The two faces of L-DOPA: benefits and adverse side effects in the treatment of Encephalitis lethargica, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis

doi:10.1016/S0306-9877(03)00318-9

Medical Hypotheses

Volume 62, Issue 2, February 2004, Pages 177-181

https://doi.org/10.1016/S0306-9877(03)00318-9 Get rights and content

Abstract

Parkinson’s disease, encephalitis lethargica, multiple sclerosis and amyotrophic lateral sclerosis patients all display two distinct types of symptoms. Some of these are due directly to a deficiency of dopamine and are quickly reduced by laevodihydroxyphenylalanine (L-DOPA). The second set, however, are the result of neurological damage caused by metabolites of dopamine, which include dopachrome and other chrome indoles that are both hallucinogenic and neurotoxic. If this hypothesis is correct, three corollaries follow. Patients of all four disorders should display excessive oxidative stress, natural methyl acceptors should delay development and elevated antioxidant supplementation, given with L-DOPA, ought to prolong the “honeymoon” period in which the benefits of the drug out weigh its subsequent disadvantages. A literature review suggests that all three corollaries are probably correct.

Section snippets

Historical background

Parkinson’s disease was the first disorder in which specific neurochemical deficits were identified in particular brain regions. In the early 1960s, Barbeau and Sourkes in Montreal and Birkmayer and Hornykiewicz in Vienna provided strong evidence that the affected sections of the brains of Parkinson’s disease patients were receiving inadequate amounts of the neurotransmitter dopamine [1]. Since dopamine itself could not access the brain directly, its natural precursor,

Implications

The evidence just presented suggests that dopamine deficiency probably plays an important role, not just in Parkinson’s disease, but also in Encephalitis lethargica, multiple sclerosis and amyotrophic lateral sclerosis. However, attempts to correct such deficiencies with L-DOPA, especially at high dosages, while initially beneficial appear to quickly produce a wide range of negative side effects. This paper, seeks to explain why this is the case and how it may be possible to prevent or mitigate

Hypothesis

The most logical interpretation of the L-DOPA experience is that patients with untreated Parkinson’s disease, Encephalitis lethargica, multiple sclerosis and amyotrophic lateral sclerosis all display two distinct types of symptoms. Some of these are due directly to a deficiency of dopamine and are quickly improved by L-DOPA. A second set of symptoms, however, are the result of neurological damage caused by the metabolites of dopamine. The use of L-DOPA, therefore, increases the severity of

Corollaries

If this hypothesis is correct, three corollaries must follow. Firstly, patients suffering from the four neurological disorders previously described should display evidence of excessive oxidative stress. Secondly, high doses of natural methyl acceptors should delay the development of these disorders. Thirdly, elevated antioxidant supplementation, given with L-DOPA, ought to prolong the “honeymoon” period in which the benefits of the drug outweigh its subsequent disadvantages.

Corollary one: oxidative stress

Encephalitis lethargica is a viral epidemic encephalitis that occurred in many parts of the world between 1915 and 1926. Also known as sleeping sickness or sleepy sickness, those who survived the initial infection typically displayed long term apathy, paralysis of the extrinsic eye muscles and extreme muscular weaknesses [5]. There is still disagreement over which virus was involved in this disease but the disorder often preceded Parkinsonism, suggesting that there must have been similarities

Corollary two: high doses of natural methyl acceptors may delay disorder development

If the oxidation products of dopamine, such as dopachrome and other chrome indoles, play key roles in the four neurological illnesses under discussion then it follows that high doses of natural methyl acceptors, such as thiamin (vitamin B₁), riboflavin (vitamin B₂), niacin (vitamin B₃) and ubiquinone (Coenzyme Q₁₀) should delay disorder progression. This is because they are capable of decreasing the conversion of dopamine to dopachrome and so preventing the toxic impacts of this and other

Corollary three: high dose antioxidant supplementation may mitigate the adverse side effects of L-DOPA

There is some evidence to suggest that high doses of antioxidants may reduce the oxidative stress caused by dopachrome and other toxic indoles that can be produced by the metabolism of L-DOPA. To illustrate, the Swank [29] diet, which is very elevated in the antioxidant vitamin A, has been shown to delay the progression of symptoms normally seen in multiple sclerosis patients. Indeed, high dose antioxidant supplementation is now recommended for such patients and has been shown to help normalize

Conclusions

At least part of the neurological damage seen in Encephalitis lethargica, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis appears to be caused by dopachrome and other chrome indoles, produced by the oxidation of dopamine. The use of L-DOPA in these patients probably accelerates production of such neurotoxins. If this hypothesis is correct, it follows that combining L-DOPA with very high dose antioxidants may permit the beneficial use of this drug in all four

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The two faces of L-DOPA: benefits and adverse side effects in the treatment of Encephalitis lethargica, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis

Abstract

Section snippets

Historical background

Implications

Hypothesis

Corollaries

Corollary one: oxidative stress

Corollary two: high doses of natural methyl acceptors may delay disorder development

Corollary three: high dose antioxidant supplementation may mitigate the adverse side effects of L-DOPA

Conclusions

Medical Hypotheses

Neuroscience

Free Radic Biol Med

J Neurol Sci

J Neurol Sci

Int J Biochem

Lancet

The L-DOPA story revisited. Further surprises to be expected

J Neural Transm Suppl

Aromatic amino acids and modification of Parkinsonism

N Engl J Med

Dopamine and disease

Can Med Assoc J