Postdoctoral researcher York College, City University of New York New York, New York, United States
Background: The increasing use of cannabis for both recreational and therapeutic applications has brought attention to THC, the primary cannabinoid responsible for its psychoactive effects. Although THC is known for inducing the sensation of "feeling high," its effects vary significantly across individuals. While this psychoactive response is often sought recreationally, it can lead to adverse effects such as impaired driving. Therefore, it is critical to understand the dose-exposure-response relationship between THC and the effect of “feeling high”. This study aimed to develop and verify a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model to understand this relationship better. Methods: The PD modeling was linked to our previously verified PBPK model for THC and its active metabolite, 11-OH-THC, using Simcyp™. The Visual Analogue Scales (VAS) score for "feeling high" (ranging from 0 to 100 mm) was used as an indicator for the PD effect. Both direct and indirect PD models were tested, using THC and 11-OH-THC brain concentrations as inputs. The PBPK-PD model was developed to simulate single-dose intravenous (IV) THC and inhaled THC with escalating doses. The model was subsequently verified using data from published clinical studies on oral or inhaled THC in healthy adults. The accuracy of the predictions was assessed by determining whether the observed mean VAS values fell within the 5th-95th percentile of the predictions. Results: A direct nonlinear Emax model best described the "feeling high" effect following THC administration, driven by the sum of total THC and 11-OH-THC concentrations in their effect compartments, linked to the brain compartment, driving the response. The model accurately predicted VAS scores, with 88% of observed values falling within the 5th–95th percentile of predictions across 12 simulated clinical studies. These studies covered THC doses ranging from 0.5 to 86.0 mg. Conclusion: Our study demonstrated that the verified PBPK-PD model accurately predicts the "feeling high" effect following THC administration based on the concentrations of THC and 11-OH-THC in the brain. The model can be used to assess and predict the psychoactive effects in cannabis users and improve the safety of cannabis use.
