A small clinical trial found that high-dose oral N-acetyl cysteine (NAC) may reduce a key marker of brain damage in people with progressive multiple sclerosis, though the treatment did not affect another well-known biomarker of nerve injury.
The phase 2 study, published in the Multiple Sclerosis Journal, tested a four-week course of NAC in 15 adults with progressive MS. Participants who received the drug showed a significant drop in levels of glial fibrillary acidic protein (GFAP), a marker linked to astrocyte damage, while those given a placebo saw GFAP levels rise. Neurofilament light chain (NfL), a protein associated with nerve fiber injury, remained unchanged in both groups.
Trial details and biomarker shifts
The randomized, double-blind trial was led by Emmanuelle Waubant, a neurologist at the University of California, San Francisco. Of the 15 participants, 10 received NAC at a dose of 1,250 mg three times daily, while five were given a placebo. One person in the placebo group did not provide blood samples, leaving four in that arm for analysis.
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Blood samples were collected at the start and end of the four-week period to measure 20 proteins. GFAP levels fell by a median of 10.1 pg/mL in the NAC group, compared with a 39.5 pg/mL increase in the placebo group. This difference remained after adjusting for age differences. NfL levels stayed essentially flat in both arms.
Two other markers showed possible signals. Myelin oligodendrocyte glycoprotein (MOG), which reflects myelin damage, trended lower in the treatment group after age adjustment, though the change was not statistically significant. Levels of interleukin-12 subunit beta (IL-12B) and soluble CD6 also moved in a direction favoring NAC, but neither reached the threshold for significance.
Progressive MS remains one of the most difficult forms of the disease to treat. Current therapies have limited impact on disability progression that occurs independently of relapses, known as progression independent of relapse activity (PIRA). The underlying mechanisms—oxidative stress, metabolic dysfunction, and chronic demyelination—are not well addressed by existing drugs.
GFAP has emerged as an early indicator of damage in progressive MS. Earlier work found that people experiencing PIRA have GFAP levels roughly 50% higher than those with stable disease. The protein is released by astrocytes, cells that support neurons and maintain the blood-brain barrier. In progressive MS, astrocytes may become damaged before neurons begin to die, making GFAP a potential target for early intervention.
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NAC, a precursor to the antioxidant glutathione, has been studied for years in neurological conditions. It crosses the blood-brain barrier at high doses and neutralizes reactive oxygen species, which contribute to tissue damage in MS. Previous research using MRI spectroscopy found lower glutathione levels in the brains of people with MS compared to healthy controls, supporting the idea of testing NAC in progressive disease.
The trial’s short duration and small size limit its conclusions. Four weeks may not be enough to detect changes in disability, and the imbalance in group sizes—10 in the NAC arm versus four in placebo—weakens the findings. The drop in GFAP, however, suggests NAC might have a biological effect worth further study.
A 2021 pilot study found NAC had no clear impact on fatigue, a common MS symptom. Fatigue and disability progression involve different processes, and the new trial’s focus on biomarkers provides a different perspective. The results match post-mortem studies indicating that astrocyte and oligodendrocyte injury may occur before neuronal loss in slowly expanding MS lesions.
A step toward larger trials
The authors avoided overstating the findings. They called the biomarker results “hypothesis-generating,” meaning they suggest a possible mechanism but do not prove clinical benefit. The trial was not designed to measure disability changes, and the brief treatment period leaves unanswered whether the GFAP drop would slow progression over time.
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A larger trial is already testing NAC as an add-on therapy in progressive MS. The NACPMS study, which began enrolling in 2022, includes more participants and longer follow-up. It may provide clearer answers about whether the biomarker changes seen in this pilot lead to meaningful disability improvements.
The findings contribute to research on oxidative stress in MS. If NAC or similar drugs can slow astrocyte damage, they might address a part of the disease process that current treatments overlook. For now, the results offer a small but important signal in a field where progress has been limited.
Regulation of such treatments remains a key concern as research advances.