N-acetylcysteine
(NAC) and glutathione may be a useful adjunct in COVID-19 treatment due
to the role they play in combating oxidative stress. NAC may also
combat the abnormal blood clotting seen in many cases
Research has
demonstrated that NAC can attenuate symptoms of influenza and improve
cell-mediated immunity. For every two people treated with NAC, one will
be protected against symptomatic influenza
NAC also
inhibits viral replication and expression of pro-inflammatory cytokines,
such as interleukin-6 (IL-6), in cells infected with highly pathogenic
H5N1 influenza virus, and reduces acute respiratory distress syndrome
(ARDS)
NAC may protect
against coagulation problems associated with COVID-19, as it
counteracts hypercoagulation and breaks down blood clots
According to a
case report, two patients with COVID-19 treated with 2 grams of
intravenous glutathione experienced reduced shortness of breath within
one hour of use
N-acetylcysteine (NAC) is a precursor
to reduced glutathione, and both of these play important roles in
health and fitness. NAC has a long history of use as a first-aid remedy
for acetaminophen (known as paracetamol in Europe) poisoning.
It's given in cases when you've taken an overdose of Tylenol
or other acetaminophen products. It neutralizes the toxic effects of
the drug by recharging glutathione, thereby preventing liver damage.
NAC and glutathione may also be important in COVID-19, as explained
by pulmonologist Dr. Roger Seheult in the MedCram lectures above. The
reason for this is because of the role they play in combating oxidative
stress, which is a main cause of inflammation and disease in general,
and the cytokine storm associated with COVID-19 in particular. NAC may
also combat the abnormal blood clotting seen in many cases.
Biochemistry Primer
As explained and illustrated by Seheult, when you add an electron to
an oxygen (O2) molecule, you get superoxide (O2), a reactive oxygen
species (ROS). When you add another electron (for a total of two
electrons), you get hydrogen peroxide (H2O2). An oxygen molecule with
three electrons added becomes hydroxyl (O3), and oxygen with four
electrons added becomes water (H2O).
Oxygen is the most oxidized form, while water is the most reduced
form. Your body has built-in defenses against oxidative stress like1
superoxide dismutase (SOD). SOD converts damaging superoxide into
hydrogen peroxide. Another is catalase, which converts hydrogen
peroxide into oxygen and water. A third is glutathione peroxidase
(GSHPX).
GSHPX does two things simultaneously. While reducing hydrogen
peroxide into water, it also converts the reduced form of glutathione
(GSH) into glutathione disulfide (GSSG), which is the oxidized form of
glutathione. In other words, as GSHPX turns hydrogen peroxide into
harmless water, glutathione becomes oxidized.
The oxidized GSSG is then "recharged" or regenerated by NADPH (the
reduced form of NADP+), turning it back into GSH (the reduced form of
glutathione). NADPH is also converted into NADP+ through an enzyme
called GSH reductase.
The reason this is important is because superoxide plays a crucial
role in the oxidative stress occurring in the chronic illnesses
identified as comorbidities for COVID-19, such as obesity, heart
disease and diabetes.
As noted by Seheult, serious COVID-19 infection triggers a perfect
storm of superoxide-driven oxidative stress, as SARS-CoV-2 attaches to
the ACE2 receptor, triggering angiotensin 2 (AT-2), which stimulates
superoxide. Simultaneously, there's a deficiency of AT-1,7, which
inhibits superoxide. So, this deficiency allows superoxide to accumulate
further.
SARS-CoV-2 also attracts polymorphonuclear leukocytes (PMNs), a type
of white blood cell, which also produces superoxide in its efforts to
destroy pathogens. All of that superoxide is then converted into other
ROS that destroy endothelial cells.
This down-spiral can be inhibited by N-acetylcysteine (NAC), which
boosts GSSG. As illustrated by Seheult, when you add two GSH molecules
and hydrogen peroxide together, you end up with oxidized glutathione and harmless water, thus alleviating the oxidative stress.
