Oral Glutathione

Oral glutathione supplementation has become very popular in the past decade.

Glutathione dietary supplements are known as L-glutathione, reduced glutathione or GSH. They come in pills, capsules, tablets, in powedered and liquid form, as sublingual drops or slow-melt tablets.

More and more people hear about glutathione (GSH) and its vital importance for proper detoxification, strong immune health, energy levels, endurance, muscle strength, anti-aging, master antioxidant role, and overall disease prevention.

People with various health concerns turn to glutathione pills, too, because they read in a health magazine or heard from TV gurus that raising glutathione would improve their condition.

Doctors who are aware of the benefits of elevated glutathione suggest glutathione supplementation to their patients, and/or prescribe NAC for them (while NAC is not glutathione, it is a pharmaceutical cysteine delivery system that raises GSH but can have some adverse side effects).

Oral glutathione supplementation is also very convenient – just take a pill once a day as you would do with a multivitamin. In our fast lives convenience is often as important as the end result of taking a supplement, if not more.

Our logic assumes that if a supplement is sold at all health food stores, pharmacies and online, and if it is advertised in mass media, it means the supplement must work well.

However, most people, including medical professionals, are not aware of the fact that glutathione pills may not be very helpful to the body. (Out of all the decades of research only one recent study showed an increase in blood GSH levels in healthy adults with oral supplementation. See the details below.)

Only very small amounts of pre-manufactured glutathione are able to enter bloodstream. Most of it is lost in the digestive tract and cannot effectively raise intracellular glutathione levels in the most important detoxification organs, such as liver, kidneys and lungs, because glutathione is a small protein molecule and gets digested.

It is very important to educate yourself to be able to make wise choices about how to raise glutathione effectively – that is why it is important to look at scientific research.

There still aren’t that many studies done using oral glutathione, especially on human subjects. The few studies that were performed so far are mostly the studies on mice or rats, some on healthy adults with no acute or chronic diseases, and a few on adults and children with certain serious diseases such as cystic fibrosis and autism.

Let’s examine what science has to say about usefulness of glutathione supplements.


ORAL GLUTATHIONE IN STUDIES ON MICE AND RATS


Some studies done on mice and rats show increased GSH in tissue, blood plasma and organs (liver, kidney, heart, lung, brain, small intestine and skin) after administration of oral glutathione.

However, there are several interesting observations:

  • Mice that were not previously depleted of glutathione showed an increase in plasma glutathione only in lungs.
  • Mice that showed significant increase in glutathione concentration were chemically pretreated for 5 days to deplete their glutathione levels. Still, glutathione rose in all organs except in the liver where it is most needed for detoxification.
  • The effect of raised glutathione lasted 3 hours on average.
  • All mice and rats received glutathione supplementation in doses much higher than the typical 500 mg dosage in human glutathione pills: 100mg/kg of weight for mice. If we do a comparison with human dosages for an average adult weighing 70 kg (approx. 154 lbs.) one 500 mg glutathione pill contains only 7.5 mg of glutathione per kg of weight.

So, to achieve similar results an adult will have to be severely glutathione deficient and take a minimum of 14 glutathione pills. To maintain the result of raised glutathione an adult will have to take this many pills several times a day.

Studies:

“Oral glutathione increases tissue glutathione in vivo”, Chemico-Biological Interactions, 1991;80(1):89-97.
Aw TY, Wierzbicka G, Jones DP.

“Bioavailability of dietary glutathione: effect on plasma concentration”, The American Journal of Physiology, 1990 Oct; 259(4 Pt 1):G524-9.
Hagen TM, Wierzbicka GT et al.




ORAL GLUTATHIONE IN STUDIES ON ADULTS AND CHILDREN WITH DISEASES


Research has proven that most known diseases are associated with low glutathione levels. In cases of acute and chronic conditions, and while undergoing harsh treatments, patients are severely glutathione deficient, and usually benefit even from slight elevation of GSH levels.

Research into the role of glutathione supplementation in disease is very limited. Studies that have been done so far are on autistic patients and patients with cystic fibrosis.

