The global demographic shift toward aging populations has intensified the need for innovative therapeutic interventions targeting late-life mental health conditions, notably depression, loneliness, and existential distress. Traditional pharmacological treatments often exhibit limited efficacy and poor tolerability in older patients, primarily due to age-related physiological changes and the challenges associated with polypharmacy. Recently, psychedelic-assisted therapy, particularly psilocybin, has gained attention for its potential antidepressant and psychological benefits. This comprehensive review critically evaluates the current evidence supporting psilocybin's effectiveness in older populations and elucidates its neurobiological mechanisms, including serotonergic modulation, enhanced neuroplasticity, and the disruption of maladaptive default mode network activity. Clinical trials in general adult samples demonstrate sustained improvements in depressive symptoms, existential anxiety, and social connectedness following psilocybin administration, suggesting its distinct therapeutic potential beyond conventional treatments. However, geriatric populations are underrepresented in psychedelic research, creating significant knowledge gaps regarding dosing, safety profiles, and long-term outcomes. Pharmacokinetic complexities, cardiovascular risks, and drug interactions necessitate age-specific therapeutic protocols. Ethical considerations, including the complexities of informed consent in cases of cognitive impairment, further underscore the importance of tailored approaches. Future directions must prioritize dedicated geriatric studies that incorporate rigorous safety assessments and integrate findings into existing geriatric care frameworks to fully assess the potential of psilocybin for enhancing late-life mental health and quality of life.
