Not long after COVID-19 became synonymous with the collapse of tourism, businesses and overburdened health systems, reports of people surfaced who suffered from a condition that became known as Long Covid. In essence, Long Covid is a lingering illness in people who have contracted COVID-19 and then presumably recovered because the virus was no longer detectable. Regardless of how severe the initial onset of COVID-19 manifested itself, a significant proportion of patients report debilitating symptoms long after the virus has been eliminated from their body ^[1].

An Irish study found that over 50% of patients with COVID-19 reported persistent fatigue more than 10 weeks after initial symptoms ^[2]. Likewise, researchers in Italy confirmed troublesome symptoms sixty days after initial onset ^[3]. The US Centers for Disease Control and Prevention similarly concluded ongoing symptoms such as fatigue and cough. They found this to be more prevalent in older people or those suffering from chronic diseases.

But is this a hallmark of SARS-CoV-2 and entirely unexpected? The short answer is no, because there is a range of viruses that cause post-infectious fatigue syndrome. Similar conditions have been reported for Ross River virus, Ebola virus, Dengue Fever virus and SARS coronavirus ^[1], just to name a few. Although the progression of disease and the organ damage they cause is quite different, chronic fatigue is a lingering condition they all share. Interestingly, the symptoms of post-infectious chronic fatigue are remarkably similar to those experienced by people who have Myalgic Encephalomyelitis, commonly known as Chronic Fatigue Syndrome . In fact, Dr Anthony Fauci, the Director of the National Institute for Allergy and Infectious Diseases, reported that patients who had COVID-19 often develop a post-viral syndrome that is remarkably like Chronic Fatigue Syndrome ^[4]. It is too early to tell how long this condition will last post-COVID-19.

The indirect cost of Chronic Fatigue Syndrome is staggering, up to 836 000 and 2.5 million individuals are affected in the United States alone before COVID-19 struck ^[5]. It remains to be seen how many additional cases will be added as a result of this pandemic.

So, what causes post-infectious chronic fatigue? We know that viruses such as SARS-CoV-2 can damage the heart, lungs or kidneys, and the impaired function of these organs would be sufficient to produce chronic fatigue.  Also, patients who have been on ventilators can suffer from post-traumatic stress disorder. Others may develop depression due to their reduced quality of life post-infection. It is highly likely that these psychiatric disorders also lead to chronic fatigue. However, many patients do not present with either physiological symptoms, such as organ damage, or psychiatric conditions and still suffer from post-infectious chronic fatigue ^[1].

To study this further, we can look at earlier research conducted on sufferers of Chronic Fatigue Syndrome. Even back in 1999, it was suspected that Chronic Fatigue Syndrome may have its roots in oxidative stress ^[6]. That lead to the conclusion that acute glutathione depletion may be involved. Some studies have revealed that glutathione is chronically depleted in some sufferers ^[7].

The role of glutathione in preventing oxidative stress is well understood. As an antioxidant, it performs many vital functions inside the cell. In the case of chronic fatigue, there appears to be a tug of war for this critical molecule. The immune system places great demands on glutathione when challenged, as is the case in Chronic Fatigue Syndrome. This can lead to competition for glutathione precursors since the muscular system also relies on glutathione for aerobic muscular contraction ^[8]. As the immune system takes priority in survival, insufficient glutathione may express itself as fatigue since skeletal muscles cannot sustain normal aerobic metabolism.

Time will tell how post-infectious chronic fatigue will progress in COVID-19 patients. It is hoped that further research will identify specific causes that lead to effective treatments. This may ultimately also relieve the symptoms of Chronic Fatigue Syndrome. Glutathione will most likely play a significant role in these studies, and an effective way to supplement cellular glutathione will be needed. Supplementation with gamma-glutamylcysteine has been demonstrated in a human clinical trial to increase cellular glutathione levels regardless of its initial (basal) concentration. And, most importantly, this increase occurred rapidly (within hours) ^[9]. With other supplements, a slight increase in glutathione (GSH) could only be observed after many months of daily supplementation. The recent commercial availability of gamma-glutamylcysteine means that researchers are now able to successfully test the effectiveness of increasing cellular glutathione (GSH) in treating the symptoms of Long Covid and Chronic Fatigue Syndrome.

