Glutathione: A Review on Dosing via Various Routes of Administration

Glutathione in its reduced form (GSH) has been studied for a variety of conditions due to its mechanism of action as an antioxidant that can scavenge reactive oxygen species.¹ Glutathione is an endogenous antioxidant that is part of a redox pair. Oxidized glutathione is abbreviated to GSSG representing the link formed at the sulfur atom as the product is oxidized. When glutathione is supplemented, the reduced form (GSH) is used. The USP monograph for glutathione corresponds with L-glutathione reduced. The importance of glutathione for the management of reactive oxygen species and the link between low glutathione and a variety of conditions have led to the product being studied for an extremely wide range of indications including Parkinson’s disease, cystic fibrosis, autism spectrum disorder (ASD), and hyperpigmentation among others.^1-5  

Intravenous Dosing

Glutathione has been studied via the intravenous route for a variety of conditions. One study on glutathione 1200mg IV twice weekly for six weeks found a benefit over placebo for skin lightening, but these benefits faded after six months. Generally, given data regarding topical or oral use for this condition and the inherent safety risks of IV use, this route of administration is not common for hyperpigmentation.³ Glutathione has also been studied IV for Parkinson’s disease.⁶ One placebo-controlled trial evaluated 1,400mg administered three times per week for four weeks in patients with Parkinson’s disease. Though treatment was well tolerated, the benefit was noted to be mild. The study was small (only 11 patients total in the treatment group) so authors conclude that larger trials are needed to determine clinical or statistical significance.⁷  Another study of 600mg twice daily for 30 days in patients with early Parkinson’s disease not currently on other treatments, found a 42% decline in disability, with a therapeutic impact extended for two to four months after treatment cessation.⁸

Glutathione has also been evaluated via the intravenous route for treatment of chronic fatty liver disease. One study of chronic steatotic liver disease unrelated to alcohol or hepatitis viral infection noted that intravenous administration with 1800mg/day of glutathione improved some measures of hepatic health such as bilirubin levels.⁹ Another study on glutathione in patients with chronic alcoholic liver disease treated patients with 1800mg/day glutathione intravenously for 10 days, followed by 600mg of glutathione intramuscularly every day for 20 days. At the end of the 30 total days of treatment, patients had significant reductions in serum hepatic enzymes.^14,15

The role of glutathione as a potential adjuvant for prevention of chemotherapy induced neurotoxicity has also been evaluated. One study, aiming to evaluate the potential of glutathione to prevent neurotoxicity associated with cisplatin, studied a 1.5g/m² glutathione in 100mL normal saline over 15 minutes, followed by 600mg intramuscular doses on days two to five after cisplatin administration. The study evaluated patients after nine weeks of treatment with cisplatin alone or with cisplatin and glutathione. It found that no patients in the glutathione treatment arm demonstrated clinically relevant neuropathy, whereas 16 of the 18 patients in the cisplatin alone group did. After the 15^th week of the study, four of the 24 patients in the glutathione group went on to develop neurotoxicity compared to 16 of 18 still reporting neurotoxicity in the placebo group.¹³

Note: Intravenous dosing for various conditions is most commonly between 600-1,800mg per dose with varying administration schedules. For some conditions, initial IV dosing is followed up with regular IM injections.

Intramuscular Dosing

Data on glutathione via injectable routes is mainly on intravenous dosing, but limited studies have evaluated glutathione intramuscularly as well. One small placebo-controlled, double-blind, crossover trial looking to measure the impact of glutathione on sperm had patients administer 600mg of glutathione intramuscularly every other day for two months. The study noted that treatment with glutathione led to improvement in sperm motility and morphology in their small sample of 20 patients.^10,11 Intramuscular use is also sometimes used to continue therapy after initial treatment via the IV route. The study on glutathione in patients with chronic alcoholic liver disease treated patients with 1800mg/day glutathione intravenously for 10 days, followed by 600mg of glutathione intramuscularly every day for 20 days. At the end of the 30 total days of treatment, patients had significant reductions in serum hepatic enzymes.^14,15  The study on glutathione for neurotoxicity had patients initially use IV glutathione before continuing with 600mg IM doses for several days.¹³ Other protocols for the use of glutathione, generally for age related disease, sometimes start intramuscular dosing at just 200mg per week and increase as tolerated up to a maximum of 1000mg per week. However, these protocols have yet to be evaluated in published literature.  

