Smoked Marijuana Discrimination and Marijuana Choice in Humans: A Laboratory Mode

描述(申请人提供)：尽管大麻相关疾病(CRD)的高流行率和相关问题，但我们缺乏有效的药物，研究还处于起步阶段。药物歧视(DD)已被用于评估治疗CRD以外的物质使用障碍的药物。只进行了一项关于大麻DD的人体研究，没有人测试过药物对大麻歧视的影响。DD模型的优点包括有效、可靠、灵敏、选择性和适应主观和生理测量。药物选择程序为测试CRD药物提供了另一种有效的方法。多项选择程序(MCP)可以有效地评估一种药物相对于另一种替代药物(例如金钱)的强化效果。药物治疗的选择应该从大麻转向非药物增强剂。只有一项关于大麻的MCP研究是在人类身上进行的；没有人用这一指数来测试药物对大麻强化的效果。因此，DD和MCP方法有明显的益处，它们是相容的，但它们的优势尚未在CRD药物开发中得到充分发挥。该项目将在人体内开发和测试吸食大麻结合DD/CHOICE范式的敏感性和选择性，使我们能够将大麻的歧视性刺激、主观和相对强化效果以及药物减弱这些作用的程度联系起来。长期目标是证明这种组合模式是一种省时、经济、全面的CRD药物筛选方法。这项概念验证研究的短期目标如下。参与者将接受培训，以辨别吸烟大麻的影响。然后，将在大麻剂量与训练剂量不同的情况下生成剂量-反应函数，以测试模型的敏感性，并将对药理上与大麻相似的药物(口服THC)和不同的药物(d-苯丙胺)进行泛化测试，以确定模型的选择性。接下来，将确定口服THC减弱大麻的主观刺激、生理刺激、强化刺激和辨别刺激作用的能力。这一应用的中心假设是，组合的DD/MCP模型将是一个敏感和选择性的范例，可以检测到药物“信号”(即一系列措施中一个或多个影响的衰减)，这将预示着发展前景。具体目的是确定：(1)吸食大麻时是否有剂量依赖性的大麻适宜反应(DD敏感性)和(2)强化效应(MCP)；(3)口服THC和(4)D-苯丙胺场合大麻适宜反应(DD选择性)；口服THC是否剂量依赖性地减弱(5)辨别性刺激和(6)吸烟大麻的强化效应。我们将探索大麻的歧视性刺激、强化、主观(例如渴望)和生理效应之间的关系，以及口服THC阻止这些效应的相对能力。拟议的工作在结合两种现有范式(DD、MCP)以帮助尚未在对照实验室研究中进行研究的药物类别的药物开发方面具有很高的创新性。该模型具有科学和健康意义，因为它有潜力在进行昂贵和耗时的临床试验之前，快速和全面地筛选，从而识别出有希望用于CRD的化合物。 与公共卫生相关：尽管大麻滥用和依赖的发生率很高，但目前还没有治疗这些重要疾病的药物，开发药理治疗方法的研究还处于初级阶段。由于临床试验既昂贵又耗时，有一个可控和有效的实验室模型来筛选新的化合物，从而确定最有希望的药物，值得进一步测试，这将是有利的。目前的申请建议开发和利用人类的大麻药物歧视/大麻自我给药范例，这将为评估药理化合物提供一种有效和成本效益高的方法，以及一种结合循证干预措施(即行为治疗)测试药理治疗的战略，这两种方法结合在一起可能最有可能导致大麻相关疾病的综合和成功治疗。

DESCRIPTION (provided by applicant): Despite the high prevalence and problems associated with cannabis related disorders (CRDs), we lack effective medications and research is nascent. Drug discrimination (DD) has been used to evaluate medications for treating substance use disorders other than CRDs. Only one human study of marijuana DD has been conducted, and none have tested the effects of a medication on marijuana discrimination. Strengths of the DD model include being valid, reliable, sensitive, selective, and accommodating subjective and physiological measures. Drug choice procedures offer another valid approach for testing CRD medications. The Multiple Choice Procedure (MCP) can efficiently assess the reinforcing effects of a drug relative to an alternative (e.g. money). Medications should shift choice from marijuana to non-drug reinforcers. Only one MCP study of marijuana has been conducted with humans; none have tested the effect of a medication on marijuana reinforcement with this index. Thus, DD and MCP methods have distinct benefits and they are compatible, but their advantages have not yet been exploited in CRD medication development. This project will develop and test the sensitivity and selectivity of a smoked marijuana combined DD/choice paradigm in humans, enabling us to link the discriminative stimulus, subjective and relative reinforcing efficacy of marijuana, and the extent to which these are attenuated by medications. The long-term goal is to show this combined model is a time-efficient, cost-effective and comprehensive screen of putative CRD medications. Short-term goals of this proof-of-concept study are as follows. Participants will be trained to discriminate the effects of smoked marijuana. Dose-response functions will then be generated with marijuana doses different than the training dose to test the model's sensitivity, and generalization tests will be conducted with drugs that are pharmacologically similar to marijuana (oral THC) and different (d-amphetamine) to determine the model's selectivity. Next, the ability of oral THC to attenuate the subjective, physiological, reinforcing, and discriminative stimulus effects of smoked marijuana will be determined. The central hypothesis of this application is that the combined DD/MCP model will be a sensitive and selective paradigm that can detect a medication "signal" (i.e. attenuation of one or more effects in the array of measures) that would suggest promise for development. Specific aims are to determine whether: (1) smoked marijuana occasions a dose-dependent increase in marijuana-appropriate responding (DD sensitivity) and (2) reinforcing effects (MCP); (3) oral THC and (4) d-amphetamine occasion marijuana-appropriate responding (DD selectivity); oral THC dose- dependently attenuates the (5) discriminative stimulus and (6) reinforcing effects of smoked marijuana. We will explore relations among marijuana's discriminative stimulus, reinforcing, subjective (e.g. craving) and physiological effects, and the relative ability of oral THC to block these effects. The proposed work is highly innovative in combining two existing paradigms (DD, MCP) to aid medication development for a drug class that has not yet been studied in controlled laboratory studies. This model has scientific and health significance for its potential to rapidly and comprehensively screen, and thus identify, promising compounds for CRDs prior to undertaking expensive and time-consuming clinical trials. PUBLIC HEALTH RELEVANCE: Despite the high prevalence of marijuana abuse and dependence, there are no medications available to treat these important disorders and research on the development of pharmacological treatments is in its infancy. As clinical trials are both expensive and time-consuming, it would be advantageous to have a controlled and validated laboratory model to screen new compounds and thus identify the most promising medications that warrant further testing. The current application proposes to develop and utilize a marijuana drug discrimination/marijuana self-administration paradigm in humans that would provide an efficient and cost-effective method for evaluating pharmacological compounds, as well as a strategy for testing pharmacologic treatments in combination with evidence- based interventions (i.e., behavioral treatments), which together might have the greatest potential to lead to integrative and successful treatment for cannabis related disorders.