Mitochondrial Enhancers for ME/CFS and Fibromyalgia Pt IV: N-Acetyl Cysteine (NAC)

by Cort Johnson | Sep 9, 2021 | Energy Production, Homepage, NAC, Neuroinflammation, Oxidative Stress, Supplements | 49 comments

In the 4th part of a series focusing on Mitochondrial Enhancers for ME/CFS and Fibromyalgia we turn to a surprising supplement – N-acetyl-cysteine (NAC). You don’t often hear of NAC as a mitochondrial supplement. Lee Know’s book “Mitochondria and the Future of Medicine” doesn’t even mention it.

The Mitochondrial Enhancers for Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Series

NAC is thought of as more of an antioxidant – and quite an antioxidant it is. NAC has been described as “the epitome of an antioxidant“. One paper called it the most widely studied antioxidant of all. It has been and it’s is being studied in dozens of diseases – yet we’re still not completely clear how it works.

Researchers first thought that NAC had been scavenging up reactive oxygen species (ROS – free radicals) but “reaction kinetic” studies suggest that NAC does not react effectively with ROS.

That suggested NAC was being transformed into an antioxidant that does effectively scavenge free radicals. Since NAC (N-acetyl-cysteine) provides the building block (cysteine) for the production of glutathione (GSH)- it was thought NAC was providing a boost to glutathione (GSH) – and it was! Back in the 1970s, NAC was found to be quite effective at treating the severe glutathione depletion that occurs during acetaminophen poisoning.

(If NAC is providing cysteine, why not just take cysteine then? Cysteine is not nearly as effective and can be quite toxic when taken in higher doses. NAC, on the other hand, is quite safe.)

NAC is often thought more of as an antioxidant but it has mitochondria enhancing properties as well.

When studies found, though, that NAC was providing protection even when the GSH biosynthesis pathway had been blocked, it became clear that NAC had another trick up its sleeve. In 2018 German and Japanese researchers offered (in their own words) a “new and unexpected perspective on the antioxidative prowess of NAC” – which may provide the answer.

Theirs and other studies suggested that NAC’s antioxidant benefits came out of its ability to squelch free radicals being produced by the mitochondria – not the rest of the cell. Besides producing energy our mitochondria are the greatest producers of free radicals in the body. When they go bad – which David Systrom’s work suggests happens in a subset of people with ME/CFS – they can produce tremendous levels of reactive oxygen species.

It appears that NAC is being transformed into hydrogen sulfide (h2S) in the mitochondria. The H2S is then being oxidized to create sulfur species, and it’s these sulfur species that appear to be producing NAC’s antioxidant and protective features. Given that it’s interesting that the hydrogen donors produced during this process may also able to enhance a cell’s “mitochondrial bioenergetics” by stimulating its ATP production.

This, of course, brings up the question of whether hydrogen sulfide products could kill two birds with one stone: protect against the oxidative stress associated with mitochondrial problems and enhance ATP production as well. A blog on the evolving and very intriguing hydrogen sulfide field is coming up.

The Shungu Study

NAC, then, functions as an antioxidant, in part, because of its ability to enhance glutathione production. It’s able to enhance glutathione production, though, only in people with very low glutathione levels. NAC also appears able, as was noted above, to trigger the production of small amounts of hydrogen sulfide in the mitochondria which also have antioxidant and energy enhancing effects.

It’s that first part of the equation that Shungu focused on in his unusual NIH-funded (that’s right an NIH-funded) clinical trial in ME/CFS. The NIH has been fiercely resistant to funding clinical trials for ME/CFS. In fact, the NIH states in the title of its two 2020 Program Announcements for ME/CFS that it will not fund clinical trials.

So how did Shungu manage to get the NIH to fund a 5-year $2 million-plus clinical trial in ME/CFS? Shungu did that by bypassing the ME/CFS Program Announcement (PA) and used one (PA-18-345) specifically designed to support clinical trials. It’s been thought that anti-ME/CFS bias would preclude any clinical trial from being funded through such a generic PA – yet Shungu managed to get his through.