These studies indicate beneficial effect of oral GSH on raising Glutathione levels. But it is important to note that oral GSH was used in conjunction with either glutathione injections, or inhaled glutathione, or transdermal glutathione (skin patches). Thus, the beneficial result cannot be attributed solely to oral GSH.

One study examined the effects of oral glutathione in combination with inhaled glutathione on 13 cystic fibrosis patients 1-27 years old. Dosages ranged from 66 to148 mg/kg of weight a day in divided doses for the duration of 5.5 months. That translates into approximately 8 to 19 oral glutathione pills a day – again, the dosages were much higher than normal, and patients were monitored by medical personnel. At the end of this study it was concluded that “the use of a daily GSH regimen appears to be associated in CF patients with significant improvement in lung function and weight, and a significant decline in bacteria cultured in this uncontrolled study. These findings bear further clinical investigation in larger, randomized, controlled studies”.

The most recent 2015 placebo-controlled trial with pediatric cystic fibrosis patients registered a significant improvement in growth rates, BMI and gut inflammation markers in a group of children who were administered oral glutathione at a dose of 65 mg/kg of body weight daily for 6 months.


Studies:

“Improvement in clinical markers in CF patients using a reduced glutathione regimen: an uncontrolled, observational study”, Journal of Cystic Fibrosis, September 2008; 7(5):433-6.
 Visca A, Bishop CT et al.

“A clinical trial of glutathione supplementation in autism spectrum disorders”, Medical Science Monitor, December 2011; 17(12):CR677-82.
 Kern JK, Geier DA, Adams JB et al.

"Oral reduced l-glutathione improves growth in pediatric cystic fibrosis patients: a randomized clinical trial", J Pediatr Gastroenterol Nutr. 2015 Jan Visca A, Bishop CT et al.



ORAL GLUTATHIONE IN STUDIES ON HEALTHY ADULTS


Research published before 2013 using healthy human subjects proves very poor bioavailability of oral and dietary glutathione:

1.“Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers”, Journal of Alternative and Complementary Medicine, September 2011; 17(9):827-33.
Allen J, Bradley RD.

The effect of glutathione supplementation on biomarkers of systemic oxidative stress was examined in 40 healthy adult volunteers. This was a randomized, double-blind, placebo-controlled clinical trial. There were no differences in oxidative stress biomarkers between treatment groups before the study began. Then one group of volunteers were given 500 mg of oral GSH supplement twice daily for 4 weeks, another group received placebo. At the end of the study total reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH to GSSG (indicator of oxidative stress) were unchanged in both groups compared to the results obtained before supplementation. It was concluded that no significant changes were observed in biomarkers of oxidative stress, including glutathione status, in this clinical trial of oral glutathione supplementation in healthy adults.


2.“The systemic availability of oral glutathione”, European Journal of Clinical Pharmacology, 1992; 43(6):667-9.
Witschi A, Reddy S, et al.

Supplementation with glutathione pills was studied in 7 healthy volunteers. During 4.5 hours after the administration of glutathione in a massive dose of 3 g (3,000 mg) the concentrations of glutathione, cysteine, and glutamate in plasma did not increase significantly, suggesting that the systemic availability of glutathione is negligible in man. It was concluded that dietary glutathione is not a major determinant of circulating glutathione, and it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g (3,000 mg) of glutathione.


3. “Dietary glutathione intake in humans and the relationship between intake and plasma total glutathione level”, Nutrition and Cancer, 1994;21(1):33-46.
Flagg EW, Coates RJ, Eley JW et al.

This study investigated the associations between glutathione intake from food and plasma glutathione level (supplements were not used in this study). Concentrations of plasma total glutathione were measured in 69 white men and women before and after consumption of dietary GSH. Daily glutathione intake ranged from 13 to 109.9 mg (mean 34.8 mg). One of the observations was small negative correlations between dietary and plasma glutathione meaning that there is a possible decrease in blood GSN after ingestion of GSH containing foods. This negative correlation was higher in those with higher serum vitamin C levels indicating that high C levels may actually decrease Glutathione. It was concluded that factors regulating plasma Glutathione concentration are complex and not simply related to dietary glutathione intake.


