In response to yesterday's update about glutathione and COVID-19, a number of questions came in on social media about whether glutathione can be absorbed intact, whether supplements need to be liposomal, and whether N-acetyl-cysteine (NAC) would be just as effective or even better.
Glutathione is absorbed intact in laboratory animals, and crosses human intestinal cells intact. There are known transporters that do this, and oral glutathione increases glutathione status in both animals and humans.
Experiments in animals suggest that glutathione is taken up intact in kidney, heart, lung, brain, small intestine, and skin but possibly not in the liver.
In principle, there is no reason to believe that reduced L-glutathione taken orally as a capsule would not directly increase glutathione concentrations in the lung, where it would protect against oxidative stress, increase the fluidity of mucous, combine with nitric oxide to dilate the bronchial passages, and protect against respiratory distress.
The case for liposomal glutathione rests on experiments using isolated cells. For example, liposomal glutathione is 100 times more effective at delivering glutathione to astrocytes, a particular type of brain cell. However, liposomes have great difficulty surviving digestion unless they are modified to survive the harsh digestive environment by techniques such as coating them with polyethylene glycol (pegylation). Since glutathione appears to be transported intact in the intestine and lung, liposomes shouldn't be necessary to allow oral glutathione to increase lung glutathione and might even be counter-productive.
I am not aware of any randomized controlled trials testing liposomal and non-liposomal glutathione head-to-head in humans.
A small randomized crossover study with 20 people lasting three weeks compared NAC with oral and sublingual glutathione. A randomized crossover trial is one where each subject gets each treatment, but in randomized order, and it helps improve statistical power with small numbers of people. Sublingual glutathione and NAC led to a 5-7% higher plasma level of reduced glutathione, but the authors didn't perform a statistical analysis on this difference. Sublingual glutathione and NAC led to a 26-27% higher ratio of reduced to oxidized glutathione, and this was statistically significant, meaning there is only a small likelihood that the difference would be observed if it resulted from random chance alone.
The doses were 450 mg per day of sublingual or oral glutathione, or 200 mg per day of NAC, which provides enough cysteine to synthesize 600 mg glutathione. It seems from the difference in dose that the comparison between oral glutathione and NAC is not useful from this study. While sublingual glutathione may be slightly better than oral glutathione at the same dose, it costs almost five times as much. It's hard to justify a 5x-higher cost based on a very small study suggesting a 7-27% better effect for an equivalent dose.
Although NAC has been studied much more than oral glutathione has, I personally prefer oral glutathione on theoretical grounds.
Glutathione is a tripeptide made from glutamate, cysteine, and glycine. Glutamate is rarely limiting except in severe disease states because it is the most common amino acid in the diet. Cysteine is usually limiting. However, glycine can be limiting, as evidenced by the excretion of 5-L-oxoproline (pyroglutamate) in the urine, its higher excretion in vegetarians than omnivores, and its suppression by dietary protein. Also known as pyroglutamate, this is a substance that is excreted when the first step of glutathione synthesis, the joining of glutamate and cysteine, exceeds the capacity of the second step, the joining of glycine. This shows that glycine can often be limiting.
Furthermore, glutathione synthesis is regulated by insulin and oxidative stress, and the activity of the synthetic enzymes themselves can be limiting. This is the case in diabetes, where low insulin signaling as a result of insulin resistance leads to poor glutathione status. A euglycemic hyperinsulinemic clamp, which administers large amounts of insulin while keeping blood glucose stable, rescues the poor glutathione status of diabetes. Synthesis also depends on magnesium and ATP, which could also be limiting under conditions of magnesium deficiency or any problems that impact energy metabolism.
The principle of NAC is that it provides cysteine to the cell, which is limiting for glutathione status. But if glycine is limiting, NAC won't help. Glutathione, which contains glycine, will. If synthetic activity is limiting due to insulin resistance, genetics, or low levels of magnesium or ATP, NAC won't help. Glutathione, which is already synthesized, will. In fact, cysteine could be limiting right up until NAC is supplemented, at which point the next most important thing would become limiting, and maybe that would be glycine, magnesium, ATP, or enzyme activity.
Thus, while NAC is well demonstrated to be effective, I believe oral glutathione should be more robust to contextual factors that could make glycine, magnesium, ATP, or enzymatic activity limiting.
Doses as high as 1000 mg of glutathione per day have been shown to be safe over six months and to improve glutathione status. I am not aware of any studies showing the doses used for respiratory distress, but in my personal experience I have found 1000 mg to have an acute effect, and in the case report discussed yesterday 2000 mg, along with 1200 mg NAC, was used each day for five days.
I don't have a strong brand preference, but based on my trust in their quality and their low prices, I personally keep a bottle of Jarrow glutathione in my cabinet. I have more details on supplements as well as food sources of glutathione in my 2017 article, Consuming Glutathione in Foods and Supplements, which contains a searchable database of glutathione in 285 foods.
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* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.