843. Not all who wander are lost – Might psychedelics alleviate neurodegeneration and depression in dementia?

Abstract Background Serotonin 2A receptor (5-HT2AR) agonists play a crucial role in multiple cognitive processes, namely executive functions, learning and memory. Owing partly to this, psychedelics such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), mescaline and ayahuasca might be valuable adjuvants in improving memory deficits and language impairment. Thanks to their purported increase in neuroplasticity, neurogenesis, and neuroprotective and anti-inflammatory effects, they may theoretically aid in delaying atrophy of brain tissue in such conditions as traumatic brain injury, stroke and dementia, among which Alzheimer’s disease (AD) stands as a hallmark. Neuroinflammation plays a fundamental role in both AD and major depressive disorder pathogenesis. 5-HT2AR activation by psychedelics modulates cytokine production, regulates microglial and oligodendrocytic activity and alters cell signaling activity, primarily through BDNF/TrkB but also notably through the NF-κB, PI3K/Akt, and mTOR pathways, which interact in complex ways to induce synaptogenesis, dendritic spine budding and reduce inflammatory pathways. A reduction in oxidative stress has also been theorized to help attenuate Aβ peptide generation. Although available evidence is accumulating toward a clear benefit of psychedelics in the treatment of depression, it is unclear whether that benefit remains in dementia-associated depressive symptomatology. Aims & Objectives The aim of this review was to summarize existing evidence regarding the use of serotonergic psychedelics in the treatment of AD and other neurodegenerative conditions, including preclinical studies.

Method: A narrative review of PubMed and Scopus databases was conducted using keywords pertaining to 5-HT2AR agonist psychedelic compounds, neurocognitive disorders, AD and associated depressive disorder or symptoms. Relevant findings were summarized.

Results: No clinical trials on psychedelic use in patients with dementia have been published to date. One pilot study (NCT04123314) is currently underway to evaluate the effects of psilocybin for depression in patients with mild cognitive impairment or early AD, with no neuroimaging endpoint measures evaluating brain connectivity or volume. Concerning safety profiles, a double-blinded placebo-controlled study in an older adult cohort found no difference in adverse events (including cognitive impairment) between placebo or LSD doses ranging from 5-20 μg doses every 5 days for four weeks. Surprisingly few studies with animal or molecular models of dementia or aging exist. Using a murine model of AD, one study reported that both 5-HT1AR and 5-HT2AR agonists showed significant independent and synergistic neuroprotective effects in the mouse hippocampus. Many review articles explore potential neurobiological mechanisms of action. Discussion & Conclusions Clinical evidence supporting the use of serotonergic psychedelics in neurocognitive disorders remains extremely limited. Although multiple mechanistic pathways suggest potential relevance to AD pathophysiology, these hypotheses lack confirmation in adequately powered clinical studies. Carefully designed trials, particularly in early-stage disease and in patients with comorbid depressive symptoms, are required to determine safety, tolerability, and therapeutic efficacy.