Department of Pharmaceutical Sciences, College of Pharmacy, University of Iowa, Iowa City, Iowa, USA.
Regeneron Pharmaceuticals, Tarrytown, New York, USA.
J Clin Pharmacol. 2022 Dec;62(12):1539-1547. doi: 10.1002/jcph.2109. Epub 2022 Jul 8.
The purpose of this study is to evaluate the development of tolerance, using a population modeling approach, in recreational marijuana users after acute pulmonary administration of tetrahydrocannabinol (THC), a primary ingredient in marijuana. A total of 85 subjects in 3 separate studies smoked marijuana cigarettes (dose = 13-49 mg) under controlled conditions. Each study was designed as a randomized, crossover, double-blind, and placebo-controlled study. Up to 5 THC plasma samples and corresponding user-reported psychological highness were pooled for population modeling analyses. Age, sex, user status, and body mass index were evaluated as covariates. Population pharmacokinetic (PK) parameters were estimated in the 2-compartment PK model. PK parameters were fixed in the effect compartment model to describe the relationship between THC plasma concentration-psychological highness. The distribution rate constant in the effect compartment was estimated to be 0.988 (95%CI 0.964-1.010)/h. The population mean half-maximal effective concentration (EC ) was 23.8 (95%CI 22.7-24.9) ng/mL. Covariate analysis revealed that user status was a significant covariate, and that chronic users appear to need higher plasma concentrations compared with occasional users to achieve a similar degree of highness. The modeling results conclude that chronic users develop tolerance to euphoria, which is the primary central nervous system effect of smoking marijuana.
本研究旨在采用群体建模方法评估娱乐性大麻使用者在急性肺内给予大麻主要成分四氢大麻酚（THC）后耐受性的发展。共有 85 名受试者在 3 项独立研究中在受控条件下吸食大麻香烟（剂量为 13-49mg）。每项研究均设计为随机、交叉、双盲和安慰剂对照研究。多达 5 个 THC 血浆样本和相应的使用者报告的心理兴奋度被汇总进行群体建模分析。年龄、性别、使用者状态和体重指数被评估为协变量。在 2 隔室 PK 模型中估算群体药代动力学（PK）参数。PK 参数在效应隔室模型中固定以描述 THC 血浆浓度-心理兴奋度之间的关系。效应隔室的分布速率常数估计为 0.988（95%CI 0.964-1.010）/h。群体平均半数最大有效浓度（EC ）为 23.8（95%CI 22.7-24.9）ng/mL。协变量分析显示，使用者状态是一个重要的协变量，与偶尔使用者相比，慢性使用者似乎需要更高的血浆浓度才能达到相似程度的兴奋度。建模结果表明，慢性使用者对欣快感产生了耐受性，这是吸食大麻对中枢神经系统的主要影响。
