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Have you heard of glutathione? It has become increasingly popular in health and wellness circles as a panacea, a solution for a myriad of symptoms and health conditions.

Why has it become such a favorite for health? The answer is complex, but it is likely in large part due to the combination of its ubiquity in the body and the significant role it plays. Glutathione is found in all tissues and plays a role in fighting oxidative stress, the body’s detoxification process, and your immune system, to name just a few.

Glutathione plays a hand in so many processes, many of which we probably have yet to identify. Some of the many functions of glutathione include:

• Cell proliferation and apoptosis (cell death)
• Epigenetic mechanisms
• Free-radical scavenging and redox balance
• Metabolism of xenobiotics involvement
• Modulates the function of the immune system
• As one of the conjugators for Phase II biotransformation (detoxification)

Your body produces and recycles glutathione, but that does not mean there is an endless well. There are times when the oxidative stress or toxic load may be more than your body’s current capacity to synthesize sufficient levels of glutathione or other underlying reasons for lower glutathione levels, such as poor nutrition or chronic stress.

Research has found that many chronic diseases are associated with a reduction in glutathione levels, leading to the hypothesis that increasing glutathione levels can help prevent and/or mitigate the progression of these diseases. Below is a list of some of the diseases and issues associated with glutathione deregulation or deficiency:

• Aging and related disorders
• Alzheimer’s disease
• Cancer (ovarian, bladder, etc.)
• Chronic liver disease
• Cognitive impairment
• Cystic fibrosis
• Diabetes, especially uncontrolled diabetes
• HIV/AIDS
• Hypertension
• Infertility in both men and women
• Lupus
• Mental health disorders
• Multiple sclerosis
• Neurodegenerative disorders
• Parkinson’s disease
• Preeclampsia
• Ulcerative colitis

There are some common polymorphisms or SNPs that impact glutathione and associated processes. These code for the enzyme glutathione S-transferase, or GST, which conjugate the reduced glutathione to substrates during the detoxification process. During times of oxidative stress, the GST genes are upregulated. One of the most common polymorphisms, affecting 20 to 50% of certain populations, is an absence of the GSTM1 gene (GSTM1 null), which decreases detoxification ability among other possible outcomes. GSTT1 (null) and GSTP1 (AB/BB) are additional polymorphisms related to a reduction in GST activity. Having one or more of these polymorphisms is associated with an increased risk of certain diseases, especially when impacted by environmental triggers such as pollution, smoking, heavy metals, and other toxins. A few examples of associated disorders include:

• Alzheimer’s disease
• Asthma and allergies
• Autism
• Cancer
• Cardiovascular disease
• Diabetes
• Hypertension
• Reproductive disorders

Nutrition to Support Glutathione Levels

Luckily, you do not have to sit back and watch your glutathione levels diminish as your oxidative stress, inflammation, and toxic load increase beyond your capacity to make glutathione. There are several nutrients of note necessary to produce glutathione and for which studies have found that increasing the amount relates to a boost in glutathione levels. Let’s see what the evidence has to say about the best nutrition and/or supplementation to support your glutathione levels.

Foundations: Glycine, Cysteine, and Glutamic Acid

The amino acids glycine, cysteine, and glutamic acid combine to form glutathione, so the body requires all three to make sufficient quantities of glutathione. Cysteine is frequently identified as rate-limiting, or limiting the ability of glutathione synthesis based on lack of availability. That is one reason why NAC (N-acetylcysteine) is frequently studied and suggested as a supplement for glutathione support. Below is a snapshot of some supporting research:

