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: 10810597
• 负责人: ZIVA D COOPER
• 金额: $ 7.04万
• 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/10810597
• 关键词: Absence of pain sensation; Acceleration; Acute; Address; Agonist; Analgesics; Award; Biological; CNR1 gene; Cannabinoids; Cannabis; Cannabis Abuse; Chronic; Clinical Research; Development; Dose; Double-Blind Method; Drug Kinetics; Epidemiology; Estradiol; Exhibits; Female; Frequencies; Human; Intervention; Knowledge; Laboratory Animals; Laboratory Study; Light; Medical Marijuana; Menstrual cycle; Pain; Parents; Participant; Placebo Control; Placebos; Prevention; Public Health; Report (document); Reporting; Sex Differences; Smoke; Tetrahydrocannabinol; Woman; abuse liability; antinociception; cannabis self-administration; male; marijuana use; marijuana use disorder; marijuana user; men; preclinical study; prospective; recruit; response; sex

Project Summary (Parent Award) 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

项目摘要 （家长奖） 大麻使用障碍（CUD）的发病率在过去十年中翻了一番。虽然 尽管大麻使用率和CUD使用率不断上升，但妇女的总体使用率和CUD使用率仍然低于男子。然而，在这方面， 流行病学报告记录了一种伸缩效应;妇女从首次使用过渡到CUD的速度更快， 比男人高。实验室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，也许可以解释加速进展， 流行病学报告中观察到的CUD。到目前为止，还没有研究前瞻性地探讨大麻的性别- 人类滥用倾向的依赖性差异。为了了解大麻的急性效应， 在女性中观察到加速的CUD轨迹，拟议的研究将比较剂量依赖性 吸用大麻对与轻度和重度滥用责任直接相关的终点的影响 使用大麻的男性和女性，包括积极的主观效果和大麻自我管理。在 除了滥用相关终点外，了解吸烟镇痛反应的性别差异 大麻对公共卫生有重大影响。近50%的医用大麻使用者是女性， 疼痛被认为是寻求治疗的主要适应症。因此，评估滥用 大麻的易患性和止痛功效与性别的关系至关重要。 临床前研究指出了三个因素，有助于对Δ-9- 四氢大麻酚（THC）和其他大麻素1受体（CBR 1）激动剂; 1）雌二醇增加 对CBR 1激动剂滥用相关效应的敏感性，2）THC的药代动力学（pK）不同，女性 表现出比男性更快地从THC转化为其主要精神活性代谢物，以及3）增强 慢性给药后雌性动物对镇痛作用（而非其他终点）的耐受性的发展 局拟议的前瞻性临床研究将直接解决性别依赖性差异， 大麻的作用是这些因素的函数。我们将1）比较以下药物的滥用相关和镇痛作用： 男性与女性之间吸食大麻，同时控制月经周期的影响，2）评估差异 男性和女性之间THC及其代谢产物的pK，以及3）研究大麻的性别- 依赖性效应是大麻使用频率的函数（轻度与重度大麻使用者）。具体地说， 将招募健康的轻度（N=60，30 M，30 F）和重度（N=60，30 M，30 F）大麻使用者参加这3个阶段， 双盲、安慰剂对照、实验室研究。所有参与者将被给予安慰剂（0%THC）， 较低（3%THC）和较高（10%THC）的大麻强度呈反平衡顺序。大麻滥用- 相关效应、镇痛和药代动力学将作为性别和频率的函数进行评估。 使用大麻这项研究的结果将填补我们知识中的一个关键空白，

项目成果

Patterns of Use and Self-reported Effectiveness of Cannabis for Hyperemesis Gravidarum.

• DOI: 10.1055/a-1749-5391
• 发表时间: 2022-05
• 期刊: Geburtshilfe und Frauenheilkunde
• 影响因子: 2.7

Considering abuse liability and neurocognitive effects of cannabis and cannabis-derived products when assessing analgesic efficacy: a comprehensive review of randomized-controlled studies.

在评估镇痛功效时考虑大麻和大麻衍生产品的滥用倾向和神经认知影响：随机对照研究的全面回顾。

• DOI: 10.1080/00952990.2019.1669628
• 发表时间: 2019
• 期刊: The American journal of drug and alcohol abuse
• 作者: Cooper,ZivaD;Abrams,DonaldI
• 通讯作者: Abrams,DonaldI

Understanding Cannabis Use Disorder Diagnoses in the U.S. Veterans Health Administration in the Era of Legalization.

了解合法化时代美国退伍军人健康管理局的大麻使用障碍诊断。

• DOI: 10.1176/appi.ajp.20220675
• 发表时间: 2022
• 期刊: The American journal of psychiatry
• 作者: Lake,Stephanie;Cooper,ZivaD
• 通讯作者: Cooper,ZivaD

A systematic review and meta-analysis of sex differences in cannabis use disorder amongst people with comorbid mental illness.

• DOI: 10.1080/00952990.2021.1946071
• 发表时间: 2021-09-03
• 期刊: AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE
• 影响因子: 2.7
• 作者: Kozak, Karolina;Smith, Philip H.;Lowe, Darby J. E.;Weinberger, Andrea H.;Cooper, Ziva D.;Rabin, Rachel A.;George, Tony P.
• 通讯作者: George, Tony P.

Drugs of Misuse: Focus on Vascular Dysfunction.

• DOI: 10.1016/j.cjca.2022.04.011
• 发表时间: 2022-09
• 期刊: CANADIAN JOURNAL OF CARDIOLOGY
• 影响因子: 6.2
• 作者: Middlekauff, Holly R.;Cooper, Ziva D.;Strauss, Sasha B.
• 通讯作者: Strauss, Sasha B.