Part 2: What is NAC?
Understanding the Basics
N-Acetyl Cysteine (NAC) and glutathione are antioxidants. NAC is one of many intracellular antioxidants, molecules that include vitamins and enzymes that catalyze chemical reactions.
Antioxidants:
· Catalase
· Glutathione
· Glutathione peroxidase (GSHpx)
· NAC
· Superoxide dismutase (SOD)
· Thiols
· Thioredoxin
· Vitamin C
· Vitamin E
NAC and GLUTATHIONE
N-acetyl cysteine (NAC) is a powerful thiol antioxidant that scavenges free radicals, especially oxygen free radicals. It also supports vital functions of organs and builds protein. As a precursor of L-cysteine, it biosynthesizes glutathione.
Glutathione is not only a master antioxidant; it is crucial to our antioxidant defense, a key contributor to overall wellness. Cysteine is a key micromolecule needed to maintain optimal health because it is essential as an amino acid that produces glutathione. Cysteine also helps the body make proteins.
Being an acetylated form of L-cysteine, NAC is easier to absorb through the gut than L-cysteine, which has poor bioavailability. The gut tends to oxidize it into another form, so the acetyl group is added to allow NAC to be deacetylated, resulting in cysteine.
We know that the U.S. Food and Drug Administration (FDA) is always working to ban supplements that help Americans, like NAC.
By increasing glutathione levels, NAC can improve overall health and reduce symptoms of chronic disease. Additionally, NAC is commonly used in clinical settings to help replenish glutathione levels in patients with certain medical conditions such as chronic bronchitis, cystic fibrosis, post-COVID lung injury, acetaminophen overdose, and more.
The reason NAC can be so helpful in an array of disease states is due to its ability to support the body with antioxidant and nitric oxide support. NAC assists cellular functions during times of stress, seeming to shine when the body needs it most:
Cellular Processes Utilizing NAC:
Infection.
Inflammation.
Overconsumption of oxygen and reactive oxygen species.
The generation of oxygen and reactive oxygen species in the capillary system, mitochondria.
After oxidative bursts by inflammatory cells.
Stress.
Toxicity.
ROLES OF NAC:
· Antioxidant.
· Detoxification of xenobiotics that are electrophilic.
· Modulating redox reaction-regulated signal transduction.
· Cysteine storage and transport.
· Regulation of cellular proliferation.
· Synthesis of deoxyribonucleotides.
· Regulation of immune responses.
· Regulation of leukotriene metabolism.
· Regulation of prostaglandin metabolism.
ACTIONS OF NAC
· Is a potent antioxidant, due to its being a glutathione precursor.
· Increases intracellular glutathione.
· Is an excellent source of sulfhydryl groups.
· Is a free radical scavenger with molecules such as OH • and H2O2.
· Prevents apoptosis or cell suicide.
· Vasodilates through nitric oxide.
· Decreases mitochondrial membrane depolarization.
· Potentiates nitrate-induced vasodilation.
· Reduce inflammation.
· Is mucolytic, clearing mucous.
· Suppress viral replication, with one study showing decreased flu frequency in seniors; another H1N1 study showed 25% infection rate in NAC group vs 79% in placebo group.
· RNA viruses need active NF-κB pathway support within host cells in order to replicate.
CLINICAL USES OR STUDIES USING NAC
Acetaminophen overdose-induced liver failure, its most known use.
Baby take-home rate with premature birth and recurrent pregnancy loss.
Hearing loss caused by gentamycin for patients on dialysis, when taken preventatively.
Idiopathic pulmonary fibrosis.
Influenza virus illness, when taken preventatively.
Insulin metabolism in patients with Polycystic Ovary Syndrome (PCOS).
Infertility treatment in patients with PCOS resistant to clomiphene.
Neurodegenerative disorders: myoclonus epilepsy (Unverricht-Lundbor type), tardive dyskinesia, spino-cerebellar disease.
Parkinson’s disease.
Prevention of contrast-induced kidney damage.
Ulcerative colitis.
In a very detailed 2020 paper, Shi and Puyo detail an evidence review as to why NAC should combat COVID-19:
Modulates the immune system.
Suppression of NF-κB.
Possible direct inhibitor of SARS-CoV-2.
Changes the redox reactions toward reduction, not oxidation.
Modulates cytokine production and chemotactic signals.
Suppresses elastase release from neutrophils induced by formyl-methionyl-leucyl-phenylalanine (fMLP).
Inhibits monocyte chemotaxis.
Reduces oxidative bursts from neutrophils induced by the stimulants C. albicans, fMLP, and PMA.
