Levodopa-accelerated frailty: a hypothesis for a cumulative iatrogenic burden in Parkinson’s disease

as a testable hypothesis to explore this possibility. This framework synthesizes evidence across seven pathways that may interact or overlap in contributing to frailty: dyskinesia, psychosis, orthostatic hypotension, weight loss, impulse control disorders, sleep disturbances, and elevated homocysteine. Each complication has been associated with increased risks of dementia, hospitalization, falls, or mortality in observational studies, with reported hazard ratios generally ranging from approximately 1.5 to over 6. Together, they form a synergistic web of decline that may transform a highly effective symptomatic therapy into a contributor to late-stage vulnerability. This hypothesis reframes a potential therapeutic paradox: a treatment that improves early symptomatic outcomes may also interact with mechanisms that contribute to frailty later in the disease course. The clinical implication is not levodopa phobia, but a healthspan-preservation strategy focused on minimizing cumulative iatrogenic burden. This involves adhering to the lowest effective dose, continuous reassessment, and integration with exercise, nutrition, and adjunctive therapies. Recognizing this potential pattern of levodopa-accelerated frailty may help reconcile the discrepancy between early symptomatic success and the later emergence of vulnerability. We emphasize that this model is a hypothesis and call for long-term, prospective studies to test whether cumulative levodopa exposure contributes to frailty and reduced healthspan.