Variable Delta-9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics After Cannabis Smoking in Regular Users

Supplemental Digital Content is Available in the Text. Background:Despite its federally restricted status, cannabis is widely used medicinally and recreationally. The pharmacokinetics (PK) and central nervous system (CNS) effects of tetrahydrocannabinol (THC), the major psychoactive cannabinoid, are not well understood. The objective of this study was to develop a population PK model of inhaled THC, including sources of variability, and to conduct an exploratory analysis of potential exposure-response relationships.Methods:Regular adult cannabis users smoked a single cannabis cigarette containing 5.9% THC (Chemovar A) or 13.4% THC (Chemovar B) ad libitum. THC concentrations in whole blood were measured and used to develop a population PK model to identify potential factors contributing to interindividual variability in THC PK and to describe THC disposition. Relationships between model-predicted exposure and heart rate, change in composite driving score on a driving simulator, and perceived highness were evaluated.Results:From the 102 participants, a total of 770 blood THC concentrations were obtained. A two-compartment structural model adequately fit the data. Chemovar and baseline THC (THCBL) were found to be significant covariates for bioavailability, with Chemovar A having better THC absorption. The model predicted that heavy users-those with the highest THCBL-would have significantly higher absorption than those with lighter previous use. There was a statistically significant relationship between exposure and heart rate, and exposure and perceived highness.Conclusions:THC PK is highly variable and related to baseline THC concentrations and different chemovars. The developed population PK model showed that heavier users had higher THC bioavailability. To better understand the factors affecting THC PK and dose-response relationships, future studies should incorporate a wide range of doses, multiple routes of administration, and different formulations relevant to typical community use.