• In one very small study on five people with mild to moderate Parkinson’s disease and three controls, a high dose of NAC (a total of 6,000 mg/day taken orally which diminished the bioavailability of the dose) for a period of 4 weeks led to an increase of cysteine levels and antioxidant measures (GSH/GSSG—a ratio of the reduced to oxidized glutathione which relates to oxidative stress with higher ratio levels associated with healthier cells—and catalase), but it did not demonstrate any improvement in the oxidative stress measurements (4HNE and MDA) nor did it increase the level of glutathione in the brains. Additionally, some of the participants actually experienced a worsening of the Parkinson’s symptoms that were then alleviated upon stopping the NAC supplementation.
• Another study looking at those with neurodegenerative disorders found that an infusion of NAC led to an increase of the blood GSH/GSSG ratio and levels of glutathione in the brain. Those who had the greatest percent change in that ratio also had a greater percent change in their levels of glutathione in their brains.
• In a small study, blood catalase and GSH/GSSG levels significantly increased after administration of 6000mg NAC for 6 weeks in patients with Parkinson’s disease and 3 healthy participants. However, other measures remained unchanged. Further studies are needed to confirm the results.
• A systematic review on NAC supplementation for neuroinflammation and neurodegenerative diseases found that there are promising studies demonstrating the potential of NAC, but more studies are necessary due to the differences in the studies.
• Another trial on children with autism found that although there was no significant impact on the social impairment associated with autism, there was a significant impact on boosting the glutathione levels in the children. The trial period was 12 weeks and the dose was 60 mg/kg/day in three doses with a maximum of 4,200 mg/day.
• A recent small review study of patients with autism treated with varying doses of NAC presented no adverse effects and a reduction in social irritability.
• GST polymorphisms may play a role in the efficacy of NAC. In one study looking at the impact of NAC on noise-induced hearing loss, taking 1,200 mg per day for 14 days led to a significant reduction of noise-induced temporary threshold shift. Upon looking at the impact on the GST genotypes, only those with the null genotypes experienced a significant effect from taking NAC.

Although NAC is promising as a supplement to both boost glutathione levels and potentially mitigate some of the issues related to oxidative stress, the research is not conclusive, and some of the findings are disease-specific. There have also been studies with no significant impact by taking NAC.

When it comes to supplementing with substrates, glycine may be just as important as cysteine. The formation of glutathione begins with the conjugation of cysteine and glutamate, then glutathione synthase links this molecule with glycine. When the availability of glycine is lower than necessary for sufficient glutathione synthesis, the initial molecule of cysteine and glutamate converts into a compound that is excreted. Thus, sufficient quantities of glycine may be just as necessary and rate-limiting as cysteine.

It may be best to supplement with both cysteine and glycine to see a boost in glutathione, especially among those who may not have sufficient quantities of the amino acids or require higher levels of glutathione. For example, a small study with eight healthy elderly adults and a control group of eight younger subjects had the elderly take 0.81 mmol NAC per kg per day (around 132 mg/kg/day) and 1.33 mmol glycine/kg/day (roughly 100 mg/ kg/day) for 14 days. In the beginning, the elderly had 55.2% less glycine and 24.4% less cysteine in their red blood cells. They also had a 46.2% lower glutathione level than the controls.

After the supplementation, the glycine levels increased by 117.6% and the cysteine by 55.1%. Furthermore, they had a 94.6% higher glutathione concentration in their red blood cells, which also led to no statistical difference between the young controls and the elderly subjects in their glutathione levels. The researchers surmised that the typical reduction of glutathione in the elderly was due to a lower supply of glycine and cysteine, the precursors to glutathione synthesis, and that upon supplementation, they had the ability to stimulate synthesis and restore levels. Although impressive, it is important to recognize that this was a small study.

Additional Amino Acids and Protein

The precursors and foundation of glutathione are amino acids, so getting sufficient protein may ensure there is a sufficient pool from which to draw to synthesize glutathione. Changes in protein consumption, including reducing protein levels but remaining within the safe levels, may alter plasma glutathione synthesis levels contributing to a reduction in antioxidant capacity. An additional concern is the capacity for an individual to properly break down and absorb the protein consumed. Protein digestion begins in the stomach when your stomach acid (hydrochloric acid or HCl) starts to break down the protein and also activates digestive enzymes known as proteases. Then, in your small intestine, more enzymes are released to further break down the protein into amino acids. Thus, if you have low levels of HCl (known as hypochlorhydria), or if you have low levels of your digestive and/or pancreatic enzymes that target protein, you may not be able to absorb sufficient levels of the amino acids required for glutathione synthesis even if you consume adequate levels. Hypochlorhydria is more common in the elderly, and certain medications can also impact your HCl levels. Stress and certain nutrient deficiencies may also contribute to low stomach acid levels.

Although it is not necessary for most people to supplement with protein to get sufficient levels, one potential beneficial source when additional protein is necessary is whey protein, likely due to its higher cysteine content. In one small randomized control study on cancer patients, consuming 40 grams of whey protein isolates along with zinc and selenium increased the glutathione levels as well as immunity markers, including an increase of 4.8% in their immunoglobulin G levels compared to the control. Another small study on patients with Parkinson’s disease found that supplementing with whey protein led to a significant increase in the glutathione levels in the blood and the GSH/GSSG ratio, although there was no significant impact on the clinical markers of the disease.

