Psilocybin in Older Adults: Therapeutic Opportunities in Inflammation-Driven Disorders of Aging—From Depression to Neurodegeneration

Aging is associated with chronic, low-grade inflammation (“inflammaging”), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer’s disease, and Parkinson’s disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug-drug interactions. Psilocybin, a serotonergic psychedelic acting primarily as a 5-HT2A receptor agonist and currently undergoing accelerated clinical development, has emerged as a potential multimodal therapeutic agent addressing these challenges. Acting via its active metabolite psilocin, 5-HT2A-mediated signaling biases cortical glutamatergic transmission, enhances TrkB/BDNF pathways, and modulates neuro-immune cascades (including NF-κB), with convergent systems-level effects such as re-organization of the default mode network. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP, consistent with an immunomodulatory profile. Pharmacokinetically, psilocybin shows properties advantageous in geriatric care: rapid onset, short half-life, and predominant phase-II glucuronidation, reducing interaction risk. Controlled studies demonstrate rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging feasibility signals in neurodegeneration. Together, these find-ings support the hypothesis that a time-limited, mechanism-based intervention may improve mood and cognition while attenuating inflammation. This review integrates current evidence on psilocybin’s neuroimmune and pharmacokinetic mechanisms rel-evant to aging, outlining its potential role in inflammation-related disorders and high-lighting the need for targeted studies in older adults, who remain underrepresented in psychedelic research.