UPDATE #1 on oral GSH in healthy adults:

A recent 2013 study with 54 healthy adults registered a 30-35% increase in blood plasma GSH levels after 6 months of supplementing with oral glutathione at 1,000 mg/day. The GSH levels returned back to baseline one month after the end of the trial. Setria GSH brand was used in this study. ("Enhanced Glutathione Levels in Blood and Buccal Cells by Oral Glutathione Supplementation". Richie JP, Nichenametla S et al. The FASEB Journal. April 2013;27:862.32).

These new oral glutathione results sound very interesting and promising. However, there are several concerns that I would like to address:

  1. It took six (!) months to achieve results that could potentially affect immune health. Most people with health issues that require immediate attention do not have that much time to wait to raise their GSH levels – for example, those who cannot shake off that flu, or cannot breathe due to asthma or emphysema, or those who prepare to undergo cancer treatments, or those who are in constant pain like Ray used to be when his peripheral neuropathy progressed. It would be interesting to see a study investigating oral GSH supplementation in people with diseases.
  2. This is an isolated study with a specific brand of oral glutathione. Can the results be duplicated? Will other brands (and there are quite a few of them) produce the same results at the same dose and within the same timeframe? Will the results be consistent from brand to brand? More studies with this and other brands of oral glutathione are needed to answer these questions.
  3. Setria GSH is produced by a Japanese company Kyowa Hakko Bio Co. at its facilities in the Yamaguchi prefecture not far from the site of the Mitsui Petrochemical Complex where there were two explosions and a fire in April 2012. It’s been reported that several tons of radioactive waste and uranium were in storage at this site. The officials stated there was no leakage of radioactive material in the air. But for me this fact still raises a question of Setria GSH safety. (you can google “Yamaguchi plant explosion” for details).

UPDATE #2 on oral GSH:

Another Japanese company, Kohjin, funded and published a study in June 2014 that showed a considerable increase in protein-bound glutathione in blood plasma 60-120 minutes after supplementation with this company's oral glutathione made from Torula yeast. There was no significant difference in glutathione contents in the deproteinized fraction of plasma and blood cell fraction after ingestion. This study was conducted in healthy volunteers who took the supplement at a single dose of 50 mg/kg of body weight. This dose is equivalent to a massive dose of 3,500 mg in an average 150 lbs. adult. (Increase in the Protein-Bound Form of Glutathione in Human Blood after the Oral Administration of Glutathione. Park EY, Shimura N et al. J Agric Food Chem. 2014 Jul 2;62(26):6183-9. doi: 10.1021/jf501338z. Epub 2014 Jun 11)

Protein-bound glutathione cannot be readily used by the cells. The amino acid components can be utilized to make intracellular glutathione only after the protein is disassembled by the special enzymes and the constituent amino acids are transported through the cell membrane. And in the case of cysteine, this amino acid needs to be in the bioavailable form that can enter the cell.

Also, the safety of prolonged use of very high doses of glutathione in humans has not yet been studied.


IMPORTANT SAFETY INFORMATION TO KEEP IN MIND


As we know, natural production of glutathione occurs only intracellularly. Most of glutathione is used inside the cells for antioxidant defense, detoxification and many other processes that require glutathione.

Glutathione is also exported outside the cells where it is needed to protect red and white blood cells and keep GSH/GSSG ratio balanced. How much glutathione is produced and exported by cells is very tightly regulated by the enzyme glutamate-cysteine ligase (GCL), the first enzyme in the synthesis of glutathione.

Flooding the bloodstream with oral glutathione may slow down and over time even shut down the natural intracellular production because cells “detect” that excess and mistakenly perceive it as a sign that the stores are adequate. The same phenomenon can be observed with the hormones - for example, natural production of melatonin or testosterone decreases with the synthetic supplementation.

Liver is the organ where glutathione is produced at the highest rate and where most of the bloodstream glutathione comes from. Depletion of liver glutathione because of this “misinterpreting” would be devastating to health.