References

1. Komaroff, A.L. and L. Bateman, Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Frontiers in Medicine, 2021. 7(1132)
   https://www.frontiersin.org/article/10.3389/fmed.2020.606824
2. Townsend, L., A.H. Dyer, K. Jones, J. Dunne, A. Mooney, F. Gaffney, L. O’Connor, D. Leavy, K. O’Brien, J. Dowds, J.A. Sugrue, D. Hopkins, I. Martin-Loeches, C. Ni Cheallaigh, P. Nadarajan, A.M. McLaughlin, N.M. Bourke, C. Bergin, C. O’Farrelly, C. Bannan, and N. Conlon, Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One, 2020. 15(11): p. e0240784.
   https://doi.org/10.1371/journal.pone.0240784
3. Carfì, A., R. Bernabei, and F. Landi, Persistent Symptoms in Patients After Acute COVID-19. Jama, 2020. 324(6): p. 603-605. 10.1001/jama.2020.12603.
4. Topol, E. and A. Verghese, Fauci to Medscape:‘We’re All In It Together and We’re Gonna Get Through It’. 2020, Medscape.
5. Clayton, E.W., Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An IOM Report on Redefining an Illness. JAMA, 2015. 313(11): p. 1101-1102.
   https://doi.org/10.1001/jama.2015.1346
6. Bounous, G. and J. Molson, Competition for glutathione precursors between the immune system and the skeletal muscle: pathogenesis of chronic fatigue syndrome. Med Hypotheses, 1999. 53(4): p. 347-9. 10.1054/mehy.1998.0780
7. Shungu, D.C., N. Weiduschat, J.W. Murrough, X. Mao, S. Pillemer, J.P. Dyke, M.S. Medow, B.H. Natelson, J.M. Stewart, and S.J. Mathew, Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed, 2012. 25(9): p. 1073-87. 10.1002/nbm.2772
8. JAMMES, Y., J.G. STEINBERG, O. MAMBRINI, F. BRÉGEON, and S. DELLIAUX, Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal of Internal Medicine, 2005. 257(3): p. 299-310.
   https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2005.01452.x
9. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5284489/pdf/main.pdf

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Low levels of glutathione are a hallmark in kidney disease and this is thought to be caused by diminished levels of an enzyme called GCL which is the first step in the production of cellular glutathione. This enzyme is responsible for the production of gamma-glutamylcysteine, the direct precursor to glutathione. Since cysteine is removed from the blood in dialysis patients, supplementing with cysteine has a positive effect on glutathione levels, however it only addresses a small part of the problem. The diminished levels of GCL are of much greater concern. To address this problematic enzyme in dialysis patients, supplementation with gamma-glutamylcysteine has been shown to bypass GCL altogether by providing cells with the first building block of glutathione.  Not only does gamma-glutamylcysteine readily enter cells, once inside it is quickly and easily converted to glutathione.[1]  [2, 3]

References

1. Alhamdani, M.S., Impairment of glutathione biosynthetic pathway in uraemia and dialysis. Nephrol Dial Transplant, 2005. 20(1): p. 124-8.
2. Santangelo, F., et al., Restoring glutathione as a therapeutic strategy in chronic kidney disease. Nephrology Dialysis Transplantation, 2004. 19(8): p. 1951-5.
3. Ashworth, A. and S.T. Webb, Does the prophylactic administration of N-acetylcysteine prevent acute kidney injury following cardiac surgery? Interact CardioVasc Thorac Surg, 2010. 11(3): p. 303-308.

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Complications in the cardiovascular system arise from elevated levels of free radicals which cause tissue damage and interrupt cellular signalling mechanisms [1]. Apart from lifestyle choices, there is a wide range of medical conditions that, by their nature, produce excessive free radicals, including diabetes, hypertension, stroke, and obesity. Whilst small bouts of increased levels of free radicals is normal, indeed required for signalling purposes and immune responses, it is the oxidative stress caused by sustained and excessive free radical production that leads to deleterious health outcomes [2].

Means to prevent this sustained damage caused by oxidative stress have been studies extensively and are of major therapeutic interest [3]. Whilst there is an abundance of pharmacological means to control chronic diseases such as diabetes or hypertension, reducing excessive production of free radicals from all possible sources presents a major challenge.

