Long-term daily repeated intake of traditional levodopa (L-dopa)/dopa decarboxylase inhibitor (DDI) formulations increases the homocysteine synthesis in plasma of Parkinson's disease patients with unforeseen consequences, like an augmented vulnerability for onset of concomitant non-motor symptoms. Homocysteine decrease may therefore be a future therapeutic challenge, which may be achieved by supplementation with certain vitamins or by combination of a catechol-O-methyltransferase (COMT) inhibitor with L-dopa/DDI administration. Monitoring of plasma homocysteine concentration may also serve as biomarker for the detoxification potential of endogenous, exogenous, and environmental toxins. These substrates may also accumulate in the nervous system, since homocysteine formation is associated with O-methylation which has a broad detoxification potential.