Glutathione 

Glutathione and Parkinsons

 

Parkinson’s disease is a progressive neurodegenerative disorder that is associated with the presence of Lewy bodies and the loss of dopaminergic neurons within the substantia nigra. We now know that oxidative stress is a significant contributor to the pathogenesis of Parkinson’s disease. Additionally, research suggests that glutathione, a thiol tripeptide that is involved in the scavenging of reactive oxygen species, may play a crucial role in protecting dopaminergic neurons from oxidative stress. As a result, glutathione is currently being investigated as a potential therapeutic agent in the treatment of Parkinson’s disease.

 

The reduced form of glutathione plays a critical role in the substantia nigra, where it serves as a mediator of oxidative stress. Research demonstrates lower levels of glutathione in the substantia nigra of postmortem Parkinson’s disease patients relative to age-matched controls, while glutathione levels in other parts of the brain remained unchanged.1 Glutathione levels in the substantia nigra of patients with other neurodegenerative diseases involving the basal ganglia, such as Supranuclear Palsy and Multiple System Atrophy, were not altered, suggesting that lower glutathione levels in the substantia nigra is, in fact, a feature of Parkinson’s disease and not necessarily of neurodegenerative disorders in general.

 

Because of glutathione’s ability to protect the brain from oxidative stress-induced damage and because of the facts that glutathione levels are depleted early in the course of Parkinson’s and the glutathione levels appear to be inversely related to disease severity, researchers hypothesized that glutathione may be an efficacious therapy in the treatment of Parkinson’s disease. While studies regarding glutathione and Parkinson’s are comparatively limited, we do have some data on the intranasal and intravenous routes of administration.

 

In a randomized, double-blind, placebo-controlled trial involving intranasal glutathione at two different dosages (100 mg and 200 mg) and a saline control, each administered three times per day for three months, all cohorts improved during the intervention period.2 This included the placebo group. The 200 mg glutathione group did experience improvements in the total Unified PD Rating Scale (UPDRS) and UPDRS motor subscore over baseline, but neither treatment group was superior to placebo. Researchers concluded that larger studies that were longer in duration were necessary to elucidate whether or not intranasal glutathione is superior to placebo in the treatment of Parkinson’s disease.

 

In an open-label, small-scale study where researchers administered 600 mg of intravenous glutathione twice daily for 30 days to early-stage, treatment-naïve Parkinson’s patients, all nine of the patients improved during the course of the study with a 42% decline in disability.3 These benefits lasted 2-4 months after discontinuation of the infusions.

 

Another study, a randomized, double-blind, placebo-controlled trial, administered 1400 mg of intravenous glutathione or placebo three times per week for four weeks to 20 individuals with Parkinson’s disease. At the end of the study, the changes in UPDRS scores weren’t significant, although the glutathione group did experience improvements in UPDRS ADL and motor subscores during the duration of the study. The glutathione group then saw a worsening of those scores in the 8 weeks directly following the study. Researchers noted that although the study results point to symptomatic effect with the administration of intravenous glutathione, larger studies are needed to draw more concrete conclusions.4

 

The differences in results between the two available studies on intravenous glutathione in the treatment of Parkinson’s disease may be attributable to a variety of different factors, including the fact that one study was open label while the other was a randomized clinical trial and the differences in the degree of disease progression between participants in the two studies. The open-label, uncontrolled nature of the first study makes its results less reliable than the first, while it is also highly likely that the recently-diagnosed, treatment-naïve nature of the individuals in the first study led to a more exaggerated response to the therapy.

 

Researchers remarked that limited transport of glutathione across the blood brain barrier and into the substantia nigra could be a potential explanation for the limited efficacy seen with the administration of glutathione in a condition like Parkinson’s which we know is associated with insufficient glutathione levels. Researchers are continually seeking to create forms of glutathione that would be transported more efficiently into the brain.5

 

Intravenous administration of glutathione was found to be safe. No participants withdrew from the study because of adverse effects, and reported adverse effects were similar to those reported in the placebo group.4

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Glutathione and Skin

 

Glutathione, a thiol tripeptide, has been utilized in the treatment of conditions of hyperpigmentation, such as melasma, lentigines, and post-inflammatory hyperpigmentation. Its anti-melanogenic properties may be due to inhibition of tyrosinase enzyme, skewing of melanogenesis from the darker eumelanin to the lighter phaeomelanin, and/or scavenging of free radicals.1 While glutathione has been used in oral, topical, and intravenous forms to accomplish these results, there are very few randomized, controlled trials to either support or discourage its use.