As the principal intracellular antioxidant, Glutathione has been extensively researched. This interest stems from numerous studies into chronic diseases in which elevated levels of free radicals cause sustained oxidative stress. Glutathione acts directly by scavenging free radicals and several studies have reported that patients with heart disease have lower levels of glutathione. Furthermore, a reduction of glutathione levels was also reported in subjects with asymptomatic CVD, which suggest that measuring and supplementing glutathione levels may help detect and treat such cases early. [1-9]

References

1. Bajic, V.P., et al., Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease. Oxid Med Cell Longev, 2019. 2019: p. 5028181.
2. Goszcz, K., et al., Antioxidants in Cardiovascular Therapy: Panacea or False Hope? Front Cardiovasc Med, 2015. 2: p. 29.
3. Li, H.G., S. Horke, and U. Forstermann, Oxidative stress in vascular disease and its pharmacological prevention. Trends in Pharmacological Sciences, 2013. 34(6): p. 313-319.
4. van der Pol, A., et al., Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail, 2019. 21(4): p. 425-435.
5. Mistry, R.K. and A.C. Brewer, Redox-Dependent Regulation of Sulfur Metabolism in Biomolecules: Implications for Cardiovascular Health. Antioxid Redox Signal, 2019. 30(7): p. 972-991.
6. Kanaan, G.N. and M.E. Harper, Cellular redox dysfunction in the development of cardiovascular diseases. Biochim Biophys Acta Gen Subj, 2017. 1861(11 Pt A): p. 2822-2829.
7. Go, Y.-M. and D.P. Jones, Cysteine/cystine redox signaling in cardiovascular disease. Free Radical Biology and Medicine, 2011. 50(4): p. 495-509.
8. Houston, M.C., Nutraceuticals, Vitamins, Antioxidants, and Minerals in the Prevention and Treatment of Hypertension. Progress in cardiovascular diseases, 2005. 47(6): p. 396-449.
9. Mills, B.J., et al., Blood glutathione and cysteine changes in cardiovascular disease. Journal of Laboratory & Clinical Medicine, 2000. 135(5): p. 396-401.

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Treatments that focus on enhancing the cellular antioxidant defense mechanism therefore play an important role in combating infertility and complications during pregnancy. Glutathione has shown to be the most effective antioxidant in the body due to its ability to not only boost the antioxidant defense, but also recycle other key antioxidant such as Vitamin C. ^[1-4]

References

1. Agarwal, A. and L.H. Sekhon, The role of antioxidant therapy in the treatment of male infertility. Human Fertility, 2010. 13(4): p. 217-225.
2. Adeoye, O., et al., Review on the role of glutathione on oxidative stress and infertility. JBRA Assist Reprod, 2018. 22(1): p. 61-66.
3. Ross, C., et al., A systematic review of the effect of oral antioxidants on male infertility. Reproductive biomedicine online, 2010. 20(6): p. 711-723.
4. Lanzafame, F.M., et al., Oxidative stress and medical antioxidant treatment in male infertility. Reproductive biomedicine online, 2009. 19(5): p. 638-659.

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Additionally, both type 1 and 2 diabetes are associated with low glutathione. [1-9] The resulting oxidative stress and depletion of the cellular antioxidant defense system contributes to the progress of coronary artery disease. This plays a major role in the development of diabetes and its ongoing complications.

Glutathione in its role as a free radical scavenger has been shown to drastically reduce the occurrence and duration of oxidative stress. Enhancing cellular glutathione is therefore of paramount importance in managing diabetes and reducing negative medical outcomes.

References

1. Whillier, S., P.W. Kuchel, and J.E. Raftos, Oxidative Stress in Type II Diabetes Mellitus and the Role of the Endogenous Antioxidant Glutathione, in Role of the Adipocyte in Development of Type 2 Diabetes, C. Croniger, Editor. 2011.
2. Robertson, R.P., et al., Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes, 2003. 52(3): p. 581-7.
3. Ballatori, N., et al., Glutathione dysregulation and the etiology and progression of human diseases. Biological Chemistry, 2009. 390(3): p. 191-214.
4. Sekhar, R.V., et al., Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine. Diabetes Care, 2011. 34(1): p. 162-167.
5. Sheikh-Ali, M., J.M. Chehade, and A.D. Mooradian, The Antioxidant Paradox in Diabetes Mellitus. American Journal of Therapeutics, 2011. 18(3): p. 266-278 10.1097/MJT.0b013e3181b7badf.
6. van der Crabben, S.N., et al., Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans. Metabolism, 2011. 60(1): p. 99-106.
7. Furfaro, A.L., et al., Impaired synthesis contributes to diabetes-induced decrease in liver glutathione. International Journal of Molecular Medicine, 2012. 29(5): p. 899-905.
8. Pastore, A., et al., All glutathione forms are depleted in blood of obese and type 1 diabetic children. Pediatric Diabetes, 2012. 13(3): p. 272-277.
9. Darmaun, D., et al., Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation. Pediatr Diabetes, 2008. 9(6): p. 577-82.

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After more than 50 years of practice, by far two of the most difficult concepts to explain to patients are antioxidants and their nemeses, free radicals. Yet balancing these two powerful forces is essential to achieving a long healthspan, which is the amount of time you spend on this earth in good health.

