Glutathione is the single most powerful antioxidant manufactured by the human body itself. It’s vital for acne, with 20% reduced levels in pimple-covered skin, and deficiencies are common in the 21st century.
But the eternal question which no man or woman can answer is whether supplements work.
For years, the consensus was that oral glutathione simply shattered in the human stomach, like the natural serotonin found in melons. Its molecular size was tiny (true), it couldn’t withstand the digestive acids and enzymes, and it couldn’t enter your bloodstream to perform its antioxidant magic. I believed it myself, and the entire glutathione supplement industry has often been dismissed as a joke.
Recently, however, the balance of evidence has swung the other way. There’s several details to be ironed out – for example, why were the old studies so negative in the first place?
But if I had to guess right now, I would say that oral glutathione does work, including for clear skin.
Where we stand
Firstly, some important background. Glutathione is manufactured by combining the amino acids cysteine and glutamine, which requires the enzyme glutamate cysteine ligase. This enzyme itself requires either manganese or magnesium as a co-factor, which is partially why I recommend magnesium for acne. Simultaneously, this process requires ATP cellular energy, which magnesium is required to create. Finally, the amino acid glycine is added to form the finished glutathione, a tripeptide molecule.
Therefore, the conundrum with supplements is straightforward: is the glutathione really being absorbed, or is it being broken down into its three amino acids and recycled?
This is why there’s so much controversy on oral glutathione. Analysing the evidence is particularly tricky. If the subjects weren’t eating much protein, the glutathione ingredients will be missing, and seemingly fantastic results can prove nothing.
I already recommend the three amino acids for acne, particularly glycine, which is rare in the modern diet but plentiful in gelatin, whey protein, boiled eggs and more. Therefore, if oral glutathione isn’t absorbed directly into the bloodstream, then taking it is pointless.
If oral glutathione is absorbed, then supplements could push your antioxidant defences to new heights, which would be particularly useful in these troubled acne times. Air pollution might have fallen from the smog-filled days of 19th century London (when outsiders widely called it “the big smoke”), but cigarette smoke, pesticides, and unstable soybean oil show no sign of loosening their grip. Because glutathione also acts as detoxification agent, this piles up the pressure on its antioxidant duties.
One substance is widely believed to scupper oral glutathione – gamma-glutamyl transferase (Y-GT), a small intestinal enzyme which breaks down glutathione into its constituent parts. Supposedly, because of Y-GT, only a monster dosage will allow any glutathione through unscathed. In humans, Y-GT is more abundant than in rats, which is partly why people dismiss positive-looking animal studies. Remember the name of Y-GT.
Part 1 – a new wave of optimism
For years, the scepticism was understandable, as the experiments all looked dire compared to simply eating glycine. One 1992 study deflated the balloon of excitement particularly well, as 7 people took 3 grams of oral glutathione. Over the next 270 minutes, their bloodstream glutathione failed to significantly increase.
The study flatly concluded that “the systemic availability of glutathione is negligible in man“. They stated that dietary glutathione (such as in asparagus and cabbage) was resoundingly unimportant. They specifically blamed the hydrolysis by gamma-glutamyl transferase (Y-GT) in the small intestine.
For two long decades, the question was seemingly put to bed, but it was merely dormant. The debate was revived with full force in a 2014 study that sent shockwaves through the world of glutathione science.
54 human beings swallowed either 250mg of glutathione per day, or 1000mg. 6 months later, the normal dosage group averaged at 17% higher bloodstream glutathione, and 29% higher in red blood cells. Team 1000 achieved 31% and 35% increases respectively. 1000mg achieved a 260% rise in buccal cells, or the inside of your cheek.
After ceasing supplementation, their glutathione returned to normal within 1 month.
Better, the body’s own production of glutathione held steady. This is the second fear – that glutathione is absorbed after all, but cripples your own indigenous supply, out of the frying pan and into the fire. It’s similar to taking steroids, and feeling like superman for 2 weeks before your own testosterone suddenly shuts down. Luckily, the enzyme glutamate cysteine ligase (GCL) did not decrease, the one that combines cysteine and glutamine. GCL is the “rate-limiting” enzyme in glutathione production, the first one scientists check. Additionally, the 1992 doomsday study examined just 7 volunteers, although testing humans gives them reliability points.
The study reveals a bonus detail – that if absorption does happen, then it tapers off. The 31% absorption for 1000mg is nowhere near 4 times higher than 17%. It’s possible that 500mg is the limit. It meshes with vitamin C, which is also believed to taper off above 500mg (although this is still far above the 100mg RDI, which I advise exceeding).
Oral glutathione achieved the exact kind of cherry on top increase that acne patients need.
Part 2 – real absorption spotted
If these studies were all the evidence we had, then our verdict would be a firm “undetermined”. However, scientists with microscopes have now spotted several real absorption pathways.