 

Two studies examined the efficacy of orally administered glutathione, one in the form of capsules and the other in the form of lozenges.2-3 Both studies reported decreases in melanin indices after 2-4 weeks of use. There were no serious adverse effects, although researchers noted that long-term safety had yet to be established.

 

A third study evaluated the efficacy of oxidized glutathione, administered topically.4 In this randomized, double-blind, matched-pair, placebo-controlled clinical trial, participants applied 2% oxidized glutathione lotion to one side of the face and placebo lotion to the other side twice daily for ten weeks. Researchers noted decreases in melanin indices on the side of the face treated with oxidized glutathione relevant to control, as well as increased moisture in the stratum corneum, suppression of wrinkle formation, and improvement in skin smoothness.

 

All three studies involving the oral and topical use of glutathione demonstrated objectively verifiable but reversible results on skin tone.

 

The fourth study was a placebo-controlled trial involving 50 participants, 25 in the treatment group and 25 controls. Researchers administered injections of a product called GSH Detox Forte to the 25 participants in the treatment group at a rate of two injections per week for 6 weeks, while the 25 participants in the control group received normal saline.5 The ingredients of the treatment product included aqua, glutathione 1200 mg, ascorbic acid, hydrolyzed collagen 35 mg, and sodium chloride.

 

Nine participants were excluded from the treatment group analysis during the course of the study because eight developed abnormal liver function and one experienced anaphylaxis. Their matched controls were also excluded, resulting in a total of 32 participants.

 

Researchers noted that six of the 16 participants in the treatment group experienced skin lightening by the Taylor scale. However, there are a few potential problems with this study. Firstly, three of the 16 participants in the control group also experienced similar results. Secondly, unlike evaluation with melanin indices using a Mexameter MX-18, the Taylor scale is visual and therefore highly subjective. Third, the treatment group had a very high dropout rate with nine of the original 25 participants in this group discontinuing. And finally, eight of the nine who dropped out discontinued because of abnormalities in liver function tests. Because of the fact that glutathione is commonly used to treat a variety of liver concerns and typically results in improvements in liver function tests,6 these abnormalities may be attributable to another ingredient in the product used or to some other cause.

 

There were no adverse effects noted with the use of oral or topical glutathione.2-4 In the only study available that evaluated the efficacy of intravenous glutathione for skin hyperpigmentation, adverse effects of liver function abnormalities and anaphylaxis were observed. However, as previously noted, there were some potentially confounding factors. Additional long-term, well-designed studies are required to draw more sound conclusions regarding the use of intravenous glutathione to address hyperpigmentation.

 

Reference List

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1. Sian J, Dexter DT, Lees AJ, Daniel S, Jenner P, Marsden CD. Glutathione- related enzymes in brain in Parkinson’s disease. Ann Neurol. 1994;36:356–361.

2. Mischley LK, Lau RC, Shankland EG, Wilbur TK, Padowski JM. Phase IIb Study of Intranasal Glutathione in Parkinson's Disease. J Parkinsons Dis. 2017;7(2):289–299. doi:10.3233/JPD-161040

3. Sechi G, Deledda MG, Bua G, Satta WM, Deiana GA, Pes GM, Rosati G. Reduced intravenous glutathione in the treatment of early Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20(7):1159-70.

4. Hauser RA, Lyons KE, McClain T, Carter S, Perlmutter D. Randomized, doubleblind, pilot evaluation of intravenous glutathione in Parkinson's disease. Mov Disord. 2009;24(7):979-83.

5. Smeyne M, Smeyne RJ. Glutathione metabolism and Parkinson's disease. Free Radic Biol Med. 2013;62:13–25. doi:10.1016/j.freeradbiomed.2013.05.001

6. Villarama CD, Maibach HI. Glutathione as a depigmenting agent: an overview. Int J Cosmet Sci. 2005;27:147–153.

7. Arjinpathana N, Asawanonda P. Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study. J Dermatolog Treat. 2012;23(2):97-102.

8. Handog EB, Datuin MS, Singzon IA. An open-label, single-arm trial of the safety and efficacy of a novel preparation of glutathione as a skin-lightening agent in Filipino women. Int J Dermatol. 2016;55(2):153-7.

9. Watanabe F, Hashizume E, Chan GP, Kamimura A. Skin-whitening and skin-conditionimproving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial in healthy women. Clin Cosmet Investig Dermatol. 2014;7:267–274.

10. Zubair S, Hafeez S, Mujtaba G. Efficacy of intravenous glutathione vs. placebo for skin tone lightening. J Pak Ass Dermatol. 2016;26:177–181.

11. Honda Y, Kessoku T, Sumida Y, et al. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. BMC Gastroenterol. 2017;17(1):96