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：随着大麻法规的快速变化（即合法化）并扩大了可用性 在整个美国（美国），大麻使用和大麻使用障碍（CUD）的速度增加了 在遭受Delta-9-四氢大麻酚（THC）的负面影响的人群中，主要影响 精神活性构成大麻。这些人口包括新兴成年人（18-25岁），年龄较大 成人（≥55岁）和女性。在新兴成年人中，大麻使用的患病率最高。这是 鉴于在此期间的后期，THC暴露的已知风险特别关注 神经发育和大脑成熟。虽然女性的使用率曾经是男性的一半，但 性别之间的差距正在闭合，有5.6％的女性新兴成年人每天都有报道。对 THC在女性中的影响也被认为导致负面结果，包括加速 进展到cud。大麻使用的最显着增加是老年人。过去的流行 在2013年至2019年之间，年龄在55-64岁的成年人中使用的月份增加了一倍以上，超过25％ 报告报告的成人每周使用1-4次。由于身体和神经生物学的变化 在衰老期间，老年人可能特别容易受到THC的负面影响。尽管有所增加 在这些群体中使用大麻，迄今为止尚无研究证明急性的不利影响 THC遍布成年。影响老年人和女性脆弱性的另一个趋势 大麻的不利影响是这些人群中医用大麻使用的高率，被认为是疼痛为 主要使用症状。这一趋势进一步确定了评估THC镇痛的迫切需求 除了增加风险的不利影响，包括滥用责任，中毒和损害。 了解大麻的急性影响，表明这些脆弱的风险增加 人群，拟议的研究将比较烟熏和口服THC的剂量依赖性作用，两个 流行的管理途径，在与使用的不利后果直接相关的端点上 责任，中毒和损害与年龄和性别的关系。特别是健康的男性和女性 新兴的成年人（18-25岁； n = 30，15m，15f），中年成年人（35-45岁； n = 30，15m，15f）和迟到 中年成年人（55-65岁； n = 30，15m，15f）偶尔会使用大麻 双盲，双人，安慰剂对照研究。使用受试者内设计，所有参与者都将 通过安慰剂（0mg THC），2，5mg单位剂量THC（10mg）和4，5mg单位剂量THC（20mg）通过 烟熏大麻和口服给药。不良影响，镇痛和THC药代动力学将是 抽烟和口服THC给药后几次评估。这项研究的发现将是工具性的 在预防，干预和治疗负面的生物学变量中，建立年龄和性别 与大麻使用相关的后遗症。