As physicians, we can and should do more than just tell patients to eat their blueberries and green, leafy vegetables. I’ve found that people are much more inclined to follow my advice when they understand why I’m telling them to do something. The human body is the most marvelous machine ever made. Patients may not completely understand how it works; they just know they depend on it to function properly 24/7. That’s similar to something else most of us depend on daily: our cars.

Here’s how I often introduce people to antioxidants

In my book “The Inflammation Solution,” I explain that your car engine produces exhaust from burning fuel. Your body’s engine is its metabolism. It produces “exhaust,” or by-products, called oxidants. If produced in just the right amount, these microscopic oxidants (also known as free radicals) act like antibiotics to attack germs that get into our cells. But if we have an excessive amount of exhaust (called oxidative stress), the free radicals damage our cells and tissues.

Enter antioxidants. These are molecules you make and eat to mute the damaging effects of oxidative stress. The antioxidants that your body makes and the ones you eat in smart foods and supplements act like microscopic fire extinguishers to blunt tissue damage from the exhaust of your natural metabolism. Health is oxidant (free radical)/antioxidant balance. Illness is an imbalance.

We should also discuss glutathione

Glutathione is one of the most-studied antioxidants, and for good reason. It is the master antioxidant, and it is made by the body. It has a tremendous ability to neutralize excess oxidants and help maintain that critical balance. Yet, as we age, the body becomes less efficient at making glutathione. If your body isn’t effective at increasing glutathione levels within the cells, where it’s needed, it may need your help to top off those levels.

Biography: William Sears, MD (Dr. Bill)

William Sears, MD, has been advising busy parents on how to raise healthier families for more than 40 years, and now has turned his attention to the specialty of lifestyle medicine. He is the cofounder of AskDrSears.com and the Dr. Sears Wellness Institute, which has certified over 10,000 Health Coaches around the world. He has served as a voluntary professor at the University of Toronto, University of South Carolina, University of Southern California’s Keck School of Medicine, and University of California, Irvine. Together with his wife, Martha, he has written more than 45 books on parenting, nutrition and healthy aging. Dr. Sears and his contribution to family health were featured on the cover of Time magazine.

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Supplementation with glutathione (GSH) is incapable of increasing cellular glutathione (GSH) since the glutathione (GSH) concentration found in the extracellular environment is much lower than that found intracellularly by about a thousand-fold. This large difference means that there is an insurmountable concentration gradient that prohibits extracellular glutathione entering cells and it is only inside the cell where glutathione performs its essential functions.

Gamma-Glutamylcysteine (GGC) is not subject to such a concentration gradient as it occurs in human plasma in the range of 1 – 5 µM ^{[2, 3]} and intracellularly at 5 – 10 µM ^[4]. The intracellular concentration of gamma-glutamylcysteine (GGC) is generally low allowing it (GGC) to diffuse into the cell. Once inside the cell it (GGC) rapidly bonds to glycine to form glutathione (GSH). This second and final reaction step in glutathione (GSH) biosynthesis is catalyzed by the activity of the ATP dependent glutathione synthase (GS) enzyme. Although currently unproven, gamma-glutamylcysteine (GGC) may be the pathway intermediate of glutathione transportation in multicellular organisms ^{[5, 6]}.

A human clinical study in healthy, non-fasting adults demonstrated that orally administered gamma-glutamylcysteine (GGC) can significantly increase lymphocyte glutathione (GSH) levels indicating systemic bioavailability, validating the therapeutic potential of gamma-glutamylcysteine (GGC) ^[7]. Gamma-glutamylcysteine (GGC) is also capable of being a powerful antioxidant in its own right as well ^[8-10].

Since the production of cellular gamma-glutamylcysteine (GGC) in humans slows down with age, as well as during the progression of many chronic diseases, it has been postulated that supplementation with gamma-glutamylcysteine (GGC) could offer health benefits. Other benefits of gamma-glutamylcysteine (GGC) supplementation may extend to situations where glutathione (GSH) has been acutely lowered below optimum such as following strenuous exercise, and during trauma or episodes of poisoning.

Several review articles have been published regarding the therapeutic potential of gamma-glutamylcysteine (GGC) to replenish glutathione (GSH) in age related ^[11] and chronic disease states such as Alzheimer’s disease ^[12].

As gamma-glutamylcysteine (GGC) has become commercially available several researchers have reported invitro, animal and human studies investigating a potential therapeutic role for gamma-glutamylcysteine (GGC) in both the reduction of oxidant stress-induced damage in tissues including the brain ^{[13, 14]} and as a treatment for sepsis ^[15].

