Story at-a-glance

• Sulfur is the third most abundant mineral in your body. Sulfur-containing amino acids increase your levels of glutathione and N-acetylcysteine (NAC), which play important roles in health and fitness
• Glutathione metabolism influences the control of epigenetic mechanisms at several levels, including substrate availability, enzymatic activity for DNA methylation and the expression of microRNAs
• NAC supplementation may be useful for the prevention of cardiovascular problems in older people by lowering oxidative stress and improving mitochondrial function
• Glutathione deficiency can induce epigenetic changes in genes that regulate vitamin D metabolism in the liver, and research suggests glutathione supplementation could help reduce the risk of vitamin D deficiency in obese individuals
• Glutathione and NAC also ameliorate exercise-induced stress and reduce muscle fatigue. Glutathione may also play a central role in chronic fatigue syndrome

As explained in "The Health Benefits of MSM," sulfur is the third most abundant mineral in your body and plays important roles in a variety of bodily processes, including metabolism and detoxification, and for maintaining the proper shape and structure of proteins and enzymes.

Sulfur-containing amino acids increase your levels of glutathione and N-acetylcysteine (NAC), and these two play important roles in health and fitness.

Glutathione Basics

Glutathione comprises three amino acids: cysteine, glutamate and glycine. It's commonly referred to as "the master antioxidant," as it is your body's most powerful antioxidant, and is found inside every cell in your body.

Antioxidants combat free radicals — highly reactive particles that bounce around the cell, damaging everything they touch. Most originate during the process of metabolism but they can also arise during exercise, and from exposure to toxins, irradiation and toxic metals.

Because free radicals are so destructive, cells have a network of defenses designed to neutralize them. This antioxidant network is composed of numerous components that include vitamins, minerals and special chemicals called thiols (glutathione and alpha-lipoic acid).

Glutathione differs from other antioxidants in that it is intracellular, and has the unique ability of maximizing the activity of all the other antioxidants, including (but not limited to) vitamins C and E, CoQ10 and alpha lipoic acid. It also removes toxins from your cells and protects you from the damaging effects of radiation, chemicals and environmental pollutants.

NAC Basics

NAC is a precursor to and rate-limiting nutrient for the formation of glutathione.1 Glutathione is poorly absorbed so, in many cases, it's easier to raise your glutathione by taking NAC instead.

In emergency medicine, NAC is used as an antidote for acetaminophen toxicity resulting from an overdose.2 Mortality due to acetaminophen toxicity has been shown to be virtually eliminated when NAC is promptly administered.

It is believed the liver damage acetaminophen causes is largely due to the fact that it can deplete glutathione, which is secreted by your liver in response to toxic exposure.

On a side note, NAC supplementation can also help "pre-tox" your body when taken before alcohol, thereby minimizing the damage associated with alcohol consumption — a tidbit that may be useful to know in light of approaching New Year's celebrations.

Taking NAC (at least 200 milligrams) 30 minutes before you drink can help lessen the alcohol's toxic effects. Vitamin B6 may also help to lessen hangover symptoms.

While the most common use of NAC is for liver support, it's also showing promise as a neuroprotectant.3 Scientists are currently investigating it as a treatment for Parkinson's disease, which has been linked to glutathione deficiency in the substantia nigra, a region that houses dopamine neurons.4

Research looking at autopsied brains suggests Parkinson's patients have barely detectable levels of glutathione in this brain region. Subsequent studies have found glutathione deficiency in the substantia nigra is common in a number of other neurodegenerative conditions as well, including Alzheimer's disease.5

Another area where NAC shows particular promise is in the treatment of mental health disorders, including post-traumatic stress disorder,6 depression7 and substance use disorders.8 Dozens of additional health benefits are also reviewed in a November 29, 2019, SelfHacked article.9

Glutathione Helps Regulate Epigenetic Disease Mechanisms

One factor that can help explain the wide-ranging benefits of NAC and glutathione is glutathione's role in the regulation of epigenetic disease mechanisms.10 As noted in a November 2017 paper in Free Radical Biology and Medicine:11

"Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence.

