Levodopa becomes standard treatment

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

W. Birkmayer and O. Hornykiewicz for the 1961 trial; G. C. Cotzias with M. H. Van Woert and L. M. Schiffer (N Engl J Med, February 1967) for the oral regimen.

What happened

After dopamine was found missing in the brain (landmark 1), Hornykiewicz reviewed in 2010 how a replacement was tried: "in 1961, the first highly successful clinical trial with i.v. levodopa was carried out", and in 1967 "the chronic, high dose oral levodopa regimen was introduced". The 1961 paper is titled in German ("The L-DOPA effect in Parkinson akinesia", Wien Klin Wochenschr). Cotzias's 1967 paper is titled "Aromatic amino acids and modification of parkinsonism". It was a controlled trial (it appears as a clinical trial in PubMed) of oral D,L-dopa, a mixture of both mirror forms (a 1971 paper's reference list labels it so). The 1969 follow-up by Cotzias, Papavasiliou and Gellene reported chronic treatment with L-dopa itself (N Engl J Med 1969;280:337–345, DOI 10.1056/NEJM196902132800701). So the 1967 date marks the oral high-dose regimen; pure levodopa followed in 1969.

Why it moved us toward a cure

It gave the field its first proof that Parkinson's symptoms can be reversed by acting on a known chemical defect. That justified the whole dopamine-replacement approach that came later, including graft trials (landmark 3). It also sets the baseline against which every new drug is compared, and it raised the question of whether levodopa itself helps or harms the disease course. That question was tested in ELLDOPA (landmark 161) and LEAP (landmark 166). LEAP found no difference at 80 weeks.

Outcome

Advanced. Levodopa is still the most effective symptom treatment, but it has not been shown to slow the disease. Long-term use brings movement complications (not covered in the sources read here).

Sources

• Hornykiewicz, "A brief history of levodopa", J Neurol 2010;257(Suppl 2):S249-52, DOI 10.1007/s00415-010-5741-y, PMID 21080185 (abstract)
• Birkmayer & Hornykiewicz, Wien Klin Wochenschr 1961;73:787-788, PMID 13869404 (title only; no abstract)
• Cotzias, Van Woert & Schiffer, N Engl J Med 1967;276:374-379, DOI 10.1056/NEJM196702162760703, PMID 5334614 (title only; no abstract)
• Cotzias, Papavasiliou & Gellene, N Engl J Med 1969;280:337-345, DOI 10.1056/NEJM196902132800701, PMID 4178641 (citation only)
• Schmidt & Greer, "Levodopa and relief of parkinsonian symptoms", Arq Neuropsiquiatr 1971 (reference list only: calls Cotzias 1967 oral D,L-dopa)
• Not yet verified: the number of patients and doses in either paper (a search summary of an unnamed historical article gave 17 patients and a 16 g top dose; not checked); the size of the benefit; the "no slowing" statement beyond ELLDOPA/LEAP results as summarised in this project.