S-Acetylglutathione

Glutathione is the main antioxidant made inside cells. Plain oral glutathione is mostly broken down in the gut and liver. In one early study, 3 g did not raise blood glutathione at all over the next four and a half hours [5], and a 4-week trial of 1 g a day found no change in red-cell glutathione or oxidative stress markers [6]. A longer 6-month trial did find body stores rising 30–35% at 1 g a day [7], and liposomal glutathione has been tested for the same reason [8].

SAG was developed as a way round the absorption problem. Adding an acetyl group to the sulfur is described as making the molecule more stable in plasma and letting cells take it up whole, then convert it back to glutathione [1]. In rat tissue preparations it was only slowly hydrolysed in plasma and raised glutathione inside red blood cells [9].

Human absorption. The only human pharmacokinetic study compared 3.5 g of SAG with 3.5 g of plain glutathione in 17 healthy adults. No intact SAG appeared in the blood. Plasma glutathione peaked a little higher after SAG, while red-cell glutathione peaked a little higher after plain glutathione. Both changes were small and varied widely between people, and EFSA concluded that the glutathione curve after SAG did not substantially differ from plain glutathione's [3]. The comparison was by weight, not by number of molecules, so the SAG arm actually delivered about 14% less glutathione [3].

Cell and animal work. SAG raised glutathione back to normal in cultured skin cells from patients with glutathione synthetase deficiency, an inherited disorder [10]. In cells infected with herpes simplex virus it restored glutathione more effectively than plain glutathione, and in mice it reduced herpes deaths where plain glutathione did not [1]. Injected into muscle in a mouse model of retroviral immunodeficiency, it lowered viral load in the spleen and lymph nodes [11]. In mice given carbon tetrachloride to cause liver fibrosis, 30 mg/kg by mouth for 8 weeks restored liver glutathione and antioxidant enzymes, lowered inflammatory cytokines and liver enzymes, and reduced collagen scarring. Each group had five mice [2].

Studies of combination products. In 18 people with mild Alzheimer's disease, 10 took a supplement with 50 mg of SAG, 80 mg of oleuropein (an olive polyphenol), bacopa, piperine and four vitamins twice a day for 6 months, and 8 had no supplement. The authors reported gains on all 14 cognitive and behavioural measures against the untreated group, 13 of them statistically significant, including a 1.7-point MMSE improvement against no change. There was no placebo and no blinding, enrolment stopped at 18 of a planned 40 because of the COVID-19 pandemic so the crossover never ran, and one author was a shareholder in the company that developed the product [4]. In 24 dogs with liver disease, a supplement with SAG, silybin and vitamins raised red-cell glutathione and lowered liver enzymes over five weeks, while untreated dogs' values stayed level [12]. Neither study can separate SAG's contribution from the other ingredients.

SAG carries glutathione's sulfur group capped with an acetyl group. The proposed advantage is that the capped molecule resists breakdown in plasma, enters cells intact and is then unmasked to glutathione by enzymes inside the cell [1][9]. Plain glutathione, by contrast, has to be broken down into its amino acids and rebuilt inside the cell [1]. In human blood, however, intact SAG was not detected after a large oral dose, which suggests it is deacetylated before or during absorption [3].

In the mouse liver-injury model, SAG restored the Nrf2 antioxidant pathway (Nrf2, HO-1, NQO1) and the mitochondrial clean-up proteins PINK1 and Parkin, and damped TLR4/NF-κB inflammatory signalling [2].

One cell study complicates the simple "more glutathione" picture. In three lymphoma cell lines, SAG lowered glutathione and triggered cell death, while leaving normal lymphocytes alone [13]. An earlier study found the same selective effect on cancer cells with both SAG and plain glutathione at 1–2 mM [14].

The ingredient EFSA assessed is at least 97% SAG, with around 1% reduced glutathione and under 1% oxidised glutathione as impurities. It dissolves poorly in acidic water (under 20 g/L at pH 3) and is stable for three years at room temperature [3].

Plain oral glutathione, liposomal glutathione and SAG all aim at the same goal. The only direct comparison of SAG with plain glutathione in people was one single-dose study, which found no substantial difference in the blood glutathione curve [3]. SAG has not been compared with liposomal glutathione, which raised blood and immune-cell glutathione in a 12-person open-label study [8].

SAG was not mutagenic in bacteria and did not cause chromosome damage in human cells, and its acute oral LD50 is above 2,000 mg/kg [3][16]. In a 90-day rat study at up to 1,500 mg/kg a day, the manufacturer's authors found no treatment-related damage on histology and set the no-adverse-effect level at the top dose [16]. EFSA read the same study more cautiously. It judged the roughly 10% rise in relative liver weight at the top dose to be adverse, because it was outside historical control ranges and had not reversed in males after the recovery period. It also noted lower thyroid T4 in male rats at the middle and top doses, which it did not consider relevant without matching pathology. From the liver finding it set a safe level of 4.39 mg/kg a day, or 300 mg a day for adults [3].

There are no human safety studies of SAG itself. EFSA relied instead on 10 trials of plain oral glutathione (230 adults, 250–1,000 mg a day for 3 weeks to 6 months), which reported no serious adverse events and no harmful changes in blood counts or liver and kidney markers [3]. The ingredient contains traces of perchlorate (about 27 mg/kg). At 300 mg a day this adds little to normal dietary intake and stays below EFSA's tolerable limit [3].

The toxicology studies were funded by Gnosis by Lesaffre, which sells SAG as Emothion, and the human pharmacokinetic study was part of the same company's EU application [3][16].

No interactions with drugs or other compounds have been studied.