Histone H3, one of the basic proteins in the nucleosomes that make up chromatin, is S-glutathionylated in mammalian cells and tissues, making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a physiological antioxidant and second messenger in cells, a new post-translational modifier of the histone code that alters the structure of the nucleosome.

However, the role of GSH in the epigenetic mechanisms likely goes beyond a mere structural function. Evidence supports the hypothesis that there is a link between GSH metabolism and the control of epigenetic mechanisms at different levels (i.e., substrate availability, enzymatic activity for DNA methylation, changes in the expression of microRNAs, and participation in the histone code)."

The following graphic12 illustrates how glutathione influences pathological changes in gene expression.

NAC Improves Cardiovascular and Mitochondrial Function

According to a 2018 study,13 NAC supplementation may be useful for the prevention of cardiovascular problems in older people. As you might expect, oxidative stress can over time induce metabolic and functional changes that speed cardiovascular aging and dysfunction, and your glutathione levels declines with age, putting you at greater risk.

In this study, aging mice received either NAC or a combination of NAC and glycine. After seven weeks, their cardiac function was assessed, showing those receiving NAC plus glycine had improved several parameters of their cardiovascular function, including:

• Improved diastolic function
• Increased peak early filling velocity
• Reduced relaxation time
• Reduced left atrial volume
• Reduced left ventricle end diastolic pressure

NAC alone did not impart these cardiovascular benefits, although both groups had decreased levels of inflammatory mediators. The NAC and glycine combination also improved mitochondrial function and upregulated mitochondrial genes in the heart that are normally downregulated with age.

According to the authors, "Our data indicate that NAC+Gly supplementation can improve diastolic function in the old mouse and may have potential to prevent important morbidities for older people."

Glutathione Deficiency Lowers Vitamin D Levels in the Obese

Other recent research14 published in Scientific Reports shows that glutathione deficiency can induce epigenetic changes in genes that regulate vitamin D metabolism in the liver. Emerging evidence also suggests glutathione metabolism plays a role in the epigenetic regulation of oxidation-reduction (redox) reactions, the authors note.

According to this paper,15 obesity has been correlated with low levels of glutathione and 25-hydroxyvitamin D3 — especially in Type 2 diabetics and the obese16 — and when obese mice were fed a glutathione-deficient diet, it downregulated vitamin D metabolism genes and vitamin D receptors in the liver. As a result, oxidative stress increased.

According to the authors, their findings suggest glutathione supplementation could help reduce the risk of vitamin D deficiency in obese individuals. Supplementation with L-cysteine, a rate-limiting precursor to glutathione, has also been shown to increase vitamin D levels and reduce oxidative stress, the paper notes, which supports the link between glutathione and vitamin D.

Glutathione and NAC Ameliorate Exercise-Induced Stress

As mentioned earlier, exercise is one of the ways through which free radical production increases and, with it, oxidative stress. Provided you get enough rest between bouts, this oxidative stress is actually part of what makes exercise so beneficial.

That said, as noted in a 2005 paper,17 "Effective regulation of the cellular balance between oxidation and antioxidation is important when considering cellular function and DNA integrity as well as the signal transduction of gene expression." In other words, excessive exercise can cause more harm than good. As explained by the authors:18

"Exercise enthusiasts and researchers have become interested in recent years to identify any means to help minimize the detrimental effects of oxidative stress that are commonly associated with intense and unaccustomed exercise. It is possible that a decrease in the amount of oxidative stress a cell is exposed to could increase health and performance …

To protect against the deleterious effects of ROS [reactive oxygen species], our bodies have a complex system of endogenous antioxidant protection in the form of enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Under normal, resting conditions reactive oxygen species are removed from the cell preventing any subsequent damage.

