Psilocybin for dementia prevention? The potential role of psilocybin to alter mechanisms associated with major depression and neurodegenerative diseases

Abstract

Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) 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 are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases. Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, 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 modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.

Keywords: Dementia; Depression; Hippocampal neurogenesis; Microglia; Psilocybin.

Fig. 1

Potential overlapping mechanisms underlying major depression and dementia relating to impaired adult hippocampal neurogenesis and microglial activity. There is a complex relationship between major depression and dementia where cognitive dysfunction and neuropsychiatric symptoms may clinically manifest in both conditions suggesting an underlying common pathophysiology. Hippocampal volume loss, seen in MDD, may precede progressive neurodegeneration and cognitive decline in dementia (A). Increased levels of pro-inflammatory cytokines (B) may modulate HPA axis function (C) and microglial activity leading to glucocorticoid receptor downregulation (D), alterations in BDNF signalling and subsequent reduction of AHN (E). Microglia phagocytose apoptotic newborn neurons in the hippocampal niche. Newborn neurons in the dentate gyrus may also not become functionally mature, if BDNF impacted due to microgliosis, impacting hippocampal integrity and functional connectivity (A, F). Aberrant microglial activity may also lead to synapse uptake contributing to cognitive impairment (G). AHN may be influenced by low 5-HT levels (H) due to the presence of pro-inflammatory cytokines driving a shift in tryptophan metabolism leading to quinolinic acid production and further contributing to neurotoxicity in this region (I). (Created with BioRender.com)

Fig. 2

Proposed mechanism of action of psilocybin involving different cell types in the hippocampal niche. (A) Psilocybin is dephosphorylated to active metabolite, psilocin. (B) In vitro, psilocin increases BDNF concentration while simultaneously enhancing its activity via positive allosteric modulation of tropomyosin receptor kinase B (TrkB) (Moliner et al., 2023) and may potentially influence mTOR signalling (Ly et al., 2018), to promote neuroplasticity. Further, TrkB binding is associated with increasing hippocampal DGC survival and neurogenesis relative to attenuating depressive-like behaviours in mice (Moliner et al., 2023). Supporting this, Du et al. (2023) also report increased proportion of DCX+ and BrdU+ cells in the dentate gyrus 7 days post-psilocybin administration, corresponding to higher concentrations of BDNF and associated with fear-extinction in mice (Du et al., 2023). (C) Hippocampal progenitor cells in the dentate gyrus also express 5-HT2aRs and binding by psilocin may putatively modulate neurogenesis via this receptor. (D) Clinical evidence suggests psilocybin may also be immunomodulatory by moderating cortisol release, HPA axis activity and pro-inflammatory mediator production, notably TNF-α, CRP and IL-6 (Mason et al., 2022). This may directly influence AHN via GR activity. (E) In vitro, Kozlowska et al., 2021 find psilocin may upregulate TREM2 expression, neuronal phagocytosis and modify morphology of primary mouse microglia stimulated with LPS (Kozłowska et al., 2021). Psilocin may putatively bind 5HT2bRs and other 5-HT subtype receptors expressed by microglia perhaps influencing downregulation of pro-inflammatory transcription factors but this has not yet been established. (F) This may also affect pro-inflammatory mediator release by microglia with downstream consequences on other cells in the niche, such as astrocytes, to further influence AHN. (Created with BioRender.com)