Note: Intramuscular dosing is typically between 200-600mg per dose and is sometimes used as long term treatment after initial IV therapy.

Inhalation Dosing

Glutathione has been studied in a limited capacity for cystic fibrosis via direct inhalation. Studies have noted depletion of glutathione in the extracellular lining of the lungs in patients with cystic fibrosis. One placebo-controlled trial in patients eight years of age or older evaluated the impact of glutathione 646mg in 4mL every 12 hours for six months vs placebo on markers of lung function. The study, unfortunately, did not note significant benefits with this dosing over placebo markers of lung function. However, the glutathione group did demonstrate a trend towards improved forced expiratory volume (FEV1).¹² Though a statistically significant benefit was not demonstrated in that study, other studies looking at similar dosing have noted statistically significant benefit. One study of glutathione 10mg/kg (up to a maximum of 600mg per dose in 8mL of water) twice daily for 12 months evaluated the treatment in both pediatric and adult patients. In pediatric patients there was no statistically significant benefit, but in adult patients FEV1 values were significantly improved starting at three months, and the benefit persisted at the six- and nine-month evaluations.¹⁶

In addition to studies on glutathione for cystic fibrosis, it has also been studied for rhinosinusitis. One small study in 13 patients of glutathione 600mg daily for 10 days found increased glutathione levels in the nasal mucosa accompanied by improvements in nasal obstruction, rhinorrhea, and ear fullness.¹⁷  

Note: Inhalation dosing is typically 600mg/dose in 4-8mL of water.

Intranasal Dosing

Though much of the data for glutathione in Parkinson’s disease is on the IV route. Some studies have looked at intranasal doing at 300mg or 600mg daily as well.⁶ One study of 100mg glutathione or 200mg glutathione nasally three times daily for three months did not note benefit over placebo, though, the study noted greater than typical improvement in the placebo group as well, which researchers noted may have acted as a confounding factor.¹⁸ Other studies of high quality (randomized placebo-controlled trials) have noted benefit with these same doses with regards to measurements of Parkinson’s disease severity such as the Unified Parkinson’s Disease Scale Rating (UPDRS) which assess mentation, behavior, mood, activities of daily living, and motor skills among other areas impacted by Parkinson’s disease. One study of 30 patients on nasal glutathione dosed at either 300mg or 600mg daily in three divided doses vs placebo over a three month period found significant improvement in UPDRS scores in the treatment arms over placebo while other measures of toxicity such as cell counts, liver enzymes, creatinine, blood urea nitrogen, and urinalysis were not significantly different between placebo and treatment groups.¹⁹ Some researchers have posited the potential utility of nasal glutathione in other neurodegenerative diseases such as Alzheimer’s Disease, however, studies are not yet available evaluating glutathione as a potential treatment.²⁰

Note: Intranasal dosing is typically between 300-600mg/daily in divided doses, often 100-200mg three times daily.

Oral and Sublingual Dosing

Oral supplementation with glutathione has been shown to increase levels of glutathione in the body; doses between 250-1000mg a day have demonstrated significant increases in glutathione levels. In association with this increase in glutathione levels, a reduction in oxidative stress was noted. Increases in glutathione returned to baseline within a month of cessation of oral therapy.²¹ Glutathione has been studied orally for a variety of conditions; 500mg orally daily has been associated with improvement in hyperpigmentation and reduction in Melasma Area and Severity Index (MASI) score.³ Although limited data supports the use of glutathione via the IV route for liver health, one study of glutathione 500mg per day in combination with pyridoxine HCl 50mg per day found supplementation not to significantly improve severity of liver cirrhosis.²²

