After the introduction of levodopa, mortality in Parkinson disease (PD) was reduced substantially. By the metric of survival alone, it could be argued that levodopa robustly modified the natural history of PD, unlike any previous intervention. Through a marked improvement of motor symptoms, levodopa has facilitated the resumption of active lifestyles and exercise routines, which may have possibly extended lives.

Alternatively, through its molecular effects, levodopa may have a direct disease-modifying effect. Such was one of the interpretations from the Earlier vs Later Levodopa Therapy in Parkinson Disease (ELLDOPA) trial¹ that examined 3 doses of levodopa (150 mg/d, 300 mg/d, and 600 mg/d) against placebo in 361 treatment-naïve patients with PD. At 40 weeks, all 3 groups were doing better than placebo after 2 weeks of washout and even after 4 in a smaller subgroup (n = 38). However, a question lessened the certainty of a presumed disease-modifying effect by levodopa: could a 4-week washout period have been too short for eliminating the long-duration effect of levodopa, with symptomatic effects explaining the difference between groups?