Neurology & Psychiatry · 1967
L-DOPA for Parkinson disease (Cotzias)
In the years before 1967, Parkinson disease had no treatment capable of producing meaningful, sustained motor improvement. Anticholinergic drugs and surgical thalamotomy offered modest benefit for tremor in selected patients, but rigidity and akinesia progressed regardless. The problem was not a lack of understanding of the underlying neurology; by the early 1960s, Oleh Hornykiewicz in Vienna had measured near-total dopamine depletion in the striata of postmortem Parkinson brains, and Arvid Carlsson at the University of Gothenburg had already shown in animal models that DOPA could reverse the motor effects of dopamine depletion.
The gap was clinical translation. When Hornykiewicz and others tested intravenous DOPA in small trials in the early 1960s, improvements appeared but lasted only minutes to hours. George Cotzias, working at Brookhaven National Laboratory on Long Island, took a different approach: he started patients on low oral doses and titrated upward over weeks, accepting early side effects while gradually reaching doses far higher than anyone had tried before. The regimen required patience and careful dose adjustment, but it produced something no prior treatment had achieved.
Cotzias published his 1967 results in the New England Journal of Medicine, reporting marked and sustained reduction in rigidity, tremor, and akinesia in 16 patients with Parkinson disease. Some patients who had been largely immobile regained the ability to walk and dress themselves. The improvements persisted with continued dosing, not merely during a brief window after administration. The key was the titration strategy: Cotzias had found a way to get enough drug into the brain to restore meaningful dopaminergic tone.
The initial compound, DL-DOPA, contained both the active L-isomer and the inactive D-isomer, which contributed to side effects including nausea and cardiac dysrhythmia. Within a few years, the purified L-isomer, levodopa, became the standard form. The further addition of carbidopa, a decarboxylase inhibitor that reduces peripheral conversion of levodopa to dopamine, lowered the effective oral dose needed and reduced nausea substantially. The carbidopa-levodopa combination, introduced commercially in 1975, remains the most effective symptomatic treatment for Parkinson disease available.
Arvid Carlsson received the Nobel Prize in Physiology or Medicine in 2000, shared with Paul Greengard and Eric Kandel, recognized in part for the foundational dopamine pharmacology that made Cotzias's clinical results interpretable. The long-term complications of levodopa therapy, including motor fluctuations and dyskinesias that emerge after years of use, drove subsequent research into dopamine agonists, monoamine oxidase inhibitors, and deep brain stimulation, none of which has displaced levodopa from the center of Parkinson management.
Key People
- George Cotzias — Neurologist who established high-dose oral levodopa as effective Parkinson therapy.
- Arvid Carlsson — Pharmacologist who showed in animal models that DOPA could reverse the motor effects of dopamine depletion.
- Oleh Hornykiewicz — Neurochemist who measured dopamine depletion in Parkinson postmortem brains.
N Engl J Med. 1967
Related landmarks
- 1965 · Methadone maintenance treatment for heroin addiction (Dole and Nyswander) (Neurology & Psychiatry)
- 1958 · Imipramine, the first tricyclic antidepressant (Kuhn) (Neurology & Psychiatry)
- 1952 · Chlorpromazine in psychosis (Delay & Deniker) (Neurology & Psychiatry)
- 1949 · Cade's lithium for mania (Neurology & Psychiatry)