Healthy cells require the correct balance between free radicals (reactive oxygen species, or ROS) and antioxidants. This equilibrium is called redox (oxidation reduction) homeostasis. To maintain this critical balance our cells naturally produce glutathione to detoxify free radicals and attenuate oxidative stress.
What is oxidative stress?
Oxidative stress is a phenomenon in the body caused by a disturbance in the balance between the production of free radicals and the cell’s ability to detoxify these products. Sufficient antioxidants are necessary to maintain the critical equilibrium between ROS production and scavenging. Accumulation of free radicals can result in damaged mitochondrial DNA and protein.
Glutathione is a tripeptide antioxidant consisting of three amino acids: cysteine, glycine and glutamine. Low levels are associated with several pathological health conditions due to the crucial role glutathione plays in shielding macromolecules from free radicals. However, like various other cellular constituents, glutathione concentration levels decrease due to aging, excessive toxic load and detrimental environmental factors.
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The Multifaceted Roles of L-Glutathione Supplementation*
L-Glutathione (GSH), a tripeptide composed of glutamate, cysteine, and glycine, is a ubiquitous, endogenous, and essential molecule in mammalian cells, renowned for its role as a potent antioxidant and regulator of cellular processes. As the most abundant low molecular weight thiol in animal cells, GSH is integral to detoxification, redox homeostasis, and cellular regulation, making it a focal point in health and disease research. (1) This literature review synthesizes current knowledge on GSH’s biological functions, pharmacokinetics, pharmacology, safety, and therapeutic potential, drawing from a broad range of animal and human studies.
Biological and Physiological Functions of L-Glutathione
GSH serves as a cornerstone of cellular antioxidant defense, neutralizing reactive oxygen species (ROS) and acting as a cofactor for enzymes, such as glutathione peroxidase (GSHPx), which converts hydrogen peroxide into water. (2) Its ability to scavenge free radicals and protect biological membranes from lipid peroxidation underscores its protective role in oxidative stress. (3) In addition to its antioxidant properties, GSH detoxifies xenobiotics, metals, and electrophilic compounds by conjugation, facilitating their excretion. (4) This dual functionality makes GSH a critical player in maintaining cellular health.
Recent research highlights GSH’s broader physiological roles, including protein glutathionylation, a post-translational modification that regulates processes such as apoptosis and vascularization. (5) GSH also supports amino acid transport, nucleic acid synthesis, and enzyme activity modulation while maintaining mitochondrial integrity and modulating immune responses. (6) These multifaceted roles suggest that GSH deficiency is implicated in oxidative stress-related diseases including neurodegenerative disorders, cancer, and cardiovascular diseases.* (7)
Pharmacokinetics of L-Glutathione Supplementation
The pharmacokinetics of GSH supplementation remains an area of ongoing investigation owing to some limitations related to oral bioavailability, which is attributed to its hydrophobicity and enzymatic degradation in the gastrointestinal tract. (8) Despite these limitations, oral GSH supplementation (1 g/day for 2 weeks) in humans suppressed exercise-induced blood lactate elevation and reduced fatigue, suggesting systemic absorption. In mice, a higher dose (2.0%, 5 μL/g body weight) prevented exercise-induced pH reduction in the muscle, further supporting bioavailability. (9) However, specific pharmacokinetic parameters, such as absorption rates and plasma half-life, necessitate further research to clarify the metabolic fate of GSH following GSH supplementation.
Pharmacology of L-Glutathione Supplementation
Pharmacologically, GSH supplementation has diverse effects on various physiological systems. In a 12-week trial, a combination of L-cystine (500 mg) and GSH (250 mg) daily lightened skin and reduced facial dark spots in Asian women more effectively than either compound alone. (10) This finding suggests a synergistic effect that enhances GSH’s dermatological benefits of GSH. In children with autism spectrum disorders, both oral and transdermal GSH supplementation increased plasma levels of sulfate, cysteine, and taurine, and oral supplementation also elevated reduced GSH levels, indicating potential metabolic benefits. (11)
Exercise performance studies further illustrate GSH’s pharmacological versatility of GSH. GSH supplementation in mice and humans improves lipid metabolism and reduces muscle acidification during exercise. (9) Conversely, high doses of LSD1 inhibitors depleted GSH in natural killer (NK) cells, impairing their function; this effect was reversed by GSH supplementation. (12) These findings highlight GSH’s context-dependent effects of GSH ranging from metabolic enhancement to immune modulation.
