Does Levodopa Increase Serotonin Levels?
No, levodopa does not increase serotonin levels—in fact, it decreases brain serotonin concentrations, and chronic use causes damage to the serotonin system.
Mechanism of Serotonin Depletion
Levodopa actively reduces serotonin through multiple mechanisms:
Acute depletion: Levodopa administration reduces both tryptophan (the serotonin precursor) and serotonin levels in the brain within 1-2 hours of administration 1
Chronic neurotoxicity: Long-term levodopa treatment causes oxidative stress that directly damages serotonin neurons, leading to decreases in both serotonin cell bodies within the dorsal raphe nucleus and serotonin neurotransmitter concentrations in forebrain regions 2
Structural damage: Chronic levodopa produces deficits in serotonin neurotransmission through actual loss of serotonergic neurons, not just functional changes 2
Clinical Evidence in Parkinson's Disease Patients
The relationship between levodopa and serotonin is complex and clinically significant:
Caudate-specific depletion: PD patients on levodopa demonstrate marked serotonin loss in the caudate nucleus (though interestingly not in the putamen) compared to controls 3
Preserved serotonin terminals paradoxically worsen dyskinesias: Patients who develop levodopa-induced dyskinesias actually show relative preservation of serotonergic terminals, which allows these terminals to inappropriately convert levodopa to dopamine and release it as a "false neurotransmitter" 4, 5
Serotonin neurons hijack levodopa: The intact serotonin system takes up levodopa, converts it to dopamine, and releases dopamine in an unregulated manner, contributing to motor complications 4, 5
Therapeutic Implications
Understanding this serotonin-dopamine interaction has important clinical consequences:
Restoration strategy: When L-tryptophan (500 mg/kg) is co-administered with levodopa, it can restore serotonin levels to normal range without significantly altering the therapeutic increases in dopa and dopamine 1
Potential mechanism for mental side effects: The normalization of brain serotonin (not competitive reduction of dopamine) may be the basis for improvement in mental status when tryptophan is added to levodopa therapy 1
Serotonergic modulation for dyskinesias: Serotonin receptor type 1A agonists like buspirone can reduce levodopa-evoked striatal dopamine increases and attenuate dyskinesias by modulating the aberrant serotonin-mediated dopamine release 4
Common Pitfall to Avoid
Do not assume that serotonin supplementation or serotonergic drugs will interfere with levodopa's therapeutic dopaminergic effects—the evidence shows that restoring serotonin can actually improve tolerability without compromising motor benefit 1. However, be aware that SSRIs have been associated with REM sleep behavior disorder in some case reports, though this relationship remains controversial 6.