The endocannabinoid system has only been discovered during the last few decades, and scientific progress in understanding the relevance of this system in health and disease has been limited and... Show moreThe endocannabinoid system has only been discovered during the last few decades, and scientific progress in understanding the relevance of this system in health and disease has been limited and slow. CB1 antagonists were considered a __miracle drug__ for the treatment of obesity and smoking with __blockbuster__ potential. But due to central side effects (such as depression and suicidal behaviour) and a lack of systematic clinical pharmacologic research, market access of a CB1 antagonists failed. In this thesis, we explored some improvements in the early development of cannabinoids, and by systematically investigating, we found that the new cannabinoid antagonist TN38837 seems effective with a reduced propensity for central side effects, and that a new oral THC formulation enhances the pharmacological activities by its seemingly superior pharmacokinetics. Also, we experiment with new methodology to optimise effect measurement, including resting state-FMRI which we found suitable for early phase cannabinoid research, and including new concentration-effect models to improve the simulation and prediction of future studies. The research in this thesis shows that a revival of research on the cannabinoid system requires novel approaches to the administration of cannabinoids, to the measurements and the study designs, and to the analyses of the effects. This reflects the complexity of the highly integrated endocannabinoid system, but also sets the stage for other innovative drug development programs Show less
