Pharmacokinetics and Pharmacodynamics of Oral and Vaporized THC in Older Adults

老年人口服和汽化 THC 的药代动力学和药效学

基本信息

批准号：
10705257
负责人：
Joao Paulo De Aquino
金额：
$ 19.64万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705257
关键词：
Absence of pain sensation Accidents Acute Adult Adverse effects Adverse event Affect Age Aging Analgesics Behavioral Benchmarking Benefits and Risks Biological Availability Blood Pressure Blood specimen Cannabinoids Cannabis Cardiovascular system Clinical Clinical Trials Cognitive Consumption Cross-Over Studies Data Dopamine Receptor Dose Double-Blind Method Drug Kinetics Elderly Glucuronides Health Health Professional Heart Rate Hepatic Hour Human Individual Inhalation Intravenous Kidney Knowledge Laboratories Laboratory Study Measures Mediating Medicine Memory Methods Midbrain structure Neuropsychology Oral Outcome Pain Pain Threshold Participant Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase Physiological Placebo Control Placebos Plasma Policies Population Preparation Randomized Reaction Time Recreation Rewards Risk Factors Route Sensory Sex Differences System Techniques Testing Tetrahydrocannabinol Therapeutic Translating Woman abuse liability age related aged antinociception cohort computerized cost effective design drug reinforcement experience fall risk functional loss indexing insight lean body mass marijuana use marijuana user men neuroadaptation older men older women pain relief pain sensitivity pharmacokinetics and pharmacodynamics response risk/benefit ratio side effect

项目摘要

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.

项目概要/摘要在本提案中，我们寻求研究药代动力学（PK）和药效（PD）效应大麻的主要镇痛和精神活性成分，δ9-四氢大麻酚（THC），其中老年人——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尽管 THC 的镇痛潜力已被广泛研究，但大多数研究是在年轻人中进行的；因此，THC 如何影响老年人的疼痛仍然存在。首先，由于与年龄相关的生理变化，老年人可能会出现这种情况。经历更频繁的 THC 引起的不良事件尽管如此，仍缺乏有关 PK 影响的数据。其次，THC 对老年人的 PD 影响尤其重要。成年人——例如镇痛和滥用倾向——在年轻人中产生的数据仍然未知。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——可能影响镇痛效果和滥用倾向此外，老年人可能对 THC 的心血管和认知/精神运动影响更敏感。 THC。这些不良事件可能不利于他们的健康，增加跌倒和事故的风险。为了弥补这一关键的知识差距，我们设计了一项人体实验室研究来表征通过口服和吸入途径施用 THC 对老年人的急性 PK 和 PD 影响。提出一项双盲、安慰剂对照、交叉研究，随机分组 20 名 65 岁的男性和女性或以上，口服两剂 THC（5 毫克和 10 毫克）和汽化 THC（2 毫克和 4 毫克）。 NOT-DA-21-049，这些剂量转化为一或两个标准单位 (SU) 口服 THC，以及 0.4 和 0.8 SU 在 6 次测试中，参与者将收到 6 种情况的随机序列：口服 5 毫克。 THC；10 mg 口服 THC；2 mg 汽化 THC；4 mg 汽化 THC；将在给药后 8 小时内定期从静脉管线采集样本，以评估 THC 及其 I 期和 II 期代谢物的 PK（目标 1） THC 对疼痛反应的 PD 影响将是。通过定量感官测试 (QST) 进行测量，这是一种可靠的计算机化技术，用于测量 THC 的镇痛功效（目标 2a）将使用已确定的药物来衡量。 THC 的强化范例（目标 2b）。我们还将通过行为、生理和神经心理学方法来评估性别。最后，为期一周的冲洗将分开测试。这项及时的研究将作为评估大麻素作为缓解疼痛的疗法的基准结果将告知患者、医疗保健专业人员和政策利益相关者有关风险的信息。大麻素在增长最快的大麻消费者群体中的受益率。