The thesis describes the use of extensive pharmacodynamic effect profiling to characterise the clinical pharmacology of classic and non-classical analgesia. Analgesic drugs that modulate widespread targets in the nervous system can be expected to affect numerous CNS functions, which requires multimodal characterisation of pain processing and neurocognition. This is illustrated on the basis of two case studies of pharmacological agents that target cannabinoid CB1 and GABA-ergic GABAA receptors: two of the most widely distributed systems of receptors and neurotransmitters that are involved in a myriad of physiological functions. The distribution of receptors throughout the central nervous system render an oral formulation of ∆9-THC and a positive allosteric modulator of α2/3/5 subunit-containing GABAA receptors, ideal candidates for extensive neurophysiological and analgesic effect profiling in early phase clinical research. Profiling human pharmacology with a strong focus on pharmacodynamics may help to better understand the therapeutic potential and safety limitations of a compound before selection of doses and patient populations for phase II proof-of-concept studies.LUMC / Geneeskund
