Background and ObjectiveThe introduction of cannabis as a legalized recreational drug in Canada has led to significant changes in public health policy. Tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and its absorption, distribution, metabolism, and elimination are poorly understood. The use of THC can impair an individual's ability to operate a motor vehicle, leading to an increased risk of accidents. Thus, additional research must be conducted to gauge the inter-individual differences in effect and duration of THC's effect. MethodsIn this study, a comprehensive whole-body physiologically-based pharmacokinetic (PBPK) model for THC metabolism was developed to track blood THC concentrations accounting for interindividual variations such as age, sex, body composition, bioavailability and drug metabolizing enzyme (DME) polymorphisms after various dosages. This model was fitted and validated with clinical human cannabis smoking data. ResultsUsing this model, we found effects of various factors on THC concentrations in different tissue compartments, and that the wild-type form of Cytochrome P450 2C9 (CYP2C9) DME showed faster metabolism of THC than other isoforms. The nature of the our PBPK model allowed for the investigation of non-blood compartments as well. To gauge the effects on driving, we compared the Standard Deviation of Lateral Position under the effects of THC and ethanol, and found that ethanol has a stronger but shorter-lasting effect. ConclusionWe anticipate that this model can be used to better predict the effects of a “standard THC unit” and help advise public health policies for safe cannabis usage.