Does N-Acetylcysteine (NAC) increase the severity of Covid-19?
E-Published 3/31/2020 Author Manuscript
Introduction:
Claims of the efficacy of the compound N-acetylcysteine (NAC) in improving Covid-19 outcomes have been circulating of late in health and wellness circles. When asked of my own personal opinion with NAC in supplement form, I replied that I had ceased taking or recommending its use because of the risk for cancer initiation often accompanying protein isolate or amino acid supplementation (1,2,3,4). However, since very recently being challenged on this hypothesis, I have looked deeper into the voluminous amount of research surrounding this substance. The purpose of this report is to share some of my findings. If you are currently taking this as a dietary supplement I strongly encourage you to read this article in its entirety.
NAC - A little hairy?
Here’s a little background info I found surprising… L-cysteine, the main ingredient in N-Acetylcysteine, has been historically manufactured in foreign countries (in particular China) from human hair (a potent source of the amino acid). Other sources may include bird feathers or even synthetic derivation (5). One of the more popular processes in which L-cysteine is then “acetylated" into NAC is described as follows: “we have prepared […NAC…] using 1 equiv. of acetic anhydride [which is basically vinegar without moisture] and a variety of acid acceptors in aqueous tetrahydrofuran)” (6). Furthermore, undesired byproducts (from 35-20%) will need to be removed although even higher purity varieties may contain some degree of contaminants (7).
Therapeutic effects:
There are many studies showing benefit in vitro (outside the body) and vivo (inside the body), of the indirect free radical scavenging effects of NAC (8). However as one researcher wrote: “NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH [Glutathione] in deficient cells and it is likely to be ineffective in cells replete in GSH” (9).
The role of NAC in the treatment of many diseases is still unclear and controversial. Therapeutically, it has been shown to possess strong mucolytic properties (by breaking the disulfide bonds in mucus) and is frequently given in cases of acetaminophen overdose to decrease liver toxicity (10). However, one article, reviewing over one hundred and three research studies related to the clinical use of this compound, found that “numerous, mainly small clinical trials with variable doses have yielded inconsistent results in a wide variety of diseases” (11). Furthermore, some of the reported benefits of NAC were shown to be due to dosages that would be difficult to achieve in the clinical setting, in particular with oral supplementation (12).
Unexpected side effects:
Besides potentially increasing the risk of cancer (1,2,3,4), NAC has been found to decrease the cancer-fighting effectiveness of a large class of naturally medicinal substances, such as curcumin (13), berberine (14), vitamin D (15), melatonin (16), selenium (17), and cucurbitacin (18). This is due to the fact that these compounds utilize oxidation (aka production of free radicals) to initiate cancer cell death (apoptosis) (13,14,15,16,17,18) and the robust and persistent repletion of glutathione by NAC neutralizes this effect.
This point deserves further elaboration due to the misconception that antioxidants are usually seen as “good” and free radicals “bad.” While persistently disarming free radicals (aka reactive oxygen species or R.O.S.) is a great idea in many disease processes it can be dangerous in others. In the case of pulmonary disease: “based on this knowledge, some researchers suggested that a faster clearance of ROS could reduce lung damage and improve lung function.” (19) However, “ROS generation by […] pathogens has also been established in respiratory epithelial cells, and the modulation of ROS was reported to be important for respiratory virus–induced innate immune mechanisms” (ibid).
An example of the positive effects of NAC’s action are the studies showing significant reduction of the severity of some influenza infections (20, 21, 22). This may be due largely to the fact that the virus is spread readily through replication (multiplication inside the cell) and consequent rupture of the cell membrane (apoptosis) (23). According to one study: “apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death” (ibid). This allows the virus, after sufficient intracellular replication, to exit the cell in masse. Apoptosis is triggered by the overwork of the virus-hijacked cell’s organelles (mitochondria and endoplasmic reticulum) and production of large amounts of oxidative stress. NAC can suppress these free radicals and reverse the trend toward apoptosis and subsequent release of virons, thus slowing the spread of the Influenza virus.
While this process may be potentially beneficial in influenza infection, it may actually be dangerous in human coronavirus infection. One reason is that the coronavirus can efficiently exit the host cell via the process of viral budding instead of apoptosis (24). In fact, cells infected with coronavirus can even adhere and fuse with neighboring cells “..lead[ing] to the formation of giant, multinucleated cells, which allows the virus to spread within an infected organism without being detected or neutralized by virus-specific antibodies” (Ibid). In theory, this could lead to a much greater risk of asymptomatic transmission of the virus.
