Lightning overview of N-acetylcysteine (NAC) for Long COVID with difficulty breathing (dyspnea)

TLDR: NAC seems to help LC/dyspnea and is relatively safe.

WHY:
A small study found "three out of 3 (100 %) of the PASC/LC patients supplementing their diet with NAC decreased vWF values to normal levels at the time of subsequent evaluations, whereas none (0 %) of the 6 symptomatic PASC/LC control patients did so" [0]

REVIEW:

"N-acetylcysteine reduces severity and mortality in COVID-19 patients" right in the title [8]

"mortality was the most meaningful outcome of NAC therapeutic efficacy in patients with COVID-19 [...] mortality was significantly reduced in the NAC-treated group compared to the placebo group [RR, 0.65; 95% CI: 0.56 to 0.75; p-value 0.0001]" [8]

"Two grams of oral or IV GSH, a precursor to NAC therapy, has effectively reduced dyspnea in COVID-19 patients. Later on, in a large cohort study of 19,208 hospitalized COVID-19 cases, 2,071 of whom were treated with 600 mg/kg oral NAC, mortality was significantly reduced."

"mice treated with NAC presented markedly reduced CS-induced pulmonary injury and ameliorated CS-induced pulmonary fibrosis and inflammation" [2]

"After pretreatment with NAC at low, moderate, and high concentration, respectively, intracellular reactive oxygen species (ROS)" [2]

"N-acetyl cysteine is likely safe for most adults" [3]

"properties of NAC include enhancing glutathione S-transferase activity, repleting glutathione, scavenging free radicals, and stabilizing protein structures by crosslinking cysteine disulfide molecules along with its antioxidant, anti-inflammatory, and mucolytic properties" [4]

Back in 2021:
"Collectively this data supports the notion that 1200 mg of oral NAC can effectively reduce ROS production without compromising phagocytosis of SARS-Cov-2 in neutrophils" [5]

"N-acetylcysteine (NAC) is inexpensive, has very low toxicity, has been FDA approved for many years, and has the potential to improve therapeutic strategies for COVID-19. [...] Potential therapeutic benefits of NAC include, extracellularly scavenging ROS radicals, replenishing intracellular GSH, suppression of cytokine storm, and T cell protection, thus mitigating inflammation and tissue injury" [5]

"in in vivo experiments, NAC inhibited several profibrotic mechanisms in murine models" [6]

In humans, "NAC may restore defective autophagy [...] NAC may prevent and eliminate biofilms resulting from airway infections, particularly of Pseudomonas aeruginosa" [6]

"In COPD, beneficial effects of NAC have not been clearly confirmed in the clinical studies, probably due to insufficient doses, short time of observation, inactivation of NAC by oxidative stress, and/or the choice of inadequate outcome parameters" [6]

"supplementing GlyNAC (combination of glycine and N-acetylcysteine, a cysteine donor) for a relatively short period of 14 days improves/corrects GSH deficiency in OA, HIV-patients and diabetic patients, and these data suggest the possibility that similar supplementation of GlyNAC in COVID-19 patients could improve GSH deficiency" [7]

"Glutathione (GSH) is the most abundant" antioxidant, and "Compared to controls, RBC concentrations of total-GSH (tGSH) and reduced-GSH (rGSH) in COVID-19 patients were 60% lower"; "Because GlyNAC (combination of glycine and N-acetylcysteine) supplementation has been shown in clinical trials to rapidly improve GSH deficiency, OxS and oxidant damage, GlyNAC supplementation has implications for combating these defects" [7]

Safety-wise, in "Forty-one articles where NAC has been used at 600 mg and above, up to 3000 mg/day, and with a specific report on safety, were considered. [...] the safety profile was similar at both the high and standard doses with the oral formulation; gastrointestinal symptoms were reported but they were no more common than in the control group." [9]

"N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia" [10] is not COVID-19 specifically but if LC-driven oxidative stress is causally contributing to dyspnea then that result applies.

Trial check:
https://clinicaltrials.gov/study/NCT04545008 - stopped due to poor accrual
https://clinicaltrials.gov/study/NCT04455243 - never recruited
https://clinicaltrials.gov/study/NCT04466657 - never enrolled
https://clinicaltrials.gov/study/NCT04370288 - never ran?
https://clinicaltrials.gov/study/NCT04374461 - active, estimated completion 2025-05
https://clinicaltrials.gov/study/NCT04419025 - completed, unpublished - likely signifies a lack of result

[0] https://www.sciencedirect.com/science/article/pii/S2352578925000074
[1] https://www.sciencedirect.com/science/article/pii/S0753332225000496
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC6639458/
[3] https://medlineplus.gov/druginfo/natural/1018.html
[4] https://pmc.ncbi.nlm.nih.gov/articles/PMC8211525/
[5] https://pmc.ncbi.nlm.nih.gov/articles/PMC7649937/
[6] https://pmc.ncbi.nlm.nih.gov/articles/PMC10526097/
[7] https://pmc.ncbi.nlm.nih.gov/articles/PMC8773164/
[8] https://pmc.ncbi.nlm.nih.gov/articles/PMC10390689/
[9] https://pmc.ncbi.nlm.nih.gov/articles/PMC7892733/
[10] https://pmc.ncbi.nlm.nih.gov/articles/PMC6250560/

Note I am NOT a doctor, this is a lay review!