Pharmacokinetics and Pharmacodynamics of Oral and Vaporized THC in Older Adults

项目总结/摘要 在本提案中，我们试图研究以下药物的药代动力学（PK）和药效学（PD）效应： 大麻的主要镇痛和精神活性成分δ-9-四氢大麻酚， 老年人-大麻消费者增长最快的群体，也是最有可能使用大麻的年龄组 大麻素来缓解疼痛虽然THC已因其抗伤害感受潜力而被广泛研究，但大多数 在年轻人中进行了研究;因此，THC如何影响老年人的疼痛仍然存在 接受调查首先，由于年龄相关的生理变化的组合，老年人可能 更频繁地经历THC引起的不良事件。尽管如此，仍然缺乏关于 老年人中的THC。第二，THC对老年人特别重要的结果的PD效应 成年人-如镇痛和虐待倾向-仍然未知。数据来自年轻人 不能推广到老年人，因为越来越多的研究表明，衰老会产生功能性 疼痛和奖励系统中的神经适应-可能影响镇痛功效和滥用倾向 四氢大麻酚此外，老年人可能对心血管和认知/精神影响更敏感， 四氢大麻酚这些不良事件可能对他们的健康有害，增加福尔斯和事故的风险。 为了缩小这一关键的知识差距，我们设计了一项人类实验室研究， 在老年人中，通过口服和吸入途径给药THC的急性PK和PD效应。我们 我建议进行一项双盲、安慰剂对照、交叉研究，随机选择20名65岁的男性和女性 或更老，口服THC（5 mg和10 mg）和汽化THC（2 mg和4 mg）的两个剂量。符合 NOT-DA-21-049，这些剂量转化为一个或两个标准单位（SU）的口服THC，以及0.4和0.8 SU的口服THC。 汽化的四氢大麻酚在6个测试阶段中，参与者将接受6种条件的随机序列：5 mg口服 THC; 10 mg口服THC;口服安慰剂; 2 mg汽化THC; 4 mg汽化THC;和汽化安慰剂。血液 将在给药后8小时内定期从静脉管路中采集样本，以评估 THC及其I相和II相代谢物的PK（目的1）。THC对疼痛反应的PD效应将是 用定量感官测试（QST）测量，这是一种可靠的计算机化技术， 镇痛效果（目标2a）。四氢大麻酚的滥用倾向将使用一种确定的药物来衡量 强化范式（Aim 2b）。THC的一般不良、心血管和认知/精神影响 将通过行为、生理和神经心理学方法进行评估。我们也会评估性别 PK/PD结局的差异（探索性目的）。最后，一个为期一周的清洗将单独的测试会议。 这项及时的研究将作为一个基准，以评估大麻素作为治疗，以减轻疼痛， 老年人结果将告知患者，医疗保健专业人员和政策利益相关者有关风险- 大麻素在增长最快的大麻消费者中的受益比例。

PROJECT SUMMARY/ABSTRACT In this proposal, we seek to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of the main analgesic and psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol (THC), among older adults – the fastest growing population of cannabis consumers, and the most likely age cohort to use cannabinoids to relieve pain. Although THC has been widely studied for its antinociceptive potential, most studies were conducted among younger individuals; as a result, how THC affects pain in older adults remains to be investigated. First, due to a combination of age-related physiological changes, older adults may experience more frequent THC-induced adverse events. Still, there is a dearth of data on the PK effects of THC among older adults. Second, the PD effects of THC for outcomes that are especially important for older adults – such as analgesia and abuse liability – remain unknown. Data generated among younger individuals cannot be generalized to older adults, as accumulating studies indicate that aging produces functional neuroadaptations in pain and reward systems – likely influencing the analgesic efficacy and abuse liability of THC. Further, older adults may be more sensitive to the cardiovascular and cognitive/psychomotor effects of THC. These adverse events may be detrimental to their health, increasing the risk of falls and accidents. To close this critical knowledge gap, we have designed a human laboratory study to characterize the acute PK and PD effects of THC, administered through the oral and inhaled route, among older adults. We propose a double-blind, placebo-controlled, crossover study, randomizing 20 men and women aged 65 years or older, to two doses of oral THC (5 mg and 10 mg) and vaporized THC (2 mg and 4 mg). Consistent with NOT-DA-21-049, these doses translate to one or two standard units (SU) of oral THC, and 0.4 and 0.8 SU of vaporized THC. Across 6 test sessions, participants will receive a random sequence of 6 conditions: 5 mg oral THC; 10 mg oral THC; oral placebo; 2 mg vaporized THC; 4 mg vaporized THC; and vaporized placebo. Blood sampling will be collected from an intravenous line, at regular intervals, up to 8 hours post-dose, to assess the PK of THC and its phase I and II metabolites (Aim 1). The PD effects of THC on pain responses will be measured with Quantitative Sensory Testing (QST), a reliable computerized technique used to measure analgesic efficacy (Aim 2a). The abuse liability of THC will be measured using an established drug reinforcement paradigm (Aim 2b). General adverse, cardiovascular, and cognitive/psychomotor effects of THC will be assessed with behavioral, physiological, and neuropsychological methods. We will also assess sex differences in PK/PD outcomes (Exploratory Aims). Finally, a one-week washout will separate test sessions. This timely study will serve as a benchmark to assess cannabinoids as therapeutics to relieve pain in older adults. Results will inform patients, healthcare professionals, and policy stakeholders about the risk- benefit ratio of cannabinoids among the fastest growing population of cannabis consumers.