Postdoctoral researcher York College, City University of New York New York, New York, United States
Background: Tachycardia, which has resulted in death, has been observed in both cardiac patients and healthy young adults following the administration of THC. As cannabis becomes legal in several U.S. states, the risk of THC-induced tachycardia increases. However, a quantitative understanding of the relationship between THC dose, exposure, and changes in heart rate remains lacking. The mechanism by which THC affects heart rate is not fully understood. Experiments in isolated rat hearts have shown that THC directly increases heart rate. This study aimed to develop and verify a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to assess the impact of THC and its active metabolite, 11-OH-THC, on heart rate in healthy adults. Methods: First, a PBPK-PD model for intravenous (IV) 11-OH-THC was developed and verified. Next, a PBPK-PD model for IV THC, combined with the metabolized 11-OH-THC, was established and verified. In these two steps, both direct and indirect PD models, driven by the heart concentrations of THC and 11-OH-THC, which were predicted using our previously verified PBPK model for THC and 11-OH-THC in Simcyp™, were tested. Finally, the combined PBPK-PD model for THC and 11-OH-THC was verified using data from published clinical studies on oral or inhaled THC in healthy adults. The accuracy of the model predictions was assessed by comparing the observed mean heart rate or heart rate changes with the predicted values, ensuring they fell within the 5th-95th percentile range. Results: The PD model for heart rate after THC administration was best described by a direct nonlinear Emax model driven by the sum of total THC and 11-OH-THC concentrations in their effect compartments linked to the heart compartment. In 49 simulated clinical studies, with THC doses ranging from 2 to 54 mg, 90% of the observed heart rate or heart rate changes following THC administration fell within the 5th-95th percentile range of model-predicted values. Conclusion: Our verified PBPK-PD model successfully describes the relationship between THC and 11-OH-THC concentrations and heart rate changes in healthy adults after IV, oral, and inhaled administration of THC. This model enhances our understanding of the cardiovascular effects of THC, offering valuable insights for assessing the risk of tachycardia in both clinical and recreational cannabis use.
