CFIDS: Restore Glutathione Levels

Glutathione (GSH): Increasing the “Great Protector” of the Cell From Oxidative Stress (Free Radicals)

Intravenous GSH (see Appendix: Expert: Dr David Perlmutter)

Liposomal GSH (see  Appendix: Expert: Dr. Tim Guilford)

RGSH (see Appendix)

Oral GSH (see Appendix: Research +/- on Effectiveness)

Precursors of GSH: (see Appendix)

Cellgevity: A New Modified Cysteine Precursor of GSH (see Appendix)

Glutathione deficiency is increasingly recognized as a risk factor in chronic fatigue, coronary artery disease, asthma, neurodegenerative disorders, cognitive-behavioral problems, and various types of cancer.

Dr. Mehmet Oz did several segments on glutathione on his TV program, calling it the “Superhero of Antioxidants.” It has also been called the “Great Protector,” and the “Mother of Antioxidants” with good reason.

In addition to being an antioxidant, glutathione is also a powerful detoxifier and also plays a major role in immune function.

A Key to Detoxification

As a detoxifier, glutathione is unparalleled. It binds metals and other toxins and transforms them into compounds that can be excreted in bile or urine. Once bound, these toxins become water-soluble and can be transported out of cells.

However, the binding of toxins to glutathione creates a demand on the body to make new glutathione. Deficiency results when a tissue or system cannot keep pace with the demand.

Because it is the primary organ of detoxification, the liver harbors the body’s largest stores of glutathione, which plays a role in detoxifying environmental pollutants, radiation, drugs, carcinogenic chemicals, and heavy metals.

Glutathione s-transferases (GST) are a group of enzymes that work in concert with glutathione, and they are critical for removal of many toxins. The loss of GST function may contribute to both acute and chronic illnesses (Ashfaq 2008; Chinta 2006).

In discussing the role GSTs with patients, I often refer to them as matchmakers that introduce glutathione to toxins. When the GST for a specific toxin is present, it can facilitate conjugation of the toxin to glutathione very efficiently. When the GST is absent, the likelihood of the toxin-GSH conjugation is diminished.


Glutathione levels in blood can be measured in both red blood cells (RBC) and plasma. While RBC levels are used in many research papers there is some confusion about which approach should be used clinically. One study using a specific brand of liposomal glutathione in children with autism shows that after glutathione supplementation, plasma levels change first, followed by RBC levels (Kern JK, et al. Med Sci Monit. 2011;17(12):CR677-82)

The confusion also stems from the observation that in normal individuals, the infusion of glutathione intravenously increases plasma levels for only 10 minutes (Hong SY, et al. J Korean Med Sci. 2005;20(5):721-6. Fukagawa NK, et al. Am J Physiol. 1996;270(2 Pt 1):E209-14). Studies of this phenomenon have been hampered by the challenge of identifying patient populations that consistently have low glutathione levels.

Clinical labs offer testing for glutathione levels in both plasma and RBC. The plasma testing generally reflects both the reduced and oxidized forms of glutathione. The normal ranges for glutathione in plasma, according to the Health Diagnostics and Research Institute, are as follows:

Reduced GSH: 3.8 – 5.5 umol/L

GSS (oxidized glutathione): 0.16 – 0.50 umol/L

Total glutathione (GSH+GSSG): 3.8 – 5.5 umol/L

Total glutathione can also be measured in RBCs, which contain much larger amounts of glutathione. The standard reference range for total glutathione in RBCs is 1,000-1,900 umol/L. Some clinicians consider levels in the range of 1,100 -1,200 umol/L to be “low.”

Some investigators hold that the ratio of GSH/GSSG is useful in identifying individuals at risk for atherosclerosis, even when they are in apparently normal health (Ashfaq S, et al. Hypertension. 2008; 52(1):80-5). The findings suggest that heart disease is associated with either increased oxidative stress or the lack of antioxidant support. The authors conclude that these markers may help identify healthy individuals at risk for early atherosclerosis independent of traditional risk factors and presence of inflammation.

There are several additional useful biomarkers for identifying patients in whom glutathione is low. One such indicator is elevated Gamma glutamyltransferase (GGT), the enzyme that breaks down glutathione from the blood to allow its importation into the cells. Up-regulation of GGT has been observed in cells deficient in glutathione (Chinta SJ, et al. Free Radic Biol Med. 2006;40(9):1557-63).

Glutathione (GSH) is a tripeptide comprised of the amino acids glutamine, cysteine and glycine. It  is a naturally occurring protein made by and used by every cell in the body. It contains a sulfur molecule, which plays a major role in its antioxidant and detoxification functions. It also gives glutathione its distinctive sulfurous aroma.