However, under more extreme conditions such as: 1) inadequate intake of foodstuffs containing the antioxidants, 2) excessive intake of pro-oxidants, 3) exposure to noxious chemicals or ultraviolet light, 4) injury/wounds, and/or 5) intense exercise, especially eccentric exercise, the body's endogenous antioxidant system is not able to effectively remove excessive ROS production.

In situations such as the ones listed above in which the production of pro-oxidant molecules increase to a point where the antioxidant system cannot effectively remove them is when oxidative stress is known to occur.

Oxidative stress has been implicated in a number of diseases which include atherosclerosis, pulmonary fibrosis, cancer, Parkinson's disease, multiple sclerosis, and aging. Research on oxidative stress during exercise has begun to indicate that regular training enhances the ability of these mechanisms to effective respond to the increase of oxidative product."

Exercise Boosts Your Glutathione Level

The 2005 paper above goes on to explain how exercise affects your glutathione level, and thus your health, fitness and risk of disease. In short, when you engage in intense exercise, your blood level of glutathione significantly decreases while circulating levels of oxidized glutathione increases, indicating that it's been used inside the muscle to quench free radicals produced during the exertion.19

Considering the importance of glutathione to counteract free radicals, effective regulation of glutathione levels when exercising is a significant concern. The good news is that the more you exercise, the higher your base levels of glutathione get.

This adaptation allows your body to effectively deal with the increase in free radicals that the exercise brings about. While exercise itself will boost your glutathione level over time, raising glutathione through supplementation is an oft-used strategy among athletes.

As mentioned, glutathione supplementation is ineffective due to its poor absorption, so NAC is generally considered a much better choice. According to the authors of the 2005 paper cited above:20

"In addition to the role glutathione and other thiols have on maintaining the cellular redox state, many studies have begun to explore if NAC supplementation can actually improve performance due to its ability to promote a more favorable cellular environment to achieve higher levels of performance …

One of the first studies to utilize NAC to determine its role in improving muscle performance was conducted by Reid and colleagues. They pretreated subjects with n-acetyl-cysteine infusion (150 mg/kg) or a 5% dextrose placebo while undergoing an extended fatiguing bout of electrical stimulation of the ankle dorsiflexors.

N-acetyl-cysteine was found to have no impact over the nonfatigued muscle, but a significantly increased force output of approximately 15% was found after 3 minutes of repetitive contractions which persisted throughout the 30-minute protocol. The authors concluded that NAC resulted in improved performance suggestive of oxidative stress having a causal role in the fatigue process."

Other studies have also confirmed that NAC supplementation helps delay muscle fatigue during exercise, thereby improving endurance. In one study,21 NAC infusion increased the time to exhaustion by 26.3%.

NAC's ability to reduce fatigue and improve cellular redox (oxidation reduction) also hints at its potential benefit for those struggling with chronic fatigue syndrome (CFS).

The Glutathione Depletion Theory of CFS

As explained by the U.S. Centers for Disease Control and Prevention, CFS, also known as myalgic encephalomyelitis or ME, is characterized by "overwhelming fatigue that is not improved by rest."22 The fatigue is frequently such that it challenges your ability to perform even the most common of daily life tasks, such as showering or preparing a meal.

The role of glutathione in this condition is addressed in "A Simple Explanation of the Glutathione/Methylation Depletion Theory of ME/CFS"23 by the late Rich Van Konynenburg, Ph.D., developer of the methylation protocol used by many in the CFS community.24,25

According to Van Konynenburg, oxidative stress "is probably the best-proven biochemical aspect of chronic fatigue syndrome," and in order for your oxidative stress to overwhelm your system, something must be placing excessive demands on your glutathione supply.

Several examples were already listed above, such as inadequate antioxidant and/or excessive pro-oxidant intake, toxic exposures and physical injuries. Long-term emotional stress can also be a factor. As noted in Van Konynenburg's article:

"All people experience a variety of stressors all the time, and a healthy person's body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed.

However, if a person's body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low …

One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins … When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins.