This concern has even been voiced by some renowned specialists:

A quote from Dr. Mercola’s article on glutathione: “Glutathione supplementation can help people with immunodeficiency but only to a certain degree, and only temporarily—kind of like recharging a dead battery. Ironically, glutathione supplements may actually interfere with your body’s own glutathione production. The human body is programmed to self-produce its own antioxidant enzymes such as glutathione… And synthetic supplementation of these compounds actually signals your body to stop its own production – which leaves you dependent on synthetic substances…”

In his book “Glutathione. Your body’s most powerful protector” Dr. Jimmy Gutman refers to a study that registered a decrease in blood glutathione after ingestion of GSH-containing foods. It was not statistically significant but consistent among all groups of participants. It is worth noting that GSH concentration in foods is much lower than what is recommended for oral supplementation. (Dietary glutathione intake in humans and the relationship between intake and plasma total glutathione. Flagg EW et al. Nutrition and Cancer. 21:33-46, 1994).

Dr. Alan Pressman, the author of "Glutathione, the Ultimate Antioxidant", warns against the use of oral glutathione supplements by patients with ulcers caused by H. pylori bacteria. The reason for this concern is that some researchers believe these bacteria survive by feeding on macrophages and neutrophils abundant at the site of inflammation caused by the ulcer. Since glutathione can improve the numbers and activity of macrophages the problem can be exasperated by oral glutathione.

Dr. Pressman also warms against the use of supplemental l-cysteine or NAC in ulcer patients because these supplements thin mucus which can further deteriorate the damaged mucus lining in the stomach.

More research is needed to fully assess the consequences of long-term high-dose oral glutathione supplementation. However, for ethical reasons human trials are unlikely to be performed.



ORAL GLUTATHIONE: CONCLUSIONS


Several human trials performed before 2013 have shown that over-the-counter oral glutathione supplementation has negligible effect on raising Glutathione levels in humans. Only one recent 2013 trial done by Dr. Richie showed that oral supplementation raises blood GSH levels in healthy adults after 6 months on 1,000 mg/day of a specific GSH brand. Another study showed an increase in protein-bound GSH after a single 3,500 mg dose of a specific oral glutathione formulation. More studies are needed to confirm these results, and also to prove that oral supplementation is effective in raising GSH levels in major detoxification organs - liver, kidneys and lungs.

More research is needed to prove complete safety of prolonged high-dose glutathione supplementation and its effect on natural intracellular glutathione production. 

Oral glutathione is able to raise GSH levels in blood and organs of mice that were first chemically depleted of glutathione. However, GSH levels in liver were still unchanged where it was most needed for detoxification. Oral glutathione supplementation was at extremely high doses and had short-term effect.

Oral glutathione used at high doses and in combination with GSH injections, patches or inhalers appears to be beneficial for patients with autism and cystic fibrosis who are usually glutathione deficient. This regimen may be of benefit also to patients with other lung diseases - asthma, emphysema and bronchitis.


OTHER FORMS OF ORAL GLUTATHIONE


Liposomal (lipoceutical) glutathione

This form of oral glutathione differs from GSH in pill form. In this case GSH molecule is encapsulated in water inside a fat ball that is so small that it cannot be seen with a naked eye. The digestive system is “tricked” into interpreting it as a fat cell and does not digest and break it down as it would do with GSH pills, thus allowing it to enter the cell.

There are studies on cell culture (in a tube) and rodents proving that liposomal glutathione is in fact effective in maintaining GSH levels under the conditions of exposure to dangerous toxins or induced disease.

Cell culture studies cannot be applied to human physiology, and rodents also absorb oral GSH pills quite well, so no wonder they would absorb liposomal GSH.

