The potential of psychedelics for the treatment of Alzheimer's disease and related dementias
This literature review (2023) examines the potential of natural and synthetic psychedelics in treating Alzheimer's Disease (AD) and related dementias. It highlights the plastogenic effects of serotonergic psychedelics and their ability to promote neuronal survival, glutamate-driven neuroplasticity, and reduce Aβ-induced neurotoxicity, illustrating the potential for these substances to address multiple facets of AD pathology.
Authors
- Attila Szabo
- Ede Ottó Frecska
- Michael Winkelman
Published
Abstract
Alzheimer's Disease (AD) is a currently incurable but increasingly prevalent fatal and progressive neurodegenerative disease, demanding consideration of therapeutically relevant natural products and their synthetic analogues. This paper reviews evidence for effectiveness of natural and synthetic psychedelics in the treatment of AD causes and symptoms. The plastogenic effects of serotonergic psychedelics illustrate that they have efficacy for addressing multiple facets of AD pathology. We review findings illustrating neuroplasticity mechanisms of classic (serotonergic) and non-classic psychedelics that indicate their potential as treatments for AD and related dementias. Classic psychedelics modulate glutamatergic neurotransmission and stimulate synaptic and network remodeling that facilitates synaptic, structural and behavioral plasticity. Up-regulation of neurotrophic factors enable psychedelics to promote neuronal survival and glutamate-driven neuroplasticity. Muscimol modulation of GABAAR reduces Aβ-induced neurotoxicity and psychedelic Sig-1R agonists provide protective roles in Aβ toxicity. Classic psychedelics also activate mTOR intracellular effector pathways in brain regions that show atrophy in AD. The potential of psychedelics to treat AD involves their ability to induce structural and functional neural plasticity in brain circuits and slow or reverse brain atrophy. Psychedelics stimulate neurotrophic pathways, increase neurogenesis and produce long-lasting neural changes through rewiring pathological neurocircuitry. Psychedelic effects on 5-HT receptor target genes and induction of synaptic, structural, and functional changes in neurons and networks enable them to promote and enhance brain functional connectivity and address diverse mechanisms underlying degenerative neurological disorders. These findings provide a rationale for immediate investigation of psychedelics as treatments for AD patients.
Research Summary of 'The potential of psychedelics for the treatment of Alzheimer's disease and related dementias'
Introduction
Alzheimer's disease (AD) is a progressive, fatal neurodegenerative disorder and the commonest cause of dementia, with prevalence rising steeply with age (above 30% in people over 85). Current therapies do not cure AD, and the disorder involves multiscale dysfunctions from synaptic and cellular pathology (amyloid-β plaques, hyperphosphorylated tau tangles) to network-level degeneration and chronic neuroinflammation. Earlier preclinical work implicates the serotonergic system in learning and memory and suggests that loss of serotonergic signalling contributes to cognitive decline in AD. Winkelman and colleagues set out to review evidence that both classic (predominantly serotonergic) and non-classic psychedelics — and some related compounds — might address causes and symptoms of AD via neurotrophic, plastogenic and anti-inflammatory mechanisms. Rather than focusing solely on 5-HT2A-mediated effects, the authors expand the discussion to additional receptor systems (sigma receptors, cholinergic, GABAergic, glutamatergic) and to non-neuronal cell types (glia and immune cells), aiming to synthesise molecular, cellular, animal and limited human findings that bear on the therapeutic potential of psychedelics for AD and related dementias.
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Winkelman, M. J., Szabo, A., & Frecska, E. (2023). The potential of psychedelics for the treatment of Alzheimer's disease and related dementias. European Neuropsychopharmacology, 76, 3-16. https://doi.org/10.1016/j.euroneuro.2023.07.003
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