Sex-dependent effects of cannabis: Assessing abuse-related and pharmacokinetic differences between men and women

大麻的性别依赖性影响：评估男性和女性之间滥用相关和药代动力学的差异

• 批准号: 10421409
• 负责人: ZIVA D COOPER
• 金额: $ 70.9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10421409
• 关键词: Absence of pain sensation; Acceleration; Acute; Address; Agonist; Analgesics; Behavioral; Biological; CNR1 gene; Cannabinoids; Cannabis; Cannabis Abuse; Chronic; Clinical Research; Development; Dose; Double-Blind Method; Drug Kinetics; Epidemiology; Estradiol; Exhibits; Female; Frequencies; Gender; Human; Intervention; Investigation; Knowledge; Laboratories; Laboratory Animals; Laboratory Study; Light; Marijuana Smoking; Medical; Medical Marijuana; Menstrual cycle; Pain; Participant; Pharmaceutical Preparations; Placebo Control; Placebos; Plasma; Prevention; Progesterone; Prospective Studies; Public Health; Rattus; Recreation; Report (document); Reporting; Risk; Self Administration; Sex Differences; Smoke; Smoking; THC exposure; Testing; Tetrahydrocannabinol; Treatment Efficacy; Woman; abuse liability; antinociception; cannabis self-administration; design; epidemiology study; male; marijuana smoker; marijuana use; marijuana use disorder; marijuana user; men; pre-clinical; preclinical study; prevent; proliferative phase Menstrual cycle; prospective; recruit; response; sex; trend; volunteer

Project Summary: Rates of Cannabis Use Disorder (CUD) have doubled over the last ten years in the US. Although increasing, overall rates of cannabis use and CUD are still lower among women relative to men. However, epidemiological reports document a telescoping effect; women transition from first use to CUD at a faster rate than men. Preclinical studies with laboratory animals demonstrate that relative to males, females are more sensitive to the reinforcing effects of cannabinoids, perhaps explaining the accelerated progression to CUD observed in the epidemiological reports. To date, no studies have prospectively probed cannabis’s sex- dependent differences in abuse-liability in humans. To understand cannabis’s acute effects that underlie the accelerated trajectory to CUD observed in women, the proposed study will compare the dose-dependent effects of smoked cannabis on endpoints directly associated with abuse-liability between light- and heavy- cannabis using men and women, including positive subjective effects and cannabis self-administration. In addition to abuse-related endpoints, understanding sex differences in the analgesic responses to smoked cannabis have significant public health implications. Nearly 50% of medical cannabis users are women, with pain cited as the primary indication for which treatment is sought. Thus, assessing both the abuse liability and analgesic efficacy of cannabis as a function of sex is of critical importance. Preclinical studies point to three factors that contribute to sex-dependent responses to Δ-9- tetrahydrocannabinol (THC) and other cannabinoid 1 receptor (CBR1) agonists; 1) estradiol increases the sensitivity to CBR1 agonist abuse-related effects, 2) pharmacokinetics (pK) of THC differ, with females exhibiting faster conversion from THC to its primary psychoactive metabolite than males and 3) enhanced development of tolerance to the antinociceptive effects (but not other endpoints) in females after chronic administration. The proposed prospective clinical study will directly address sex-dependent differences in cannabis’s effects as a function of these factors. We will 1) compare the abuse-related and analgesic effects of smoked cannabis between men to women while controlling for menstrual cycle effects, 2) evaluate differences in the pK of THC and respective metabolites between men and women, and 3) investigate cannabis’s sex-dependent effects as a function of frequency of cannabis use (light versus heavy cannabis users). Specifically, healthy light (N=60, 30M, 30F) and heavy (N=60, 30M, 30F) cannabis users will be recruited for this 3-session, double-blind, placebo-controlled, laboratory study. All participants will be administered placebo (0% THC), lower (3% THC), and higher (10% THC) strengths of cannabis in counter- balanced order. Cannabis’s abuse-related effects, analgesia, and pharmacokinetics will be assessed as a function of sex and frequency of cannabis use. Findings from this study will fill a critical gap in our knowledge and be integral in understanding sex as a biological variable in predicting, preventing, and treating CUD.

项目摘要：过去十年来，美国大麻使用障碍 (CUD) 的发生率翻了一番。 尽管有所增加，但女性大麻使用率和 CUD 总体比例仍低于男性。 然而，流行病学报告记录了伸缩效应；女性从首次使用过渡到 CUD 速度比男性快。对实验动物的临床前研究表明，相对于雄性，雌性 对大麻素的增强作用更敏感，这也许可以解释加速进展的原因 流行病学报告中观察到的 CUD。迄今为止，还没有研究前瞻性地探讨大麻的性别 人类滥用责任的依赖性差异。了解大麻的急性影响 在女性中观察到 CUD 的加速轨迹，拟议的研究将比较剂量依赖性 吸食大麻对与轻度和重度滥用倾向直接相关的终点的影响 使用男性和女性的大麻，包括积极的主观效果和大麻自我管理。在 除了与滥用相关的终点外，了解吸烟镇痛反应的性别差异 大麻对公共卫生具有重大影响。近 50% 的医用大麻使用者是女性，其中 疼痛被认为是寻求治疗的主要适应症。因此，评估滥用责任和 大麻的镇痛功效与性别的关系至关重要。 临床前研究指出了导致 Δ-9- 性别依赖性反应的三个因素 四氢大麻酚 (THC) 和其他大麻素 1 受体 (CBR1) 激动剂； 1）雌二醇增加 对 CBR1 激动剂滥用相关效应的敏感性，2) THC 的药代动力学 (pK) 因女性而异 与男性相比，THC 转化为其主要精神活性代谢物的速度更快，并且 3) 增强 女性在慢性治疗后对抗伤害作用（但不是其他终点）产生耐受性 行政。拟议的前瞻性临床研究将直接解决性别依赖性差异 大麻的影响是这些因素的函数。我们将 1) 比较滥用相关效果和镇痛效果 男性与女性之间吸食大麻的比例，同时控制月经周期影响，2) 评估 男性和女性之间 THC 的 pK 和各自代谢物的差异，以及 3) 调查 大麻的性别依赖性影响与大麻使用频率的关系（轻度大麻与重度大麻） 用户）。具体来说，健康的轻度（N=60、30M、30F）和重度（N=60、30M、30F）大麻使用者将 招募参加这项为期 3 个阶段的双盲、安慰剂对照实验室研究。所有参与者都将 给予安慰剂（0% THC）、较低（3% THC）和较高（10% THC）大麻强度 平衡秩序。大麻的滥用相关作用、镇痛作用和药代动力学将被评估为 性别和大麻使用频率的作用。这项研究的结果将填补我们知识中的一个关键空白 并将性别理解为预测、预防和治疗 CUD 的生物学变量。