It’s like excavating an archaeological site and finding a thigh bone or two of a prehistoric giant ape. There’s no smoking gun, but a 1997 study blew the lid open. When examining human small intestine cell lines, scientists identified a specific transporter for glutathione. It was glutathione’s version of SLC23A1 for vitamin C, or ZIP4 for zinc.
Only compounds with a near identical molecular structure (such as glutathione ethyl ester) could enter these transporters; they weren’t vague and general vitamin transporters. They found “a remarkable affinity and specificity of this transporter for GSH“. In 1985, scientists again spotted a glutathione transporter in human cells, and better, small glutathione-like peptides blocked the glutathione’s transport.
Interestingly, the 1997 crew observed very little gamma-glutamyl transferase surrounding this transporter. Normally, Y-GT is everywhere; the body must have been reducing the glutathione-shattering enzyme in the one place where it’s unnecessary. This might be the smoking gun. Glutathione vanished in the vicinity of this receptor, and they confirmed that Y-Gt wasn’t responsible, nor y-Glutamylcysteine Synthetase, a second glutathione-metabolising enzyme.
Fantastic studies are one thing, but discover real, physical receptors and you’re approaching the truth from both sides, in an acne-clearing pincer movement. Glutathione was saturating the receptors in a near identical manner to proteins saturating amino acid transporters.
We also have a 1990 rabbit study, which went unnoticed because it wasn’t on humans. Nevertheless, intact glutathione was absorbed through the jejunum of the small intestine, and like in 1997, the absorption zones were unusually low in Y-GT. The plot thickens. Enzymes did degrade some glutathione, but apparently, this couldn’t completely account for the disappearance.
Glutathione just keeps vanishing into thin air, and there’s only one explanation – dedicated transporters.
Finishing the set was a 2014 experiment. Apparently, no advances had been made since 1997, as the intro stated that “little is known regarding GSH transport across intestinal epithelial cells“. However, intact glutathione was seen passing directly through the epithelial cells of the small intestine. Furthermore, this was a “rapid process”. The only dodgy detail was that glutathione only rose in the red blood cells and liver.
Also, in both 1997 and 1985, the transporter functioned independently of sodium. This isn’t relevant itself, but it shows that the two studies are consistent with each other – they they’d honed in on the same mystery receptor.
Part 3 – more glutathione studies
The only real flaw with the gamechanging 2014 study was that it didn’t strictly rule out amino acids. Glutamate cysteine ligase (GCL) didn’t increase either, a sign of higher indigenous production, and therefore a good sign, but other studies have more concrete proof:
ONE: despite not being on humans, this might be the clearest experiment available. Mice were simply fed a glutathione-depleting chemical for 5 days (L-buthionine-S,R-sulfoximine), followed by 100mg of oral glutathione per kilogram of bodyweight.
Bodily levels rose by “statistically significant” amounts after 30-60 minutes, but what if they were amino acid deficient? Great news: when they administered cysteine, glutamine, and glycine, glutathione failed to increase.
This is exactly what we’re looking for, the bonus fact that finally unravels this mystery. Glutathione rose in the lung, brain, small intestine, kidneys and heart, but not the liver.
TWO: another riddle-unlocking study. Rats took 15-30mM of glutathione, and this doubled their bloodstream levels, peaking at 90-120 minutes and remaining high until 3 hours.
Feeding the rats cysteine, glycine and glutamine achieved nothing (good). When the scientists gave the rats drugs which block glutathione (GSH) production, bloodstream glutathione still rose – a clear sign of absorption through the gut.
Their conclusion was fantastic: “This indicates that oral supplementation may be useful to enhance tissue availability of GSH“.
Aside from testing animals, the only flaw is that both studies tested glutathione over mere hours. There could only be a short term spike, which rapidly plummets away, meaning that only a continuous infusion of glutathione would have work. You’d have to haul around a 2 ton glutathione machine all day, or wear green-coloured glutathione injecting body armour. Luckily though, the 2014 study was over the long term – 2 months to be precise.
Part 4 – doom and gloom
As for more negative studies? There’s a couple:
THREE: in 69 white men and women, dietary glutathione failed to increase bloodstream levels over the long term, clearly hinting that gamma-glutamyl transferase was obliterating it. In fact, food lowered glutathione: “small negative correlations were observed“. So did higher vitamin C intakes; it was full of weird results. Adjusting the data for cysteine and glutamine made no difference.
Luckily, we have a great excuse to completely forget this study: it was a food-frequency questionnaire. 69 people is acceptable for a focused experiment, but for questionnaires, you want 100s, particularly with the immensely tricky statistical analysis and filtering for BMI, age, sex, smoking, etc that questionnaires require. When it’s from the diet, other nutrients can easily distort things; resveratrol in grapes increases glutathione production, so detrimental compounds probably exist too.
