Psychedelic-Inspired Approaches for Treating Neurodegenerative Disorders

The extracted text does not provide a methods section describing a formal literature search strategy, inclusion criteria or databases searched. From the content and structure, this is a narrative review synthesising prior preclinical, mechanistic and limited clinical literature rather than a systematic review or meta-analysis. Accordingly, the review integrates findings from molecular studies (receptor localisation, gene expression), in vitro experiments (neuronal and glial cultures), in vivo animal studies (rodent spine and synaptic assays, behaviour), human biomarker and imaging studies where available, and clinical trial literature in related neuropsychiatric conditions. Where specific experimental paradigms are discussed (for example, head-twitch response as a proxy for 5-HT2A activation, or use of [11C]UCB-J PET to measure SV2A), the review describes these measures but does not report a reproducible search or quality-assessment protocol. As such, it should be understood as an expert, narrative synthesis that draws on diverse primary studies rather than a protocol-driven evidence review.

Saeger and colleagues summarise converging lines of preclinical evidence that serotonergic psychedelics and related compounds promote cortical plasticity. Activation of 5-HT2A receptors is repeatedly implicated: psychedelics induce immediate early genes (IEGs) such as c-Fos, arc and egr-family members preferentially in cortex, and this IEG induction is largely prevented by 5-HT2A antagonists or genetic knockout. Several psychedelics increase BDNF transcript levels in the cortex (while decreasing hippocampal BDNF transcripts in some studies); serum increases in mature or total BDNF have also been reported, though the authors note difficulties in reliably quantifying cortical BDNF protein. In cultured neurons, DOI transiently increases spine size and, with longer exposure, spine density; multiple chemical classes of psychedelics produce neuritogenesis, spinogenesis and synaptogenesis in vitro, and single doses of compounds such as DMT or psilocybin increase cortical spine density in vivo with effects that can persist long after drug clearance. Mechanistically, psychedelic-induced growth appears to depend on glutamate release, AMPA receptor activation, TrkB signalling and mTOR activation. Short stimulations (minutes) are sufficient to initiate growth signalling, and growth is blocked by inhibitors of AMPA receptors, TrkB or mTOR. The authors caution, however, that chronic overactivation of mTOR has been associated with AD, and that sustained dosing regimens may produce different effects than single administrations. Beyond plasticity, the review summarises evidence that 5-HT2A receptor stimulation promotes mitochondrial biogenesis and improves mitochondrial function in cortical cultures, and that such effects extend beyond neurons to other cell types expressing 5-HT2A receptors. Psychedelics also exert potent anti-inflammatory and immunomodulatory effects in peripheral immune cells and in several in vitro CNS models. DOI and other 5-HT2A agonists suppress TNF-α-induced proinflammatory gene expression at low concentrations, inhibit NF-κB signalling in organoid and monocyte-derived cell models, reduce markers of inflammation in diet-induced models, and modulate microglial behaviour in culture (for example, reduced phagocytic activity and altered migration). Some unpublished in vitro data cited suggest psilocin and DMT reduce pro-inflammatory markers and increase TREM2 expression in microglia. The authors discuss functional consequences relevant to dementia. Nearly 90% of AD patients exhibit behavioural and psychological symptoms of dementia (BPSD), and psychedelics have demonstrated rapid, sustained antidepressant and anxiolytic effects in clinical trials for other conditions; preclinical studies also show facilitation of fear extinction and antidepressant-like effects. These lines of evidence motivate exploration of psychedelics to treat BPSD, though the review emphasises risk: psychedelics can exacerbate psychosis and are contraindicated in schizophrenia, and selective 5-HT2A antagonists are used clinically for dementia-related psychosis. The unique polypharmacology of botanical mixtures such as ayahuasca is highlighted. Ayahuasca contains DMT and harmala alkaloids (harmine, harmaline, tetrahydroharmine) that act at distinct targets including 5-HT2 receptors, sigma-1 receptors and DYRK1A. DMT promotes sigma-1-mediated neuroprotection and neurogenesis in some models; harmine has been shown to promote neurogenesis and to decrease tau phosphorylation. The combination could produce complementary regional effects on BDNF (for example, cortical vs hippocampal) though direct studies in neurodegenerative models are lacking. Long-term ayahuasca users reportedly show increased anterior cingulate cortical thickness but decreased posterior cingulate thickness in observational imaging studies of healthy people. The review also covers non-hallucinogenic psychoplastogens (compounds that promote plasticity without producing subjective psychedelic effects). Ketamine is cited as an established psychoplastogen with spine- and synapse-promoting effects in prefrontal cortex and emerging indications beyond depression. Novel non-hallucinogenic 5-HT2A-biased ligands such as tabernanthalog (TBG) promote circuit repair in stress models and may offer safety advantages for patients with dementia-related psychosis. The authors note both agonists and antagonists at 5-HT2A have shown protective effects in AD models, and some compounds act as agonists or antagonists depending on assay context. Key limitations and negative findings are emphasised: psychedelics have not been tested in animal models of neurodegenerative diseases according to the authors' survey; chronic or intermittent dosing can induce tachyphylaxis (rapid loss of effect) and receptor desensitisation, with reports that chronic intermittent DMT caused cortical spine retraction in female rats and chronic LSD produced deleterious phenotypes. Cardiac valvulopathy via 5-HT2B agonism is another safety concern. To guide clinical translation, the authors point to emerging biomarkers of synaptic density such as SV2A PET tracers ([11C]UCB-J and [18F]UCB-J) and cite pig data showing psilocybin increased SV2A binding, suggesting a possible translatable biomarker for psychoplastogenic effects.