In addition to studies on inhaled glutathione for cystic fibrosis, a secondary study on glutathione oral supplementation at 65mg/kg/day in pediatric patients with cystic fibrosis noted supplementation via the oral route to improve growth status and gut inflammation. Measures of lung health such as FEV₁ were not evaluated as part of the study.²³

Oral supplementation has also been studied in obese patients with or without type II diabetes to determine the impact on insulin sensitivity. In this double-blind placebo-controlled trial, patients were given 1000mg glutathione daily or placebo for three weeks. In the treatment group oral supplementation was found to improve insulin sensitivity, but not general markers of oxidative stress.²⁴

In addition to oral use, glutathione has been studied in a limited capacity sublingually as well. Given the decreased exposure to first-pass metabolism, glutathione has superior bioavailability buccally or sublingually as compared to the oral route. One study on glutathione 300mg twice daily for two months in patients with chronic obstructive pulmonary disease (COPD) found that supplementation increased levels of antioxidant biomarkers, though, decreases in inflammatory mediators such as IL-8 or TNF Alpha did not reach the level of statistical significance, despite a downward trend.²⁶

Note: Oral dosing varies wildly but is typically between 250-1000mg daily. Limited studies have evaluated sublingual dosing; one study looked at 300mg twice daily.

Topical/Transdermal Dosing

One study evaluated topical glutathione 2% compared to 500mg oral glutathione daily for management of hyperpigmentation. Improvement was more significant in the oral glutathione treatment groups as compared to the topical, but both treatments were superior to placebo for reduction of MASI score.⁴ Another double-blind, placebo-controlled clinical trial evaluated 2% glutathione lotion. Participants applied glutathione 2% to half of their face, and placebo to the other half twice daily for 10 weeks. The melanin skin index was significantly lower in the glutathione treated group at 10 weeks. Additionally, improved skin smoothness and moisture content in the skin was noted in the treatment group.⁵

In addition to cosmetic uses, glutathione has been studied for topical application for systemic use as well, especially in the context of management of autism spectrum disorder (ASD). One study compared glutathione 50-200mg/30lbs twice daily vs glutathione up to 180mg transdermal two to three times daily as tolerated for patients with ASD. This study did not evaluate any behavioral parameters but did see benefits in some serum markers that are noted to be irregular in patients with ASD.²⁵

Note: Topical concentration for hyperpigmentation is typically 2%. Insufficient data exists on transdermal dosing, but one study evaluated up to 180mg two to three times daily.

References:

1. Mischley L, Lau R, Shankland E, Wilbur T, Padwoski J. Phase IIb Study of Intranasal Glutathione in Parkison’s Disease. Journal of Parkinson’s Disease. 2017; 7: 289-299.  

2. Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011;17(12):CR677-CR682. doi:10.12659/msm.882125

3. Sarkar R, Yadav V, Yadav T, P J, Mandal I. Glutathione as a skin-lightening agent and in melasma: a systematic review. Int J Dermatol. Published online October 23, 2024. doi:10.1111/ijd.17535

4. Al-Saimaa A, Farahat M, El-Garhy L et al. Evaluation of the efficacy and safety of topical and oral glutathione in the treatment of melasma. Med J Cairo Univ. 2018; 86(6): 3083-3092.  

5. Watanabe F, Hashizume E, Chan G, Kamimura A. skin-whitening and skin-condition-improvingeffects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trialin healthy women. Clinical, Cosmetic, and Investigational Dermatology. 2-14; 7: 267-274.

6. Wang HL, Zhang J, Li YP, Dong L, Chen YZ. Potential use of glutathione as a treatment for Parkinson's disease. Exp Ther Med. 2021;21(2):125. doi:10.3892/etm.2020.9557

7. Hauser RA, Lyons KE, McClain T, Carter S, Perlmutter D. Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson's disease. Mov Disord. 2009 May 15;24(7):979-83. doi: 10.1002/mds.22401. PMID: 19230029.

8. 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 Oct;20(7):1159-70. doi: 10.1016/s0278-5846(96)00103-0. PMID: 8938817.

