N-Acetylcysteine (NAC) for COVID-19

Posted on by Jesse Santiano, M.D.

Many medical articles have discussed the potential use of N-acetylcysteine (NAC)’s anti-thrombotic, anti-inflammatory, and antioxidant properties for COVID-19. [1][2][3].

N-acetylcysteine (NAC) is an FDA-approved drug and the precursor of glutathione, one of the body’s primary antioxidants. NAC is used in acetaminophen (Tylenol) poisoning and is an effective mucolytic, especially in patients with Chronic Obstructive Pulmonary Disease (COPD).

However, there have been no published studies about its use for COVID-19 until now.

The study, Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19,  was peer-reviewed and published in the  Science Journal. [4] The study came from patients admitted to Castilla-La Mancha in Spain.

At the start of the pandemic, NAC was included in the COVID-19 treatment protocol of some hospitals. Those patients became the subject of the study. However, not all hospitals used NAC for COVID-19. Those patients became the control group for the study.

The research involved 19,208 hospitalized patients with a diagnosis of COVID-19. Almost 11% of them (2,071) used oral NAC at high doses. COVID-19 patients treated with NAC were older by about 4.2 years, predominantly male, and with more comorbidities such as hypertension, dyslipidemia, diabetes, and COPD than those not on NAC.

Results

The study found that the COVID-19 patients who took NAC had a significantly lower risk of dying from COVID-19 despite having more significant comorbidities (Odds Ratio 0.56; 95%CI 0.47–0.67). Those findings were consistent even as they adjusted for baseline characteristics and use of steroids.

NAC Dose

The dose of NAC in this study was 600 mg every 8 hours and was given together with other treatments for COVID-19.

At 600 mg/day, NAC dissolves mucus in the respiratory tract. However, NAC acts as an antioxidant at higher doses of more than 1,200 mg/day. Antioxidants are essential in COVID-19 to counter the free radicals and result in oxidative stress.

Mechanism of action of NAC

NAC can prevent SARS-CoV-2 attachment to ACE2 receptors

An in silico study showed that NAC lessens the binding affinity of the spike protein to the ACE2 receptor. SARS-CoV-2 has to attach to the ACE2 receptor in human cells before it enters and starts replicating. [5] In addition, by blocking ACE, NAC protects against the damaging effects of angiotensin II on the blood vessel, excessive blood clot formation, and inflammation.

Antioxidant

An article in ACS Infectious Disease proposed that glutathione deficiency is the most reasonable explanation for severe manifestation and death in COVID-19 patients. Glutathione deficiency leads to oxidative stress and damage to the cells and makes an individual more susceptible to environmental insults like COVID-19. [6][8]

As mentioned earlier, NAC is a precursor of glutathione. The replacement of depleted glutathione in COVID-19 restores the immune cell response and potentially reduces viral pneumonia incidence or severity.[8]

Anti-Thrombotic

NAC’s clot prevention or anti-thrombotic properties are beneficial in patients with COVID-19. Patients with serious COVID-19 tend to form blood clots inside the arteries. These clots block the oxygen supply to the heart, brain, and kidneys resulting in organ failure.

Anti-inflammatory

NAC reduces pro-inflammatory cytokines like Interleukin (IL) 1 β, IL-6, IL-8, and Tumor necrosis factor α TNF-α. NAC has beneficial uses in patients at risk for serious COVID -19 like smokers and those with comorbidities like Chronic Obstructive Pulmonary Disease, diabetes, hypertension, and cardiovascular disease.

The image below shows the effects of NAC on different pro-inflammatory enzymes. These actions modulate the immune response and prevent cytokine storms.

Major mechanisms involved in the antioxidant and anti‐inflammatory action of NAC via GSH (modified and updated from Sadowska, 2012) From De Flora et al. 2020.

Below is a brief overview of how to use NAC for COVID-19 from N-Acetylcysteine to Combat COVID-19: An Evidence Review [9]

Shi and Puyo 2021

 Parting thoughts

NAC is inexpensive, has low toxicity, and has been FDA approved and used in the hospital for many years. NAC may help reduce hospital admission and COVID-19 mortality with other drugs.

A recent article, The I-RECOVER Post-Vaccine Treatment Protocol, includes NAC as treatment for post-COVID vaccine injuries. 

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  8. Aspirin for the early treatment of COVID-19
  9. Curcumin for the Early Treatment of COVID-19
  10. Nigella Sativa or Black Seed, Black Cumin for COVID-19

References:

  1. Debnath U, Mitra A, Dewaker V, Prabhakar YS, Tadala R, Krishnan K, et al. N-acetyl cysteine: A tool to perturb SARS-CoV-2 spike protein conformation. ChemRxiv. Cambridge: Cambridge Open Engage; 2021; This content is a preprint and has not been peer-reviewed.
  2. Shi Z, Puyo CA. N-Acetylcysteine to Combat COVID-19: An Evidence Review. Ther Clin Risk Manag. 2020;16:1047-1055. Published 2020 Nov 2. doi:10.2147/TCRM.S273700
  3. Wong KK, Lee SWH, Kua KP. N-Acetylcysteine as Adjuvant Therapy for COVID-19 – A Perspective on the Current State of the Evidence. J Inflamm Res. 2021 Jul 6;14:2993-3013. Doi: 10.2147/JIR.S306849. PMID: 34262324; PMCID: PMC8274825.
  4. Izquierdo JL, Soriano JB, González Y, et al. Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19. Sci Prog. 2022;105(1):368504221074574. doi:10.1177/00368504221074574
  5. Debnath U, Mitra A, Dewaker V, Prabhakar YS, Tadala R, Krishnan K, et al. N-acetyl cysteine: A tool to perturb SARS-CoV-2 spike protein conformation. ChemRxiv. Cambridge: Cambridge Open Engage; 2021; This content is a preprint and has not been peer-reviewed.
  6. Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis. 2020 Jul 10;6(7):1558-1562. doi: 10.1021/acsinfecdis.0c00288. Epub 2020 May 28. PMID: 32463221; PMCID: PMC7263077.
  7. Jorge‐Aarón RM, Rosa‐Ester MP. N‐acetylcysteine as a potential treatment for novel coronavirus disease 2019 [published online ahead of print, 2020 Jul 14]. Future Microbiol. 2020. 10.2217/fmb-2020-0074. 
  8. De Flora S, Balansky R, La Maestra S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB J. 2020 Oct;34(10):13185-13193. doi: 10.1096/fj.202001807. Epub 2020 Aug 11. PMID: 32780893; PMCID: PMC7436914.
  9. Shi Z, Puyo CA. N-Acetylcysteine to Combat COVID-19: An Evidence Review. Ther Clin Risk Manag. 2020;16:1047-1055. Published 2020 Nov 2. doi:10.2147/TCRM.S273700
  10. Sadowska AM. N‐Acetylcysteine mucolysis in the management of chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2012;6:127‐135. 10.1177/1753465812437563. 

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