One study on humans - with autistic children - showed that the oral liposomal group (compared to the transdermal group) exhibited some increases in plasma reduced glutathione, but not in whole-blood glutathione levels following supplementation. The authors stated: "We did not see a change in whole-blood glutathione which suggests that increasing intracellular glutathione may require the use of precursors or building blocks for glutathione". Both groups also showed increases in plasma sulfate and cysteine which the authors attributed to actual breakdown of glutathione in the body.(A clinical trial of glutathione supplementation in autism spectrum disorders. Kern JK et al. Med Sci Monit. 2011 Dec;17(12):CR677-82). This human study was not blinded or placebo-controlled which is the golden standard in medical research.

The problem with liposomal GSH method is that it lacks specific human trials and claims are based on general tube/rodent research only. Secondly, liposomes (those fat balls) degrade quickly, within a few months of the date of manufacture. A product that has not been made recently may not be effective. And lastly, liposomes are made out of soy lecithin raising the question of safety since almost all soy is GMO nowadays, and also there may be an allergy concern for some people. Other common ingredients in liposomal glutathione are glycerin, vegetable oil emulsifiers, titanium dioxide and potassium sorbate as a preservative.


S-acetyl-glutathione (SGSH or Sag)

This form of oral glutathione is attached to a sulfur atom (hence the "S"), supposedly making it stronger for it to be able to survive the digestive tract.

A search on PubMed returned only 14 articles altogether. Several studies indeed concluded SGSH as more viable than simple oral GSH, and even able to kill off viruses in cells and kill cancer cells. But these several studies were done on cell culture in tubes and one study - on mice.

There are no human trials proving SGSH raises glutathione in humans. The oldest study dates back to 1994 with only a few more done since then:

1. S-acetyl- and S-phenylacetyl-glutathione as glutathione precursors in rat plasma and tissue preparations. Galzigna L, Rizzoli V, Schiappelli P, Moretto C, Bernareggi A. Enzyme Protein. 1994-1995;48(2):98-104. PMID: 7581748

2. Reduced glutathione and S-acetylglutathione as selective apoptosis-inducing agents in cancer therapy. Donnerstag B, Ohlenschlager G, Cinatl J, Amrani M, Hofmann D, Flindt S, Treusch G, Träger L. Cancer Lett. 1996 Dec 20;110(1-2):63-70. Erratum in: Cancer Lett 1997 May 19;115(2):265. PMID: 9018082

3. S-acetyl-glutathione selectively induces apoptosis in human lymphoma cells through a GSH-independent mechanism. Locigno R, Pincemail J, Henno A, Treusch G, Castronovo V. Int J Oncol. 2002 Jan;20(1):69-75. PMID: 11743644

4. Effects of S-acetylglutathione in cell and animal model of herpes simplex virus type 1 infection. Vogel JU, Cinatl J, Dauletbaev N, Buxbaum S, Treusch G, Cinatl J Jr, Gerein V, Doerr HW. Med Microbiol Immunol. 2005 Jan;194(1-2):55-9. Epub 2003 Nov 18. PMID: 14624358

5. S-Acetylglutathione normalizes intracellular glutathione content in cultured fibroblasts from patients with glutathione synthetase deficiency. Okun JG, Sauer S, Bähr S, Lenhartz H, Mayatepek E. J Inherit Metab Dis. 2004 PMID: 15617191

6. Inhibition of murine AIDS by pro-glutathione (GSH) molecules. Fraternale A, Paoletti MF, Casabianca A, Orlandi C, Schiavano GF, Chiarantini L, Clayette P, Oiry J, Vogel JU, Cinatl J Jr, Magnani M. Antiviral Res. 2008 Feb;77(2):120-7. doi: 10.1016/j.antiviral.2007.11.004. Epub 2007 Dec 17. PMID: 18164447

This evidence is not enough to state that SGSH form of oral glutathione can raise glutathione levels in humans. Cell cultures usually get doused with material in question (in this case SGSH) and they almost always respond positively because this way cells come into direct contact with whatever scientists investigate. Human physiology is much more complex than a sample of cells.


Further reading:

What are the options for raising glutathione levels effectively and safely?

What are glutathione precursors?

Cysteine – the limiting factor of Glutathione production.

What are glutathione cofactors and why you need them?

What depletes Glutathione?

Oral glutathione for skin whitening: does it really work?




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