9. Dentico P, Volpe A, Buongiorno R, Grattagliano I, Altomare E, Tantimonaco G, Scotto G, Sacco R, Schiraldi O. Il glutatione nella terapia delle epatopatie croniche steatosiche [Glutathione in the treatment of chronic fatty liver diseases]. Recenti Prog Med. 1995 Jul-Aug;86(7-8):290-3. Italian. PMID: 7569285.

10. Majzoub, Ahmad; Agarwal, Ashok1,*. Antioxidant therapy in idiopathic oligoasthenoteratozoospermia. Indian Journal of Urology 33(3):p 207-214, Jul–Sep 2017. | DOI: 10.4103/iju.IJU_15_17

11. Lenzi A, Culasso F, Gandini L, Lombardo F, Dondero F. Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility. Hum Reprod. 1993 Oct;8(10):1657-62. doi: 10.1093/oxfordjournals.humrep.a137909. PMID: 8300824.

12. Griese M, Kappler M, Eismann C et al. Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial. American Journal of Respiratory and Critical Care Medicine. 2014; https://doi.org/10.1164/rccm.201303-0427OC   

13. Cascinu S, Cordella L, ferro E et al. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. Journal of Clinical Oncology. 1995; 13(1): https://doi.org/10.1200/JCO.1995.13.1.26

14. Chakravorty S, Malvi A, Chaturvedi A et al. Glutathione – the master antioxidant. IJMRPS. 2020; 7(2): DOI- 10.5281/zenodo.3700161

15. Bettini, R.; Azimonti, R.; Mairani, E.The use of reduced glutathione in alcoholic liver disease. Gazzetta Medica Italiana Archivio per le ScienzeMediche.1993;152(4): 117-120

16. Calabrese C, Tosco A, Abete P. Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis. Journal of Cystic Fibrosis. 2015; 14(2): 203-210.  

17. Testa B, Mesolella M, Testa D, Giuliano A, Costa G, Maione F, Iaccarino F. Glutathione in the upper respiratory tract. Ann Otol Rhinol Laryngol. 1995 Feb;104(2):117-9. doi: 10.1177/000348949510400205. PMID: 7857012.

18. 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

19. Mischley LK, Leverenz JB, Lau RC, et al. A randomized, double-blind phase I/IIa study of intranasal glutathione in Parkinson's disease. Mov Disord. 2015;30(12):1696-1701. doi:10.1002/mds.26351

20. Lana JV, Rios A, Takeyama R, Santos N, Pires L, Santos GS, Rodrigues IJ, Jeyaraman M, Purita J, Lana JF. Nebulized Glutathione as a Key Antioxidant for the Treatment of Oxidative Stress in Neurodegenerative Conditions. Nutrients. 2024; 16(15):2476. https://doi.org/10.3390/nu16152476  

21. Richie, J.P., Nichenametla, S., Neidig, W. et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr 54, 251–263 (2015). https://doi.org/10.1007/s00394-014-0706-z

22. Lai C-Y, Cheng S-B, Lee T-Y, Hsiao Y-F, Liu H-T, Huang Y-C. Impact of Glutathione and Vitamin B-6 in Cirrhosis Patients: A Randomized Controlled Trial and Follow-Up Study. Nutrients. 2020; 12(7):1978. https://doi.org/10.3390/nu12071978

23. Visca A, Bishop C, Hilton S, Hudson V. Oral reduced L-glutathione improves growth in pediatric cystic fibrosis patients. JPGN. 2015; https://doi.org/10.1097/MPG.0000000000000738

24. Sondergard S, Cintin I, Kuhlman A et al. The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: a randomized trial. Applied Physiology, Nutrition, and Metabolism. 2021. 46(9): https://doi.org/10.1139/apnm-2020-1099

25. Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011;17(12):CR677-CR682. doi:10.12659/msm.882125

26. Farag A, Abass W, Qassem H. Evaluation of the antioxidant and anti-inflammatory effect of sublingual glutathione on COPD patients. J Med Life. 2023;16(12):1796-1801. doi:10.25122/jml-2023-0161

‍