There are other amino acids beyond the glutathione precursors that support glutathione synthesis. Some studies point to the ability of serine, a nonessential amino acid, to boost glutathione production, potentially through increased cysteine availability and a decrease of hypermethylation.

Cysteine is a sulfur amino acid, so in those who can tolerate sulfur foods, consuming sulfur-rich foods, especially those containing the sulfur amino acids, may also support glutathione synthesis.

Anti-Inflammatory and Antioxidant Support

In addition to its work as an antioxidant, glutathione plays a role in the immune system and maintaining a healthier inflammatory response, and chronic inflammation can contribute to oxidative stress and exhaust glutathione stores. As such, other compounds known for their anti-inflammatory properties can also help support glutathione levels.

One such anti-inflammatory agent is omega-3 fatty acids. In one study, taking 4,000 mg of omega-3 supplements daily for 12 weeks led to a better GSH-creatine ratio and reduced depressive symptoms in older adults who had a higher risk of developing depression. Another study looking at patients with Parkinson’s disease found that taking 1,000 mg omega-3 fatty acids from flaxseed oil along with 400 IU of vitamin E for 12 weeks led to an increase in the glutathione concentrations as well a total antioxidant capacity and a reduction in C-reactive protein, an inflammatory marker.

One study looking at the impact of the GST polymorphisms on the relationship between omega 3 fatty acids and breast cancer risk found an increased protective effect of dietary intake of fish omega-3 fatty acids in the women with the genetic polymorphisms for reduced GST activity. The high consumers of marine sources of omega 3 fatty acids with the reduced GST activity polymorphisms had at least a 64% reduction of risk compared to the low consumer counterparts, with some polymorphisms experiencing an even greater protection. Another study reported mixed results from omega-3 supplementation, with a call for further studies.

Similarly, curcumin has also been found to provide support to glutathione through enhancing antioxidant capacity and relieving inflammation, at least in animal and mechanistic studies.

Glutathione may be the mother of all antioxidants, but it does not work by itself. It is part of a complex antioxidant system that works synergistically to retain redox balance. Therefore, ensuring adequate levels of other key antioxidants can also support glutathione levels. A few key ones include:

• Selenium: Selenium is a known antioxidant and the right balance is essential to health. One reason may be its role as a cofactor of glutathione peroxidase. In a mouse study, selenium supplementation increased the expression of certain glutathione enzymes as well as increasing their activity. Another study found a positive relationship between selenium levels and selenium supplementation and glutathione levels, although there may be a racial component to the effects of selenium. However, excess selenium may contribute to oxidative stress rather than relieve it. A review article discusses the various roles of selenium and its impact on health.
• Vitamin C: In one study, taking 500 or 1,000 mg per day of vitamin C for 13 weeks led to an increase of 18% of the glutathione levels in lymphocytes. Another study found that taking 500 mg for weeks two and three and 2,000 mg per day for weeks four and five in a six-week trial led to an increased level of glutathione in red blood cells. In another study, purple grape juice supplementation and its high vitamin C content and antioxidant capacity had a significant impact on smokers with GST polymorphisms, leading to a significant reduction in DNA damage for all participants. Plasma vitamin E was increased in the GSTM1-null group, while glutathione levels were increased in the GSTM1-present group, and blood vitamin C levels were increased in the GSTT1-present genotype, demonstrating the antioxidant impact of the grape juice differed based on the genotype of the participants. The impact on blood pressure also differed based on genetic type. Likewise, consuming kale juice for six weeks had a different impact based on GST subtype, especially in the vitamin C levels and DNA damage, with the GSTM1 null genotype experiencing the best impact from the kale juice.

Additional antioxidant support linked to enhanced glutathione levels includes ALA (alpha-lipoic acid) and Vitamin E. Increased fruit and vegetable intake, especially to levels higher than 500 grams per day, has been linked to positive modification of GST polymorphisms that bring the GST activity closer to normal levels and improve antioxidant parameters.

Other Support:

There are other ways to support your glutathione levels as well as your overall health. A few that have research support behind them include:

• B vitamins – Riboflavin is a necessary coenzyme for the activity of glutathione reductase, which converts the oxidized glutathione into its reduced form, which is the antioxidant function. Thus, it is likely that a riboflavin deficiency would impact glutathione function and may even impact the levels in the body. Pantothenic acid may also help support glutathione synthesis through its position in ATP production. B12 deficiency is associated with lower glutathione levels.
• Gut microbiome – Maintain a healthy microbiome, as the gut microbiota may just modulate glutathione metabolism.