Glutathione levels are maintained in cells through de novo production, as well as through the recycling of its oxidized form, glutathione disulfide (GSSG).

As an antioxidant, glutathione protects cells against the oxidative stress that damages cell membrane proteins. Without adequate glutathione, mitochondrial oxygen metabolism produces large numbers of free radicals, which causes cells to perform poorly or die. A number of studies have shown that oxidative stress increases with aging, and leads to degenerative diseases: heart disease, memory problems, cancer, diabetes, arthritis.

Glutathione is considered the most important antioxidant because it is the only one capable of working with enzymes. One enzyme, glutathione peroxidase (GPx), works with glutathione to prevent membranes from becoming oxidized. Glutathione also helps activate the better-known antioxidants, vitamin C and vitamin E. When researchers discuss oxidative stress, they almost always describe it as a state of “low glutathione.”

Appendix: Intravenous Glutathione

There are a number of clinical studies of IV glutathione, including a well-known study by Sechi, which led a wave of interest in this therapy for Parkinson’s Disease (Sechi G, et al. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20(7):1159-70). A subsequent, double blind placebo controlled study did not confirm the benefits observed in the Sechi trial (Hauser RA, et al. Mov Disord. 2009).

A small randomized, double-blind, placebo-controlled trial of IV glutathione in people with peripheral artery disease showed increased pain-free walking distance and improvement of macrocirculatory and microcirculatory parameters (Arosio E, et al. Mayo Clin Proc. 2002; 77(8): 754-9). Numerous studies document the safety of IV glutathione.

Appendix: Liposomal GSH

  • Liposomal GSH was shown to penetrate brain cells 100 times more effectively than oral (see below)
  • Liposomal GSH restores Th1 status for those with excessive Th2 immune bias (Ly et al. 2005)
  • Liposomal GSH improves neutrophil function ( Venketaraman V,  Morris D)

Liposomal ‘encapsulation’ of the reduced (active) form of glutathione, often referred to as liposomal glutathione, is now available in a number of formulations. This form has proven functional both in cells (Zeevalk GD, et al.Neurochem Res. 2010;35(10):1575-87), and in animal tissue after oral absorption (Rosenblat M, et al. Atherosclerosis. 2007;195(2):e61-8).

A clinical study in children with autism showed that oral supplementation with liposomal glutathione can raise glutathione levels in plasma after oral ingestion (Kern 2011). In the children using this preparation, plasma levels of reduced glutathione rose from low to the low end of normal after two months.

Neurochem Res. 2010 Oct;35(10):1575-87.

Liposomal-glutathione provides maintenance of intracellular glutathione and neuroprotection in mesencephalic neuronal cells.

Zeevalk GD1Bernard LPGuilford FT.


A liposomal preparation of glutathione (GSH) was investigated for its ability to replenish intracellular GSH and provide neuroprotection in an in vitro model of Parkinson’s disease ,,, repletion to control levels occurred over 4 h with liposomal-GSH or non-liposomal-GSH however, liposomal-GSH was 100-fold more potent; EC(50s) 4.75 μM and 533 μM for liposomal and non-liposomal-GSH, respectively. Liposomal-GSH utilization was also observed in neuronal cultures, but with a higher EC(50) (76.5 μM), suggesting that glia facilitate utilization. Blocking γ-glutamylcysteine synthetase with buthionine sulfoxamine prevented replenishment with liposomal-GSH demonstrating the requirement for catabolism and resynthesis. Repletion was significantly attenuated with endosomal inhibition implicating the endosomal system in utilization. Liposomal-GSH provided dose-dependent protection against PQMB with an EC(50) similar to that found for repletion. PQMB depleted intracellular GSH by 50%. Liposomal-GSH spared endogenous GSH during PQMB exposure, but did not require GSH biosynthesis for protection.,,These findings indicate that glutathione supplied in a liposomal formulation holds promise as a potential therapeutic for neuronal maintenance

J Interferon Cytokine Res. 2015 Nov;35(11):875-87.

Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals.

Ly J1,2, et al.

Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4(+) T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response, which may be relieved with lGSH supplementation enhancing the TH1 response.

