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.

美国超过 120 万注册医用大麻患者中的大多数将缓解疼痛作为主要治疗方法 使用大麻产品的原因虽然大麻及其成分（大麻素）具有潜在的用途。 在慢性疼痛的治疗中，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 (eCB) 水平的影响。 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，但大麻使用对循环系统的影响 人们对不同浓度大麻的影响知之甚少。 口服 D9-四氢大麻酚 (THC) 和大麻二酚 (CBD)，这两种最常用的大麻素 该项目旨在回答三个问题，这将填补我们的重要空白。 对持续使用大麻的理解：1）对镇痛和滥用相关作用是否产生耐受性 重复施用具有不同比例的 THC 和 CBD 的大麻，这种耐受性是否可逆 戒断一段时间后；2) 突然停止使用不同比例的 THC 和 CBD 大麻； 与戒断引起的痛觉过敏相关；3）反复服用大麻与不同的药物有何关系？ THC 和 CBD 的比例调节循环 eCB 的水平，这些变化与 在住院测试大麻给药之前，我们将使用应急措施 使健康大麻使用者持续戒断的管理程序，以尽量减少 然后，我们将招募住院 15 天的参与者 (N=100)。 四种大麻状况之一（n = 25/组）：1）高 THC：低 CBD，2）低 THC：低 CBD，3）高 THC：高 CBD，4) 低 THC：高 CBD 将在前 7 个住院日重复施用，然后进行。 在 7 天的禁欲期内，最后一个研究日（第 15 天）将重新引入指定的活性大麻剂量。 为了评估耐受性的逆转，我们将在每种情况下的设定时间点测量与滥用相关的影响。 （“良好的药物效果”）、血浆 eCB 水平和两种不同类型的实验疼痛：冷加压测试 鉴于大麻​​的广泛使用，定量感官测试热时间总和。 疼痛，了解每天重复服用大麻的后果，THC：CBD 比例 是大多数医用大麻产品在疼痛、滥用责任方面的代表，ECB 势在必行。 对与滥用相关但非镇痛作用的耐受性是有益的，但反之亦然。 与在医用大麻患者中观察到的大麻使用障碍的较高发生率类似，如果突然的话。 戒除大麻会加剧疼痛，医用大麻患者将很难停止使用大麻。 证明循环 eCB 与疼痛敏感性之间的关系可用于帮助开发安全的 总体而言，该提案将提供重要的公共健康。 大量患者使用一系列汽化大麻产品来缓解疼痛的数据。