How? Probably because the clinical trial grew directly out of Shungu’s successful NIH-funded ME/CFS research effort. Working with Dr. Natelson and others, Shungu, from 2009-2017 demonstrated in a series of five studies that lactate was increased and glutathione decreased in the brains (ventricles) of people with ME/CFS.

One thing to note about Shungu’s successful run: it was made possible by three vital seed grants from the Solve ME/CFS Initiative which have ultimately mushroomed into millions of dollars in NIH funding and now a real rarity – an NIH-funded clinical trial.

In 2009 Shungu found that ventricular lactate levels were 300-350% higher in people with ME/CFS than in people with anxiety or in healthy controls. In 2017 he found higher levels of ventricular lactate in people with fibromyalgia as well.

Shungu then set out to try to fix the oxidative stress issues. After getting an NIH R21 grant (a smaller NIH grant) he assessed the ability of NAC to raise glutathione levels in the brains of people with ME/CFS. Glutathione is the master antioxidant in the body and plays a major role in maintaining redox balance in the mitochondria. Shungu gave 12 people with ME/CFS and 12 healthy controls 1800 mg/NAC for four weeks and then checked their brain glutathione, oxidative stress, and symptom levels using MRS spectroscopy

At the 2017 IACFS/ME Conference Shungu reported what may be the oddest finding ever. NAC, he reported, had worked – too well. It wasn’t that ME patients’ brain glutathione levels rose, or that their levels of reactive oxidative species (free radicals) called isoprostanes fell – those findings were acceptable. The symptom response, though, was simply too good to be true. Shungu presumed that a strong placebo response must have occurred and stated that larger studies were needed to get the full story on NAC and ME/CFS.

The fact that the NAC treatment had no effects on the brain chemistry or free radical levels or symptoms of the healthy controls confirmed what past studies had found: unless your glutathione levels are very low NAC supplementation has no effects at all on them. Once a glutathione ceiling is reached a feedback inhibition process keeps it at that level.

Treating Chronic Fatigue Syndrome (ME/CFS): The IACFS/ME Conference Overviews Part V

With the pilot data in hand, the NIH funded Shungu’s 60-person “Assessment of N-Acetylcysteine as Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (NAC ME/CFS)” study to the tune of several million dollars in 2020.

This study has all the bells and whistles one would expect: it’s a double-blinded, placebo-controlled, randomized trial that will assess the effects of three doses (0 mg/day; 900 mg/day; 3600 mg/day) on symptoms, blood flows to the brain, brain chemistry (lactate), and oxidative stress (glutathione, isoprostanes, protein carbonyl) levels. It also has a most unusual prerequisite – it’s only open to patients found to have low brain glutathione levels via MRS imaging.

This is the kind of study the NIH is capable of but rarely funds in ME/CFS. The RO1 grant mechanism that Shungu got his grant through, inevitably produces large, expensive, complex, and comprehensive studies. They’re wonderful things if you can get them.

The study started in 2020 and is taking place at Cornell University in Ithaca, New York. It’s slated to last through 2025 and is still is listed as still recruiting patients. Contact information:

Jihyun Lee, MPH	2127462481	jil4015@med.cornell.edu
Xiangling Mao, MS	2127462632	xim2004@med.cornell.edu

An Oxidative Stress-induced Micro-circulatory Disease?

Shungu, interestingly, does not believe ME/CFS is a mitochondrial disorder. The mitochondria are affected in ME/CFS but at its heart, Shungu believes ME/CFS is an oxidative stress-induced micro-circulatory disease. High levels of oxidative stress are causing the blood vessels to shut down, making it impossible for the oxygen the mitochondria need to get through. Shungu’s hypothesis, which was produced some time ago, is circling around the same blood flow issues that other hypotheses are.

Could Poor Microcirculation Be Causing Chronic Fatigue Syndrome (ME/CFS)?