Additionally, taking the steps to reduce your oxidative stress and inflammatory levels through healthy lifestyle choices such as exercise and sufficient sleep may also support your overall glutathione levels.

Glutathione Supplementation

Can you just skip the above and simply take glutathione supplements to increase your levels and see a difference? The results are inconclusive, but there are some promising results so far:

In one small study with just 12 (healthy middle-aged non-smoker) subjects (taking either 500 or 1,000 mg per day liposomal glutathione for four weeks), there was a trend for increasing glutathione levels, although it only became significant in the 500 mg dose after two weeks, which was also the largest increase at 25%. There was also an improvement in the ratio of GSSG to GSH, with the largest decrease in this ratio among those taking the higher dose in the first and second weeks. There was also a decrease in the biomarkers for oxidative stress and an improvement in immune markers.

In another small study in healthy men with cardiovascular risk factors, those with abnormal reactive hyperemia index (RHI) which measures peripheral endothelial function and stiffness, experienced a significant reduction in arterial stiffness after taking sublingual glutathione. In another study, oral supplementation of 50 mg/kg of glutathione led to an increase in the protein-bound fraction of plasma glutathione levels but did not impact the glutathione content in the blood cell or deproteinized plasma.

One six-month, randomized, double-blinded, placebo-controlled trial found that taking oral glutathione at either 250 or 1,000 mg/day led to significant increases in the body stores of glutathione in a dose-dependent manner. There was also a decrease in the markers for oxidative stress. In a separate study, researchers measured GSH in patients with metabolic syndrome who were dosed with oral vs. sublingual GSH and NAC. Patients who supplemented with 400 mg of sublingual GSH and 200 mg of oral NAC demonstrated increases in GSH and the GSH/GSSG ratio.

Similar to NAC, not all studies confirm the efficacy of glutathione supplementation. There is also debate as to the best delivery system, whether liposomal, oral, or intravenous. IV and liposomal can bypass the breakdown that may occur in digestion, which is why some recommend them more than oral supplementation.

Below is a table bringing together all the above glutathione support nutrients and the recommended dosage based on research studies. Most people do not require all of these to get their glutathione levels to the optimal level, and you may just need one or two depending on your circumstances. It is best to talk with your doctor, nutritionist, or another healthcare practitioner about the best option for you—and whether you have different dosing requirements.

Nutrient	Recommended Dosage
ALA	300 mg 3 x day; 200 – 600 mg/ day
Curcumin	Doses up to 12 g/day safe; 1 – 2 grams/day found to benefit antioxidant capacity; increased bioavailability with piperine
Glutathione (Liposomal)	500 – 1,000 mg/day
Glutathione (Oral)	500 – 1,000 mg/day
Glycine	100 mg/kg/day
NAC	600 – 1,200 mg/day in divided doses, but up to 6,000 mg/day have been shown effective in studies
Omega-3	4,000 mg/day
Selenium	247 μg/d of selenium enriched yeast; 100 – 200 ug/day. Anything above 400 ug/day watch for toxicity
Vitamin C	500 – 2,000 mg/day
Vitamin E	100 – 400 IU/ day
Whey Protein	40 grams/day

Conclusion

Whether glutathione is truly the panacea its reputation currently promotes remains to be seen, but it is definitely an important component of overall health and wellbeing, especially in terms of your antioxidant capacity and redox balance. Additionally, there are promising studies supporting the potential for nutritional support and possibly supplementation to improve glutathione levels and possibly symptoms of chronic disease. Therefore, it may be beneficial to take a look at your current diet to determine whether you have sufficient levels of the foundational nutrients of this key antioxidant discussed above.

If you worry that your glutathione levels are not sufficient to counter the oxidative stress, toxins, inflammation, and other potential problems you may have, or if you have a chronic disease and are looking for natural ways to support the body and counter some of the symptoms and other effects of the disease, then talk with your doctor, nutritionist, or another healthcare provider. You can discuss ways to support your endogenous glutathione synthesis through diet and lifestyle changes, including some of the nutrients discussed above, or whether it may be best to supplement.

Additional Resources:
Gaby, A. (2011). 62: Alpha-lipoic acid. Nutritional Medicine. Concord, NH: Fritz Perlberg Publishing.
Gaby, A. (2011). 51: N-Acetylcysteine. Nutritional Medicine. Concord, NH: Fritz Perlberg Publishing.
Gaby, A. (2011). 34: Selenium. Nutritional Medicine. Concord, NH: Fritz Perlberg Publishing.