During the replication of coronaviruses "massive amount[s] of structural proteins [are] synthesized to assembly progeny virions. The production, folding, and modification of these proteins undoubtedly increase the workload of the ER [endoplasmic reticulum]” (24). However, coronaviruses naturally block a critical pathway (the integrated stress response) that would normally trigger a decrease of viral replication and apoptosis of the infected cell. This is at least in part by limiting the secretion of the cell’s red alert compounds known as “interferons” (Ibid). However, interferon (alpha) production can still occur (leading to apoptosis) due to the massive amount of oxidative stress generated by viral production (ibid). Thus, production of functional interferon after infection with SARS-CoV-1 is purported to be "essential for the control of potentially lethal coronavirus infections” (25, 26).
NAC and coronavirus replication:
Reducing the free radical generation by stressed organelles with N-acetylsysteine (a potent and persistent replenisher of intracellular glutathione) has been shown to potentially encourage an environment supporting enhanced viral replication in human coronavirus infection (resulting in enhanced endoplasmic reticulum folding capacity) (27). To make matters worse, NAC may alter the profile of the normal production of cytokines (chemical messengers mediating the inflammatory response) (19, 27). The latter is concerning seeing that immune dysregulation is already a hallmark of coronavirus infection. A study in the journal Clinical Infectious Diseases “observed leukopenia in 47% of patients, lymphopenia in 84%, and T lymphopenia in 95%. CD4(+) T lymphocyte levels were reduced in 100% of patients, CD8(+) T lymphocyte levels were reduced in 87%, B lymphocyte levels were reduced in 76%, and natural killer cell levels were reduced in 55%” (28).
Also of interest, in HIV infection, dosages of NAC typical of oral administration, but not intravenously, caused an increase in the infection rate of monocytes (27). After viral infection these giant immune cells are themselves at increased risk for aberrant behavior, potentially letting go of their munitions in the lungs and causing a devastating condition known as cytokine storm- the single most deadly end result of Covid-19 infection (29, 30)
Recommendations:
Ultimately we will need to weigh the evidence ourselves and make an educated decision. The good news is that we can safely enjoy the benefits of dietary bioavailable cysteine and thereby ensure healthy normalization of glutathione levels. For example, raw garlic contains natural forms of this amino acid, such as S-allyl-cysteine, which also shows potent anti-cancer effects (31, 32, 33). Furthermore, adequate amounts of vitamin D have been shown to safely regulate levels of glutathione (34).
In summary:
The Biblical concept of temperance is shown to apply even at the molecular level: moderate use of that which is good, and abstinence of that which is harmful. Normal levels of intracellular glutathione have a positive effect upon our health, however, given the raw materials, the body can do a better job of managing the fine line of production so that the compound is not used as a cloak for cancer or viral development.
References:
1) JCI Insight. 2019 Oct 3;4(19). pii: 127647. doi: 10.1172/jci.insight.127647.
2) Sci Transl Med. 2014 Jan 29;6(221):221ra15. doi: 10.1126/scitranslmed.3007653.
3) Rejuvenation Res. 2014 Jun;17(3):306-11. doi: 10.1089/rej.2014.1577.
4) Sci Transl Med. 2015 Oct 7;7(308):308re8. doi: 10.1126/scitranslmed.aad3740.
5) https://oukosher.org/…/consumer-kosher/what-could-be-wrong…/
6) N-Acylation of Cysteine Tellis A. Martin, John R. Corrigan, and Coy W. Waller
The Journal of Organic Chemistry 1965 30 (8), 2839-2840 DOI: 10.1021/jo01019a509
7) https://www.sigmaaldrich.com/catalog/product/sial/a7250…
8) Oxid Med Cell Longev. 2018; 2018: 2835787.
9) Pharmacol Ther. 2014 Feb;141(2):150-9. doi: 10.1016/j.pharmthera.2013.09.006. Epub 2013 Sep 28.
10) Sci Transl Med. 2015 Feb 25; 7(276): 276ra27. doi: 10.1126/scitranslmed.3010525
11) Br J Clin Pharmacol. 2006 Jan; 61(1): 5–15.
12) J Cardiovasc Pharmacol. 2009 Oct;54(4):319-26. doi: 10.1097/FJC.0b013e3181b6e77b.
13) Korean J Physiol Pharmacol. 2010 Dec;14(6):391-7. doi: 10.4196/kjpp.2010.14.6.391.
14) Int J Oncol. 2011 Feb;38(2):485-92. doi: 10.3892/ijo.2010.878.
15) J Steroid Biochem Mol Biol. 2011 Jan;123(1-2):85-9. doi: 10.1016/j.jsbmb.2010.11.010.