“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”
Increase intracellular glutathione in human T cells.
Reduces influenza pneumonia incidence.
Improves lung function, reduces mortality when given 40 mg/kg/day for 3 days, IV.
Case Reports
Case Report: Low-dose hydroxychloroquine and IV NAC: helped one patient with COVID-19. Discharged after 12 days.
Case Report: COVID patient with respiratory failure given 10-15 mg NAC inhalation for 11 days, discharged after 26 days of mechanical ventilation.
Case Report: 2 patients with shortness of breath treated with oral + IV glutathione, NAC, and alpha lipoic acid successfully treated.
Case Report: 10 ventilated patients (one with Glucose-6Pphosphate Dehydrogenase (G6PD) deficiency) treated with IV NAC decreased inflammatory markers and improved lung function, with 8 patients discharged, 2 better.
ANIMAL STUDIES ON NAC
· Adjunct to eradicate Helicobacter pylori
· Alzheimer’s disease.
· Amyotrophic lateral sclerosis (ALS).
· Cancer chemo preventative.
· Down Syndrome.
· Human Immunodeficiency Virus (HIV) infection.
· Huntington’s disease.
· Metal toxicity.
· Multiple Sclerosis.
· Respiratory Syncytial virus (RSV).
NATURAL SOURCES OF CYSTEINE
There are no natural sources of NAC proper; Larsson et al described that natural sources of cysteine, its precursor, include:
Chicken meat.
Eggs.
Garlic.
Turkey meat.
Yogurt.
PREGNANCY AND FETAL EXPOSURE
There are no known maternal or fetal harms described after NAC treatment and it has been used to treat unexplained pregnancy loss.
GLUTATHIONE
One cannot talk about an NAC without talking about glutathione, and vice versa. Like NAC, glutathione is a powerful antioxidant that plays a key role in protecting the body against oxidative stress and free radical damage. It supports the immune system, helps detoxify the body, and participates in many other essential processes. Low glutathione levels are linked to a range of chronic diseases: cancer, Alzheimer's disease, and Parkinson's disease.
All cells make glutathione, so it is one of the most extensively studied antioxidants.
In the same 2020 paper cited above listing actions of NAC, Shi and Puyo also cited 6 NAC clinical trials that had not yet recruited any patients. Three years later:
1. A Phase I Clinical Trial of the Combination of Famotidine (FAM) and Oral N-Acetyl Cysteine (NAC) Open Label for Outpatient Treatment of Subjects With Newly Diagnosed SARS-CoV-2 Infection. NCT04545008: This Phase 1 study used NAC 600 mg three times a day (low dose). This study was first posted on September 10, 2020. It estimated 42 enrollees and cites it enrolled 2 male patients with a posting on July 28, 2021. The actual completion date was June 2, 2021. Results posted February 18, 2022. The study was terminated “due to poor accrual” (https://clinicaltrials.gov/ct2/show/NCT04545008) where the limitation was a “decrease in COVID-19 infections in the area followed by other treatment options led to poor enrollment and early termination of this study”.
The Sponsor was Prisma Health-Upstate; the Collaborator was Clemson University, and the information was provided by the Responsible Party, Prisma Health-Upstate with a contact person Dr. Julie Martin, the Director of Cancer Research at Julie.martin@prismahealth.org. The Principal Investigator was John J. O’Connell, MD, from Prisma Health. There are no publications listed.
On April 17, 2023, a PubMed Search shows no publications under either a John J. O’Connell, MD or Julie Martin, MD.
2. Determination of Efficacy of N-Acetylcysteine in Preventing Those with Mild or Moderate COVID-19 from Progressing to Severe Disease. NCT04419025: This 2-armed Phase 2 randomized study studied mild or moderate COVID-10, with dosed NAC for inpatient (25 mg/kg by mouth every 4 hours until discharge, then 1200 mg orally twice a day for one week; or outpatient use: NAC 2400 mg orally once, then 1200 mg twice a day for 14 days. It enrolled 165 patients. The actual study start date was September 23, 2020, with an actual completion date of May 14, 2021; with the last update on May 28, 2021.
The original enrollment estimated at 200; the actual enrollment was 165 persons (https://beta.clinicaltrials.gov/study/NCT04419025). The Results Overview section states, “No Study Results Posted on clinicaltrials.gov for this study. Study results have not been submitted. This may be because the study isn't done, the deadline for submitting results has not passed, or this study isn't required to submit results.”
