Antioxidant questions: N-acetylcysteine vs glutathione

Which supplement is best for patients seeking answers to antioxidant questions?

There’s been a lot of buzz in the integrative health field around N-acetylcysteine (NAC) and glutathione. Both are powerful antioxidants. However, for patients with antioxidant questions, most probably think of vitamin C, beta-carotene, or maybe green tea.

Mention the word “glutathione” and you may be met with a blank stare. But when you explain that this master antioxidant affects virtually every aspect of their health, from combating simple oxidative stress to potentially reducing the risk of Parkinson’s disease or cancer, you’ll promptly gain their attention.

What are the health benefits of NAC?

NAC is a derivative of the amino acid L-cysteine. Cysteine is a sulfur-containing amino acid. Sulfur is an essential part of many biological processes, including enzymes and protein construction.

Of the three amino acids required to make glutathione (cysteine, glycine and glutamic acid), only cysteine contains sulfur. Therefore, cysteine is generally considered the rate-limiting step for endogenous glutathione production.

In addition to its major role as a precursor to glutathione, NAC is widely used for its mucolytic actions. One of the keys to breaking up mucus is disrupting the sulfur-sulfur (S-S) bonds, which is exactly what NAC can do. NAC reduces disulfide (S-S) bonds and thereby decreases the viscosity of mucus.

When it comes to mental health, NAC has been studied for its impact on obsessive-compulsive disorder, depression and substance use disorders. It’s also the primary treatment, used intravenously, for people hospitalized with acetaminophen poisoning  which affects more than 70,000 people per year. Why is acetaminophen so dangerous? Because it depletes hepatic glutathione levels and can cause irreversible liver damage.

NAC sounds like a miraculous natural medicine — and it is. However, much of the research on NAC has revealed that its benefits are largely due to its role as a precursor to glutathione.

Glutathione: crucial for overall health

Glutathione is one of the most important antioxidants we create and is present in virtually every cell in the body.

Research has demonstrated that the glutathione concentration in most cells is roughly equivalent to the amount of glucose and cholesterol, which is incredible. We focus so much on glucose control and cholesterol balance, but what about ensuring we have enough glutathione on board?

There are many factors that can interfere with optimal glutathione levels: aging, genetics, toxins and health conditions. By the fourth decade of life, we are making 30% less glutathione. By age 65, we produce around 50% less glutathione. Those reductions are found in healthy individuals. How many people come to see you when they are healthy? Probably a small percentage of patients.

That means when it comes to patient antioxidant questions, most of them are either glutathione-insufficient or downright deficient. One clinical study found that low glutathione levels in older individuals were associated with a 24% difference in the risk of morbidity compared to those with higher levels.

Glutathione needs to be converted into its active form, and the liver is the primary organ involved in this process. With over 30% of adults in the United States dealing with nonalcoholic fatty liver disease, we can then speculate at least that many people struggle with converting raw materials (NAC) into usable, active glutathione. There are many other health conditions themselves that may be both the cause and result of deficiencies in glutathione.

As established, NAC is a precursor to glutathione. However, just because the body has precursors to a final product does not mean that it can or will be made. A patient can take folic acid daily, but if they have a methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, no bioactive folate can be produced. The same idea is paralleled in the conversion of NAC to glutathione, where genetic variants can also play a role.

Put another way, it’s like receiving a blueprint (genetics) and all the pieces (precursors) to something you need to assemble. Sure, you have all the pieces, but how much energy will it take for you to put that TV stand together? Wouldn’t it be easier if it came pre-assembled?

Antioxidant questions: reduced (active) vs. oxidized (inactive) glutathione

It’s important to differentiate between the two forms of glutathione when addressing patient antioxidant questions. Glutathione that is active, also called reduced, is commonly referred to as GSH. Glutathione that is inactive, also called oxidized, is commonly referred to as GSSG.

The GSH molecule has an S-H bond that is capable of bonding free radicals and heavy metals, whereas the GSSG compound is two glutathione molecules combined through an S-S (disulfide) bond. In a perfect world, our ratio of GSH to GSSG would be around 99:1. For many people, their ratio is far from ideal, sometimes even less than 50:50.

Rheumatoid arthritis research has found a strong correlation between inflammation, oxidative stress and lowered glutathione levels in the bloodstream. In fact, a clinical study in Jordan found that patients with RA showed a 50% depletion of reduced glutathione compared to healthy controls. This makes glutathione a serious contender for integrative treatment.

Direct glutathione supplementation

Until recently, supplementing with active glutathione (GSH) was difficult and expensive, primarily used in an intravenous setting with high out-of-pocket costs to patients. When it comes to oral glutathione supplementation, many of these supplements end up hydrolyzed into the three amino acids or the glutathione becomes oxidized (GSSG) and further adds to the oxidative burden of the patient.

So, while glutathione is definitely valuable in clinical settings, it needs to be in a form that is both effective and easy for patient adherence. And beyond raising blood levels of active glutathione (GSH) for a healthy ratio to oxidized glutathione (GSSG), it needs to be a one-supplement solution in order to remove the guesswork that seems inherent in NAC supplementation.

Fortunately, there’s good news for practitioners and their patients on that front.

French research scientists have developed a way to enhance glutathione’s bioavailability in a supplemental form, so it is easy to use and doesn’t suffer the oxidizing damage of typical oral supplements. Instead, as a sublingual tablet, the glutathione is protected with additional antioxidants. This way, the glutathione is transported directly into the bloodstream as it dissolves under the tongue. This capillary-rich sublingual environment is much more conducive to retaining glutathione in an active form than oral supplements that can undergo oxidation in the digestive tract.

In 11 days, this unique sublingual glutathione increased active glutathione in the bloodstream by 38 points. However, the unprotected oral glutathione actually reduced the active glutathione amount by 40 points, creating a 78-point difference between the two groups.

This sublingual form also improved glutathione ratios (the ratio of active glutathione [GSH] to the oxidized form [GSSG]) by 230% compared to unprotected glutathione and 65% better than NAC. Interestingly, this study was conducted on participants with metabolic syndrome, so the results are promising for many patients today dealing with similar issues.

There are many reasons why it is crucial that we find efficient ways to raise levels of active glutathione. A sublingual form that easily absorbs into the bloodstream and avoids the oxidative conditions of the digestive tract is an intriguing way to achieve that, and it may yield incredibly positive results in future research and practice.

LEXI LOCH, ND, is an author, educator and integrative medicine practitioner. With a passion for botanical medicine, dietary supplements and collaborative care, she integrates nature, science and intuition to cultivate vitality. For the past seven years she has been a member of the Scientific Affairs and Education team at EuroPharma USA®, makers of the EuroMedica® brand of dietary supplements. Learn more at doclexiloch.com.