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

项目摘要：在美国，大麻使用障碍(CUD)的发病率在过去十年中翻了一番。 虽然有所增加，但女性的总体大麻使用率和大麻吸毒率仍然低于男性。 然而，流行病学报告记录了伸缩效应；妇女从第一次使用过渡到CUD 速度比男人还快。对实验室动物进行的临床前研究表明，相对于雄性、雌性 对大麻素的强化作用更敏感，也许可以解释 CUD在流行病学报告中观察到。到目前为止，还没有研究前瞻性地探索大麻的性别- 人类在虐待责任方面的不同。为了了解大麻的急性影响， 在女性中观察到CUD的加速轨迹，建议的研究将比较剂量依赖关系 吸烟大麻对直接与滥用有关的终点的影响--轻-重-之间的责任- 使用大麻的男性和女性，包括积极的主观影响和大麻自我管理。在……里面 除了与滥用有关的终点外，了解吸烟止痛反应中的性别差异 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，其中 疼痛被认为是寻求治疗的主要指征。因此，评估滥用责任和 大麻的止痛效果与性别有关，这一点至关重要。 临床前研究指出，对Δ-9的性别依赖性反应有三个因素： 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)随女性不同 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 慢性应激后女性对抗伤害效应(但不包括其他终点)的耐受性 行政管理。拟议的前瞻性临床研究将直接解决性别依赖在 大麻的影响作为这些因素的函数。我们将1)比较滥用和止痛的效果 在控制月经周期影响的情况下，男性与女性之间吸烟大麻的比例，2)评估 男性和女性THC及其代谢物PK的差异，以及3)调查 大麻的性别依赖效应作为大麻使用频率的函数(轻大麻与重大麻 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 被招募参加这项为期3个疗程的双盲、安慰剂对照的实验室研究。所有参与者都将是 服用安慰剂(0%THC)、较低(3%THC)和较高(10%THC)大麻强度的反- 平衡的秩序。大麻的滥用相关影响、止痛和药代动力学将被评估为 性别和大麻使用频率的作用。这项研究的发现将填补我们知识中的一个关键空白 在预测、预防和治疗CUD时，将性别作为生物变量加以理解是不可或缺的。

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.