Age-and sex-dependent pharmacodynamics and pharmacokinetics of oral and smoked delta-9-THC

口服和吸食 delta-9-THC 的年龄和性别依赖性药效学和药代动力学

• 批准号: 10570124
• 负责人: ZIVA D COOPER
• 金额: $ 67.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570124
• 关键词: Absence of pain sensation; Acute; Adolescence; Adolescent; Adult; Adverse effects; Age; Age-Years; Aging; Analgesics; Behavioral; Biological; Brain; Cannabis; Clinical Research; Dose; Double-Blind Method; Drug Kinetics; Elderly; Epidemiology; Exhibits; Exposure to; Female; Human; Impaired cognition; Impairment; Intervention; Intoxication; Knowledge; Laboratory Study; Lead; Legal; Medical Marijuana; Metabolism; Neurobiology; Oral; Oral Administration; Outcome; Pain; Participant; Patients; Pharmaceutical Preparations; Physiological; Placebo Control; Placebos; Plasma; Population; Prevalence; Prevention; Regulation; Reporting; Risk; Rodent; Route; Sex Differences; Signal Transduction; Smoke; Symptoms; THC exposure; Tetrahydrocannabinol; Time; Translations; United States; Vulnerable Populations; abuse liability; adverse outcome; cohort; design; drug reward; emerging adult; emerging adulthood; epidemiology study; male; marijuana use; marijuana use disorder; middle age; neurodevelopment; pharmacokinetics and pharmacodynamics; placebo controlled study; pre-clinical; preclinical study; prevent; prospective; prospective test; recruit; response; sex; trend

Project Summary: With rapid changes in cannabis regulation (i.e., legalization) and expanded availability across the United States (US), rates of cannabis use and Cannabis Use Disorder (CUD) have increased among populations vulnerable to the negative effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. These populations include emerging adults (18-25 years of age), older adults (≥ 55 years of age), and females. Prevalence of cannabis use is highest among emerging adults; this is of particular concern given the known risks of THC exposure during this period of late-adolescent neurodevelopment and brain maturation. While rates of use among females used to be half that of males, the gap between sexes is closing with 5.6% of female emerging adults reporting near daily use. Sensitivity to THC’s effects in females is also hypothesized to lead to negative outcomes including the accelerated progression to CUD. The most remarkable increase in cannabis use is among older adults. Prevalence of past month use among adults ages 55-64 years more than doubled between 2013 to 2019, with over 25% of older adults reporting use 1-4 times per week. Because of physiological and neurobiological changes that occur during aging, older adults may be particularly vulnerable to the negative effects of THC. Despite the increase in cannabis use among these groups, no studies to date have prospectively probed the adverse effects of acute THC exposure across adulthood. Another trend impacting the vulnerability of older adults and females to adverse effects of cannabis is the high rate of medical cannabis use in these populations with pain cited as the predominant symptom for use. This trend further establishes the urgent need to assess THC analgesia alongside adverse effects that increase risk including abuse liability, intoxication, and impairment. To understand cannabis’s acute effects that indicate increased risk of exposure among these vulnerable populations, the proposed study will compare the dose-dependent effects of smoked and oral THC, two popular routes of administration, on endpoints directly related to adverse consequences of use including abuse liability, intoxication, and impairment as a function of age and sex. Specifically, healthy male and female emerging adults (18-25 years; N=30, 15M, 15F), middle-aged adults (35-45 years; N=30, 15M, 15F) and late middle-aged adults (55-65 years; N=30, 15M, 15F) who occasionally use cannabis will be recruited for this double-blind, double-dummy, placebo-controlled study. Using a within-subjects design, all participants will be administered placebo (0mg THC), 2, 5mg unit-doses of THC (10mg), and 4, 5mg unit-doses of THC (20mg) via smoked cannabis and by oral administration. Adverse effects, analgesia, and THC pharmacokinetics will be assessed several times after smoked and oral THC administration. Findings from this study will be instrumental in establishing age and sex as biological variables in the prevention, intervention, and treatment of negative sequelae associated with cannabis use.

项目摘要：随着大麻监管（即合法化）的迅速变化和供应范围的扩大 在美国 (US) 各地，大麻使用率和大麻使用障碍 (CUD) 有所增加 在易受 delta-9-四氢大麻酚 (THC) 负面影响的人群中，主要 这些人群包括新兴成年人（18-25 岁）、老年人。 成年人（≥ 55 岁）和女性 大麻使用率在新兴成年人中最高； 鉴于青春期后期接触 THC 的已知风险，特别值得关注 虽然女性的使用率过去是男性的一半，但现在 性别之间的差距正在缩小，5.6% 的女性新兴成人表示对日常使用很敏感。 THC 对女性的影响也会导致负面结果，包括加速 大麻使用率增长最显着的是老年人。 2013 年至 2019 年间，55-64 岁成年人的月使用量增加了一倍多，其中超过 25% 的老年人 成人报告每周使用 1-4 次，因为会发生生理和神经生物学变化。 在衰老过程中，尽管 THC 含量有所增加，但老年人可能特别容易受到 THC 的负面影响。 在这些群体中使用大麻，迄今为止还没有研究前瞻性地探讨了急性大麻的不良影响 整个成年期接触四氢大麻酚的另一个趋势影响了老年人和女性对四氢大麻酚的脆弱性。 大麻的不利影响是这些人群中医用大麻的使用率很高，并被认为是造成疼痛的原因 这一趋势进一步表明了评估 THC 镇痛作用的迫切需要。 以及增加风险的不利影响，包括滥用倾向、中毒和损伤。 了解大麻的急性影响表明这些弱势群体接触大麻的风险增加 人群中，拟议的研究将比较吸烟和口服 THC 的剂量依赖性影响，两种 流行的给药途径，与使用不良后果（包括滥用）直接相关的终点 责任、中毒和损伤与年龄和性别有关，特别是健康男性和女性。 新兴成人（18-25岁；N=30、15M、15F）、中年成人（35-45岁；N=30、15M、15F）和晚期 为此，将招募偶尔使用大麻的中年成年人（55-65岁；N=30、15M、15F） 采用受试者内设计的双盲、双模拟、安慰剂对照研究。 通过给予安慰剂（0mg THC）、2、5mg单位剂量的THC（10mg）和4、5mg单位剂量的THC（20mg） 吸食大麻和口服给药会产生镇痛和 THC 药代动力学不良反应。 这项研究的结果将在吸烟和口服 THC 后进行多次评估。 将年龄和性别确定为预防、干预和治疗负面影响的生物学变量 与使用大麻有关的后遗症。