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

项目摘要：慢性疼痛是一种重大的公共卫生负担，目前几乎没有有效的治疗方法 治疗；慢性疼痛患者是当前阿片类药物流行的中心组成部分。Delta-9- 四氢大麻酚(THC)是大麻的主要精神活性化学物质，有望作为一种治疗药物 治疗慢性疼痛的候选人。然而，镇痛伴随着中毒和滥用的倾向，因此 限制了它的临床应用。萜烯是一种有机化合物，有助于香料的芳香性质和风味。 据推测，这些化合物可能与THC协同作用，以增强其 减少不良后果的治疗效果。因此，萜类化合物可以增强止痛作用。 低剂量、最低剂量的THC，和/或减少高剂量THC的不良后果。 临床前研究表明月桂烯和石竹烯(BCP)具有抗伤害性作用 有效，并具有阿片类药物的节约性。这些效应在一定程度上是由u-阿片受体介导的。它是 尚不清楚这些发现是否适用于人类。了解这些萜类化合物是否具有止痛特性 单独使用或与THC联合使用是开发基于大麻素的新型治疗药物的基础 疼痛。此外，调查这些萜类化合物的不良影响(滥用倾向、醉酒)将澄清它们的 临床潜力。在药物治疗策略减少对阿片类药物止痛依赖的时候 是迫切需要的，探索1)止痛效果，2)潜在的THC和阿片类药物节省特性，以及 3)这些萜类化合物的作用机理具有重要意义。拟议的双盲、安慰剂对照 将首次严格评估与生态相关的药物的剂量依赖止痛效果。 并确定它们的四氢呋喃和阿片类药物的节制效果。研究结果将是 了解萜类化合物单独或与四氢呋喃合用治疗疼痛的临床潜力 管理层。 拟在娱乐吸食大麻者中进行的双盲、安慰剂对照、受试者内研究(N=30， 15M，每项研究中的15F)将首先确定挥发的月桂烯和 单用BCP和联合亚止痛剂(5毫克)和止痛剂(15毫克)剂量的THC(特定目的 1)。月桂烯/THC和BCP/THC的剂量组合产生最大的止痛和最小的 然后将测试醉酒和滥用责任，以确定其阿片类药物的节制效果(具体目标2)。阿片类药物 联合使用阿片类药物纳曲酮将评估对萜烯/THC联合镇痛的调节作用。 拮抗剂(特异靶2)。这些研究的结果涉及到一个重要的公共卫生优先事项，即 研究萜类化合物作为一种安全、耐受性良好的新型止痛药物治疗策略。这是一个 作为阿片类药物替代品的迫切研究领域和减少大剂量阿片类药物使用的战略 迫切需要。

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.