Safety and Toxicity of L-Glutathione Supplementation
GSH supplementation is generally considered safe and has a low-toxicity profile. Oral acute toxicity studies in mice have reported an LD50 exceeding 5 g/kg, indicating a substantial safety margin. (13) Human trials have reported no serious adverse effects, even with prolonged use. (10, 14) However, long-term safety in specific populations, such as those with chronic conditions such as inflammatory bowel disease, requires further investigation, as some studies suggest potential adverse effects during chronic treatment. (15) Overall, GSH’s endogenous production, as well as the biocompatibility of GSH (supplemented), reinforces its safety for supplementation within the tested limits.
Animal Trials of L-Glutathione Supplementation
Animal studies have provided robust evidence for GSH’s therapeutic potential. Oral GSH supplementation in BALB/c mice reduced UVB-induced oxidative stress and lipid peroxidation, highlighting the photoprotective effects of GSH. (16) In exercise models, GSH supplementation in mice increases mitochondrial DNA levels and improves lipid metabolism, suggesting benefits for muscle function. (9) Similarly, L-glutamine supplementation in rats enhanced the glutamine-glutathione axis, reducing oxidative stress and boosting heat shock protein expression during resistance exercise. (17)
Reproductive health studies have demonstrated GSH’s efficacy of GSH. GSH supplementation during cryopreservation improved sperm quality in Guanzhong dairy goats (18) and enhanced sperm quality and testicular morphology in diabetic mice. These findings underscore GSH’s protective role of GSH across diverse physiological contexts, ranging from oxidative stress mitigation to reproductive and metabolic health. (19)
Human Trials of L-Glutathione Supplementation
Human trials have revealed mixed but promising results. Oral GSH supplementation (500 mg twice daily for four weeks) in already healthy adults did not significantly alter oxidative stress biomarkers, suggesting limited efficacy in healthy populations. (20) In contrast, sublingual GSH outperformed oral GSH and N-acetylcysteine in improving plasma GSH levels and GSH/GSSG ratio in individuals with metabolic syndrome, emphasizing the importance of delivery methods. (21)
Dermatological applications show consistent benefits, such as skin lightening effects with combined L-cystine and GSH supplementation (10), corroborated by improvements in certain skin conditions. (22) Immune function studies have found that liposomal GSH supplementation elevates GSH levels and enhances immune markers, particularly in individuals with compromised immunity, such as those with type 2 diabetes. (14, 23) These findings suggest that GSH’s efficacy of GSH is population- and delivery-dependent, warranting tailored dietary supplementation strategies.
