Analgesic and subjective effects of terpenes administered alone and in combination with THC: Potential THC- and opioid-sparing effects of myrcene and ß-caryophyllene

萜烯单独使用以及与 THC 联合使用的镇痛和主观效果：月桂烯和 α-石竹烯的潜在 THC 和阿片类药物节约作用

• 批准号: 10339426
• 负责人: ZIVA D COOPER
• 金额: $ 76.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339426
• 关键词: Absence of pain sensation; Address; Adverse effects; Analgesics; Area; Beta-caryophyllene; Cannabinoids; Cannabis; Chemicals; Clinical; Data Reporting; Dependence; Dose; Double-Blind Method; Drug Kinetics; Elements; Human; Individual; Intoxication; Mediating; Naltrexone; Nature; Opioid; Opioid Antagonist; Outcome; Outpatients; Oxycodone; Pain; Pain management; Patient Self-Report; Patients; Placebo Control; Placebos; Property; Public Health; Research; Smoke; Study Subject; Terpenes; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Effect; Time; Translating; United States; abuse liability; adverse outcome; antagonist; base; chronic pain; chronic pain management; chronic pain patient; effective therapy; innovation; interest; marijuana smoker; mu opioid receptors; novel; novel therapeutics; opioid epidemic; opioid sparing; pain patient; pain relief; placebo controlled study; pre-clinical; pre-clinical research; public health priorities; therapeutic candidate; therapy outcome; vapor; volunteer

Project Summary: Chronic pain is a significant public health burden for which there are few effective treatments; individuals with chronic pain are a central component to the current opioid epidemic. Delta-9- tetrahydrocannabinol (THC), the primary psychoactive chemical of cannabis, holds promise as a therapeutic candidate to treat chronic pain. However, analgesia is accompanied by intoxication and abuse liability, thus limiting its clinical utility. Terpenes are organic compounds that contribute to the aromatic nature and flavor of cannabis; it has been hypothesized that these compounds may interact synergistically with THC to enhance its therapeutic effects with reduced adverse consequences. As such, terpenes may increase the analgesic effects of low, minimally intoxicating, doses of THC, and/or reduce adverse consequences of higher THC doses. Preclinical research demonstrates that the terpenes myrcene and ß-caryophyllene (BCP) elicit antinociceptive effects and have opioid-sparing properties. These effects are, in part, mediated by the mu-opioid receptor. It is unknown if these findings translate to humans. Understanding if these terpenes have analgesic properties alone, or in combination with THC, is fundamental to developing novel cannabinoid-based therapeutics to treat pain. In addition, investigating adverse effects of these terpenes (abuse liability, intoxication) will clarify their clinical potential. At a time when pharmacotherapeutic strategies to decrease reliance on opioids for pain relief are desperately needed, probing the 1) analgesic effects, 2) potential THC- and opioid-sparing properties, and 3) mechanism of these terpenes is of significant interest. The proposed double-blind, placebo-controlled studies will be the first to rigorously assess the dose-dependent analgesic effects of ecologically-relevant doses of myrcene and BCP and determine their THC- and opioid-sparing effects. Study findings will be essential in understanding the clinical potential of terpenes alone and in conjunction with THC for pain management. The proposed double-blind, placebo-controlled, within-subject studies in recreational cannabis smokers (N=30, 15M, 15F in each study) will first ascertain the dose-dependent analgesic potential of vaporized myrcene and BCP alone and in combination with sub-analgesic (5 mg) and analgesic (15 mg) doses of THC (Specific Aim 1). The myrcene/THC and BCP/THC dose combinations that produce the greatest analgesia and minimal intoxication and abuse liability will then be tested for their opioid sparing effects (Specific Aim 2). Opioid modulation of combined terpene/THC analgesia will be assessed with co-administration of naltrexone, an opioid antagonist (Specific Aim 2). Findings from these studies address a significant public health priority by investigating terpenes as a safe, well tolerated novel pharmacotherapeutic strategy to manage pain. This is an urgent area of research as alternatives to opioids and strategies to decrease use of high opioid doses are desperately needed.

项目概述：慢性疼痛是一个重大的公共卫生负担， 治疗;患有慢性疼痛的个体是当前阿片类药物流行病的核心组成部分。三角洲-9- 四氢大麻酚（THC）是大麻的主要精神活性化学物质， 治疗慢性疼痛的候选人然而，镇痛伴随着中毒和滥用倾向，因此， 限制了其临床应用。萜类是有机化合物，其有助于植物的芳香性质和风味。 大麻;据推测，这些化合物可能与四氢大麻酚协同作用，以提高其 具有减少的不良后果的治疗效果。因此，萜类化合物可能会增加镇痛作用 低的、最低限度的中毒剂量的THC，和/或减少较高THC剂量的不良后果。 临床前研究表明，萜烯月桂烯和β-香芹烯（BCP）引起抗伤害感受 效果并具有阿片样物质保留特性。这些作用部分由μ-阿片受体介导。是 不知道这些发现是否适用于人类。了解这些萜烯是否具有镇痛作用 单独使用或与THC联合使用，是开发新的基于大麻素的治疗药物的基础， 痛苦此外，调查这些萜烯的不良影响（滥用倾向，中毒）将阐明其 临床潜力在减少对阿片类药物止痛依赖的药物治疗策略 是迫切需要的，探索1）镇痛作用，2）潜在的THC和阿片类药物节省属性， 3)这些萜烯的作用机制具有重要意义。拟定的双盲、安慰剂对照 研究将是第一个严格评估生态相关的剂量依赖性镇痛作用的研究。 剂量的月桂烯和BCP，并确定其THC和阿片类药物的节省效果。研究结果将 对于了解萜烯单独使用以及与THC联合使用治疗疼痛的临床潜力至关重要 管理 在娱乐性大麻吸烟者中进行的拟议双盲、安慰剂对照、受试者内研究（N=30， 每项研究中15 M，15 F）将首先确定汽化月桂烯的剂量依赖性镇痛潜力， 单独使用BCP以及与亚镇痛剂量（5 mg）和镇痛剂量（15 mg）的THC联合使用（特定目标 1）。月桂烯/THC和BCP/THC剂量组合产生最大的镇痛作用和最小的 中毒和滥用倾向，然后将测试其阿片类药物节省效果（具体目标2）。阿片 将通过共同施用阿片样物质纳洛酮来评估萜烯/THC联合镇痛的调节 拮抗剂（具体目标2）。这些研究的结果解决了一个重要的公共卫生优先事项， 研究萜烯作为一种安全、耐受性良好的新型药物治疗策略来控制疼痛。这是一 作为阿片类药物的替代品和减少使用高剂量阿片类药物的战略的迫切研究领域是 迫切需要的。