Open New York, USA: Assessment of N-Acetylcysteine as Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (NAC ME/CFS)

[John Mac]

Sponsor: Weill Medical College of Cornell University
Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)

Brief Summary:
Chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS) is an unexplained multisymptom/multisystem disorder for which there are currently no validated treatments.

The present exploratory clinical trial aims to advance our understand of the mechanisms of in situ GSH synthesis control through assessment of the response of brain GSH and plasma markers of oxidative stress to different doses of NAC in comparison to placebo, as a potential treatment for ME/CFS that would provide neuroprotection against oxidative stress by restoring cortical GSH reserves.

If successful, this exploratory clinical trial would address a significant public health concern by shedding new light onto the mechanisms of action of NAC in brain GSH restoration, which could open a new avenue for the development of potentially effective treatments for a disorder, ME/CFS, that currently has none.

https://www.clinicaltrials.gov/ct2/show/NCT04542161

 

[James Morris-Lent]

As I understand it a number of patients have reported very bad reactions to NAC. In this light one wonders about the ethics of such a trial. I doubt we can expect much benefit considering this has been one of those supplements floating around forever with nothing to show for it.

 

[Tom Kindlon]

This was presented at a previous IACFS/ME conference:

N-Acetylcysteine Alleviates Cortical Glutathione Deficit and Improves Symptoms in CFS: An In Vivo Validation Study using Proton Magnetic Resonance Spectroscopy

N. Weiduschata, X. Maoa, D. Vub, M. Blateb, G. Kanga, H.S. Mangatc, A. Artisd, S. Banerjeed, G. Langeb, C. Henchcliffec, B.H. Natelsonb, D.C. Shungua
a Departments of Radiology, c Neurology and Neuroscience, and d Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA; b Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, NY, USA;

OBJECTIVES We previously reported a robust 36% deficit of occipital cortex glutathione (GSH) – the primary tissue antioxidant – in patients with CFS compared to healthy comparison (HC) subjects, a finding that implicated oxidative stress in the disorder. The primary objective of the present study was to assess whether supplementing CFS patients with the GSH synthetic precursor N-acetylcysteine (NAC) daily for 4 weeks would spur in situ synthesis and significant elevation of cortical GSH compared to baseline, as assessed in vivo with proton magnetic resonance spectroscopy (1H MRS).

METHODS For this pilot clinical study, we recruited 16 medication-free patients meeting the CDC criteria for CFS and 15 HC subjects. Following baseline measurement of occipital cortex GSH with 1H MRS and administration of a battery of clinical assessments, both CFS and HC participants received a 4-week supplement of 1800mg NAC/day. After 4 weeks, identical 1H MRS scan and clinical assessments were conducted to determine the effect of NAC on cortical GSH levels and on CFS symptoms as assessed with the CDC CFS symptom inventory.

RESULTS At baseline, controlling for age and race, cortical GSH levels were 15% lower in CFS than in HC (95%CI: -0.0005,0; p=0.04, one-tailed as the differences and direction of changes were postulated a priori). Following 4 weeks of daily NAC supplementation, cortical GSH levels rose significantly relative to baseline (95%CI: 0.0001,0.0006; p=0.004, one-tailed) in CFS patients to match those in HC, which did not differ compared to baseline (95%CI: -0.0002,0.0003; p=0.33, one-tailed). Lastly, NAC supplementation markedly improved symptoms in CFS patients, with significant decreases in CDC CFS symptom inventory total scores (95%CI: -51.5-9.6; p=0.006), case definition scores (95%CI: -28.2-2 .0; p=0.03) and “other symptoms” scores (95%CI: -24.0-7.3; p<0.001). However, GSH levels did not correlate with any clinical measure.

CONCLUSION The results of this study have provided the very first direct evidence that NAC crosses the blood-brain barrier to spur in situ synthesis and elevation of cortical GSH. Significantly, increasing cortical GSH levels with NAC ameliorated symptoms in CFS patients. Future studies evaluating the clinical efficacy, and optimal dose and treatment duration of NAC are warranted.

Dikoma C. Shungu, Ph.D., Professor of Physics in Radiology, Fellow of the International Society for Magnetic Resonance in Medicine (FISMRM); Chief, Laboratory for Advanced MRS Research Citigroup Biomedical Imaging Center, Weill Cornell Medicine; 516 E 72nd Street, New York, NY 10065. Email: dcs7001@med.cornell.edu. Funding source: NIH Grant # 1 R21 NR013650. There are no conflicts of interest to declare or disclose.

 

[InitialConditions]

Honestly, this seems like a waste of money to me. We would know by now if NAC had a significant effect on ME symptoms in a significant number of patients.

 

[Rain]

Honestly, this seems like a waste of money to me. We would know by now if NAC had a significant effect on ME symptoms in a significant number of patients.

Exactly. Every time limited resources are spent on things most of us has tried and dismissed already, it feels like a step back, not forward.

 

[Dancer]

I do think the finding of low glutathione is interesting - I definitely had that. But I tried NAC and also glutathione IV treatments and none of it helped. What is CAUSING the low glutathione? Otherwise it seems like trying to pour into a bucket full of leaks.

