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

人类吸食大麻的歧视和大麻选择：实验室模式

• 批准号: 7686631
• 负责人: LESLIE H Lundahl
• 金额: $ 34.31万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686631
• 关键词: Address; Agonist; Attenuated; Behavior Therapy; Cannabinoids; Cannabis; Cannabis-Related Disorder; Clinical Trials; Data; Dependence; Development; Dextroamphetamine; Discrimination; Disease; Dopamine; Dose; Drug-sensitive; Evaluation; Evidence based intervention; Goals; Health; High Prevalence; Human; Individual; Knowledge; Laboratories; Laboratory Finding; Laboratory Study; Lead; Link; Marijuana; Marijuana Abuse; Marijuana Smoking; Measures; Methods; Modeling; Oral; Participant; Pharmaceutical Preparations; Pharmacological Treatment; Physiological; Placebos; Procedures; Psychological reinforcement; Public Health; Relative (related person); Reporting; Research; Research Design; Screening procedure; Self Administration; Signal Transduction; Stimulus; Substance Use Disorder; Testing; Time; Training; Variant; Work; attenuation; base; cost; cost effective; craving; drug discrimination; human study; indexing; infancy; innovation; non-drug; public health relevance; reinforcer; response

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.

描述（由申请人提供）：尽管与大麻相关疾病（CRD）相关的高患病率和问题，但我们缺乏有效的药物，研究尚处于起步阶段。药物歧视（DD）已被用于评估药物治疗物质使用障碍以外的CRD。只有一项关于大麻DD的人类研究已经进行，没有一项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。药物选择程序提供了另一种有效的方法来测试CRD药物。多项选择程序（MCP）可以有效地评估药物相对于替代品（例如金钱）的强化作用。药物治疗应该从大麻转向非药物治疗。只有一个大麻的MCP研究已经进行了与人类;没有测试药物对大麻加固与此指数的影响。因此，DD和MCP方法具有明显的益处并且它们是相容的，但是它们的优点尚未在CRD药物开发中被利用。该项目将开发和测试的敏感性和选择性的吸食大麻结合DD/选择范式在人类中，使我们能够连接的歧视性刺激，主观和相对增强大麻的功效，以及在何种程度上这些被药物衰减。长期目标是证明这种组合模型是一种省时、经济和全面的CRD药物筛选方法。本概念验证研究的短期目标如下。参与者将接受培训，以区分吸食大麻的影响。然后，将使用不同于训练剂量的大麻剂量生成剂量响应函数，以测试模型的灵敏度，并将使用与大麻相似的药物（口服THC）和不同的药物（d-安非他明）进行泛化测试，以确定模型的选择性。接下来，将确定口服THC减弱吸食大麻的主观、生理、强化和辨别刺激作用的能力。本申请的中心假设是，组合的DD/MCP模型将是一种灵敏的和选择性的范例，其可以检测药物“信号”（即，一系列测量中的一种或多种效应的衰减），该药物“信号”将表明开发的前景。具体目的是确定：（1）吸食大麻是否引起大麻适当响应（DD敏感性）和（2）强化效应（MCP）的剂量依赖性增加;（3）口服THC和（4）d-安非他明引起大麻适当响应（DD选择性）;口服THC是否剂量依赖性地减弱吸食大麻的（5）辨别刺激和（6）强化效应。我们将探讨大麻的歧视性刺激，强化，主观（如渴望）和生理效应之间的关系，以及口服THC阻止这些影响的相对能力。拟议的工作是高度创新的结合两个现有的范例（DD，MCP），以帮助药物开发的药物类，尚未在对照实验室研究。该模型具有科学和健康意义，因为它有可能在进行昂贵且耗时的临床试验之前快速全面地筛选并因此确定有希望的CRD化合物。 公共卫生关系：尽管大麻滥用和依赖的发病率很高，但目前还没有药物可以治疗这些重要疾病，而且药物治疗开发的研究仍处于起步阶段。由于临床试验既昂贵又耗时，因此拥有一个受控和经验证的实验室模型来筛选新化合物，从而确定需要进一步测试的最有前途的药物，这将是有利的。本申请提出在人类中开发和利用大麻药物辨别/大麻自我给药范例，其将提供用于评估药理学化合物的有效且成本有效的方法，以及用于测试药理学治疗与基于证据的干预（即，行为治疗），这两者结合起来可能最有可能导致大麻相关疾病的综合和成功治疗。