L-Glutathione in Disease Management*
GSH supplementation holds therapeutic promise for diseases characterized by oxidative stress.* In type 2 diabetes, long-term GSH supplementation reduced HbA1c and oxidative damage markers (24), while also enhancing immune responses.* (23) In cancer, GSH’s role of GSH is dual-edged; high levels in tumor cells can confer chemotherapy resistance (25), yet depletion strategies, such as those using BSO, enhance chemotherapeutic efficacy.* (26) GSH’s involvement of GSH in ferroptosis regulation further suggests its potential use in cancer therapy.* (27)
Patients with neurodegenerative and cardiovascular diseases also benefit from GSH.* GSH has been shown to have protective effects on brain endothelial cells, while also improving arterial stiffness in subjects with cardiovascular risk factors.* (28, 29) These studies highlight GSH’s broad therapeutic applicability, although its effectiveness varies according to the disease context and administration method.*
L-Glutathione in Mitochondrial Health, Aging, and Neuroprotection
GSH is critical for mitochondrial health, protection against reactive oxygen species (ROS), and supporting energy production. SLC25A39 has been identified as a key regulator of mitochondrial GSH transport, which is essential for cellular proliferation. (30) In aging, GlyNAC supplementation increased the mouse lifespan by 24%, correcting GSH deficiency and mitochondrial dysfunction. (31) Neuroprotection studies have shown GSH’s ability of GSH to reduce oxidative neuronal damage, while the addition of NAC supplementation improved cognition, suggesting GSH’s role of GSH in combating cognitive decline.* (16, 32)
L-Glutathione in Immune Function and Athletic Recovery
GSH enhances immune function by supporting lymphocyte activity and cytokine production.* (33) Supplementation of GSH in immunocompromised populations has immune-boosting effects.* (14, 23) Additionally, reduced muscle fatigue and improved aerobic metabolism were observed with GSH supplementation in healthy athletes, highlighting its role in mitigating exercise-induced oxidative stress and enhancing recovery. (9, 34)
Conclusion
L-Glutathione has emerged as a versatile therapeutic agent with significant potential in health and disease.* Its roles in antioxidant defense, detoxification, and cellular regulation, coupled with its favorable safety profile, make it a promising candidate for supplementation. While animal and human trials have demonstrated benefits in oxidative stress reduction, immune enhancement, and disease management, challenges related to bioavailability and context-dependent effects necessitate further research.* Optimal delivery methods and further research are key to unlocking the full therapeutic potential of GSH.
*This literature review has not been evaluated by the Food and Drug Administration, and therefore the information contained herein is not intended to diagnose, treat, cure, or prevent any disease. According to the FDA, only drugs can make those claims.
References
1. Wu, G., Yang, S., Fang, Y.-Z., Lupton, J. R. & Turner, N. D. Glutathione Metabolism and Its Implications for Health. The Journal of Nutrition 134, 489–492 (2004).
2. Pompella, A., Visvikis, A., Paolicchi, A., Tata, V. D. & Casini, A. F. The changing faces of glutathione, a cellular protagonist. Biochemical Pharmacology 66, 1499–1503 (2003).
3. Bray, T. M. & Taylor, C. G. Tissue glutathione, nutrition, and oxidative stress. Canadian Journal of Physiology and Pharmacology 71, 746–751 (1993).
4. Wang, W. & Ballatori, N. Endogenous Glutathione Conjugates: Occurrence and Biological Functions. Pharmacological Reviews 50, 335–355 (1998).
5. Dominko, K. & Đikić, D. Glutathionylation: a regulatory role of glutathione in physiological processes. Archives of Industrial Hygiene and Toxicology 69, 1–24 (2018).
6. Grant, C. M. & Dawes, I. W. Synthesis and role of glutathione in protection against oxidative stress in yeast. Redox report : communications in free radical research 2, 223–229 (1996).
7. Vairetti, M. et al. Changes in Glutathione Content in Liver Diseases: An Update. Antioxidants 10, 364 (2021).
8. Bhagavan, H. N. & Chopra, R. K. Coenzyme Q10: Absorption, tissue uptake, metabolism and pharmacokinetics. Free Radical Research 40, 445–453 (2006).
9. Aoi, W. et al. Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism. Journal of the International Society of Sports Nutrition 12, (2015).
10. Duperray, J., Perin, F., Tachalerdmanee, P., Chalothorn, K. & Sergheraert, R. The effects of the oral supplementation of L-Cystine associated with reduced L-Glutathione-GSH on human skin pigmentation: a randomized, double-blinded, benchmark- and placebo-controlled clinical trial. Journal of Cosmetic Dermatology 21, 802–813 (2021).
11. Kern, J. K. et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Medical Science Monitor 17, CR677–CR682 (2011).
12. Bailey, C. P., Figueroa, M., Gangadharan, A., Lee, D. A. & Chandra, J. Scaffolding LSD1 Inhibitors Impair NK Cell Metabolism and Cytotoxic Function Through Depletion of Glutathione. Frontiers in Immunology 11, (2020).
13. Weschawalit, S., Phutrakool, P., Thongthip, S. & Asawanonda, P. Glutathione and its antiaging and antimelanogenic effects. Clinical, Cosmetic and Investigational Dermatology 10, 147–153 (2017).
