Is levodopa toxic?

Shortly after the introduction of high-dosage levodopa for the treatment of Parkinson's disease (PD), adverse motor effects of dyskinesias and clinical fluctuations ("wearing-off" and "on-off" phenomena) were seen [see ^[1] for historical review]. This soon led to the suggestion ^[2] that the introduction of levodopa for the treatment of PD should be delayed in an effort to postpone the development of such effects. For the past 20 years, this suggestion has been debated in the literature (Table 1 and Table 2), at national and international neurologic meetings, ^[3-7] and in two separate courses at the American Academy of Neurology meeting in March 1996. The debate will likely continue until a definitive study can be conducted to provide the correct answer.

Historically, when motor complications with chronic levodopa therapy became known, concern was raised that the medication was responsible (see Table 1). Others countered that the duration or dosage of levodopa was not responsible, but rather these complications occurred because of the severity of the disease, which continues to progress despite levodopa therapy (see Table 2). Concern over motor complications has largely been superseded by concern regarding increased oxidant stress from levodopa therapy and the possibility that such stress can lead to more rapid progression of the disease itself, i.e., enhance further neurodegeneration. This suspicion that levodopa might be toxic to patients with PD is the focus of this article. Before presenting the arguments for and against this toxicity hypothesis, we will briefly review the question whether duration and dosage of levodopa could be the responsible factors in the motor complications because this could be one overt manifestation of levodopa toxicity.

Does levodopa induce motor complications?

When levodopa therapy is first initiated, there is a long-duration …