References

1. Orlowski, M. and A. Meister, The gamma-glutamyl cycle: a possible transport system for amino acids. Proc Natl Acad Sci U S A, 1970. 67(3): p. 1248-55.
2. Meister, A. and M.E. Anderson, Glutathione. Annu Rev Biochem, 1983. 52: p. 711-60.
3. Anderson, M.E. and A. Meister, Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis. Proceedings of the National Academy of Sciences of the United States of America., 1983. 80(3): p. 707-11.
4. Mårtensson, J., Method for determination of free and total glutathione and γ-glutamylcysteine concentrations in human leukocytes and plasma. Journal of Chromatography B: Biomedical Sciences and Applications, 1987. 420(0): p. 152-157.
5. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
6. Stark, A.A., et al., The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 2003. 17(1-4): p. 139-49.
7. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.
8. Quintana-Cabrera, R. and J.P. Bolanos, Glutathione and gamma-glutamylcysteine in the antioxidant and survival functions of mitochondria. Biochemical Society Transactions, 2013. 41: p. 106-110.
9. Quintana-Cabrera, R., et al., γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nat Commun, 2012. 3: p. 718.
10. Nakamura, Y.K., M.A. Dubick, and S.T. Omaye, γ-Glutamylcysteine inhibits oxidative stress in human endothelial cells. Life Sciences, 2011(0).
11. Ferguson, G. and W. Bridge, Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of γ-glutamylcysteine. Archives of Biochemistry and Biophysics, 2016. 593: p. 12-23.
12. Cao, P., et al., Therapeutic approaches to modulating glutathione levels as a pharmacological strategy in Alzheimer’s disease. Curr Alzheimer Res, 2015. 12(4): p. 298-313.
13. Le, T.M., et al., gamma-Glutamylcysteine ameliorates oxidative injury in neurons and astrocytes in vitro and increases brain glutathione in vivo. Neurotoxicology, 2011. 32(5): p. 518-25.
14. Braidy, N., et al., -glutamylcysteine (GGC)-mediated upregulation of glutathione levels can ameliorate toxicity of natural beta-amyloid oligomers in primary adult human neurons, in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2013, Elsevier. p. P854.
15. Yang, Y., et al., γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology, 2019. 20: p. 157-166.

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Some recent studies have shown that profoundly serious infections with COVID-19, and its associated high risk of death, are due to glutathione deficiency ^[3]. Additionally, a preliminary pilot trial with two COVID-19 patients found some improvement in respiratory symptoms after dosing with glutathione ^[4]. This has led to several researches advocating the use of either glutathione itself ^{[3, 5]} or N-acetylcysteine ^[6] as a treatment for COVID-19 patients. Although the intention to increase cellular glutathione is likely to be of benefit for the reasons outlined below. The newly available precursor to glutathione called gamma-glutamylcysteine is more likely to be a more effective and rapid way of increasing cellular glutathione ^[7].

COVID-19, like the common influenza virus, belong to the family of RNA viruses. Much evidence has accumulated over the past decade suggesting that patients infected with such RNA viruses are under chronic oxidative stress ^[8] associated with glutathione depletion because oxidative stress, and the associated overproduction of reactive oxygen species, is a hallmark of RNA viruses. More importantly, an oxidative state promotes protein glutathionylation (S-S disulphide binding of glutathione to a cysteine residue). This provides a mechanism for RNA viruses to regulate and sequentially control the activity of the enzymes responsible for their replication cycle ^{[3, 9]}. This is particularly concerning if you already have low glutathione. An infection with COVID-19 could lower your glutathione below a critical point where oxidative stress progressively leads to tissue damage and organ failure.

Glutathione is the most important antioxidant defense in the lungs ^[10] and there is diverse scientific and medical literature that points to glutathione as a key player in not only preventing oxidative stress but also strengthening your immune system ^[11]. The elderly, and those affected by chronic disease, especially the respiratory and immuno- compromised, seem to be most vulnerable to COVID-19 infection and its complications ^[2]. This section of the population is well known to have lower than normal glutathione levels and often suffer extensively from oxidative stress ^[12-16].

There is also evidence to support that increasing your glutathione may also act as a prophylactic to viral infection. A study published in 2003 ^[17] demonstrated that glutathione has anti-influenza properties. COVID-19, just like influenza, affects the oral, nasal, and upper airway and therefore oxidative stress, or other conditions that deplete glutathione, make you more vulnerable to such RNA virus infections.