 

[Fizzlou]

For me NAC has had a hugely beneficial effect on the 'wired and tired' insomnia. It was the insomnia that really pushed me to my wits end so I'm positive about it. I have to watch my glutamate levels. My spreadsheet of self experimentation of strategies continues to grow and some things that work for others have a bad effect on me e.g. probiotics and glycine. The same old story with many studies seems to be about 1/3 good responders. A reflection of heterogeneity?

 

[TigerLilea]

I do think the finding of low glutathione is interesting - I definitely had that. But I tried NAC and also glutathione IV treatments and none of it helped. What is CAUSING the low glutathione? Otherwise it seems like trying to pour into a bucket full of leaks.

Years ago when I had testing done, my glutathione was the only thing that tested out of range. I started taking NAC, however, I did not notice any improvement with my ME. Whether or not my glutathione levels went up at all I don't know as I didn't want to pay to have testing done again.

 

[Arnie Pye]

*** Disgusting post warning ***

I have been taking NAC for years. As an ex-long-term-heavy-smoker my lungs don't clean themselves out very well. NAC makes lung secretions thinner and they can be coughed up more easily than when the secretions are really thick. Without NAC my lungs would be left full of junk that could encourage infection.

My husband and I got help to stop from the NHS. I asked the stop smoking counsellor if or when my lungs would start to clean themselves out and she said it could take anything from 24 hours to never. Since my lungs still felt "full" two years later I was one of the "never" group. Then I read about NAC and once I started taking it finally the junk in my lungs started to come up.

If NAC became something that could only be prescribed rather than bought OTC I would be devastated, as well as being far more likely to get chest infections.

 

[Rain]

@Arnie Pye NAC is widely used to break up thick mucus regardless of cause. I am happy to use it for some symptom relief for longer or shorter periods myself, but don’t find it particularly interesting for a complex set of ME-symptoms.

 

[Louie41]

Hmmm---I've taken NAC for a couple of years now and it has ended my "tired but wired" feeling. So
I've found it extremely useful.

 

[NelliePledge]

I don’t think I’ve ever picked up on NAC being something that helps some with tired but wired insomnia.
Very interesting and one I will look into.

 

[Louie41]

I believe it was looked at in a study cited by @Hip. Sorry, but don't remember the name of the investigator.

The study referenced by @Tom Kindlon above, by Dr. Shungu et al., is the one that @Hip cited, I'm quite certain.

There's a discussion in this thread:
NAC - how best to take it
@NelliePledge

ETA: NelliePledge flag
ETA: confirm Shungu study as the one cited by @Hip.

 

[FMMM1]

As I understand it a number of patients have reported very bad reactions to NAC. In this light one wonders about the ethics of such a trial. I doubt we can expect much benefit considering this has been one of those supplements floating around forever with nothing to show for it.

I hadn't picked that up i.e. "very bad reactions to NAC". I recall that this group demonstrated low levels of "(GSH) glutathione, an antioxidant capacity and redox state marker", i.e. in the brains of people with ME. Glutathione levels, in the brain, can be measured using MRI/MRS; you can't actually measure the levels of very many compounds in the brain - MRI/MRS isn't that sensitive.
Since glutathione levels have been shown to be low in people with ME, then in principle increasing the levels, and monitoring the effects, seems like a good idea.

I think this study emphasises the need to deliver a large GWAS study; that way we may have more promising leads to investigate. @Simon M @Michiel Tack

 

[FMMM1]

I do think the finding of low glutathione is interesting - I definitely had that. But I tried NAC and also glutathione IV treatments and none of it helped. What is CAUSING the low glutathione? Otherwise it seems like trying to pour into a bucket full of leaks.

If you consider Chris Armstrong's work on amino acids, and glucose, in blood (coincidentally he used the same technique i.e. MRS). Chris found low levels of certain types of amino acids and high levels of glucose. Basically indicating that people with ME utilised these amino acids for energy production i.e. rather than glucose. Fluge and Mella progressed this https://insight.jci.org/articles/view/89376

So if Glutathione is low then that may be due to use - increased oxidative stress.

So supplementing with the precursor (which crosses the blood brain barrier?) is a way of investigating what is "CAUSING the low glutathione".

 

[FMMM1]

Years ago when I had testing done, my glutathione was the only thing that tested out of range. I started taking NAC, however, I did not notice any improvement with my ME. Whether or not my glutathione levels went up at all I don't know as I didn't want to pay to have testing done again.

Assume this was blood glutathione; unfortunately testing the levels of glutathione in the brain isn't readily available (MRI/MRS).

 

[forestglip]

The primary and secondary outcomes show they will be measuring levels of 10 different chemicals, but why wouldn't they also include symptoms?

Baseline visit assessments will include blood collection, survey questionnaires, MRI and MRS imaging. Subjects whose initial screening confirms low GSH level at baseline will be provided with a 4-week supplement of anonymized NAC or placebo caplets. After 4 weeks, subjects will then undergo a follow-up visit to repeat the baseline assessments.

I assume the initial visit questionnaire will ask about symptoms. Then they'll "repeat the baseline assessments". I don't know if that includes the survey, and if so, why they wouldn't register it as an official outcome.