Clinical trials are highlighting the potential of psychedelic substances for the treatment of psychiatric indications. Yet, recent larger and well-controlled studies report great inter-individual heterogeneity in clinical responses. Unfortunately, the clinical mechanism of action of psychedelic-assisted therapy currently remains unclear. This talk will discuss our current state of knowledge with regard to the neurobiology of psychedelics and how elucidating the mechanism of action will help optimizing psychedelic-assisted therapy.