated cannabis exposure. The pharmacodynamic model relates neuroadaptive changes in the brain to a blunted response to cannabis. Downregulation of CB1 receptors in chronic cannabis users has been associated with a normalization of dopaminergic output from the ventral tegmental area to the mesolimbic circuit, and a reduction of impairment during acute cannabis exposure. Such neuroadaptions are absent in occasional users, who show strong increments of dopamine and glutamate levels in the striatum, a loss of functional connectivity within the mesolimbic circuit and neurocognitive impairments when exposed to cannabis. Evidence for a behavioral model of cannabis tolerance that poses that users can have volitional control to overcome functional impairment during cannabis intoxication is relatively weak, and at best shows limited control over a limited number of behavioral functions. Cannabis tolerance is most likely to occur in users that consume high doses of cannabis continuously, at a high pace, for a prolonged period of time. Knowledge on frequency, dose and duration of cannabis use that is needed to achieve, maintain or lessen tolerance however is very limited, but will be of importance in the context of cannabis therapeutics and in legal settings when evaluating the impact of cannabis exposure on human function.

中文翻译：

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大麻耐受性的药效学和行为模型


急性接触大麻会导致神经认知障碍，导致人为错误和伤害的风险增加。然而，有证据表明，这种急性影响在长期使用者中不太明显，这表明大麻具有耐受性。大麻耐受性模型强调反复接触大麻后神经生物学或行为适应的重要性。药效学模型将大脑的神经适应性变化与对大麻的反应迟钝联系起来。慢性大麻使用者中 CB1 受体的下调与从腹侧被盖区到中脑边缘回路的多巴胺能输出正常化以及急性大麻暴露期间损伤的减少有关。这种神经适应在偶尔吸食者中不存在，他们在接触大麻时表现出纹状体中多巴胺和谷氨酸水平的强烈增加、中脑边缘回路内功能连接的丧失以及神经认知障碍。大麻耐受行为模型的证据表明，使用者可以通过意志控制来克服大麻中毒期间的功能障碍，但充其量表明对有限数量的行为功能的控制有限。大麻耐受最有可能发生在长时间持续、高速消耗高剂量大麻的使用者身上。然而，关于实现、维持或减少耐受性所需的大麻使用频率、剂量和持续时间的知识非常有限，但在大麻治疗背景下以及在评估大麻暴露对人体功能的影响时在法律环境中非常重要。