16) Basic Clin Pharmacol Toxicol. 2011 Jan;108(1):14-20. doi: 10.1111/j.1742-7843.2010.00619.x.
17) J Trace Elem Med Biol. 2003;17(1):19-26.
18) Anticancer Agents Med Chem. 2014;14(8):1146-53.
19) Am J Respir Cell Mol Biol. 2013 Nov; 49(5): 855–865.
20) Biochem Pharmacol. 2011 Sep 1;82(5):548-55. doi: 10.1016/j.bcp.2011.05.014. Epub 2011 May 25.
21) J Negat Results Biomed. 2011 May 9;10:5. doi: 10.1186/1477-5751-10-5.
22) Eur Respir J. 1997 Jul;10(7):1535-41.
23) Cell Death Dis. 2013 Mar 28;4:e562. doi: 10.1038/cddis.2013.89.
24) Front Microbiol. 2014; 5: 296.
Published online 2014 Jun 17. doi: 10.3389/fmicb.2014.00296.
25) Blood. 2007 Feb 1;109(3):1131-7. Epub 2006 Sep 19.
26) J Virol. 2007 Aug; 81(16): 8692–8706.
27) JCI Insight. 2016 Dec 8; 1(20): e88255.
28) Clin Infect Dis. 2003 Sep 15;37(6):857-9. Epub 2003 Aug 28.
29) Intensive Care Med. 2020 Mar 3. doi: 10.1007/s00134-020-05991-x. [Epub ahead of print].
30) Semin Immunopathol. 2017; 39(5): 529–539.
31) Exp Ther Med. 2020 Feb;19(2):1511-1521. doi: 10.3892/etm.2019.8383.
32) Int J Mol Sci. 2020 Feb 6;21(3). pii: E1090. doi: 10.3390/ijms21031090.
33) Int Immunopharmacol. 2019 Apr;69:19-26. doi: 10.1016/j.intimp.2019.01.026. Epub 2019 Jan 18.
34) J Neurochem. 1999 Aug;73(2):859-66.
E-Published 3/31/2020 Author Manuscript
Introduction:
Claims of the efficacy of the compound N-acetylcysteine (NAC) in improving Covid-19 outcomes have been circulating of late in health and wellness circles. When asked of my own personal opinion with NAC in supplement form, I replied that I had ceased taking or recommending its use because of the risk for cancer initiation often accompanying protein isolate or amino acid supplementation (1,2,3,4). However, since very recently being challenged on this hypothesis, I have looked deeper into the voluminous amount of research surrounding this substance. The purpose of this report is to share some of my findings. If you are currently taking this as a dietary supplement I strongly encourage you to read this article in its entirety.
NAC - A little hairy?
Here’s a little background info I found surprising… L-cysteine, the main ingredient in N-Acetylcysteine, has been historically manufactured in foreign countries (in particular China) from human hair (a potent source of the amino acid). Other sources may include bird feathers or even synthetic derivation (5). One of the more popular processes in which L-cysteine is then “acetylated" into NAC is described as follows: “we have prepared […NAC…] using 1 equiv. of acetic anhydride [which is basically vinegar without moisture] and a variety of acid acceptors in aqueous tetrahydrofuran)” (6). Furthermore, undesired byproducts (from 35-20%) will need to be removed although even higher purity varieties may contain some degree of contaminants (7).
Therapeutic effects:
There are many studies showing benefit in vitro (outside the body) and vivo (inside the body), of the indirect free radical scavenging effects of NAC (8). However as one researcher wrote: “NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH [Glutathione] in deficient cells and it is likely to be ineffective in cells replete in GSH” (9).
The role of NAC in the treatment of many diseases is still unclear and controversial. Therapeutically, it has been shown to possess strong mucolytic properties (by breaking the disulfide bonds in mucus) and is frequently given in cases of acetaminophen overdose to decrease liver toxicity (10). However, one article, reviewing over one hundred and three research studies related to the clinical use of this compound, found that “numerous, mainly small clinical trials with variable doses have yielded inconsistent results in a wide variety of diseases” (11). Furthermore, some of the reported benefits of NAC were shown to be due to dosages that would be difficult to achieve in the clinical setting, in particular with oral supplementation (12).
Unexpected side effects:
Besides potentially increasing the risk of cancer (1,2,3,4), NAC has been found to decrease the cancer-fighting effectiveness of a large class of naturally medicinal substances, such as curcumin (13), berberine (14), vitamin D (15), melatonin (16), selenium (17), and cucurbitacin (18). This is due to the fact that these compounds utilize oxidation (aka production of free radicals) to initiate cancer cell death (apoptosis) (13,14,15,16,17,18) and the robust and persistent repletion of glutathione by NAC neutralizes this effect.
