A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine


N-acetyl cysteine is a blast from the past, a dashed hope and abit of acid flux. When I was a young a doc was convinced that N-acetyl cysteine was the answer for MS and asked us to do an EAE experiment. This person was taking it and self experimenting. We did it and it did nothing. However in hindsight it was always going to do nothing. It is not an immunosuppressive, but the evidence is that it is an anti-oxidant and it boths glutathione. So it should target neurodegeneration and not relapsing disease. At the time, I did not understand the distinction. I do know and it was the wrong experiment to do…..Fast forward and it was reported that COVID-19 enhanced glutathione and I thought N-acetyl cystine and went to the health food shop and got a supply. The Medcram Doc also had the same idea and was taking it too. Part of my anti-COVID regime. I am sure it caused heart burn, if I did take it with food. However, when we were looking for neuroprotective agents I thought of n-aceyl cystine and we did a search and decided to bin the idea because we read that it did not enter the brain. An israeli company had invented a CNS-penetrant variant, but they never gave us any to test. So I was interested to see this study in fatigue. It didnt do anything. Was that because it didnt get in the brain. This was supported by some other studies in fish, but apparently it can get in the human brain. However in the pilot study the glutathione levels didnt change and it didnt work, was the doses wrong…

Krysko KM, Bischof A, Nourbakhsh B, Henry RG, Revirajan N, Manguinao M, Nguyen K, Akula A, Li Y, Waubant E. A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine. Ann Clin Transl Neurol. 2021 Mar 6. doi: 10.1002/acn3.51325.

Objective: To assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo.

Methods: Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced-to-oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes.

Results: Fifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups.

Interpretation: NAC was well-tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half-life, or lack of effect. REGISTERED: clinicaltrials.gov NCT02804594.

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  • So lipoic acid is a much better quandidate in terms of being able to cross the blood brain barrier and that it is an antioxydant and was shown in eae models to have an immunomodulating effect.

    • That may be why trials are planned with lipoci acid, but if it is not put on top of an effective DMT, we are wasting your time

      • That is an interesting strategy in order to help focus more on the beneficial effect of Lipoic acid for the slow progression of the disease by removing new lesion formation. Unless, you use it in a secondary progressive or primary progressive cohort with no new lesion formation in the past 12-24 months which could help avoid the possibility of new lesions.

    • There are hundreds of compounds that have been reported to be immunomodulating in EAE that aren’t under clinical conditions.

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