Application of modeling-based approaches to study the cardiovascular effects of delta-9-tetrahydrocannabinol (Δ9-THC)

Currently Cannabis is one of the most abused drugs throughout the world. It is also one of the most commonly used illicit drugs in United States. Movement towards legalization of recreational Cannabis in the US and the increasing interest in the use of Cannabis for medical purposes has resulted in an increased number of Cannabis-associated adverse cardiovascular events. Thus, there is an urgent need to better understand the relationship between the cardiovascular effects and the plasma concentrations of the primary active component of Cannabis, delta-9-tetrahydrocannabinol (THC). Pharmacokinetics (PK) is the study of the time course of absorption, distribution, metabolism, and excretion of a drug in the body, while pharmacodynamics (PD) is the study of the relationship between the concentration of drug in the body and the exerted pharmacological effect. The overarching objective of this research was to study the pharmacokinetics and pharmacodynamics of THC after pulmonary administration of Cannabis with respect to the related cardiovascular effects including changes in heart rate, blood pressure and rate-pressure product. With technical advancements in computing and specialized software designed to evaluate pharmacokinetics and pharmacodynamics, modeling and simulation tools are now available to explore and describe the pharmacokinetics and pharmacodynamics of a drug in humans.

In this work, an E_max pharmacodynamic model was developed to relate the measure plasma THC concentration to observed cardiovascular responses (heart rate/blood pressure). A direct relationship was established between THC concentration and cardiovascular effects. User status has found to be necessary to include in the model suggesting that chronic users are developing tolerance to the increases in heart rate and rate pressure product (multiple of heart and systolic blood pressure). In addition, plasma THC concentrations was related to the psychological highness, the central nervous system effect of THC, using an effect compartment model. Again, chronic users displayed tolerance to the psychological highness as well.

Using modeling and simulation to contribute to the understanding the PK-PD relationships associated with THC is critical in the design of therapeutic treatment regimens for medical Cannabis use and to provide guidance in the clinical setting as well as to improve the safety of recreational products in the light of increasing reports of adverse cardiovascular events.