Glutathione or NAC: What's the Difference

Glutathione is called "the cell's master antioxidant", and NAC "the precursor of glutathione". Because of this they are often regarded as two ways of achieving one and the same thing. Yet one is a ready-made tripeptide that the body is not very willing to absorb, and the other a modified amino acid with a long history of medical use. The editorial team has examined what the difference is.

What glutathione is and what NAC is

Glutathione (GSH) is a tripeptide consisting of three amino acids: glutamate, cysteine and glycine. An unusual feature of its structure is the bond of glutamate with cysteine through the gamma-carboxyl group, which protects the molecule from ordinary peptidases. The functional part is the thiol (SH) group of cysteine, which donates electrons to neutralize oxidants.

N-acetylcysteine (NAC) is a derivative of the amino acid cysteine, to whose nitrogen atom an acetyl group is attached. This modification makes the molecule more stable than free cysteine, which oxidizes quickly. In the body NAC is deacetylated, and the released cysteine can be used for the synthesis of glutathione and proteins.

So the fundamental difference is this: glutathione is the end product, an active antioxidant, whereas NAC is a source of one of its components. Cysteine is usually the limiting component of glutathione synthesis, so supplying it is a logical way to support one's own production.

NAC also has its own effects, independent of glutathione. It breaks the disulfide bonds in mucins, thinning phlegm (hence its use as a mucolytic), and can affect glutamatergic transmission in the brain through the cystine-glutamate exchanger, which became the basis for research in psychiatry.

How the body synthesizes glutathione

Glutathione is synthesized inside cells in two stages, both consuming ATP. First the enzyme glutamate-cysteine ligase (GCL) joins glutamate and cysteine, then glutathione synthetase attaches glycine. The first stage is rate-limiting, and its activity depends on the availability of cysteine and is regulated by feedback from glutathione itself.

The highest concentration of glutathione is in the liver, which also exports it into the blood for other tissues. In cells it exists predominantly in the reduced form GSH; when neutralizing oxidants, two molecules form oxidized glutathione GSSG, which the enzyme glutathione reductase reduces again using NADPH.

The functions of glutathione are broader than "antioxidant capacity". It is a substrate for the glutathione peroxidases, which neutralize peroxides; it takes part in the detoxification of xenobiotics through glutathione S-transferases; it keeps vitamins C and E in the reduced state; it regulates protein activity through glutathionylation.

The level of glutathione falls with oxidative stress, some chronic diseases, and age, as well as in paracetamol poisoning, when the toxic metabolite NAPQI depletes the liver's glutathione stores. This last case became the most famous medical story of NAC.

Absorption: direct delivery or "raw material"

For a long time it was believed that oral glutathione practically does not raise its level in the blood. The study by Witschi and colleagues (1992) showed that a single intake of a large dose of glutathione did not increase its concentration in plasma, since the tripeptide is broken down in the intestine by the enzyme gamma-glutamyltransferase.

Later data proved less clear-cut. In the randomized study by Richie and colleagues (2015), prolonged daily intake of glutathione over six months increased its stores in the blood and other tissues in a dose-dependent manner. That is, chronic intake probably does have some effect, though the mechanism and practical significance are still debated.

NAC also has low bioavailability in unchanged form — a significant part is metabolized already in the intestine and liver. But for NAC this is not a problem but part of the mechanism: its task is to supply cysteine, which enters the bloodstream and tissues. The review by Rushworth and Megson (2014) emphasizes that it is precisely the conversion into intracellular glutathione that explains most of NAC's antioxidant action.

Manufacturers of glutathione offer liposomal and sublingual forms and S-acetylglutathione, intended to bypass destruction in the intestine. Some of them have shown promising results in small studies, but there are few comparative data with NAC on equal terms.

Medical status and the evidence base

NAC is a registered medicinal product in most countries. Intravenous acetylcysteine is the standard antidote for paracetamol overdose, which is included in medical guidelines. Oral forms are used as mucolytics in respiratory diseases. So the pharmacology and safety of NAC are very well studied.

In the US, the status of NAC as a dietary supplement became the subject of regulatory debate in the 2020s, since the drug was approved as a medicine before it appeared on the supplement market. The FDA subsequently announced an approach that allows its sale as a supplement under certain conditions. The status differs across countries.

Glutathione as a medicinal product is used far more narrowly — mainly in intravenous forms in some countries. Oral glutathione is primarily a food supplement with a smaller body of clinical data. The intravenous "skin lightening" with glutathione that is popular in cosmetology has no proper evidence base and is associated with risks.

• NAC:antidote for paracetamol poisoning, mucolytic, research in pulmonology and psychiatry.
• Glutathione:predominantly a supplement; research on tissue stores and individual conditions.
• Sport:for both there is a small body of work on oxidative stress, without convincing evidence of improved results.

In the athletic context the work by Paschalis and colleagues (2018) is interesting: NAC improved performance measures and reduced markers of oxidative stress only in people with initially low glutathione levels. For those with a normal level there was no benefit. This underscores the principle: antioxidant support makes sense mainly in a deficiency.

Safety and side effects

Oral NAC is usually well tolerated. The most common adverse effects are nausea, vomiting, diarrhea and an unpleasant sulfurous smell and taste. Intravenous administration at the high doses used in paracetamol poisoning can cause anaphylactoid reactions, so it is carried out only in a hospital.

NAC can increase bronchospasm in some people with bronchial asthma when used by inhalation, and also interacts with nitroglycerin, enhancing its vasodilatory action and headache. People who take medications continuously should discuss its use with a doctor.

Oral glutathione was also well tolerated in studies; no serious adverse effects have been described when taken at the doses used in research. The main risks concern intravenous use outside medical facilities — from infectious complications to reactions to unknown impurities in illegal preparations.

Common to both is the risk of chronic intake of high doses of antioxidants by athletes. The review by Merry and Ristow (2016) discusses the possibility of blunted training adaptations against a background of massive antioxidant support, so for people with normal status a "preventive" daily intake is not obviously beneficial.

Editorial conclusions

Glutathione is a ready-made intracellular antioxidant; NAC is a stable source of the cysteine that limits glutathione synthesis, and an independent medicinal product with a mucolytic action.

NAC has a far broader medical history and evidence base, including its status as an antidote for paracetamol poisoning. Oral glutathione is absorbed worse, though prolonged intake, according to some data, is able to raise its stores.

The benefit of both substances is most likely highest in people with a reduced level of glutathione, not in healthy people with normal status.

How to choose between them for a specific goal, the editorial team explains in the article "Glutathione vs NAC: What to Choose and for Whom". We also recommend pieces on whey protein as a source of cysteine and on antioxidants and training adaptations.

References

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2. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141(2):150–159.
3. Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992;43(6):667–669.
4. Richie JP Jr, Nichenametla S, Neidig W, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. 2015;54(2):251–263.
5. Paschalis V, Theodorou AA, Margaritelis NV, et al. N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione. Free Radic Biol Med. 2018;115:288–297.
6. Merry TL, Ristow M. Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? J Physiol. 2016;594(18):5135–5147.