Until recently, it has not been possible to increase patient’s glutathione rapidly when needed. This is due to the many obstacles of glutathione supplementation. The most obvious solution, oral or intravenous glutathione, does not work effectively and neither does N-acetylcysteine. The latter has shown some improvement in influenza type symptoms, however they did not seem to significantly affect the rate of infection ^[18]. This is hardly surprising, since N-acetylcysteine is not an effective way of increasing cellular glutathione unless acutely depleted ^{[19, 20]}. Therefore it has been almost impossible to determine if increasing a patient’s glutathione is effective in antiviral therapy, and studies to that effect have consequently only been of limited success ^{[18, 21-24]}

There is some recent evidence coming out of China that supplementation with vitamin C is helpful in COVID-19 infection ^[25]. It is interesting to note that glutathione is responsible for recycling cellular vitamin C and, in turn, vitamin C helps to lessen glutathione depletion ^[26]. The recent availability of gamma-glutamylcysteine promises to be a game changer in the field of glutathione supplementation. It has been proven to be not only an effective way of supplementing glutathione, but also does so rapidly ^[7]. It is hypothesized that increasing glutathione by administration of gamma-glutamylcysteine will not only prevent but also treat the debilitating effects of oxidative stress on patient’s health. It will also potentially disrupt the COVID-19 virus replication cycle halting the progress of the disease.

References

1. Cecchini, R. and A.L. Cecchini, SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Medical Hypotheses, 2020. 143: p. 110102-110102.
2. Delgado-Roche, L. and F. Mesta, Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection. Archives of medical research, 2020. 51(5): p. 384-387.
3. Polonikov, A., Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS infectious diseases, 2020. 6(7): p. 1558-1562.
4. Horowitz, R.I., P.R. Freeman, and J. Bruzzese, Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respiratory medicine case reports, 2020. 30: p. 101063-101063.
5. Horowitz, R.I. and P.R. Freeman, Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials. Medical Hypotheses, 2020. 143: p. 109851.
6. Poe, F.L. and J. Corn, N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Medical Hypotheses, 2020. 143: p. 109862.
7. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.
8. Reshi, M.L., Y.C. Su, and J.R. Hong, RNA Viruses: ROS-Mediated Cell Death. Int J Cell Biol, 2014. 2014: p. 467452.
9. Checconi, P., et al., Role of Glutathionylation in Infection and Inflammation. Nutrients, 2019. 11(8): p. 1952.
10. Cantin, A., et al., Normal alveolar epithelial lining fluid contains high levels of glutathione. Journal of applied physiology, 1987. 63(1): p. 152-157.
11. Ghezzi, P., Role of glutathione in immunity and inflammation in the lung. International Journal of General Medicine, 2011. 4: p. 105-113.
12. Teskey, G., et al., Glutathione as a Marker for Human Disease. Adv Clin Chem, 2018. 87: p. 141-159.
13. Franco, R., et al., The central role of glutathione in the pathophysiology of human diseases. Archives Of Physiology And Biochemistry, 2007. 113(4-5): p. 234-258.
14. Townsend, D.M., K.D. Tew, and H. Tapiero, The importance of glutathione in human disease. Biomedicine & Pharmacotherapy, 2003. 57(3-4): p. 145-55.
15. Ballatori, N., et al., Glutathione dysregulation and the etiology and progression of human diseases. Biological Chemistry, 2009. 390(3): p. 191-214.
16. Pérez, L.M., et al., Glutathione Serum Levels and Rate of Multimorbidity Development in Older Adults. The Journals of Gerontology: Series A, 2019.
17. Cai, J., et al., Inhibition of influenza infection by glutathione. Free Radical Biology & Medicine, 2003. 34(7): p. 928-936.
18. De Flora, S., C. Grassi, and L. Carati, Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J, 1997. 10(7): p. 1535-41.
19. Rushworth, G.F. and I.L. Megson, Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharmacology & Therapeutics, 2014. 141(2): p. 150-159.
20. Aitio, M.-L., N-acetylcysteine – passe-partout or much ado about nothing? British Journal of Clinical Pharmacology, 2006. 61(1): p. 5-15.
21. Sgarbanti, R., et al., Redox regulation of the influenza hemagglutinin maturation process: a new cell-mediated strategy for anti-influenza therapy. Antioxid Redox Signal, 2011. 15(3): p. 593-606.
22. Fraternale, A., et al., Antiviral and immunomodulatory properties of new pro-glutathione (GSH) molecules. Curr Med Chem, 2006. 13(15): p. 1749-55.
23. Fraternale, A., et al., GSH and analogs in antiviral therapy. Mol Aspects Med, 2009. 30(1-2): p. 99-110.
24. Uchide, N. and H. Toyoda, Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules, 2011. 16(3): p. 2032-52.
25. Liu, F., et al., Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial. BMJ open, 2020. 10(7): p. e039519-e039519.
26. Martensson, J. and A. Meister, Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects. Proc Natl Acad Sci U S A, 1991. 88(11): p. 4656-60.