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NAC Boosts GSH and Protects Against Influenza
Seheult cites research showing low GSH and oxidative stress are
associated with a range of nose, ear and throat conditions, affecting
tissues both locally and systemically. The good news is that
glutathione can be recharged with NAC, an inexpensive and readily
available over-the-counter supplement.
Research2
has in fact demonstrated that NAC can attenuate symptoms of influenza
and improve cell-mediated immunity. According to the authors:
"N-acetylcysteine (NAC), an analogue and precursor of reduced
glutathione, has been in clinical use for more than 30 yrs as a
mucolytic drug. It has also been proposed for and/or used in the therapy
and/or prevention of several respiratory diseases and of diseases
involving an oxidative stress, in general.
The objective of the present study was to evaluate the effect of
long-term treatment with NAC on influenza and influenza-like episodes.
A total of 262 subjects of both sexes … were enrolled in a randomized,
double-blind trial … randomized to receive either placebo or NAC
tablets (600 mg) twice daily for 6 months.
Patients suffering from chronic respiratory diseases were not
eligible, to avoid possible confounding by an effect of NAC on
respiratory symptoms. NAC treatment was well tolerated and resulted in a
significant decrease in the frequency of influenza-like episodes,
severity, and length of time confined to bed.
Both local and systemic symptoms were sharply and significantly
reduced in the NAC group. Frequency of seroconversion towards A/H1N1
Singapore 6/86 influenza virus was similar in the two groups, but only
25% of virus-infected subjects under NAC treatment developed a
symptomatic form, versus 79% in the placebo group ...
Administration of N-acetylcysteine during the winter, thus,
appears to provide a significant attenuation of influenza and
influenza-like episodes, especially in elderly high-risk individuals.
N-acetylcysteine did not prevent A/H1N1 virus influenza infection but
significantly reduced the incidence of clinically apparent disease."
NAC Is a Potent Antiviral in Its Own Right
As noted by Seheult, the number needed to treat (NNT) in that study3
is 0.5, which means for every two people treated with NAC, one will be
protected against symptomatic influenza. (Remember, you can be infected
with a virus yet not become ill, i.e., symptomatic, if your immune
system is strong enough.)
That's significantly better than influenza vaccines, which have an NNT, or NNV (number needed to vaccinate) of 71,4 meaning 71 people must be vaccinated to prevent a single case of confirmed influenza. It's even better than vitamin D, which has an NNT of 33.5 (Among those who were severely vitamin D deficient at baseline, taking vitamin D still had an NNT of 4.)
NAC has also been shown to inhibit viral replication and expression
of pro-inflammatory cytokines, such as interleukin-6 (IL-6), in cells
infected with highly pathogenic H5N1 influenza virus.6 According to the authors:
"The antiviral and anti-inflammatory mechanisms of NAC included
inhibition of activation of oxidant sensitive pathways including
transcription factor NF-kappaB and mitogen activated protein kinase p38
...
NAC inhibits H5N1 replication and H5N1-induced production of
pro-inflammatory molecules. Therefore, antioxidants like NAC represent a
potential additional treatment option that could be considered in the
case of an influenza A virus pandemic."
NAC in Acute Respiratory Distress Syndrome
NAC has also been shown to reduce acute respiratory distress syndrome (ARDS),7 which is a serious complication associated with acute lung injury (ALI). One meta-analysis8
of five randomized controlled trials found a significant reduction in
intensive care unit (ICU) stays among patients treated with NAC, even
though there was no significant difference in short-term mortality
risk.
Another earlier study9
found NAC improves ARDS by "increasing intracellular glutathione and
extracellular thiol molecules" along with general antioxidant effects.
According to this study:
"In acute respiratory distress syndrome (ARDS), there is
extensive overproduction of free radicals to the extent that endogenous
antioxidants are overwhelmed, permitting oxidative cell damage.