Interestingly, fruit and vegetables contributed 50% of dietary glutathione in the questionnaire, with meat providing much less. This study dated to 1994, and was another deadly pin that sank oral glutathione’s reputation.
FOUR: a more solid experiment which we can’t simply laugh away. It featured 39 humans, but using double-blind methods. After taking 500mg of glutathione twice daily for 5 weeks, their bloodstream oxidative stress did not decrease whatsoever. This included acne-causing free radicals like isoprostanes and 8-OHdG (generated by UV radiation). Neither oxidised glutathione nor reduced glutathione were altered.
The amino acids weren’t tested, but it doesn’t matter. The study has no obvious holes.
This is why we still can’t declare oral glutathione open for business. The momentum is building, but the jury is still out. The resoundingly negative study four was on humans, while the 2014 study was resoundingly positive, but didn’t factor in the amino acids. One and two did factor in the amino acids, but were on rats and mice, which supposedly manufacture less gamma-glutamyl transferase.
There’s no single, phenomenal study which washes away all doubts in its path. There’s no experiment which answers every question at once, but overall, given the physical receptors discovered, I’m still highly optimistic.
What about the different forms?
Are the special types of glutathione mentioned any better, or worse?
Liposomal glutathione – a form encased in natural phospholipids, like the coating of your cells. Theoretically, this shields the small glutathione molecules against the fiery forces of digestive juices, allowing more to cross the intestine’s epithelial barrier intact. These liposomal bubbles are also used for vitamin C. Some claim that liposomal glutathione has a near 100% absorption rate.
Previously, I’d have nothing to say. It sounds logical, but could be as fake as the tiny molecules of replenishing light supposedly contained within the chlorophyll cells of wheatgrass. Luckily this 2017 study analysed liposomal glutathione specifically, giving 12 humans 500mg or 1000mg every day. Glutathione jumped within 1 week; the biggest increases were 40% in the blood, 25% in red blood cells, and 28% in blood plasma. Free radicals also fell, although 1000mg barely outstripped 500mg. For now, liposomal glutathione is the real deal.
S-acetyl glutathione – the form that promises to change everything, and hasn’t yet gone up in a puff of smoke. SAG is a glutathione precursor; it is the whole glutathione molecule with the sulfur atom acetylated. It’s the same concept as n-acetyl-cysteine (NAC), the emergency room painkiller antidote (and acne secret), which is superbly absorbed. Like liposomal glutathione, SAG withstands the digestive juices and passes through the gut’s epithelial barrier intact. The whole glutathione is only released inside the bloodstream, through metabolisation via enzymes called cytoplasmic thioesterases.
Those are the theories anyway. This study put them to the test, gathering 18 men and women. Instead of weeks, it measured glutathione in the bloodstream and red blood cells over 24 hours,. SAC defeated normal glutathione, which performed well itself. The worries about amino acids secretly being responsible don’t matter here, because they apply to both.
Sublingal glutathione – a form placed under the tongue. Morphine and the anti-anxiety medication lorazepam are often applied sublingally; it’s a well-proven route for drug ingestion.
That doesn’t prove anything for glutathione, but the oft-mentioned tiny molecular size will aid its passage through the tongue. This study is the best hope of humanity, finding that sublingal glutathione slashed arterial stiffness and LDL cholesterol in 16 healthy men.
The signs are good, particularly if the supplement companies flavour it with chocolate.
If you ever read an annoyingly vague supplement advert, then rest assured: these newer, shinier forms of glutathione are not based on hype.
It’s more concrete, for example, than zinc orotate. This variety supposedly has incredible absorption due to being bound with orotic acid, the body’s natural electrolyte transporter, which gives it innate gut crossing powers. However, despite being a logical theory, there’s surprisingly little evidence.
The verdict
Times are changing: it now looks like a significant chunk of oral glutathione is absorbed, enough to benefit your skin.
There will inevitably be nutritional interactions and other kinks to be ironed out, but the once-exiled oral glutathione is finally stumbling its way out of the skincare wilderness.
You can’t underestimate the importance of this homemade antioxidant for acne. The pressure from environmental toxins in drinking water, pesticides and cosmetics is immense, and lifestyle factors are important.
For example, remember the glutamate cysteine ligase (GCL) enzyme which initially combines cysteine and glutamine? Polymorphisms in its gene have been identified in humans, which decrease its activity. These carriers might benefit from extra glutathione supplementation. It’s similar to vitamin A, where an unlucky few have genes limiting the conversion of plant-based beta-carotene. Age and obesity may also decrease GCL activity.
All this makes glutathione the great sleeper of the acne world. Right now, I’m not outright recommending glutathione supplements, and as acne antioxidants go, vitamin E is undoubtedly king of the castle.
However, the evidence for oral glutathione is growing with each passing year. Which means that your acne-clearing opportunities are growing with each passing year.
Thanks for reading!