The medical use of marijuana is increasing, yet little is known about the exposure-response relationships resulting in its psychoactive effects. Δ9-tetrahydrocannabinol (THC) and its active metabolite (11-hydroxy-THC; THC-OH) are the principal psychoactive components in marijuana. It is well known that the plasma concentrations of the psychoactive components of marijuana do not directly relate to the observed psychoactive effects. The presence of a counter-clockwise hysteresis in the plasma concentrations-effect plot demonstrates a temporal delay between the plasma concentrations and observed effect following the intravenous administration of THC. The overarching objective of this research was to better understand the relationship between the plasma and brain concentrations of the psychoactive components (THC and THC-OH) and the observable psychoactive effects after intravenous administration of THC, utilizing model-based approaches. Specifically, the pharmacokinetics were explored using population pharmacokinetic (Pop PK) and physiologically-based pharmacokinetic (PBPK) modeling whereas the pharmacodynamics (PD) of the psychoactive effect (“highness”) were explored using effect-compartment modeling and linking the PD to the PBPK-derived concentrations predicted in the brain and an assumed effect-site.
A “hypothetical” effect compartment model was developed to characterize the observed delay in peak “highness” ratings. A direct relationship was established between the reported psychoactive effects (“highness” or intoxication) and the predicted effect-site concentrations of both components (THC and THC-OH) using this effect-compartment modeling approach. The faster plasma to effect compartment equilibration for THC-OH indicated a more rapid equilibration of the active metabolite between plasma and the effect-site (biophase) than for the parent THC. In addition, a PBPK modeling approach was pursued to predict and relate the brain concentrations of THC and THC-OH to the psychoactive effect. The relationship between the effect and the predicted unbound brain concentration of THC indicated an indirect relationship, suggesting a temporal delay between brain concentrations of THC and observed effect. However, a direct relationship was observed between the observed effect and the unbound brain THC-OH concentrations. In addition, the unbound concentrations of THC-OH in the brain were predicted to be higher than the corresponding THC concentrations. These findings highlight the importance for the inclusion of THC-OH, in addition to THC, when relating the observed effect to the concentrations of the psychoactive components of marijuana.
These models contribute to the understanding of the PK-PD relationships associated with marijuana use and are important steps in the prediction of the pharmacodynamic effects related to the psychoactive components in marijuana and establish an approach for investigating other THC-related effects.