The present study examined the benefit of the anti-oxidant
compound N-acetylcysteine (NAC) in the management of ARDS by measuring
patient's intracellular glutathione (inside red blood cells) and
extracellular (plasma) anti-oxidant defense biomarkers and outcome.
Twenty-seven ARDS patients were recruited from the intensive
care unit of a teaching Hospital and randomly divided into two groups.
Both groups were managed similarly by regular treatments but 17 patients
received NAC 150 mg/kg at the first day that followed by 50 mg/kg/day
for three days and 10 patients did not receive NAC.
Treatment by NAC increased extracellular total anti-oxidant
power and total thiol molecules and also improved intracellular
glutathione and the outcome of the patients. In conclusion, patients
with ARDS are in a deficient oxidant-anti-oxidant balance that can get a
significant benefit if supplemented with NAC."
NAC Improves Lung Function
Other studies that have shown NAC eto be beneficial in the treatment of lung-related problems include the following:
• A 1994 study10
found NAC enhances recovery from ALI, significantly regressing
patients' lung injury score during the first 10 days of treatment, and
significantly reducing the need for ventilation.
After three days of treatment, only 17% of those receiving NAC needed
ventilation, compared to 48% in the placebo group. According to the
authors:
"Intravenous NAC treatment during 72 h improved systemic
oxygenation and reduced the need for ventilatory support in patients
presenting with mild-to-moderate acute lung injury subsequent to a
variety of underlying diseases."
• A 2018 study11 found NAC reduces oxidative and inflammatory damage in patients with community-acquired pneumonia. • Another 2018 study12 found NAC also improves post-operative lung function in patients undergoing liver transplantation.
NAC Protects Against Blood Clots and Stroke
Importantly, with regard to COVID-19, NAC may protect against the coagulation problems associated with this illness. Many COVID-19 patients experience serious blood clots, and NAC counteracts hypercoagulation in the blood as well.13,14,15
As noted in one of these studies,16 "NAC has anticoagulant and platelet-inhibiting properties." Another study points out that:17
"… diabetes exacerbates stroke-induced brain injury, and that
this correlates with brain methylglyoxal (MG)-to-glutathione (GSH)
status. Cerebral injury was reversed by N-acetylcysteine (NAC).
Here we tested if the pro-thrombotic phenotype seen in the
systemic circulation and brain during diabetes was associated with
increased MG-glycation of proteins, and if NAC could reverse this ...
NAC treatment partly or completely reversed the effects of
diabetes. Collectively, these results show that the diabetic blood and
brain become progressively more susceptible to platelet activation and
thrombosis.
NAC, given after the establishment of diabetes, may offer
protection against the risk for stroke by altering both systemic and
vascular prothrombotic responses via enhancing platelet GSH, and
GSH-dependent MG elimination, as well as correcting levels of
antioxidants such as SOD1 and GPx-1."
A fourth paper,18
published in 2017, found NAC has potent thrombolytic effects, meaning
it breaks down blood clots. The authors concluded that "NAC is an
effective and safe alternative to currently available antithrombotic
agents to restore vessel patency after arterial occlusion." (Restoring
vessel patency means the blood vessel is now unobstructed so that blood
can flow freely.)
Seheult cites two additional papers19,20
showing the same thing. As noted by Seheult, many COVID-19 cases have
blood clots in addition to excessive oxidative stress, and NAC
addresses both of these problems.
NAC for COVID-19
Last but not least, a report21
reviewing the evidence for using NAC in the treatment of COVID-19 was
published April 14, 2020, by The Centre for Evidence-Based Medicine at
the University of Oxford.
This report focuses on acute respiratory disorders, and we now know
that COVID-19 is not just a respiratory disorder but also a blood
disorder. This is a significant shortcoming of this report, as there's
significant evidence that NAC can break down the blood clots
responsible for the hypoxia (cellular deprivation of oxygen) in
COVID-19.
