Home Glutathione Facts N-Acetylcysteine (NAC) cannot increase cellular Glutathione levels

N-Acetylcysteine (NAC) cannot increase cellular Glutathione levels



Over the years, there have been countless papers written on the importance of glutathione (GSH) and the myriad of ways to supplement this free radical scavenger. By now, we are all aware of its significance in keeping us healthy, but, unfortunately, there are many myths on how to enhance cellular glutathione (GSH) effectively.

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.


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  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.
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  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.
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  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.


  1. Please comment on this recent study showing NAC and glycine taken in combination do raise GSH. Seems promising.

    Glycine and N‐acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002905/ Clinical and Translational Medicine

    • There is no scientific or biochemical reason to mix NAC and glycine since cells always contain more than enough glycine to form glutathione. In fact, both cysteine and glycine are not only non-essential amino acids that our body synthesises, but they are also abundant in our diets. There have been countless unsuccessful attempts to increase cellular glutathione with NAC and several hundred published papers confirm this finding. Adding glycine is just another marketing hype that ignores the fact that, nutritionally, a lack of glycine is not the reason why glutathione may be low.

      The research of this mixture has many inaccuracies and the data presented does not lead to the conclusion that NAC + glycine will increase cellular glutathione levels. More importantly, none of the amino acids that make up glutathione are really ever in undersupply. Glutathione levels can become depleted because the first step enzyme in glutathione synthesis that makes gamma-glutamylcysteine is dysfunctional. Throwing more amino acids into the mix will not make a difference

      • Thank you for cutting through the hype. Should I assume in the future that the journal of Clinical and Translational Medicine is not a reliable peer reviewed publication? I also missed the connection that the study site, Baylor School of Medicine, held the patent for GlyNAC. Distressing that this medical school would lend its name to this flawed study.

        • It’s certainly disappointing to see that both the reviewers and editors of the Journal of Clinical and Translational Medicine and the Baylor School of Medicine allow such publications to be made. It does point to one observation that researchers are desperate to find some way to increase cellular glutathione. It’s just a shame that their quest is often misguided and clouded by commercial imperatives.


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