Is glutathione the elephant in the room when it comes to finding effective treatment for Parkinson’s disease? That was the question posed by a group of experts from the University of Medicine and Dentistry of New Jersey in a review paper in 2008. By the time of the study, the data supporting a potential role for glutathione supplements in Parkinson’s disease treatment had been mounting for almost two decades, piquing the interest of researchers, patients and practitioners alike. The antioxidant activity of glutathione was well-established in the field, but the reviewers also highlighted more recent evidence of the functional role of glutathione in a variety of additional processes in the central nervous system. Critically, these include the removal of peroxides and other toxins, the regulation of protein function and synthesis, the modulation of DNA synthesis and repair, the transportation of amino acids, and the cellular communications facilitated by glutamate receptors and hormonal signaling. The authors of the review believed that these factors, taken together, could account for the consistent demonstration that the levels of glutathione in the substantia nigra (a part of the brain with a role in both reward and movement) were 40 to 50 percent lower in patients with Parkinson’s disease. Replenishing and maintaining glutathione levels through supplementation, they suggest, could therefore prevent further damage in patients struggling with the effects of Parkinson’s.
In the decade since that review was published, the in vitro evidence that a glutathione supplement could make a difference for Parkinson’s disease patients has only grown stronger. Not only have cell-based studies continued to support the hypothesis that glutathione can play a functional role in opposing the pathophysiological processes associated with Parkinson’s disease, but there are also new studies that combine lab-based evidence with measurements of patient outcome measures to solidify connections between glutathione levels and disease symptoms. As yet, there have only been a few direct clinical trials on glutathione supplements for Parkinson’s disease patients, and they have produced less definitive evidence. However, the most recent trial from 2017 highlights some of the opportunities for future exploration and suggests that patients may realize therapeutic benefits.
The Latest Laboratory Evidence on the Potential Effectiveness of Glutathione Supplements for Parkinson’s Disease Patientsrecent contributions came from a group of researchers from Thomas Jefferson University in Philadelphia, who published a relevant study in the journal PLoS One in 2016. These researchers were focusing on the role of n-acetyl-cysteine (NAC), the precursor to glutathione, in protecting midbrain dopamine neurons. They found that in a tissue culture model of Parkinson’s disease, exposure to NAC led to higher levels of dopamine transmitter binding in two parts of the brain involved in Parkinson’s disease pathophysiology: the caudate and the putamen. Specifically, the glutathione level was 4.4 percent higher in the caudate and 7.8 percent higher in the putamen, both of which are considered to be statistically significant improvements. This suggests that the conversion of NAC to glutathione may help support the functioning of the dopamine system in patients with Parkinson’s disease, which has been associated with both the physical and the motor effects of the condition.
Another relevant contribution came out of a collaboration by researchers at the University of Washington, Washington State University, and the nearby Bastyr University Research Institute. Building on previous cellular-level research linking oxidative stress to the development of Parkinson’s disease progression, they sought to describe associations between glutathione status, age, and Parkinson’s disease severity, in an attempt to establish a more solid connection between glutathione status and patient symptoms.
In a study of blood samples from 58 Parkinson’s disease patients, they found that glutathione levels not only declined with age, but they were also correlated with statistically significant improvements in scores on the Unified PD Rating Scale (UPDRS), which is commonly used to measure Parkinson’s disease severity based on patients’ symptoms, as well as the Patient-Reported Outcomes in PD, another symptom-based scale. This evidence supported their conclusion that serum levels of glutathione could serve as an effective biomarker for Parkinson’s disease. Moreover, the data suggested that glutathione status could be a “modifiable risk factor” for Parkinson’s disease, warranting clinical trials on glutathione supplements in the future.
Clinical Trials: Mixed Evidence and Opportunities for Future Design Improvements
While there is now three decades’ worth of solid laboratory evidence suggesting that a glutathione supplement could help reduce symptoms in patients with Parkinson’s disease, the results from the few clinical studies that have been conducted are somewhat less convincing. So far, a total of four clinical trials have been published, with the most recent coming in 2017 from the same research group that published the previously-discussed investigation on using glutathione as a biomarker for Parkinson’s disease. This time, they conducted a double-blind, placebo-controlled trial, in which 45 individuals with mild to moderate Parkinson’s disease receive intranasal glutathione supplements.
The participants were assigned to one of three groups: a control group, in which participants received a placebo, or one of two treatment groups, in which participants received intranasal glutathione supplements of either 100mg or 200mg, three times daily for three months. To measure the effects, they again used the UPDRS to quantify patient outcomes. In the low dose treatment group, the researchers reported score improvements, but they were not statistically significant. In the high-dose treatment group, they reported statistically significant improvements in the total score, the motor subscore, and even the non-motor subscore. However, it is important to note that the statistical analysis indicated that the statistical significance of the score improvements was much stronger in the placebo group than it was in either one of the treatment groups. Therefore, the researchers were able to demonstrate that intranasal glutathione supplements could have a positive impact on patient symptoms, but they failed to demonstrate that these effects were distinct from placebo effects.
The results from the other three clinical trials have been similarly mixed, and several did not use the rigorous, controlled-trial methodology that was used in the 2017 study, so it is unwise to integrate or compare results. Nevertheless, it is clear that a placebo effect may be impacting the clarity of the results in each of the study. For instance, in both the 2017 study and another open-label study from 1996, there was a heavy emphasis on the ritual of glutathione administration (which, for the 2017 study, involved tilting the head back and inhaling deeply). These types of treatment administration rituals are well-known to be associated with placebo effects, since regular rituals associated with medication administration may have psychological impacts on patients. For this reason, more researchers are looking to tweak the methodology of future studies in order to obtain more conclusive, reliable results on the potential effectiveness of glutathione supplements.
Evidence from NAC Supplement Studies
Currently, researchers are looking to preliminary studies on NAC to justify ongoing clinical trials of glutathione supplements, as NAC is converted to glutathione in the body. Alongside their in vitro study, the Thomas Jefferson University-based research group also conducted a randomized trial in which patients were treated with either NAC for three months or received no treatment. This precluded any placebo effect, and it produced promising results. Overall, the researchers found that the intervention led to an increase in dopamine transmitter binding and a 13 percent improvement on UPDRS rating scale scores. Although they could not provide definitive proof that these findings were linked, their data offer further support for additional clinical trials on both NAC and glutathione as supplements that could prove beneficial for Parkinson’s disease patients.
In the coming years, it will be exciting for researchers to build on lab-based evidence in well-designed, large-scale clinical trials. For patients and practitioners today, it may still be worth considering a glutathione supplement as a therapy for Parkinson’s disease patients. The evidence from clinical trials remains inconclusive, but the strong evidence from the lab suggests that the effects could be significant for some patients.
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