Repeated Administration of Cannabis Varying in THC and CBD: Effects on Abuse Liability, Experimental Pain and Plasma Endocannabinoids

在美国120万登记的医用大麻患者中，大多数人认为缓解疼痛是他们的首要任务 使用大麻产品的原因。尽管大麻及其成分(大麻素)具有潜在的 在慢性疼痛的治疗方面，我们对反复疼痛的影响的认识存在严重差距 大麻管理对疼痛、滥用倾向和循环内源性大麻素水平的影响。这个 内源性大麻素系统在中枢神经系统功能中起关键作用，但大麻使用对循环的影响 人们对ECBS知之甚少。对不同浓度的大麻的影响也知之甚少。 口服D9-四氢大麻酚(THC)和大麻二酚(CBD)，这两种最常用的大麻类物质由 医用大麻患者。这个项目旨在回答三个问题，这三个问题将填补我们 对持续使用大麻的理解：1)耐受性是否会发展为止痛剂和滥用相关的效果 重复使用不同比例的THC和CBD的大麻，这种耐受性可逆吗？ 在戒除一段时间后；2)突然停止吸食具有不同比例的THC和CBD的大麻 与戒断诱导的痛觉过敏有关；3)重复使用大麻如何与 THC和CBD的比例调节循环ECB的水平，这些变化是否与改变有关 疼痛敏感和滥用责任？在住院测试大麻给药之前，我们将使用应急措施 促使健康的大麻使用者持续戒烟的管理程序，以便最大限度地减少 现有的容忍度。然后我们将招募参与者(N=100)住院15天。他们将被随机分配到 四种大麻状态之一(n=25/组)：1)高THC：低CBD，2)低THC：低CBD，3)高THC：高CBD CBD，4)低THC：高CBD。大麻将在前7天住院期间重复服用，随后 七天的禁酒期。最后一个学习日(第15天)将重新引入分配的有效大麻剂量 以评估耐受性的逆转。在每种情况下的设定时间点，我们将测量与滥用相关的影响 (“良好的药物效应”)、血浆ECB水平和两种不同类型的实验性疼痛：冷加压试验 和定量感觉测试热时间总和。鉴于大麻被广泛用于 疼痛，了解每天重复服用大麻的后果，THC：CBD比率为 是大多数医用大麻产品的代表，对疼痛、滥用负有责任，而ECBS势在必行。 对与滥用有关但没有止痛作用的容忍是有益的，但反过来也可能起到作用 由于在医用大麻患者中观察到较高的大麻使用障碍发生率。同样，如果突然 停止吸食大麻会加剧疼痛，医用大麻患者将很难停止使用大麻。 证明循环ECB和疼痛敏感性之间的关系可以用来帮助开发安全 以及有效的基于大麻素的疼痛治疗。总体而言，这项提议将提供重要的公共卫生 关于大量使用一系列蒸发大麻产品止痛的患者的数据。

The majority of the >1.2 million registered medical cannabis patients in the U.S. cite pain relief as their primary reason for using cannabis products. Although cannabis and its constituents (cannabinoids) have potential for the treatment of chronic pain, there are critical gaps in our knowledge regarding the effects of repeated cannabis administration on pain, abuse liability and circulating endogenous cannabinoid (eCBs) levels. The endocannabinoid system plays a critical role in CNS function, yet the impact of cannabis use on circulating eCBs is poorly understood. There is also little known about the effects of cannabis with varying concentrations of oral D9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most commonly used cannabinoids by medical cannabis patients. This project is designed to answer three questions that will fill important voids in our understanding of sustained cannabis use: 1) does tolerance develop to the analgesic and abuse-related effects of repeatedly administered cannabis with varying ratios of THC and CBD, and is this tolerance reversible following a period of abstinence; 2) is abrupt cessation of cannabis with varying ratios of THC and CBD associated with withdrawal-induced hyperalgesia; 3) how does repeatedly administered cannabis with varying ratios of THC and CBD modulate levels of circulating eCBs, and are these changes associated with altered pain sensitivity and abuse liability? Prior to inpatient testing of cannabis administration, we will use contingency management procedures to engender sustained abstinence in healthy cannabis users in order to minimize existing tolerance. We will then enroll participants (N=100) inpatient for 15 days. They will be randomized to one of four cannabis conditions (n=25/group): 1) high THC:low CBD, 2) low THC:low CBD, 3) high THC:high CBD, 4) low THC:high CBD). Cannabis will be administered repeatedly for the first 7 inpatient days, followed by a 7-day abstinence period. The last study day (day 15) will re-introduce the assigned active cannabis dose to assess reversal of tolerance. At set time points within each condition, we will measure abuse-related effects (“Good Drug Effect”), plasma eCB levels and two distinct types of experimental pain: The Cold Pressor Test and Quantitative Sensory Testing Thermal Temporal Summation. Given the widespread use of cannabis for pain, understanding the consequences of daily repeated administration of cannabis with THC:CBD ratios that are representative of most medical cannabis products on pain, abuse liability, and eCBs is imperative. Tolerance to the abuse-related but not analgesic effects would be salutary, but the converse could contribute to the higher incidence of cannabis use disorder observed in medical cannabis patients. Similarly, if abrupt cannabis cessation exacerbates pain, medical cannabis patients will have difficulty ceasing cannabis use. Demonstrating a relationship between circulating eCBs and pain sensitivity can be used to help develop safe and effective cannabinoid-based pain treatments. Overall, this proposal will provide significant public health data for the large number of patients using a range of vaporized cannabis products for pain relief.