Glutathione (GSH): what it is and what the studies show

Glutathione (abbreviated GSH) is a tripeptide, a small molecule made of three amino acids: glutamic acid, cysteine and glycine. Its chemical name is γ-glutamyl-cysteinyl-glycine (Lu, Biochim Biophys Acta 2013, PMID 22995213).

It is an endogenous substance: the human body makes it on its own. It is present in all mammalian tissues and is the most abundant thiol (-SH) compound that is not part of a protein. It is synthesised inside the cell, in the cytosol, in two enzymatic steps. In the first, the enzyme glutamate-cysteine ligase (GCL) joins glutamic acid to cysteine. In the second, glutathione synthetase (GS) adds glycine. The rate of synthesis depends mainly on the amount of cysteine present in the cell and on the activity of the first enzyme (Lu, Biochim Biophys Acta 2013, PMID 22995213).

The "γ" in the name matters. In most peptides the amino acids are linked in the same, standard way. In glutathione, glutamic acid is linked to cysteine from a different position on its molecule, the γ-carboxyl group. This unusual bond is one of the features that set it apart from ordinary peptides (Lu, Biochim Biophys Acta 2013, PMID 22995213).

Glutathione occurs in two main forms. The reduced form (GSH) has the thiol group of cysteine free. When two GSH molecules give up electrons in a reaction, they join through a disulphide bond and form the oxidised form, GSSG (glutathione disulphide). Inside the cell, GSSG can be turned back into GSH with the help of an enzyme, glutathione reductase, and the conversion between the two forms goes on continuously (Lu, Biochim Biophys Acta 2013, PMID 22995213).

In research, the ratio of the two forms is used as a marker of redox status. When the oxidised form rises relative to the reduced form, researchers read it as a sign of oxidative stress (Richie et al., Eur J Nutr 2015, PMID 24791752). That is why human studies measured not only total glutathione but also the two forms separately, as well as their ratio (Allen and Bradley, J Altern Complement Med 2011, PMID 21875351).

In the biochemical literature, glutathione is described as the most abundant small-molecule thiol compound synthesised by cells. The roles attributed to it are mainly three (Forman et al., Mol Aspects Med 2009, PMID 18796312):

• Removal of oxidants: it takes part in reduction reactions that convert reactive oxidising compounds into less reactive ones.
• Conjugation of foreign substances: it binds electrophilic compounds so that they can be removed from the cell.
• Redox balance: it takes part in maintaining the balance between oxidising and reducing processes inside the cell.

These roles describe the glutathione that the cell makes itself. On their own, they do not mean that glutathione taken in from outside, as a supplement, reaches the cells or has the same effect. That is a separate question, and the human studies that follow tried to answer it.

The human studies summarised here looked at one specific question: whether taking glutathione as a supplement changes its levels in the blood. The results were not the same in all of them.

• Single-intake study (Witschi et al., Eur J Clin Pharmacol 1992, PMID 1362956): in 7 healthy volunteers, plasma levels of glutathione, cysteine and glutamate were measured for 270 minutes after a single intake. The concentrations did not rise significantly. The authors attributed the finding to the breakdown of glutathione by enzymes in the intestine and liver.
• 4-week randomised trial (Allen and Bradley, J Altern Complement Med 2011, PMID 21875351): 40 healthy adults, with a placebo group. 39 participants completed it. No significant changes were recorded in urinary oxidative stress markers, nor in red blood cell glutathione (reduced, oxidised and their ratio).
• 6-month randomised trial (Richie et al., Eur J Nutr 2015, PMID 24791752): 54 non-smoking adults, with a placebo group and two groups with different amounts. Blood glutathione levels rose from baseline at months 1, 3 and 6 in both groups. At 6 months, in the higher-amount group, the mean increase was 30-35% in red blood cells, plasma and lymphocytes, and 260% in cells of the buccal mucosa. In the lower-amount group, the increase was 17% in whole blood and 29% in red blood cells. In most cases, levels returned to baseline after a one-month break. The ratio of oxidised to reduced glutathione in whole blood fell at 6 months in both groups. In a subset of participants, the cytotoxic activity of NK cells, which belong to the immune system, was measured at more than twice the placebo value at 3 months, in the higher-amount group.

The three studies differed in duration, in amount and in the sample measured: the single-intake study and the 4-week study recorded no change, while the 6-month study recorded an increase, already at month 1. It is not clear which of these factors explains the difference. The authors of the latter note that, before their study, bioavailability had been shown in laboratory animals, while efficacy in humans had not been established.

Glutathione has also been studied for its relationship with skin colour, because the literature examines whether it affects melanin production. In the human studies, the main measure was the melanin index, which is measured with a dedicated device on the skin.

• 4-week randomised trial (Arjinpathana and Asawanonda, J Dermatolog Treat 2012, PMID 20524875): 60 healthy medical students, glutathione in capsules or placebo. The melanin index fell at all six measurement sites in the glutathione group. The reduction was statistically greater than placebo at two of the six sites: the right side of the face (p = 0.021) and the sun-exposed left forearm (p = 0.036).
• 12-week randomised trial (Weschawalit et al., Clin Cosmet Investig Dermatol 2017, PMID 28490897): healthy women in three groups, reduced form (GSH), oxidised form (GSSG) or placebo. The melanin index and ultraviolet spots tended to be lower than placebo with both forms. At some measurement sites, the reduced-form group had a significant reduction in wrinkles compared with placebo.
• 8-week randomised trial (Wahab et al., Int J Dermatol 2021, PMID 33871071): 46 participants in two equal groups: one group received placebo and the other glutathione as a supplement, and all participants had placebo applied to one side of the face and glutathione to the other. The combination group (supplement plus topical application) had a significantly lower melanin index than placebo (P < 0.05).

