Supplements 101: NAC for Chronic Fatigue

N-acetyl-cysteine, or more simply NAC, is a scavenger of free radicals which cause oxidative stress. These properties make NAC a powerful tool for illnesses where oxidative stress is the hallmark. For this reason, NAC is a popular supplement among those with chronic fatigue syndrome (MECFS).

Decades of studies have shown that NAC is a safe and well-tolerated supplement without any considerable side effects. The supplement boasts over 800 review papers. But, is it a first-line choice for MECFS?

This post is part of a series on popular supplements in ME/CFS. You can read more from this series here.

Medical Uses of NAC

NAC is a well-known antioxidant but you may be surprised to know that it is also an old generic drug with several clinical applications. Since the 1960s, NAC has been a prescribed drug and is currently listed on the World Health Organization (WHO) Model List of Essential Medicines as an antidote for poisoning. Its use as an antidote is well established in paracetamol (acetaminophen) overdose. For this indication, NAC is usually administered intravenously.

It has also been prescribed as a mucolytic, or a substance that breaks up mucus, and used to be extensively prescribed for chronic bronchitis. For this medical purpose, NAC is obtained from an inhaler nebulizer. Finally, NAC is also used to mitigate the adverse effects of exposure to imaging dyes (contrast medium). It also readily binds to mercury, lead, and arsenic making it an effective metal chelator.

NAC is not Glutathione

It is often assumed that supplementing with NAC is equivalent to supplementing with the more expensive glutathione. It is however a bit misleading to assume that NAC is a direct precursor to the potent antioxidant glutathione. To make glutathione from NAC, the cysteine component of the molecule must combine with 2 additional amino acids: glycine and glutamate. So the requirement of these amino acids and the efficiency of the 2 enzymes that participate is essential for the production of glutathione.

Taking NAC does not directly dictate levels of glutathione and it is unknown precisely how effective NAC supplementation is at increasing glutathione status. Consider this small clinical trial of 5 individuals with Parkinson’s disease and 3 controls. One month of 6,000 mg of NAC led to an increase in cysteine levels (the “C” in NAC) but did not correlate with improvement in oxidative stress measurements or an increase in the level of glutathione in the brain.

Some other studies have shown that oral NAC does raise glutathione, but overall the results are mixed. Some studies measure blood glutathione, others measure NAC in the brain and glutathione in the brain. In an estimated 46 placebo-controlled clinical trials with NAC, as many as 2/3rds have reported positive effects as general measures of improvement in the quality of life or well-being of the patients. However, these positive effects are noted when there is a clear deficiency of glutathione or high levels of oxidative stress.

Food Sources of NAC

Onions, asparagus, cucumber, bell pepper, parsley, strawberry, lemon, tomato, and grapefruit all contain naturally occurring NAC. However, the amount of NAC in these foods is small and may be degraded during cooking processes.

Foods high in cysteine can be utilized by the body to be converted to NAC. Some of the highest food sources of cysteine come from animal foods: pork, beef, chicken, fish, lentils, oatmeal, eggs, and sunflower seeds. Just 6oz of meat can contain as much as 595mg of cysteine.

NAC for Chronic Fatigue Syndrome (MECFS)

Despite the popularity of NAC in those with chronic fatigue syndrome (MECFS), this supplement has not been studied for the condition. In a small pilot study from Weill Cornell in 2016, 4 weeks of NAC supplementation (1800 mg/day) increased glutathione levels as evidenced by brain imaging. At baseline, the glutathione level of patients was 15% less than in healthy controls. This finding also correlated with improved subjective symptoms.

Recent findings by Ron Davis’s group at Stanford indicate red blood cell structural anomalies in those with MECFS. Red blood cells are well-known scavengers of oxidative stress and utilize glutathione predominantly to achieve this function. In vitro studies using NAC show that it can restore up to 15% of the necessary glutathione. This factor alone may warrant the use of NAC in MECFS patients.

Get the Dosage of NAC Right

Like so many other supplements, NAC is poorly absorbed. Once ingested, it obtains a negative charge which makes it difficult to pass into the body tissues (membranes are also negatively charged). I can’t stress enough how important it is to consider the bioavailability of supplements! Few things are more important than knowing the supplements you spend so much money on getting into the body and to their desired targets.

Since 1988, the bioavailability of NAC has been known. It is also known that NAC can cross the blood-brain barrier. Yet, oral dosing of 400mg of NAC resulted in just 9% bioavailability. Newer research methods have largely supported these early findings, with ranges of 6-10% bioavailability.

Because of this, high doses of the oral supplement are necessary. Some trials have demonstrated that there were no differences in side-effect profiles between 1200, 2400, and 3600 mg per day of oral NAC. When looking at clinical trials, most use doses upwards of 1800mg per day.

A Better Form of NAC

A newer form of NAC, N-acetylcysteine amide or NACA, will likely displace regular supplemental NAC. This form has better bioavailability and more readily crosses into tissues and the brain. I am not yet aware of a commercially available option but will update here should it become known. In studies, NACA was found to be 5 times more potent than NAC. NACA applied to red blood cells is far better at restoring glutathione status than regular NAC, where it can restore up to 91%! This could provide an excellent way to restore red blood cell deformation that seems to occur in MECFS.

Bottom Line

Like so many other antioxidants, the claims about NAC are a bit overstated. It seems that much of the antioxidant and glutathione-boosting prowess of NAC comes from in vitro studies. Most clinical trials using this supplement are inconsistent. Oral NAC has low bioavailability so dosing must be very high to have any effect. NAC delivered intravenously is better but incurs high risk and is impractical. Better forms such as NACA will likely help us better understand the potential value of this supplement for conditions defined by oxidative stress.

Nonetheless, supplementing with NAC is likely a wise choice to treat clear cysteine/glutathione deficiencies. Cysteine and glutathione deficiencies may be detected by blood nutritional testing.

While this deficiency is presumed in those with MECFS, it is not definitive. A 2012 study found elevated ventricular lactate and decreased glutathione in the brains of patients with MECFS. The pilot study mentioned above was unpublished and no other studies have looked to test this avenue of treatment. Even so, NAC is a safe supplement with little risk of side effects. Be mindful that dosing should exceed 1800mg per day. Be on the lookout for better formulations including NACA.

References

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Atkuri KR et al. (2007) N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 7(4):355-9.

Mokhtari, V. et al. (2017) A Review on Various Uses of N-Acetyl Cysteine. Cell J.; 19(1): 11–17.

Dodd, S., Dean, O., Copolov, D. L., Malhi, G. S., & Berk, M. (2008). N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opinion on Biological Therapy, 8(12), 1955–1962.

Minich D & Brown B (2019) A Review of Dietary (Phyto)Nutrients for Glutathione Support. Nutrients; 11, 2073; doi:10.3390/nu11092073

Olsson, B., Johansson, M., Gabrielsson, J., & Bolme, P. (1988). Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. European Journal of Clinical Pharmacology, 34(1), 77–82.

Sunitha K et al. (2013) N-Acetylcysteine amide: a derivative to fulfill the promises of N-Acetylcysteine. Free Radic Res; 47(5):357-67.

Shungu DC et al. (2012) Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed; 25(9):1073-87.