An Elucidation of Neutrophil Functions againstMycobacterium tuberculosis Infection

1College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA

We characterized the functions of neutrophils in response to Mycobacterium tuberculosis (M. tb) infection, with particular reference to glutathione (GSH). We examined the effects of GSH in improving the ability of neutrophils to control intracellular M. tb infection. Our findings indicate that increasing the intracellular levels of GSH with a liposomal formulation of GSH (L-GSH) resulted in reduction in the levels of free radicals and increased acidification of M. tb containing phagosomes leading to the inhibition in the growth of M. tb

,,. This inhibitory mechanism is dependent on the presence of TNF-α and IL-6. polymorphonuclear leukocytes (PMN) or neutrophils are essential component of the human innate immune system and act as a first-line defense against invading microorganisms. Neutrophils are major inhabitants of the white blood cell population (WBC) since they constitute ~70% of the total WBC population [4]. Neutrophils form the bulk of early recruited leukocyte population that mediate and elicit immune responses against M. tb [4]. Neutrophils, after encountering the mycobacteria, exhibit innate immune responses such as phagocytosis which in turn triggers signaling events resulting in secretion of cytokines such as TNF-α and IL-1 that mediate early inflammatory responses [46].

The tripeptide, glutathione (GSH), protects all cells against oxidizing agents, free radicals, and reactive oxygen intermediates (ROI), either directly or through enzymatic action of GSH peroxidases and GSH-transferases [7,8]. GSH is also important for cellular homeostasis as well as many different cellular functions such as protein synthesis, enzyme catalysis, transmembrane transport, receptor action, intermediary metabolism, and cell maturation [911]. GSH is produced by nearly all cell types and exists in two forms: reduced or free GSH (rGSH) and oxidized (GSSG). rGSH is responsible for the antioxidant functions of GSH, while GSSG is the byproduct of the free radical scavenging activity of GSH and lacks antioxidant function [911].

We have previously reported that GSH has antimycobacterial effects and furthermore enhancing the levels of GSH in human macrophages resulted in inhibition in the growth of intracellular M. tb [12]. Additionally, increasing the levels of GSH in immune cells, such as natural killer (NK) cells and T cells, resulted in improved control of M. tb infection inside human monocytes indicating that GSH has both direct antimycobacterial effects as well as immune enhancing effects [13, 14].

We chose to examine the functions of neutrophils against M. tb infection for three chief reasons: first, they mirror macrophage mechanisms mainly by phagocytosing bacteria, second, they are one of the first responders to bacterial infections, and third, they are closely tied to free radical and inflammatory responses. We also characterized the underlying mechanisms by which GSH-enhanced neutrophils are able to successfully inhibit the growth of M. tb. We hypothesized that augmenting the levels of GSH in neutrophils will increase the fusion of phagosomes containing M. tb with lysosomes leading to inhibition in the growth of M. tb. The ultimate purpose of this research is to determine the ability of GSH-enhanced neutrophils to effectively control M. tbinfection. By better characterizing the role of neutrophils which form a major population of WBC, we can further advance the crusade against M. tb control and eradication.

We tested our hypothesis by examining the effects of two different GSH-enhancing agents: a GSH precursor, N-acetyl cysteine (NAC), and L-GSH, a liposomal formulation of GSH, in mediating the control of M. tb infection inside neutrophils. We correlated the inhibition in the growth of M. tb inside neutrophils with the levels of GSH and free radicals, production of inflammatory cytokines such as IL-6 and TNF-α, and the extent of phagosome lysosome fusion. Our results indicate that treatment of neutrophils with L-GSH resulted in inhibition in the growth of M. tb and this inhibition was accompanied by increased fusion between phagosomes containing M. tb with lysosomes. Our findings unveiled one of the important mechanisms by which GSH improves the ability of neutrophils to control M. tb infection

Appendix: Sublingual GSH

Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biol. 2015 Dec;6:198-205. Schmitt B1, et al.


Glutathione (GSH) is critical to fight against oxidative stress. Its very low bioavailability limits the interest of a supplementation. The purpose of this study was to compare the bioavailability, the effect on oxidative stress markers and the safety of a new sublingual form of GSH with two commonly used dietary supplements, N-acetylcysteine (NAC) and oral GSH. The study was a three-week randomized crossover trial. 20 Volunteers with metabolic syndrome were enrolled. GSH levels and several oxidative stress markers were determined at different times during each 21-days period. Compared to oral GSH group, an increase of total and reduced GSH levels in plasma and a higher GSH/GSSG ratio (p=0.003) was observed in sublingual GSH group. After 3 weeks of administration, there was a significant increase of vitamin E level in plasma only in sublingual GSH group (0.83 µmol/g; p=0.04). Our results demonstrate the superiority of a new sublingual form of GSH over the oral GSH form and NAC in terms of GSH supplementation

