Hi Matt,
Firstly, you need to take into consideration that both NAC and NAC ethyl ester are drugs – they are not natural – NAC is commonly marketed as a dietary supplement, but this is the subject of a current investigation by the USA’s FDA. It should also be noted that, unlike NAC, NAC ethyl ester is still an experimental drug, with the few published studies limited to cell culture and animal models. No animal toxicity or human bioavailability studies have as yet been reported in the literature. Why it is available for sale as a dietary supplement is a regulatory mystery as it does not seem to have FDA approval or GRAS status.

NAC was first introduced as a drug in the 1960s for the treatment of acetaminophen/paracetamol overdose, which acutely depletes glutathione in the liver. Cysteine is the rate-limiting amino acid in glutathione synthesis (i.e., the first one to run out) but cysteine itself can be toxic, particularly in the high doses required for treating such overdoses. NAC is considered a less toxic form and hence a safer treatment. The papers you cite provide evidence that NAC ethyl ester is more bioavailable than NAC i.e., it is capable of delivering more cysteine to cells than NAC and the authors suggest that this may make NAC ethyl ester a superior antidote, which they have explored in another report. The problem that NAC ethyl ester will have in replacing NAC as the approved antidote is gaining ethics approval for the required human clinical studies. Given that NAC is effective in treating overdoses, attempting to gain informed consent, from those suffering an overdose, to try something different with unknown risks and without clinical evidence of efficacy in a clinical trial should not be considered ethical. Most of the authors’ findings are based on NAC ethyl ester being more bioavailable than NAC to help cells that have been acutely depleted of glutathione (e.g., through drug overdose) get back to homeostasis. However, for those wishing to increase their glutathione levels above homeostasis then the only theoretical and clinically (human) demonstrated option is gamma-glutamylcysteine, which is the immediate natural precursor to glutathione and provides a unique option for bypassing the regulatory control of cellular glutathione homeostasis. Unlike NAC and NAC ethyl ester, gamma glutamylcysteine is ubiquitous in nature – it is produced by every cell of all life that uses oxidative phosphorylation (oxygen) to release energy. It is also a significant component of mammalian milk and egg whites and as such is an inarguable food component. We will most certainly look to including an article that describes the research, opportunities, and limitations of NAC ethyl ester

https://www.sciencedirect.com/science/article/abs/pii/S0006295212006417?via%3Dihub
https://www.sciencedirect.com/science/article/abs/pii/S0891584918311055?via%3Dihub

Dear Dwan, From what I understand of the product you are talking about is so-called nano-sized glutathione in a water solution that you swish in your mouth. Unfortunately, the producer of this product has not understood that it is impossible to get nano-sized particles of glutathione in water suspension because glutathione itself is a very water-soluble compound so as soon as those crystals of glutathione, whether they are nano-sized or normal-sized touch the water they dissolve rapidly. All they are selling is a solution of glutathione in water with a few other ingredients and flavoring thrown in. This is no different from taking a solid supplement of glutathione that dissolves in your stomach anyway. The details of why glutathione supplementation cannot increase cellular glutathione levels can be seen at this article:- https://www.glutathionereporter.com/glutathione-supplementation-cannot-increase-cellular-glutathione-levels/

Hi etrc,
We are a group of scientists that are interested in glutathione.
Please see our “About” message at https://www.glutathionereporter.com/about/
If you think any of the statements, made here are untrue or wrong, please inform us so.

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.

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.

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

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