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We have already discounted the most apparent strategy in one of our articles in which we discuss why taking glutathione itself will not increase its concentration inside the cell. So, let’s move on to the most often quoted myth that the amino acid cysteine is in limited supply in the body. We are aware that cysteine is one of the three building blocks that make up glutathione, but is there any evidence to suggest that we may be low on cysteine? And, regardless, would taking cysteine be effective in increasing cellular glutathione (GSH)? On initial observation, the principle behind the theory of cysteine deficiency being a cause of low glutathione (GSH) appears reasonably sound, but it is not that simple.

The first question is relatively easy to answer. The fact is that our diet usually contains plenty of cysteine and the other sulphur containing amino acid called methionine which can be easily converted into cysteine in the liver ^[1]. For example, the typical American diet supplies much more than the recommended required quantity of cysteine ^[2]. We can, therefore, rule out a cysteine deficiency. But would taking a cysteine supplement such as N-acetylcysteine (NAC) increase our cellular glutathione (GSH)? Unfortunately, it is not that easy, otherwise none of the chronic diseases attributed to low glutathione (GSH) would be so prevalent.

Cysteine, unlike most other amino acids, is extremely unstable and rapidly autoxidizes to cystine which is the oxidized disulphide form. It has exceedingly low solubility, and it will not be absorbed Cysteine, unlike most other amino acids, is extremely unstable and rapidly autoxidizes to cystine which is the oxidized disulphide form of cysteine. Cystine has exceedingly low solubility, and it will not be absorbed from the GI tract. Additionally, this cysteine autoxidation reaction, catalyzed by transition metal ions, generates oxygen free radicals and hydrogen peroxide. In high concentrations, this may result in cellular toxicity ^[3-6] and has the potential to be neurotoxic ^[7]. Our cells have adapted to this potential toxicity by storing cysteine in the form of glutathione (GSH) ^[8], which is far more stable to oxidation. We can therefore consider glutathione to be a safe storage for cysteine. It is important to note that consuming cysteine as part of our usual diet will never exceed the threshold to become toxic.

In summary, taking a cysteine supplement is of little use to increase glutathione (GSH) because our body tightly regulates both the storage and production of cysteine and any excess consumed is broken down into more stable byproducts. There is a notable exception which relates to acute glutathione (GSH) depletion due to acetaminophen (paracetamol) overdose as we shall see.

By far the most studied cysteine supplement is the cysteine prodrug N-Acetylcysteine (NAC). Several human clinical studies have determined the bioavailability of NAC. Orally delivered NAC undergoes extensive first-pass metabolism resulting in about 90% loss by enzymatic deacetylation to form cysteine in the small intestine ^[9]. As we have seen, this mainly gets converted to cystine and is of little use in healthy individuals or those suffering from a chronic undersupply of glutathione (GSH) due to aging or disease. Our notable exception is the observation in several studies that NAC is highly effective in elevating glutathione (GSH) under conditions where there has been a dramatic (acute depletion) drop in intracellular glutathione (GSH) levels, for instance as is the case in acetaminophen overdose. Here, the sharp decline in glutathione (GSH) levels, especially in the liver, to almost zero is effectively counteracted by NAC ^[10]. It immediately supplies available cysteine for repletion of glutathione and thus, recovery from toxicity. Unfortunately, this is where NAC has gained a false reputation as a go-to drug if low glutathione (GSH) is suspected. While immensely helpful indeed, it does not address our problem of supplementing glutathione (GSH) in cases of gradual depletion such as chronic illness or just simply getting older.

In contrast, diseases in which there is a prolonged and chronic decrease in glutathione (GSH) do not respond well to NAC treatment. An example of this is the situation that occurs in HIV/AIDS patients who experience a persistent drop in tissue glutathione (GSH) levels. In a clinical trial of AIDS patients were treated with 1.8 g/day of NAC for two weeks with the glutathione (GSH) status monitored in plasma and lymphocytes. During the treatment, no significant increase in glutathione (GSH) was observed ^[11]. Similar disappointing observations of HIV patients supplemented with NAC were also made by ^[12] and ^[13]. NAC has been tried in numerous chronic diseases with similarly disappointing results including cystic fibrosis protection against contrast-induced nephropathy and thrombosis ^[14].

