Psilocybin for Dementia Prevention: Could Treating Major Depression with Psilocybin Alter the Neurodegenerative Disease Trajectory?

Abstract

Major depression is associated with increased risk of subsequently developing dementia and may be a prodrome. Considering the increasing global dementia prevalence and current challenges in the clinical development of disease modifying therapies, research focus is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying mood and cognitive decline may reveal biomarkers to aid early identification of dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia, innate immune system macrophages in the central nervous system, carefully regulate this process via multiple mechanisms and disruption in AHN and microgliosis underlie the aforementioned conditions.Emerging evidence suggests that psychedelics promote neuroplasticity and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to alter the progression from major depression to dementia via multiple mechanisms of action.

Note:
Funding Declaration: This work was supported by the Wellcome Trust (RE20960); the Medical Research Council (MRC) Centre grant (MR/N026063/1) and the National Institute for Health Research (NIHR) (CS-2017-17-007). Prof. A.H. Young’s independent research is funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, NIHR or the Department of Health and Social Care.

Conflicts of Interest: DA, MB, TM, ST, LV and ACV declare no conflict of interest relevant to the content of this manuscript. ZRH: Investigational material received from COMPASS Pathways. DMT: Shareholder of Myogenes and 428 Pharma. JJR: Paid advisory boards for Clerkenwell Health (Past), Beckley PsyTech (Past), Delica Therapeutics (Past). Paid articles for Janssen. Assistance for attendance at conferences from Compass Pathways (past) and Janssen. Grant funding (received and managed by King’s College London) from Compass Pathfinder, Beckley PsyTech, Multidisciplinary Association for Psychedelic Studies, National Institute for Health Research, Wellcome Trust, Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust. No shareholdings in pharmaceutical companies. No shareholdings in companies developing psychedelics. AHY: Employed by King’s College London; Honorary Consultant South London and Maudsley NHS Foundation Trust (NHS UK). Editor of Journal of Psychopharmacology and Deputy Editor, BJPsych Open. Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: FlowNeuroscience, Novartis, Roche, Janssen, Takeda, Noema pharma, Compass, Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, Sage, Novartis, Neurocentrx. Principal Investigator in the Restore-Life VNS registry study funded by LivaNova. Principal Investigator on ESKETINTRD3004: “An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.” Principal Investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants”. [Continued in manuscript]

Keywords: dementia, depression, hippocampal neurogenesis, microglia, psilocybin