Saeger and colleagues interpret the assembled evidence as providing a plausible mechanistic basis for exploring psychedelic-inspired approaches in neurodegenerative disease. They argue that 5-HT2A-mediated promotion of cortical neuroplasticity, effects on neurotrophic factor signalling, mitochondrial biogenesis and anti-inflammatory actions together constitute a set of mechanisms that could be disease-modifying rather than symptom-masking. The review stresses that these mechanisms align with pathologies central to AD and FTD — cortical atrophy, synapse loss and neuroinflammation — and that the sustained structural changes observed after single administrations in preclinical models might explain durable clinical benefits seen in psychiatric indications. Positioning these conclusions relative to earlier work, the authors note that psychedelics have already yielded impressive effect sizes in some neuropsychiatric clinical trials, and that the molecular and cellular actions described extend the rationale for testing these compounds in neurodegenerative contexts. They emphasise distinctive therapeutic opportunities presented by polypharmacological preparations such as ayahuasca (combining 5-HT2A, sigma-1 and DYRK1A modulation) and by non-hallucinogenic psychoplastogens that may be more acceptable for patient groups vulnerable to psychosis. Key uncertainties and limitations are explicitly acknowledged. Primary among them is the absence of published studies testing classical psychedelics or psychoplastogens in established animal models of neurodegenerative disease; direct efficacy for slowing degeneration or restoring lost neurites/spines remains unproven. Safety uncertainties include tachyphylaxis and receptor desensitisation with repeated dosing, the potential for chronic dosing to produce spine loss or other deleterious phenotypes in some paradigms, and cardiac risks mediated via 5-HT2B receptor activation. The authors also note measurement challenges, for example limitations in reliably quantifying cortical BDNF protein and in translating preclinical spine measures to human endpoints. For future research, the review recommends systematic investigation in disease-relevant animal models, careful optimisation of dosing regimens to avoid desensitisation and off-target harms, and development of translatable biomarkers (such as SV2A PET) to monitor synaptic changes in humans. Clinical implications are framed cautiously: while the modulation of mood and anxiety by psychedelics could help address BPSD, the risk of exacerbating dementia-related psychosis argues for careful patient selection and possibly prioritising non-hallucinogenic psychoplastogens for some populations. Overall, the authors call for further preclinical and translational work rather than immediate clinical deployment.

The authors conclude that although psychedelics have not yet been tested in animal models of neurodegenerative disorders, the available evidence indicates they upregulate neurotrophic factors, promote neuronal growth and exert substantial immunomodulatory effects. These combined actions provide a rationale for investigating psychedelic-inspired compounds as potential disease-modifying therapies for neurodegenerative diseases and for addressing neuropsychiatric symptoms associated with dementia. Many open questions remain — which diseases to prioritise, which compounds to test, and what dosing regimens balance efficacy with safety — and the literature supports cautious optimism and further research rather than definitive clinical claims.