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

重复使用 THC 和 CBD 含量不同的大麻：对滥用倾向、实验性疼痛和血浆内源性大麻素的影响

• 批准号: 10366284
• 负责人: Caroline A Arout
• 金额: $ 67.82万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366284
• 关键词: 2-arachidonylglycerol; Absence of pain sensation; Abstinence; Acute; Address; Affect; Analgesics; Anorexia; Brain; Cannabidiol; Cannabinoids; Cannabis; Clinical; Controlled Study; Desire for food; Development; Dose; Endocannabinoids; Enrollment; Exposure to; Frequencies; Hyperalgesia; Incidence; Inpatients; Intoxication; Knowledge; Measures; Medical Marijuana; Modality; Oral; Oral Administration; Outcome Study; Outpatients; Pain; Pain management; Participant; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Placebos; Plasma; Play; Procedures; Public Health; Randomized; Research; Role; Sensory; Sleep disturbances; Smoke; Smoking; Substance Withdrawal Syndrome; Testing; Tetrahydrocannabinol; Time; Toxicology; Urine; Withdrawal; Work; abuse liability; anandamide; base; cannabis cessation; chronic pain; chronic pain management; contingency management; design; endogenous cannabinoid system; health data; marijuana smoker; marijuana use; marijuana use disorder; marijuana user; negative mood; pain perception; pain relief; pain sensitivity; response; reverse tolerance; vapor

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.

在美国，大多数> 120万> 120万注册的医用大麻患者将疼痛缓解为主要 使用大麻产品的原因。尽管大麻及其构成（大麻素）有可能 慢性疼痛的治疗，我们关于重复的影响的知识存在关键的差距 大麻疼痛，滥用责任和循环内源性大麻素（ECB）水平。 内源性大麻素系统在中枢神经系统功能中起着至关重要的作用，但使用大麻对循环的影响 ECB知之甚少。关于浓度不同的大麻的影响也鲜为人知 口服D9四氢大麻酚（THC）和大麻二酚（CBD），这是两个最常用的大麻素。 医用大麻患者。该项目旨在回答三个问题，这些问题将填补我们的重要空隙 对持续大麻的了解：1）耐受性会发展到与镇痛和滥用相关的效果上 反复给予THC和CBD比的大麻的反复给药，这是可逆的耐受性 一段时间的禁欲； 2）大麻的突然停止，THC和CBD的比率不同 与戒断诱导的痛觉过敏有关； 3）如何反复使用不同的大麻 THC和CBD调节循环ECB的水平的比率，并且这些变化与变化有关 疼痛敏感性和虐待责任？在进行大麻给药的住院测试之前，我们将使用意外事件 为了最大程度地减少健康大麻使用者的持续戒酒的管理程序 现有的公差。然后，我们将入学参与者（n = 100）住院15天。他们将被随机 四个大麻条件之一（n = 25/组）：1）高thc：低CBD，2）低THC：低CBD，3）高THC：高 CBD，4）低THC：高CBD）。大麻将在前7天重复管理，然后 在7天的节制期间。最后一个学习日（第15天）将重新引入分配的活性大麻剂量 评估宽容的逆转。在每个条件下的设定时间点，我们将衡量与滥用相关的效果 （“良好的药物效应”），血浆欧洲央行水平和两种不同类型的实验疼痛：冷压测试 和定量感觉测试热时间求和。考虑到大麻的宽度使用 痛苦，了解每天以THC：CBD比的每日重复给药的后果 代表大多数有关疼痛，虐待责任和ECB的医用大麻产品的代表。 对与滥用有关但无镇痛作用的容忍将是有益的，但相反可能会贡献 在医用大麻患者中观察到的大麻使用障碍的较高事件。同样，如果突然 大麻停止加剧了疼痛，医用大麻患者将难以停止使用大麻。 证明循环ECB和疼痛敏感性之间的关系可以用来帮助发展安全 和有效的基于大麻素的疼痛治疗。总体而言，该建议将提供重要的公共卫生 大量患者的数据使用一系列蒸发大麻产品缓解疼痛。