Evaluation of Cannabis Per Se Laws: A Semi-Mechanistic Pharmacometrics Model for Quantitative Characterization of THC and Metabolites in Oral Users

Recreational cannabis use has increased notably in the United States in the past decade, with a recent surge in oral consumption. This trend has raised concerns about driving under the influence. Current cannabis-impaired driving laws lack standardization, with some states implementing blood Δ9-tetrahydrocannabinol (THC) per se limits (1, 2, and 5 ng/mL). However, these limits have been criticized for their inaccuracy and unreliability, highlighting the need for legal refinement. Addressing this issue requires understanding the complex pharmacokinetics (PK) and pharmacodynamics (PD) of THC, cannabis's primary psychoactive component, which can be characterized using a population PK model. However, existing PK models mainly focus on inhalation data and do not account for the growing number of oral cannabis users. To bridge this gap, a semi-mechanistic population PK model was developed using data from 10 published studies following intravenous or oral administration of cannabis to characterize THC and its metabolites in oral users. Simulated THC plasma concentrations for doses from 2.5 mg to 100 mg in frequent and occasional users were used to evaluate the effectiveness of existing per se limits. Results showed that the 1 ng/mL limit was least effective due to a high risk of false positives, while the 2 and 5 ng/mL limits remain inconclusive due to limited PD data linking blood THC levels to impairment. These findings suggest that the existing per se laws may not fully address the complexity of cannabis impairment, underscoring the need for further research and refinement of cannabis-impaired driving laws.