William Wolowich
Nova Southeastern University
Co-Authors: Robert Greif1,2, Lorenz Theiler3, Maren Kleine-Brueggeney4
1University of Bern, 2University of Torino, 3Cantonal Hospital Aarau, 4Charité – Universitätsmedizin Berlin
Background and Objectives: Cannabis consumption is increasing in both the recreational and medical setting. Tetrahydrocannabinol (THC) is known to produce cardiovascular effects, but the specific roles of THC and its metabolites THC-OH and THC-COOH in cannabinoid-induced cardiovascular effects remain unclear. We hypothesized that THC and THC-OH mediate cannabinoid-induced increase in heart rate in either an additive or synergistic fashion.
Methods: The present study uses prospectively obtained data to evaluate the effect of THC and its metabolites on heart rate in healthy volunteers through non-linear mixed-effect pharmacokinetic/ pharmacodynamic (PK/PD) modeling.
Results: The PK/PD models reveal that THC, THC-OH and a combination of THC and THC-OH, but not THC-COOH are responsible for THC-induced tachycardia. The EC50 of the THC Emax model was 0.47 µM, twenty-five-fold the EC50 for the THC-OH Emax model. The General Empiric Dynamic Model indicates that THC and THC-OH act synergistically to increase heart rate. Neither sex nor CYP2C9 polymorphism contribute to THC-induced tachycardia.
Conclusion: THC-OH but not THC-COOH contributes to the heart rate effect of THC and THC-OH may be acting in a synergistic manner with THC. This contributes to understanding the cardiovascular effects of THC and cannabis-induced cardiovascular events. Future research including further hemodynamic and endogenous cannabinoid data will allow a detailed systems pharmacology or response surface model approach.