Title: Neurobiological effects of 5-HT2AR modulation

PhD-student: Martin Korsbak Madsen, NRU


Novel pharmacological treatment development for neuropsychiatric disorders suffers from failed drug trials. We aim to establish proof-of-concept that an experimental medicine approach can overcome this limitation using state-of-the-art neuroimaging to delineate novel effects in humans in vivo. As a highly relevant model, we will modulate the function of the serotonin 2A receptor (5-HT2AR) using an agonist (psilocybin, the active compound in magic mushrooms) and an antagonist (ketanserin). The 5-HT2AR is implicated in neuropsychiatric disease and is critical for psilocybin-induced altered states of consciousness.

The present project will include 50 healthy participants and consists of three sub-projects. First we will 1) determine brain 5-HT2AR dose-occupancy with [11C]-Cimbi-36 PET for psilocybin and ketanserin, linking brain occupancy with blood concentrations. Then we will 2) determine long-term effects of psilocybin on brain 5-HT2AR levels, a possible mechanism underlying lasting effects observed in recent studies. Finally, we will 3) compare drug effects on brain function using fMRI, elucidating neural pathways sensitive to 5-HT2AR modulation. Furthermore, we will use a comprehensive battery of validated questionnaires and neuropsychological tests to relate 5-HT2AR modulation and neuroimaging data to psychometric assessments.

Thus, this cohesive project will not only generate critical insights into the neurobiology of consciousness and psilocybin neuropsychopharmacology but also evaluate a promising concept in validation of drugs for brain disorders.