Modelling of the concentration--effect relationship of THC on central nervous system parameters and heart rate -- insight into its mechanisms of action and a tool for clinical research and development of cannabinoids.

Pharmacokinetics after pulmonary administration of delta-9-tetrahydrocannabinol (THC) and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC was quantified. Additionally, the relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic-pharmacodynamic (PK-PD) modelling. This provided insights useful for the research and development of novel cannabinoids and the physiology and pharmacology of cannabinoid systems. First, the PK-PD model gave information reflecting various aspects of cannabinoid systems. The delay between THC concentration and effect was quantified in equilibration half-lives of 7.68 min for heart rate and from 39.2 to 84.8 min for the CNS responses. This suggests that the effect of THC on the different responses could be due to different sites of action or different physiological mechanisms. Differences in the shape of the concentration-effect relationship could indicate various underlying mechanisms. Second, the PK-PD model can be used for prediction of THC concentration and effect profiles. It is illustrated how this can be used to optimise studies with entirely different trial designs. Third, many new cannabinoid agonists and antagonists are in development. PK-PD models for THC can be used as a reference for new agonists or as tools to quantitate the pharmacological properties of cannabinoid antagonists.