Also, the levels of toxins rise in the body when there isn't enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low."

The B12-Glutathione Connection

Vitamin B12 helps your body convert food into glucose for energy, and fatigue is one of the symptoms of low B12 levels.26 Interestingly, many with CFS have elevated B12 levels. Their bodies simply cannot use it properly, and one potential culprit is low glutathione.

"The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with CFS," Van Konynenburg states, adding:27

"The most important job that B12 has in the body is to form methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.

When there isn't enough methylcobalamin, methionine synthase has to slow down its reaction. Its reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles …

The methylation cycle has some important jobs to do. First, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body.

It is not a coincidence that these substances are found to be low in CFS … Not enough of them is being made because of the partial block in the methylation cycle.

The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns.

The 'reading' of DNA is referred to as 'gene expression.' Methyl groups prevent or 'silence' gene expression. Overexpression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression."

The Basic Biochemical Mechanism of CFS

The methylation cycle also regulates your body's use of sulfur, and the production of sulfur-containing substances, including glutathione. CFS patients often have abnormal levels of sulfur metabolites. Once you understand the interconnectedness of glutathione, B12 and the methylation cycle, it becomes easier to see how chronic CFS arises. As explained by Van Konynenburg:28

"When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine.

This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick … That's the basic biochemical mechanism of CFS … everything else flows from this …

Here's how I believe the fatigue occurs: The cells have little powerplants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells.

For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.

When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the 'machinery' in the little powerplants, lowering their output of ATP.

So the muscle cells then experience an energy crisis, and that's what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances."

All of these factors will ultimately decimate your immune function as well, allowing pathogenic bacteria, viruses and fungi to take over. CFS patients will frequently have several infections ongoing at the same time. Low glutathione also impedes your body's natural detoxification pathways, allowing toxicity to build over time, thereby causing ever-increasing dysfunction.

The Answer for CFS

So, how do you turn this chain of events around? As noted in Van Konynenburg's article:29

"The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified treatment approach is designed to do, and so far, the evidence is that it does do these things in most people who have CFS.

I recommend that people with CFS have the Vitamin Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment.

This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery."

An outline of Van Konynenburg's simplified methylation treatment plan for CFS can be found in HealthRising.org.30 At the core of this treatment is the use of specific supplements, including folate, B12, a multivitamin, SAMe and phosphatidyl serine.

In his protocol, he explains the theory behind the use of each of these supplements, how they impact the methylation cycle, and their interactions with other supplements.

My take-home message here is that glutathione and NAC supplementation may not always be the ideal way to go. People with CFS may be better supported by a customized assessment by an experienced clinician that may also include methyl folate and methyl vitamin B12.

General Dosing and Safety Guidelines for NAC

For many others, however, NAC can be safely used to boost glutathione levels. For more information about how NAC can benefit your health, see "The Many Benefits of NAC." It's widely available as an oral dietary supplement and is relatively inexpensive. Unfortunately, like glutathione, NAC is poorly absorbed when taken orally, although it's better than glutathione.

According to some studies,31,32 NAC's oral bioavailability may range between 4% and 10%, which is why the recommended dosage can go as high as 1,800 milligrams (mg) per day. Its half-life is also in the neighborhood of two hours, which is why most study subjects take it two or three times a day.

No maximum safe dose has yet been determined, but as a general rule, it's well-tolerated, although some do experience gastrointestinal side effects such as nausea, diarrhea or constipation. Should this occur, reduce your dosage. It's also best taken in combination with food, to reduce the likelihood of gastrointestinal effects.

Also keep in mind that since NAC boosts glutathione, which is a powerful detox agent, you may experience debilitating detox symptoms if you start with too high a dose. To avoid this, start low, with say 400 to 600 mg once a day, and work your way up.

Also, if you are currently taking an antidepressant or undergoing cancer treatment, be sure to discuss the use of NAC with your physician, as it may interact with some antidepressants and chemotherapy.