May 5, 2020, a trial was posted to ClinicalTrials.gov, for the study
of NAC in patients with COVID-19, sponsored by the Memorial Sloan
Kettering Cancer Center.22
The study aims to enroll 86 patients with severe or critical illness to
investigate whether NAC, in addition to other supportive treatments,
can reduce ICU stays and prevent the need for mechanical ventilation.
Here, they are giving 6 grams (6,000 milligrams) of NAC a day for up to
three weeks.
Seheult's hypothesis for why NAC may be useful in COVID-19 treatment can be summarized as follows:
SARS-CoV-2 attaches to and reduces the ACE2 receptor, which causes
AT-2 to increase and AT-1,7 to decrease. This in turn increases
damaging superoxide that causes oxidative stress and endothelial cell
dysfunction.
This then increases von Willebrand factor from the endothelial
space, causing thrombosis (blood clots), and it is this thrombosis that
appears to cause the hypoxia in the lungs. NAC — which recharges
glutathione — not only reduces superoxide (oxidative stress) but also
appears to reduce von Willebrand factors that form blood clots.
Glutathione for COVID-19
In the second MedCram video (second in the playlist), Seheult
reviews the blood clotting aspects of COVID-19. He also discusses the
potential effectiveness of simply taking glutathione, opposed to its
precursor, NAC.
A recent case report23
— which simply reviews one or more medical cases and is not an actual
study — reports that two patients with COVID-19 and a history of Lyme disease
(coinfection) treated with 2 grams of intravenous glutathione
"improved their dyspnea within one hour of use." Dyspnea is the medical
term for shortness of breath. According to the authors:
"Oral and IV glutathione, glutathione precursors
(N-acetyl-cysteine) and alpha lipoic acid may represent a novel
treatment approach for blocking NF-κB and addressing 'cytokine storm
syndrome' and respiratory distress in patients with COVID-19
pneumonia."
He also cites a Russian paper24
stating that glutathione deficiency may be "the most likely cause of
serious manifestation and death" in COVID-19 patients. The paper, which
is a preprint and has not yet undergone peer review, presents a
hypothesis "based on an exhaustive literature analysis and own
observations." According to the author:25
"The major risk factors established for severe COVID-19
infection and relative glutathione deficiency found in
COVID-19-infected patients with moderate-to-severe illness have
converged me to two very important conclusions:
(1) oxidative stress contributes to hyper-inflammation of the
lung leading to adverse disease outcomes such as acute respiratory
distress syndrome, multiorgan failure and death;
(2) poor antioxidant defense due to endogenous glutathione
deficiency as a result of decreased biosynthesis and/or increased
depletion of GSH is the most probable cause of increased oxidative
damage of the lung, regardless which of the factors aging, chronic
disease comorbidity, smoking or some others were responsible for this
deficit.
The hypothesis provides novel insights into the etiology and
mechanisms responsible for serious manifestations of COVID-19 infection
and justifies promising opportunities for effective treatment and
prevention of the illness through glutathione recovering with
N-acetylcysteine and reduced glutathione."
As noted by Seheult, we still do not have any trials demonstrating
that NAC will benefit COVID-19 patients specifically, "but if we
connect the dots, it looks promising." What's more, NAC is very safe
and many studies have shown there are no serious adverse effects
associated with its use.
The same can be said for glutathione. Seheult points out it would be
interesting to see what the effect might be using a combination of
both glutathione and NAC. Overall, the more we learn about this
disease, the more we realize there may be simple and inexpensive ways
to treat this perplexing illness, and NAC in particular looks like a
good candidate for consideration.
Of course, both also have many other important health benefits. To learn more, see "Glutathione and NAC Play Crucial Roles in Health and Fitness," and "The Many Benefits of NAC — One of the Most Important Supplements You've Likely Never Heard Of."
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