Paul et. Al. recently fleshed out the oxidative stress hypothesis for ME/CFS and long COVID in greater detail.

Could a Free Radical Explosion Be Causing ME/CFS and Long COVID?

The Gist

N-acetyl cysteine or NAC has been called the “epitome of antioxidants”. Able to rejuvenate the levels of the most powerful antioxidant in the body – glutathione – appears to do its work mostly in the mitochondria.
That’s good news as the mitochondria are the greatest free-radical producers in the body and dysfunctional mitochondrial – such as may be found in ME/CFS – can produce enormous amounts of oxidative and nitrosative species (otherwise known as freed radicals).
How exactly NAC works has not exactly been clear but recent research indicates that NAC also triggers the production of hydrogen sulfide which, in turn, produces antioxidant effects and perhaps enhances ATP production as well.
Dikomo Shungu of Cornell University parleyed small pilot grants from the Solve ME Initiative into millions of dollars of NIH funding, and ultimately, a rare NIH-funded clinical trial, Shungu showed that ME/CFS patients’ brains contain low glutathione and high lactate and oxidative stress levels.
Shungu’s preliminary study found 1800 mg NAC supplementation returned glutathione, lactate, and oxidative stress levels to normal and helped with symptoms in ME/CFS.
In 2020 Shungu received a large NIH grant to study the effects of 900 mg and 3600 mg of NAC daily for four weeks on symptoms, glutathione, lactate, and oxidative stress levels in ME/CFS. Particularly at the higher dose level, Shungu is using far higher doses than we ordinarily see in ME/CFS. Shungu’s study is expected to run through 2025 and is still open. (See blog for details).
Shungu does not believe the mitochondria are damaged in ME/CFS. His studies suggest to him that ME/CFS is an oxidative stress-induced micro-circulatory disease. Oxidative stressors are shutting down the blood vessels – preventing proper amounts of oxygen from getting to the mitochondria.
More effective ways to deliver NAC are under development which may be far more potent. New forms of antioxidants such as cysteamine are popping up as well which may be able to better boost antioxidant levels in the body. Hydrogen sulfide is a particular area of interest that Health Rising will delve into. Plus, a new and perhaps dramatically more potent form of the master antioxidant in the body is coming to market. Health Rising will have a blog on that as well.

Using NAC

A 2019 hypothesis paper proposed that supplements like coenzyme Q10, melatonin, curcumin, molecular hydrogen, and N-acetylcysteine could be helpful in ME/CFS patients with inflammation, increased oxidative and nitrosative stress, leaky gut, and mitochondrial dysfunction.

No one thinks NAC will cure ME/CFS but if Shungu’s initial findings that NAC supplementation can return brain glutathione levels to normal levels and reduce the levels of dangerous free radicals are correct, it will certainly deserve a place in ME/CFS patients supplement toolkit.

Shungu, interestingly, is using far NAC in his trial more than the 500 mg/day Dr. Teitelbaum uses in ME/CFS and fibromyalgia or that WebMD reports is most commonly used (600-1200 mg). Shungu used 2000 mg NAC a day in his pilot study and is assessing the effects that 900 mg and 3600 mg hae in his NIH study.

As with any treatment anyone trying NAC should probably start low and slowly ramp up. Some side-effects can occur (dry mouth, nausea, vomiting, and diarrhea) but it is considered generally safe. People with asthma or bleeding disorders should be more careful with it.

FDA Bans NAC for Use as Supplement

Last September, in what some called a sop to drug manufacturers, the FDA sent warning letters to supplement manufacturers informing them that since NAC was originally certified as a drug back in 1963 that it could not be sold as a supplement. In Feb 2021 the FDA’s determination was finalized. Trade associations and some Congressmen are fighting the decision.

N-acetyl cysteine is no longer available on Amazon (which may not be the best source of supplements anyway) but NAC is still available from Prohealth, Thorne, Jarrow, Life Extension and other vitamin companies.

New Better Forms of NAC on the Way?