The tight negative feedback control that glutathione (GSH) exerts on the first of two enzymes responsible for glutathione synthesis, GCL, can explain this phenomenon. This enzyme has the task of combining the amino acids glutamate and cysteine to form gamma-glutamylcysteine (GGC), which is used to produce glutathione (GSH) by the GS enzyme. As long as cellular glutathione is above a level considered to be adequate, which is called homeostasis, GCL is inhibited from making gamma-glutamylcysteine (GGC), no matter how much cysteine is available. However, when intracellular glutathione (GSH) is well below this homeostatic level, GCL is no longer inhibited and can actively utilize the cysteine supplied by NAC supplements. Several researchers have come to the same conclusion when trying to explain this fact ^[15]. Negative feedback controls exist as part of many of our body’s processes to tightly regulate certain functions, for example, our body temperature.

Supplementing with cysteine to increase cellular glutathione (GSH) is therefore of little use except in a few severe and limited cases mainly used in clinical settings.  The causes of glutathione (GSH) depletion in chronic diseases and how to effectively, rapidly and safely augment cellular glutathione (GSH) is now well understood.

References

1. Courtney-Martin, G., R.O. Ball, and P.B. Pencharz, Sulfur amino acid metabolism and requirements. Nutrition Reviews, 2012. 70(3): p. 170-175.
2. Lang, C.A., The impact of glutathione on health and longevity. Journal of Anti Aging Medicine, 2001. 4(2): p. 137-144.
3. Nath, K.A. and A.K. Salahudeen, Autoxidation of cysteine generates hydrogen peroxide: cytotoxicity and attenuation by pyruvate. American Journal of Physiology, 1993. 264(2): p. F306-F314.
4. Harman, L.S., C. Mottley, and R.P. Mason, Free radical metabolites of L-cysteine oxidation. Journal of Biological Chemistry, 1984. 259(9): p. 5606-11.
5. Viña, J., et al., The effect of cysteine oxidation on isolated hepatocytes. Biochem. J., 1983. 212(1): p. 39-44.
6. Wang, X.F. and M.S. Cynader, Pyruvate Released by Astrocytes Protects Neurons from Copper-Catalyzed Cysteine Neurotoxicity. The Journal of Neuroscience, 2001. 21(10): p. 3322-3331.
7. Janáky, R., et al., Mechanisms of L-Cysteine Neurotoxicity. Neurochemical Research, 2000. 25(9): p. 1397-1405.
8. Aoyama, K., M. Watabe, and T. Nakaki, Regulation of Neuronal Glutathione Synthesis. Journal of Pharmacological Sciences, 2008. 108(3): p. 227-238.
9. Olsson, B., et al., Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. European Journal of Clinical Pharmacology, 1988. 34(1): p. 77-82.
10. Yang, R.K., et al., Prolonged treatment with N-acetylcystine delays liver recovery from acetaminophen hepatotoxicity. Critical Care, 2009. 13(2).
11. Witschi, A., et al., Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS. AIDS Research & Human Retroviruses, 1995. 11(1): p. 141-3.
12. Akerlund, B., et al., Effect of N-acetylcysteine(NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. European Journal of Clinical Pharmacology., 1996. 50(6): p. 457-61.
13. Nakamura, H., H. Masutani, and J. Yodoi, Redox imbalance and its control in HIV infection. Antioxidants & Redox Signaling, 2002. 4(3): p. 455-64.
14. Rushworth, G.F. and I.L. Megson, Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharmacology & Therapeutics, 2014. 141(2): p. 150-159.
15. Nielsen, H.B., et al., N-acetylcysteine does not affect the lymphocyte proliferation and natural killer cell activity responses to exercise. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology, 1998. 275(4): p. R1227-R1231.

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Gamma-glutamylcysteine (GGC) has the advantage of being able to diffuse into cells where it is effectively converted to glutathione (GSH) by an enzymatic reaction which simply adds the amino acid glycine. Unlike cysteine prodrugs, such as NAC, which only increase cellular glutathione (GSH) following severe depletion such as in acetaminophen (paracetamol) overdose, gamma-glutamylcysteine (GGC) does so without limitations. This ability to increase glutathione (GSH) regardless of the current state of cellular glutathione (GSH) makes gamma-glutamylcysteine (GGC) unique in the vast supplement market touting effective ways to do so. The body’s biochemistry clearly indicates and research confirms that consuming gamma-glutamylcysteine (GGC) is the only way to ensure healthy glutathione (GSH) levels for all individuals including those suffering from chronic disease and inflammation.

Reference

1. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.

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