Objective: To determine the effects of the N-methyl-D-aspartate (NMDA) anta
gonist amantadine on levodopa-associated dyskinesias and motor fluctuations
in Parkinson's disease (PD). Background: NMDA receptor blockade can amelio
rate levodopa-induced dyskinesias in primates and PD patients. Amantadine,
a well-tolerated and modestly effective antiparkinsonian agent, was recentl
y found to possess NMDA antagonistic properties. Methods: Eighteen patients
with advanced PD participated in a double-blind, placebo-controlled, cross
-over study. At the end of each 3-week treatment arm, parkinsonian and dysk
inesia scores were obtained during a steady-state intravenous levodopa infu
sion. Motor fluctuations and dyskinesias were also documented with patient-
kept diaries and Unified Parkinson's Disease Rating Scale (UPDRS) interview
s. Results. In the 14 patients completing this trial, amantadine reduced dy
skinesia averity by 60% (p = 0.001) compared to placebo, without altering t
he antiparkinsonian effect of levodopa. Motor everity by 60% (p = 0.001) co
mpared to placebo, without altering the antiparkinsonian effect of levodopa
. Motor fluctuations occurring with patients' regular oral levodopa regimen
also improved according to UPDRS and patient-kept diaries. Conclusions: Th
ese findings suggest that amantadine given as adjuvant to levodopa can mark
edly improve motor response complications and support the view that hyperfu
nction of NMDA receptors contributes to the pathogenesis of levodopa-associ
ated motor complications.