Pharmacokinetics and Pharmacodynamics of Oral and Vaporized THC in Older Adults

项目摘要/摘要 在这项建议中，我们试图研究的药代动力学(PK)和药效学(PD)的影响 大麻的主要止痛药和精神活性成分三角洲-9-四氢大麻酚(THC)，其中 老年人--大麻消费者中增长最快的人群，也是最有可能使用的年龄段 止痛的大麻素。尽管THC因其抗伤害性潜力而被广泛研究，但大多数 研究是在年轻人中进行的；结果，THC如何影响老年人的疼痛仍然存在 接受调查。首先，由于与年龄相关的生理变化的组合，老年人可能 体验更频繁的THC引起的不良事件。尽管如此，关于PK效应的数据仍然很少 老年人中的THC。第二，THC对老年人特别重要的预后的PD效应 成人--如止痛和滥用责任--仍不清楚。在年轻人中产生的数据 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 疼痛和奖赏系统中的神经适应-可能影响止痛疗效和滥用倾向 太好了。此外，老年人可能对心血管和认知/精神运动的影响更敏感。 太好了。这些不良事件可能会损害他们的健康，增加跌倒和事故的风险。 为了弥合这一关键的知识差距，我们设计了一项人体实验室研究，以表征 THC口服和吸入给药对老年人的急性PK和PD影响。我们 提出一项双盲、安慰剂对照的交叉研究，随机选择20名65岁的男性和女性 口服THC(5毫克和10毫克)和雾化THC(2毫克和4毫克)。与一致 非-DA-21-049，这些剂量相当于一或两个标准单位(SU)的口服THC，以及0.4和0.8SU的口服THC 蒸发的THC。在6次测试过程中，参与者将收到6种情况的随机序列：5毫克口服 THC；10毫克口服THC；口服安慰剂；2毫克挥发性THC；4毫克挥发性THC；和挥发性安慰剂。血样 将定期从静脉输液中采集样本，最多在服药后8小时内进行，以评估 THC及其I、II相代谢物的PK(目标1)。THC对疼痛反应的PD效应将是 使用定量感觉测试(QST)进行测量，这是一种可靠的计算机技术，用于测量 止痛效果(目标2a)。THC的滥用责任将使用一种已确定的药物来衡量 强化范例(目标2b)。THC的一般不良反应、心血管和认知/精神运动影响 将通过行为、生理和神经心理学方法进行评估。我们还将评估性行为 PK/PD结果的差异(探索性目标)。最后，为期一周的测试将分开进行。 这项及时的研究将作为评估大麻类药物缓解疼痛的基准 上了年纪的人。结果将向患者、医疗保健专业人员和政策利益相关者通报风险- 在增长最快的大麻消费人群中大麻类药物的受益率。

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.