Appendix: Oral GSH

Eur J  Nutr. 2015 Mar;54(2):251-63.Randomized controlled trial of oral glutathione supplementation on body stores of glutathioneRichie JP Jr1, et a

…While oral GSH has been shown to be bioavailable in laboratory animal models, its efficacy in humans has not been established. Our objective was to determine the long-term effectiveness of oral GSH supplementation on body stores of GSH in healthy adults…trial of oral GSH (250 or 1,000 mg/day) on GSH levels in blood, erythrocytes, plasma, lymphocytes and exfoliated buccal mucosal cells,,,GSH levels in blood increased after 1, 3 and 6 months versus baseline at both doses. At 6 months, mean GSH levels increased 30-35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells in the high-dose group (P < 0.05). GSH levels increased 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P < 0.05). In most cases, the increases were dose and time dependent, and levels returned to baseline after a 1-month washout period. A reduction in oxidative stress in both GSH dose groups was indicated by decreases in the oxidized to reduced glutathione ratio in whole blood after 6 months. Natural killer cytotoxicity increased >twofold in the high-dose group versus placebo (P < 0.05) at 3 months,,,These findings show, for the first time, that daily consumption of GSH supplements was effective at increasing body compartment stores of GSH.

More evidence that oral glutathione is effective: 

J Altern Complement Med. 2011 Sep;17(9):827-33. 

The following, among others showed oral supplementation with glutathione to be not effective at raising body stores:

Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. Allen J1Bradley RD.

The tripeptide glutathione (GSH) is the most abundant free radical scavenger synthesized endogenously in humans. Increasing mechanistic, clinical, and epidemiological evidence demonstrates that GSH status is significant in acute and chronic diseases. Despite ease of delivery, little controlled clinical research data exist evaluating the effects of oral GSH supplementation.

The study objectives were to determine the effect of oral GSH supplementation on biomarkers of systemic oxidative stress in human volunteers.

The study was conducted at Bastyr University Research Institute, Kenmore, WA and the Bastyr Center for Natural Health, Seattle, WA.

Forty (40) adult volunteers without acute or chronic disease participated in this study.

Oral GSH supplementation (500 mg twice daily) was given to the volunteers for 4 weeks.

Primary outcome measures included change in creatinine-standardized, urinary F2-isoprostanes (F2-isoP) and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG). Changes in erythrocyte GSH concentrations, including total reduced glutathione (GSH), oxidized glutathione (GSSG), and their ratio (GSH:GSSG) were also measured by tandem liquid chromatography/mass spectrometry. Analysis of variance was used to evaluate differences between groups.


There were no differences in oxidative stress biomarkers between treatment groups at baseline. Thirty-nine (39) participants completed the study per protocol. Changes in creatinine standardized F2-isoP (ng/mg creatinine) (0.0±0.1 versus 0.0±0.1, p=0.38) and 8-OHdG (μg/g creatinine) (-0.2±3.3 versus 1.0±3.2, p=0.27) were nonsignificant between groups at week 4. Total reduced, oxidized, and ratio measures of GSH status were also unchanged.


No significant changes were observed in biomarkers of oxidative stress, including glutathione status, in this clinical trial of oral glutathione supplementation in healthy adults.

Appendix: Precursors of GSH:

Strategies for repletion include the use of glutathione precursors such as N-acetyl cysteine and whey protein, which can also provide cysteine in the oxidized form called cystine. Studies are now ongoing to assess the absorption and impact of supplementation with liposomal glutathione. This work includes an animal study as well as a clinical study in children with autism (Main 2012).

For oral use, precursors of glutathione such as N-acetyl cysteine (NAC), L-glutathione and L-glycine are available in capsule form. Since cysteine is the rate-limiting precursor of glutathione formation, many clinicians advocate supplementation with cysteine in the form of NAC. The compound is now available as both a dietary supplement and also as a drug (Sansone RA, Sansone LA. Innov Clin Neurosci. 2011;8(1):10-4. Atkuri KR, et al. Curr Opin Pharmacol. 2007;7(4):355-9). NAC has been shown to increase plasma levels of glutathione (Borges-Santos MD, et al. Nutrition. 2012;28(7-8):753-6).

Cysteine can also be supplied in the oxidized form (cystine) in whey protein powder. Pressurized whey protein isolate supplements can increase lymphocyte glutathione levels in healthy individuals (Zavorsky GS, et al. Int J Food Sci Nutr. 2007;58(6):429-36).

