The potential of psychedelics for the treatment of Alzheimer's disease and related dementias

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.

This paper is a narrative review that combined a targeted literature search with broader inclusion of mechanistic and preclinical studies. The authors report a PubMed search performed on 20 August 2022 using the MeSH term "Alzheimer's" combined with a set of psychedelic-related terms; that search returned only a small number of hits and no clinical trials in humans for many agents (examples reported: Psychedelic-5; Hallucinogen-5; Ibogaine-1; Muscarine-8; Muscimol-4; Harmine-8; Psilocybin-0; LSD-0). Because primary clinical data were scarce, the investigators integrated findings from in vitro studies, animal models, human psychopharmacology, and selected clinical reports to examine plastogenic, neurotrophic, immune-modulatory and receptor-level mechanisms. The review intentionally broadened scope beyond serotonergic 5-HT2A agonists to consider other receptor families (sigma-1 receptor, muscarinic, GABAA, NMDA/kappa-opioid) and non-neuronal cell types, with emphasis on downstream intracellular pathways (e.g. PLC/IP3-Ca2+, cAMP-PKA, PI3K-Akt-mTOR) that are relevant to neuroplasticity and neuroprotection. The authors did not present a formal systematic review protocol, risk-of-bias assessment, or quantitative meta-analysis model in the extracted text. Instead, this is a narrative synthesis aimed at mapping plausible mechanistic pathways and preclinical evidence that might justify future translational and clinical work.

The review summarises neuropathological features of AD (amyloid-β aggregation, tau hyperphosphorylation, synaptic loss, glial dysfunction and chronic neuroinflammation) and highlights how these processes impair network-level compensation but may still permit neuroplastic responses, particularly in earlier disease stages. Mechanistic coverage emphasises several receptor systems and intracellular cascades through which psychedelics could act. Classic serotonergic psychedelics (psilocybin, LSD, DMT and phenethylamines) principally engage 5-HT2A receptors but also affect 5-HT1A, 5-HT6/7, sigma receptors, dopamine, adrenergic and cholinergic sites. Activation of 5-HT2A triggers Gq-mediated PLC/IP3 signalling with intracellular Ca2+ mobilisation and Gi/Go-mediated cAMP changes; downstream effects include activation of TrkB/BDNF and mTOR pathways, which promote dendritic spine growth, neuritogenesis and synaptogenesis. Preclinical data cited include induction of neurogenesis in hippocampus by psilocybin, ayahuasca alkaloids and 5-MeO-DMT, and mTOR/TrkB-dependent increases in dendritic spines after psychedelic exposure. Non-serotonergic agents with potential relevance to AD are discussed in detail. Muscimol (from Amanita muscaria) is a GABAA receptor agonist that readily crosses the blood–brain barrier and, in rodent AD models, improved spatial memory and reduced markers of neuroinflammation and reactive gliosis (e.g. GFAP); muscimol also attenuated Aβ-induced neurotoxicity in cultured neurons, an effect blocked by a GABAA antagonist. Muscarine (a muscarinic agonist) is highlighted as a theoretical target for cholinergic modulation, although natural muscarine does not cross the BBB and would require modified analogues for central action. Ibogaine is reported to increase BDNF and GDNF expression in several brain regions but clinical development is constrained by safety/toxicity concerns; a non-psychoactive analogue (tabernanthalog) shows neuroplasticity-promoting effects in rodents. Harmine, a β-carboline MAO-A inhibitor present in ayahuasca preparations, exhibited neuroprotective and progenitor-stimulating effects in animals, possibly via DYRK1A inhibition, yet shows neurotoxicity at higher doses in preclinical work. Evidence from human studies is limited but suggestive. The authors note clinical psychopharmacology demonstrating 5-HT2A occupancy by classic psychedelics and some human reports of cognitive changes: psilocybin exposures were linked to positive effects on memory, attention and perception in humans in some studies, and certain trials reported increased plasma BDNF following serotonergic psychedelic administration. A recent Phase I study using low-dose LSD in older volunteers is mentioned as an emerging clinical exploration. Epigenetic and transcriptomic effects after single-dose psychedelic exposure are described from animal and organoid studies: single doses of psilocybin or 5-MeO-DMT altered neuroplasticity-related transcripts in hippocampus and prefrontal cortex, and DOI produced persistent chromatin changes at enhancer regions of synaptic genes in mice. Safety and translational barriers are also reported: toxicity and safety concerns limit ibogaine clinical research; harmine shows dose-related neurotoxicity; regulatory scheduling (most classic psychedelics are Schedule I at the time of writing) and the lack of patentability for natural compounds constrain conventional drug-development pathways. The authors note muscimol is an approved compound, opening potential off-label avenues, and suggest alternative research pathways such as citizen science and N-of-1 trials where standard large-scale funded trials are unlikely.

Winkelman and colleagues propose three convergent mechanisms by which psychedelics could exert long-term therapeutic effects in AD: 1) modulation of the brain transcriptome with upregulation of neuroplasticity-related genes (for example, increased BDNF expression following DOI and related agents); 2) epigenetic reprogramming of enhancer and regulatory regions that sustain long-lasting synaptic and structural changes (evidence includes DOI-induced chromatin alterations and LSD-associated DNA methylation changes in rodent prefrontal cortex); and 3) suppression or modulation of neuroinflammation via 5-HT2A and sigma-1 receptor signalling, which could reduce cytokine-driven neuronal dysfunction and support microglial phagocytosis of debris. The authors position these mechanisms relative to prior research by integrating molecular, cellular and animal-model data with limited human psychopharmacology. They suggest that by stimulating TrkB/BDNF and mTOR pathways, psychedelics can promote neurogenesis and dendritic remodelling in brain regions vulnerable in AD, while sigma-1 receptor agonism and other non-serotonergic actions may provide additional neuroprotective and anti-inflammatory effects. Important limitations and cautions are acknowledged. The review emphasises the vulnerability of AD patients and the need to monitor immune and inflammatory modulation carefully to avoid adverse outcomes such as immunosuppression, impaired β-amyloid clearance, or reduced cancer immunosurveillance in older adults. Safety concerns (notably for ibogaine and harmine at high doses) restrict immediate clinical application. Regulatory (Schedule I status for many psychedelics) and economic barriers (difficulty patenting natural substances) are discussed as practical constraints on large-scale clinical development. The authors recommend cautious, well-monitored early-phase clinical work (including small-dose studies in older adults), caregiver training for therapeutic settings, and consideration of alternative research models (citizen science, N-of-1 trials) to advance evaluation where conventional funding/investment pathways are limited.

Preclinical and limited human data reviewed by the authors indicate that both classic serotonergic and non-classic psychedelics engage multiple biological mechanisms — serotonin, sigma, NMDA and GABA receptor-mediated pathways — that rapidly change gene expression and can produce sustained structural and functional brain alterations. These changes include enhanced neuroplasticity, neurogenesis and anti-inflammatory effects in brain regions most affected by neurodegenerative disease. Taken together, the evidence presented provides a rationale for further investigation of psychedelics as potential disease-modifying agents for AD and related dementias, while recognising the need for cautious, safety-focused translational research.