Prof. Gitte Moos Knudsen

Gitte Moos Knudsen is Professor of Clinical Neurobiology at the University of Copenhagen and Chief Neurologist at the Department of Neurology, Rigshospitalet, Denmark, where she also chairs the Neurobiology Research Unit (NRU), a group of around 130 members publishing approximately 75 peer-reviewed papers per year. She earned her MD (1984) and DMSc (1994) at the University of Copenhagen and has held visiting positions at NIH, Stony Brook, the University of Bonn, and the Martinos Center at MGH/Harvard University. Her translational research focuses on human brain disease mechanisms using PET and fMRI neuroimaging, with a current emphasis on precision medicine for major depressive disorder and epilepsy through the BrainDrugs strategic alliance. She has served as President of the European College of Neuropsychopharmacology (ECNP, 2019–22), Chair of the Scientific Advisory Board of the Human Brain Project (2017–23), and member of the Danish Council for Strategic Research (2009–14). Among her honors, she is a member of the Royal Danish Academy of Sciences and Letters, recipient of the Carlsberg Foundation Researcher Award (2014), the Kuhl-Lassen Award (2024, US), and Adjunct Professor at the University of Vienna. She has supervised 35 completed PhD theses and published over 525 Medline-indexed papers, with an h-index of 88 and more than 31,000 citations on Google Scholar.

This lecture provides an overview of the current state of psychedelics as potential treatments for a range of psychiatric and neurological disorders. It begins by defining the classes of compounds considered psychedelics, outlining their characteristic experiential profiles, and describing their pharmacological mechanisms of action. With a particular focus on the serotonergic psychedelics, it then reviews the compounds currently under investigation, the stages of clinical trials they are in, and the broader landscape of companies driving this research.

Serotonergic psychedelics, e.g., DMT, psilocybin and LSD are characterized by exerting their psychedelic effects through stimulation of the brain’s 5-HT2A receptors. We have established the relationship between plasma drug concentration (or dose), brain 5-HT2A receptor occupancy and subjective intensity of the psychedelic experience by means of PET for psilocin, LSD, and the antagonist ketanserin. The data show that the classical psychedelics can potently block the brain’s 5-HT2A receptors, and that a brain occupancy in the order of about 60% is required to generate a substantial psychedelic experience. The question as to how the classical psychedelics can provide lasting improvements in mood and personality is particularly intriguing. We have found that the synaptic plasticity in terms of SV2A brain binding can be modified, suggesting an interaction between neuroplasticity one week after the psychedelic session with psilocybin and the setting, where being in an MR-environment during the acute phase is adversely affecting neuroplasticity.

To date, the most extensively studied application has been psilocybin for the treatment of major depressive disorder. Meta-analyses indicate that even a single psychedelic dose can produce rapid responses, robust effect sizes, and durable remission and Phase 2b/3 trials are now emerging. A particularly consistent finding is that the quality and intensity of the psychedelic experience—measured through post-session questionnaires—appears to be strongly predictive of long-term therapeutic outcomes. Nevertheless, several clinical questions remain to be answered:

• Is the subjective psychedelic experience essential for therapeutic benefit?
• Do different psychedelic compounds vary in efficacy?
• To what extent do contextual factors such as music, therapist support, or setting influence outcomes?
• Can we identify patients who are more likely than others to benefit from psychedelic treatment?
• Should psychedelic interventions be repeated, and if so, under what conditions and for which patients?

• Madsen, M. K., Fisher, P. M., Burmester, D., <...>, & Knudsen, G. M. (2019). Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology, 44, 1328–1334. doi: 10.1038/s41386-019-0324-9.
• Madsen, M. K., Petersen, A. S., Stenbæk, D. S., <...>, & Knudsen, G. M. (2024). CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity. Headache, 64, 55–67. doi: 10.1111/head.14656.
• Butlen-Ducuing, F., McCulloch, D. E-W., Haberkamp, M., <...>, & Thirstrup, S. (2023). The therapeutic potential of psychedelics: the European regulatory perspective. Lancet, 401(10378), 714–716. doi: 10.1016/S0140-6736(23)00264-7.
• McCulloch, D. E-W., Liechti, M. E., Kuypers, K. P. C., <...>, & Knudsen, G. M. (2024). Knowledge gaps in psychedelic medicalisation: Clinical studies and regulatory aspects. Neuroscience Applied, 3, 103938. doi: 10.1016/j.nsa.2024.103938.