Cannabis Modulation of Outcomes Related to Opioid Use Disorder: Opioid Withdrawal, Opioid Abuse Potential and Opioid Safety

摘要 阿片类药物和大麻素是使用最广泛和滥用最多的两类药物。在世界范围内， 估计有5300万人滥用阿片类药物。在美国，260万人符合阿片类药物使用标准 2019年，近47，000人因阿片类药物过量而死亡。与此同时，全球大麻 (i.e.,大麻）的使用也处于创纪录的高水平-2018年，美国有4350万人报告去年 使用大麻尽管合法和非法使用这些药物的比率很高，但没有受控数据。 关于大麻对最高风险群体之一-阿片类药物使用障碍者-的影响。因此 目前的项目旨在探讨如何急性（研究1）和重复（研究2）大麻管理 影响1）阿片类药物滥用的可能性，2）阿片类药物戒断的严重程度，以及3）阿片类药物的安全性/生理效应。两 在这个为期4年的项目中将进行独立的住院研究， 受试者内、双盲、安慰剂对照设计，并将招募中度至 严重的类阿片使用障碍（目前有身体依赖性）和上个月有限的大麻使用。研究1 将检查7种急性大麻剂量的影响，包括6倍剂量范围的THC（5，10，20，30毫克）， THC/CBD剂量在3倍剂量范围内（10：10 mg; 30：30 mg THC：CBD）和匹配的安慰剂， 与1）阿片类药物滥用倾向（即，急性阿片类药物激发期间的高评级、药物喜欢）， 2)戒断严重性（在阿片样物质戒断的急性情况下），和3）安全性/生理作用（例如， 呼吸驱动）的药物条件和组合。研究2将探讨重复吸入 大麻（3次/天，连续6.5天），三个随机给药区组（两种活性大麻） 剂量，匹配的安慰剂），以确定重复大麻给药模型如何影响与1） 阿片样物质滥用可能性（即，急性阿片类药物激发期间评估的高、药物喜好等级）; 2） 戒断严重程度（在阿片类药物戒断的急性情况下测量），3）安全性/生理效应 (e.g.,呼吸驱动）的药物条件和组合;和4）大麻耐受性和戒断。 还将探讨急性阿片类药物戒断发作期间大麻对睡眠质量的调节。两 研究将采用完整的药效学结局，包括主观和主观评价 措施，以及与安全性相关的全套生理和心理结果， 因此，我们需要评估大麻在OUD中的潜在风险/益处。总的来说，这些及时和 创新的研究将提供关于吸入大麻对阿片类药物依赖者的影响的第一个经验数据。 人口这些研究将提供与临床相关的潜在相互作用的新对照信息。 实践、处方和公共安全。

Abstract Opioids and cannabinoids are the two most widely used and misused drug classes. Worldwide, an estimated 53 million people misuse opioids. In the US, 2.6 million individuals meet criteria for opioid use disorder and nearly 47,000 people died in 2019 due to opioid overdose. At the same time, global cannabis (i.e., marijuana) use is also at record high levels - in 2018, 43.5 million individuals in the US reported past-year cannabis use. Despite high rates of both licit and illicit use of these drug classes, there are no controlled data on the effects of cannabis in one of the most high-risk groups – individuals with opioid use disorder. Thus, the current project aims to explore how both acute (Study 1) and repeated (Study 2) cannabis administration impacts 1) opioid abuse potential, 2) opioid withdrawal severity, and 3) opioid safety/physiological effects. Two independent inpatient studies will be conducted during this 4-year project and each will utilize a randomized, within-subject, double-blind, placebo-controlled design and will enroll samples of participants with moderate to severe opioid use disorder (with current physical dependence) and limited past-month cannabis use. Study 1 will examine the effects of 7 acute cannabis doses, including a 6-fold dose range of THC (5, 10, 20, 30 mg), THC/CBD doses across a 3-fold dose range (10:10 mg; 30:30 mg THC:CBD) and matched placebo on outcomes related to 1) opioid abuse liability (i.e., ratings of high, drug liking) during an acute opioid challenge, 2) withdrawal severity (during acute instances of opioid withdrawal), and 3) safety/physiological effects (e.g., respiratory drive) of the drug conditions and combinations. Study 2 will explore the effects of repeated inhaled cannabis (3 times/day for 6.5 consecutive days), across three randomized dosing blocks (two active cannabis doses, matched placebo), to determine how a repeated cannabis dosing model impacts outcomes related to 1) opioid abuse potential (i.e., ratings of high, drug liking) assessed during an acute opioid challenge; 2) withdrawal severity (measured during acute instances of opioid withdrawal), 3) safety/physiological effects (e.g., respiratory drive) of the drug conditions and combinations; and 4) cannabis tolerance and withdrawal. Cannabis modulation of sleep quality during bouts of acute opioid withdrawal will also be explored. Both studies will employ a full complement of pharmacodynamic outcomes, including subjective and observer-rated measures, as well as a full battery of physiological and psychomotor outcomes related to safety and impairment to fully assess the potential risk/benefit profile of cannabis in OUD. Overall, these timely and innovative studies will provide the first empirical data on the effects of inhaled cannabis in an opioid-dependent population. These studies will provide new controlled information on potential interactions relevant to clinical practice, prescribing, and public safety.