14. Sinha, R. et al. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. European journal of clinical nutrition 72, 105–111 (2017).
15. De Bruyne, E. et al. Oral glutathione supplementation drastically reduces Helicobacter-induced gastric pathologies. Scientific Reports 6, (2016).
16. Nagapan, T. S., Basri, D. F., Ghazali, A. R. & Lim, W. N. Oral supplementation of L-glutathione prevents ultraviolet B-induced melanogenesis and oxidative stress in BALB/c mice. Experimental Animals 68, 541–548 (2019).
17. Leite, J. S. M. et al. l-glutamine and l-alanine supplementation increase glutamine-glutathione axis and muscle HSP-27 in rats trained using a progressive high-intensity resistance exercise. Applied Physiology, Nutrition, and Metabolism 41, 842–849 (2016).
18. Zou, J. et al. Effect of Glutathione on Sperm Quality in Guanzhong Dairy Goat Sperm During Cryopreservation. Frontiers in Veterinary Science 8, (2021).
19. Abdullah, F. et al. Glutathione (GSH) improves sperm quality and testicular morphology in streptozotocin-induced diabetic mice. Asian journal of andrology 23, 281–287 (2021).
20. Allen, J. & Bradley, R. D. Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress Biomarkers in Human Volunteers. The Journal of Alternative and Complementary Medicine 17, 827–833 (2011).
21. Schmitt, B., Vicenzi, M., Garrel, C. & Denis, F. M. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biology 6, 198–205 (2015).
22. Dilokthornsakul, W., Dilokthornsakul, P. & Dhippayom, T. The clinical effect of glutathione on skin color and other related skin conditions: A systematic review. Journal of Cosmetic Dermatology 18, 728–737 (2019).
23. To, K. et al. Effects of Oral Liposomal Glutathione in Altering the Immune Responses Against Mycobacterium tuberculosis and the Mycobacterium bovis BCG Strain in Individuals With Type 2 Diabetes. Frontiers in Cellular and Infection Microbiology 11, (2021).
24. Kalamkar, S. et al. Randomized Clinical Trial of How Long-Term Glutathione Supplementation Offers Protection from Oxidative Damage and Improves HbA1c in Elderly Type 2 Diabetic Patients. Antioxidants 11, 1026 (2022).
25. Bansal, A. & Simon, M. C. Glutathione metabolism in cancer progression and treatment resistance. Journal of Cell Biology 217, 2291–2298 (2018).
26. Mattson, D. M. et al. Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism. Free Radical Biology and Medicine 46, 232–237 (2008).
27. Jiang, Y., Sun, M. & Glandorff, C. GSH and Ferroptosis: Side-by-Side Partners in the Fight against Tumors. Antioxidants (Basel, Switzerland) 13, 697 (2024).
28. Song, J. et al. Glutathione protects brain endothelial cells from hydrogen peroxide-induced oxidative stress by increasing nrf2 expression. Experimental Neurobiology 23, 93–103 (2014).
29. Campolo, J. et al. Medium-term effect of sublingual l-glutathione supplementation on flow-mediated dilation in subjects with cardiovascular risk factors. Nutrition 38, 41–47 (2017).
30. Wang, Y. et al. SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells. Nature 599, 136–140 (2021).
31. Kumar, P., Osahon, O. W. & Sekhar, R. V. GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage. Nutrients 14, 1114 (2022).
32. Hara, Y., Mckeehan, N., Dacks, P. A. & Fillit, H. M. Evaluation of the Neuroprotective Potential of N-Acetylcysteine for Prevention and Treatment of Cognitive Aging and Dementia. The Journal of Prevention of Alzheimer’s Disease 4, 1–6 (2017).
33. Dröge, W. & Breitkreutz, R. Glutathione and immune function. Proceedings of the Nutrition Society 59, 595–600 (2000).
34. Kwiatkowska, D. Effects of Supplementation with Glutathione and its Precursors on Athlete Performance. Biomedical Journal of Scientific & Technical Research 12, (2019).