The Sponsor was Cambridge Health Alliance and there were no Collaborators. The Investigator was Melisa Lai-Becker, Chief, CHA Everett Hospital Emergency Department; Director, CHA Division of Medical Toxicology with an Affiliation: Cambridge Health Alliance. In References, a link is given to a “website reviewing reasoning and references for using NAC as adjuvant therapy in treatment of COVID-19: https://www.nacincovid.info that provides this figure, dated November 2, 2020; it provides and email: melaibecker@cha.harvard.edu, last updated 12/12/202 and features hashtag #NACinCOVID:
On April 17, 2023, A PubMed Search of Melisa Lai-Becker shows no publications.
3. Inflammatory Regulation Effect of NAC on COVID-19 Treatment (INFECT-19). NCT04455243: This Phase 3 study cites this dose of NAC for adult inpatients with COVID-19: 150 mg/kg every 12 hours for 14 days (oral/IV) Diluted in 200 ml diluent (D5%, NS) versus placebo. The study start date was estimated to be August 1, 2020, and be completed on August 30, 2021; it was to enroll 1,180 patients. This study was first posted on July 2, 2002; last updated on July 21, 2020; and last verified in July 2020 (https://clinicaltrials.gov/ct2/show/NCT04455243).
The Recruitment Status is “Unknown”, verified July 2020 by Dr. Taariq Alhawass; Recruitment Status was: “Not yet recruiting”. Responsible Party and Sponsor: Dr. Tariz Alhawassi, Chairman of Clinical Trial Support Unit, King Saud University, Saudi Arabia; the Contact is Baian Alabdulbaqi, MD (+966114670011; email balabdulbaqi@ksu.edu.sa.
On April 17, 2023, A PubMed Search of Taariq Alhawass shows no publications.
4. Antioxidant Therapy for COVID-19 Study (GSHSOD-COVID) NCT04466657: No phase is listed, meant to study severe SARS infection. This study is listed as “Withdrawn (Study halted prematurely, prior to enrollment of first participant)”. First posted July 10, 2020, and last updated November 8, 2021. The study was projected to start November 1, 2020, and final completion was estimated to be April 30, 2021.
The Responsible Party: Obafemi Awolowo University, Nigeria, with a list of 6 collaborators in Nigeria. Under Publications”, five general reference papers are listed, none citing the responsible party. The study chair is Adeniyi Olagunju, BPharm, MRes, PhD. Last update posted November 8, 2021.
On April 17, 2023, A PubMed Search of Adeniyi Olagunju shows no publications.
In summary, two of four studies enrolled no patients, two grants were given to those who were out of the country, and one study enrolled just 2 patients. They mentioned three additional studies that were in progress:
1. Clinical Application of Methylene Blue for Treatment of Covid-19 Patients (Covid-19). NCT04370288: This Phase 1 randomized, parallel assignment ICU study was to use an intravenous mixture of methylene blue, vitamin C, and NAC. have 20 participants and start on April 19, 2020, in Iran at Imam Reza Hospital; last posted May 2020; to be completed September 21, 2020.
This study has a Recruitment Status of “Unknown”, verified by Daryoush Jamidi Almdari, Mashad University of Medical Sciences (The Responsible Party). “Recruiting”; First posted on April 30, 2020; last updated May 4, 2020. Phone +985138828574; Email hamidiad@mums.ac.ir. There are no publications.
On April 17, 2023, A PubMed Search of Daryoush Jamidi Almdari shows no publications.
2. A Study of N-acetylcysteine in Severe or Critically Ill Patients With Refractory COVID-19 Infection (NCT04374461): . This Phase II, 30-day non-randomized trial was originally to enroll 86 patients; it enrolled 48 patients on July 21, 2021; located at MSKCC’s Manhattan campus; 2-armed enrollment for mechanically ventilated patients in the ICU. The NAC dose was IV NAC 6 gram/day without an interruption for more than 48 hours, together with a peripheral whole blood draw. The study was to start on May 1, 2020, and be completed around May 2023.
The Recruitment Status says, “Active, Not Recruiting”. It was first posted on May 5, 2020, and last updated July 26, 2022. The Sponsor was Memorial Sloan Kettering Cancer Center, the Principal Investigator is Santosha Vardhana, MD, PhD, Memorial Sloan Kettering Cancer Center. There are no publications and no study results.
On April 17, 2023, A PubMed Search of Santosha Vardhana, MD, PhD shows no publications.
For more on NAC, see the chapter on sulforaphane, reputed to be more potent than NAC and having a fantastic synergy with inflammasome 3 NRF2.
As we learn of “augmented” NAC and the novel quantum technology applied to it, we better understand its ubiquitous potential. In my opinion, augmented NAC is the most bioavailable form. Learn more here.
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