A systematic review of the studies on skin colour, with a literature search up to October 2017, concluded that the evidence is not yet conclusive, because of the quality of the studies and inconsistent findings (Dilokthornsakul et al., J Cosmet Dermatol 2019, PMID 30895708).

A separate matter is skin-lightening products sold in injectable form. The US Food and Drug Administration (FDA) issued a public warning about such products, which may contain glutathione. According to the notice, the FDA had not approved any such drug for skin lightening, and these products may carry risks, may not work and may contain unknown ingredients or contaminants (FDA, Consumer Update, updated 26/09/2017). The warning concerns these products, not the studies of supplements and topical formulations described above.

It is the same molecule, but not the same situation. The body's glutathione is made inside each cell, from the amino acids available to it, and stays mostly there (Lu, Biochim Biophys Acta 2013, PMID 22995213). The glutathione in a supplement must first pass through the digestive system, where enzymes of the intestine and liver can break it down into its amino acids (Witschi et al., Eur J Clin Pharmacol 1992, PMID 1362956).

That is why findings about the roles of glutathione inside the cell do not carry over automatically to what happens after a supplement is taken. Human studies that measured blood levels gave different results, depending on their duration and design. And where an increase was recorded, what was measured was the concentration of glutathione in the blood and in certain cells, not any health outcome.

Glutathione is sold as a food supplement and as an ingredient in cosmetic products. These are finished formulations with a specific composition. Research glutathione is the substance as a powder, for laboratory use.

The human studies mentioned above concern supplements and cosmetic formulations. They do not concern the research material, and their findings do not carry over to it. For the differences between the categories of peptides, see the guide "What are peptides". Another tripeptide that has been studied for the skin is GHK-Cu, the copper peptide.

The human studies summarised here are few and small, each with a limited number of participants, and the longest duration was 6 months. The results for blood glutathione levels do not agree with each other, and it is not clear what explains the difference.

An increase in blood levels is a laboratory measurement. It has not been shown to translate into any clinical outcome. For skin colour, a systematic review, with a literature search up to October 2017, described the evidence as inconclusive (PMID 30895708), and the authors of the 4-week study noted that long-term safety has not been established and that more extensive clinical trials are needed (PMID 20524875). Research in humans is at an early stage.

A certificate of analysis records the purity of the substance measured by HPLC, its identity, the laboratory that ran the analysis and the batch number it refers to. Published certificates are in the COA library.

Yes. It is a tripeptide, a peptide of three amino acids. It differs from most peptides in the bond between glutamic acid and cysteine, which is made from the γ-carboxyl group.

GSH is the reduced form of glutathione, with a free thiol group. GSSG is the oxidised form, two glutathione molecules joined by a disulphide bond.

In a study that measured glutathione in common foods, dairy products, cereals and bread were generally low in it. Fruits and vegetables had moderate to high amounts, and freshly prepared meat relatively high amounts. Some forms of food processing led to extensive loss of glutathione (Jones et al., Nutr Cancer 1992, PMID 1574445).

In the 12-week study, no serious adverse events were recorded (PMID 28490897). In the 4-week study, the authors reported that both glutathione and placebo were very well tolerated, while noting that long-term safety has not been established (PMID 20524875). The 2019 systematic review reported that some adverse events were recorded, none of them serious (PMID 30895708). The studies were small and short.

• Witschi A et al. Eur J Clin Pharmacol. 1992. PMID 1362956 · DOI 10.1007/BF02284971
• Jones DP et al. Nutr Cancer. 1992. PMID 1574445 · DOI 10.1080/01635589209514173
• Forman HJ, Zhang H, Rinna A. Mol Aspects Med. 2009. PMID 18796312 · DOI 10.1016/j.mam.2008.08.006
• Allen J, Bradley RD. J Altern Complement Med. 2011. PMID 21875351 · DOI 10.1089/acm.2010.0716
• Arjinpathana N, Asawanonda P. J Dermatolog Treat. 2012. PMID 20524875 · DOI 10.3109/09546631003801619
• Lu SC. Biochim Biophys Acta. 2013. PMID 22995213 · DOI 10.1016/j.bbagen.2012.09.008
• Richie JP et al. Eur J Nutr. 2015. PMID 24791752 · DOI 10.1007/s00394-014-0706-z
• Weschawalit S et al. Clin Cosmet Investig Dermatol. 2017. PMID 28490897 · DOI 10.2147/CCID.S128339
• Dilokthornsakul W, Dhippayom T, Dilokthornsakul P. J Cosmet Dermatol. 2019. PMID 30895708 · DOI 10.1111/jocd.12910
• Wahab S et al. Int J Dermatol. 2021. PMID 33871071 · DOI 10.1111/ijd.15573
• U.S. Food and Drug Administration. Consumer Update on skin-lightening products. Updated 26/09/2017.

An informational text summarising published research. It is not medical advice or usage guidance.