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

描述（由申请人提供）：尽管与大麻相关疾病（CRDs）相关的患病率和问题很高，但我们缺乏有效的药物，研究尚处于起步阶段。药物歧视（DD）已被用于评估治疗药物使用障碍的药物，而不是crd。只有一项关于大麻DD的人体研究被进行过，而且没有一项研究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、敏感、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选择（如金钱）的强化效应。药物治疗应该从大麻转向非药物强化剂。只有一项大麻的MCP研究是在人类身上进行的；没有人用这个指数测试过药物对大麻的强化效果。因此，DD和MCP方法具有明显的优势和兼容性，但它们的优势尚未在CRD药物开发中得到充分利用。该项目将开发和测试吸食大麻结合DD/选择范式在人类中的敏感性和选择性，使我们能够将大麻的区别刺激，主观和相对强化功效，以及这些被药物减弱的程度联系起来。长期目标是证明这种联合模型是一种时间效率高、成本效益高且全面的CRD药物筛选方法。这个概念验证研究的短期目标如下。参与者将接受训练，辨别吸食大麻的影响。然后用不同于训练剂量的大麻剂量生成剂量-反应函数，测试模型的敏感性，用药理学上与大麻相似的药物（口服四氢大麻酚）和不同的药物（d-安非他明）进行泛化试验，确定模型的选择性。接下来，将确定口服四氢大麻酚对吸食大麻的主观、生理、强化和鉴别刺激效应的减弱能力。该应用的中心假设是，DD/MCP组合模型将是一个敏感和选择性的范例，可以检测药物“信号”（即在一系列措施中一种或多种效果的衰减），这表明有发展的希望。具体目的是确定：(1)吸食大麻是否会导致大麻适当反应（DD敏感性）的剂量依赖性增加和(2)强化效应（MCP）；(3)口服四氢大麻酚（THC）和(4)d-安非他明（d-苯丙胺）引起大麻适当反应（DD选择性）；口服四氢大麻酚剂量依赖性地减弱吸食大麻的(5)鉴别刺激和(6)强化效应。我们将探讨大麻的鉴别刺激、强化、主观（如渴望）和生理效应之间的关系，以及口服四氢大麻酚阻断这些效应的相对能力。拟议的工作在结合两种现有范例（DD， MCP）来帮助尚未在对照实验室研究中研究过的药物类别的药物开发方面具有高度创新性。该模型具有科学和健康意义，因为它有可能在进行昂贵和耗时的临床试验之前快速和全面地筛选，从而确定有希望用于crd的化合物。

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.