Shungu found some pretty darn good results in his pilot study but better forms of NAC may be on the way. NAC may be the most widely used antioxidant but one report stated that NAC actually has poor bioavailability which requires quite high doses to be taken to achieve neuroprotective effects in the central nervous system.

Technology – our great hope – may be coming to the rescue. Nanoparticle enclosed forms of NAC could be more effective at delivering the compound to the target of choice in central nervous system diseases. Indeed, nanotechnology-based approaches are currently being developed to deliver target drugs directly to the mitochondria. Attempts to produce drugs that can reach the mitochondria in the brain, however, have been rare.

Dendrimer forms of NAC could fill that bill. A 2018 paper “Targeting Mitochondrial Dysfunction and Oxidative Stress in Activated Microglia using Dendrimer-Based Therapeutics” out of Johns Hopkins University “Center for Nanomedicine” described an improved dendrimer-NAC conjugate called TPP-D-NAC which was able to target the dysfunctional mitochondria found in activated microglial cells and reduce oxidative stress levels substantially as well.

How close or far this technology is to getting into doctors’ toolkits I don’t know but the development of better drug delivery options that can transport the supplement or drug of choice straight to the target of choice is a pretty hot field. They provide hope for the future.

Are Intranasal Drugs the Future for ME/CFS and Fibromyalgia?

More Powerful Antioxidants on the Way?

More powerful antioxidants are being developed as well. A review paper, “Therapeutic Applications of Cysteamine and Cystamine in Neurodegenerative and Neuropsychiatric Disease“, Bindu Paul and Solomon Snyder of Johns Hopkins proposed using cysteamine and cystamine to treat neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s Diseases as well as autism.

Cysteamine and cystamine function both as antioxidants and potent antioxidant boosters. Cysteamine, in fact, is reportedly three times more powerful a cysteine booster than N-acetylcysteine (NAC).

The authors propose that cysteamine/cystamine will soon be added to the mix of drugs that used to treat central nervous system diseases. If the trials are successful, a new way of tamping down the oxidative stress and neuroinflammation in the brain may have been found – one that could apply to FM and ME/CFS.

Still at the Beginning? The Hunt for Better Drugs for Fibromyalgia

Then there are hydrogen sulfide-based treatments that make up a world in themselves. A blog on the role H2S may play in ME/CFS pathophysiology and treatment is coming up.

Coming up next – a new kind of glutathione that appears to be most effective yet hits the market

Conclusion

N-acetyl cysteine or NAC is a most interesting compound. Most often thought of as an antioxidant it appears to be able to enhance mitochondrial production as well.

Perhaps the most powerful antioxidant available and certainly the most widely studied, NAC is able to rejuvenate the levels of glutathione – the most powerful antioxidant in the body. It appears to do its work mostly in the mitochondria where recent research indicates it also triggers the production of hydrogen sulfide which, in turn, produces antioxidant effects and perhaps enhances ATP production as well.

Dikomo Shungu of Cornell University has been able to parley small pilot grants from the Solve ME Initiative into millions of dollars of NIH funding, and ultimately, a rare NIH-funded clinical trial involving NAC. In a series of studies, Shungu was able to show that ME/CFS patients’ brains contain low glutathione and high lactate levels. Shungu then applied for a pilot grant (R21) which found that 1800 mg NAC supplementation returned glutathione, lactate, and oxidative stress levels to normal and helped with symptoms in ME/CFS.

In 2020 Shungu received a large NIH grant to study the effects of 900 mg and 3600 mg of NAC daily for four weeks on symptoms, glutathione, lactate, and oxidative stress levels in ME/CFS. Particularly at the higher dose level, Shungu is using far higher doses than we ordinarily see in ME/CFS. Shungu’s study is expected to run through 2025 and is still open. (See blog for details).

More effective forms of NAC and other antioxidants are being developed. Hydrogen sulfide donors are an area of special interest. An upcoming blog will feature a potential breakthrough in glutathione supplementation that is hitting the market.

The Mitochondrial Enhancers for Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Series

49 Comments