Appendix:  An Improved precursor form for GSH, Cyseine, called “Cellgevity”

The Doctor  who invented it explains how it works:

Cellgevity Testimonials

Max International (the company):   “Every cell in your body is under a never-ending attack from free radicals and chemical toxins. Glutathione is the cell’s primary protector and detoxifier. It is your body’s natural safeguard against accelerated aging. Unfortunately, your cells just can’t make enough of it. Cellgevity™ provides your cells with patented nutrients that have been clinically shown to raise intercellular glutathione levels more effectively than any other supplement. Cellgevity features the patented nutrient RiboCeine™ combined with 12 synergistic ingredients scientifically selected to support and enhance the natural functions of glutathione.”  Their website is

Cam Suggs: “Six years ago I was diagnosed with chronic fatigue syndrome, which later led to depression and anxiety. I went the natural route to get help from all the issues I was having due to my illnesses. I was taking 13 different supplements 3 times a day. They worked for the most part, but I couldn’t seem to get back the energy that I had lost. For the past 3 months I have been taking Cellgevity and FINALLY I have my energy back! It is amazing how much energy I have now since I have experienced this product! I highly recommend it to anyone that has issues with their energy level!”

Brent Dillahunty: “When I began taking Cellgevity, even after taking the other Max glutathione accelerating products, I noticed an even deeper sleep and that I need less sleep altogether. This allows me more time during the day! Cellgevity is no doubt the mother of all glutathione accelerators! There is no other supplement that can do what Cellgevity can do!”

Marilyn Gallimore: “I have an inherited tendency to varicose veins; my mother’s were so bad she had vein stripping done when she was in her late 50’s or early 60’s. Mine looked so bad last summer, I rarely wore shorts when out in public, and was seriously considering having them injected to get them to disappear. They seem to be fading over the last couple of months, as well as decreasing in size. Some of the smaller ones are almost gone. Also, yesterday when I went to the pulmonologist for my 6 month check-up on my sleep apnea and use of my sleep machine, my blood pressure was 106/57. The medical assistant asked me if I had gone on BP meds, because mine has been 130’s/80’s every time she has checked it in the past. I guess the same cellular health that lowers blood pressure may also strengthen the veins to possibly improve varicose veins.”

Sandra Norris: “For the last 21 years I have struggled with a debilitating health issue that among other things has weakened my immune system. This winter there was a nasty respiratory illness that went through our community and my family was hit hard. Usually I am the first to get sick and the last to recover; many years I suffer with bronchitis. For weeks, as my family all came down with it, recovered, and then were sickagain I was amazed that my immune system was able to keep me from “catching” this illness. Wow… For the first winter, in as long as I can remember, I have not been sick with a respiratory illness or flu.”

Sandra Norris: “Six years ago I had a head injury that left me with many cognitive challenges and constant debilitating headaches. Before taking Cellgevity, simple math and even writing a simple paragraph (that would normally take someone a few minutes) would be a huge long drawn-out struggle. Sometimes I could not even accomplish the task. Having a conversation in a public place was overwhelming. The background noise would be so overwhelming I could not hear or concentrate on the conversation. I would have “sensory overload”, my brain would just shut down and I wouldn’t be able to think or even understand what was being said. It was easier and less painful, physically and emotionally, to stay home. When I was introduced to Max International I started with MaxOne and then switched to Cellgevity several weeks later when it was introduced. I noticed 10 days into taking MaxOne that some of the short term and long term memory challenges I was struggling with {and thought would be my new normal} were beginning to improve. SInce taking Cellgevity my memory, concentration, focus, and problem solving skills have all been improving. I am able to go to social events and the ‘sensory overload’ is not as common. I am thrilled that I continue to see improvements each week. Due to the constant debilitating headaches and another long term health issue, it has been years since I have had a good quality of sleep. I would be lucky to get 4 hours of sleep at a time and would always wake up more exhausted than when I went to sleep. Dreaming was rare. My doctor prescribed many natural and prescription remedies. Nothing ever helped. Since taking Cellgevity, I now get 7-9 hours of sleep, feel more rested and have very vivid dreams. I am also beginning to see improvement in the severity of my headaches.

Jim Phipps:  I am a 73-year old international nuclear consultant. Between business and travel, 90 hours of work a week is common. Cellgevity makes me feel like I am back in my forties again as far as energy, lack of body aches, and stamina. I look at college classmates and wonder who all these old people are. I am still running around the world and going strong thanks to Cellgevity.

Jess Clapier:  I had never been injured in wrestling until my senior year. I then found myself struggling with issues that threatened my performance and impaired my ability to workout. With the help of Cellgevity, Max N-Fuze, and MaxATP I put together one of the best season finales in my school’s history with three tournament championships, the outstanding athlete award, region champion and state finalist


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