Effect Compartment Model for the Evaluation of Tolerance to Psychological Highness Following Smoking Marijuana

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 (EC₅₀ ) 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.