This point deserves further elaboration due to the misconception that antioxidants are usually seen as “good” and free radicals “bad.” While persistently disarming free radicals (aka reactive oxygen species or R.O.S.) is a great idea in many disease processes it can be dangerous in others. In the case of pulmonary disease: “based on this knowledge, some researchers suggested that a faster clearance of ROS could reduce lung damage and improve lung function.” (19) However, “ROS generation by […] pathogens has also been established in respiratory epithelial cells, and the modulation of ROS was reported to be important for respiratory virus–induced innate immune mechanisms” (ibid).
An example of the positive effects of NAC’s action are the studies showing significant reduction of the severity of some influenza infections (20, 21, 22). This may be due largely to the fact that the virus is spread readily through replication (multiplication inside the cell) and consequent rupture of the cell membrane (apoptosis) (23). According to one study: “apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death” (ibid). This allows the virus, after sufficient intracellular replication, to exit the cell in masse. Apoptosis is triggered by the overwork of the virus-hijacked cell’s organelles (mitochondria and endoplasmic reticulum) and production of large amounts of oxidative stress. NAC can suppress these free radicals and reverse the trend toward apoptosis and subsequent release of virons, thus slowing the spread of the Influenza virus.
While this process may be potentially beneficial in influenza infection, it may actually be dangerous in human coronavirus infection. One reason is that the coronavirus can efficiently exit the host cell via the process of viral budding instead of apoptosis (24). In fact, cells infected with coronavirus can even adhere and fuse with neighboring cells “..lead[ing] to the formation of giant, multinucleated cells, which allows the virus to spread within an infected organism without being detected or neutralized by virus-specific antibodies” (Ibid). In theory, this could lead to a much greater risk of asymptomatic transmission of the virus.
During the replication of coronaviruses "massive amount[s] of structural proteins [are] synthesized to assembly progeny virions. The production, folding, and modification of these proteins undoubtedly increase the workload of the ER [endoplasmic reticulum]” (24). However, coronaviruses naturally block a critical pathway (the integrated stress response) that would normally trigger a decrease of viral replication and apoptosis of the infected cell. This is at least in part by limiting the secretion of the cell’s red alert compounds known as “interferons” (Ibid). However, interferon (alpha) production can still occur (leading to apoptosis) due to the massive amount of oxidative stress generated by viral production (ibid). Thus, production of functional interferon after infection with SARS-CoV-1 is purported to be "essential for the control of potentially lethal coronavirus infections” (25, 26).
NAC and coronavirus replication:
Reducing the free radical generation by stressed organelles with N-acetylsysteine (a potent and persistent replenisher of intracellular glutathione) has been shown to potentially encourage an environment supporting enhanced viral replication in human coronavirus infection (resulting in enhanced endoplasmic reticulum folding capacity) (27). To make matters worse, NAC may alter the profile of the normal production of cytokines (chemical messengers mediating the inflammatory response) (19, 27). The latter is concerning seeing that immune dysregulation is already a hallmark of coronavirus infection. A study in the journal Clinical Infectious Diseases “observed leukopenia in 47% of patients, lymphopenia in 84%, and T lymphopenia in 95%. CD4(+) T lymphocyte levels were reduced in 100% of patients, CD8(+) T lymphocyte levels were reduced in 87%, B lymphocyte levels were reduced in 76%, and natural killer cell levels were reduced in 55%” (28).
Also of interest, in HIV infection, dosages of NAC typical of oral administration, but not intravenously, caused an increase in the infection rate of monocytes (27). After viral infection these giant immune cells are themselves at increased risk for aberrant behavior, potentially letting go of their munitions in the lungs and causing a devastating condition known as cytokine storm- the single most deadly end result of Covid-19 infection (29, 30)
Recommendations:
Ultimately we will need to weigh the evidence ourselves and make an educated decision. The good news is that we can safely enjoy the benefits of dietary bioavailable cysteine and thereby ensure healthy normalization of glutathione levels. For example, raw garlic contains natural forms of this amino acid, such as S-allyl-cysteine, which also shows potent anti-cancer effects (31, 32, 33). Furthermore, adequate amounts of vitamin D have been shown to safely regulate levels of glutathione (34).
In summary:
The Biblical concept of temperance is shown to apply even at the molecular level: moderate use of that which is good, and abstinence of that which is harmful. Normal levels of intracellular glutathione have a positive effect upon our health, however, given the raw materials, the body can do a better job of managing the fine line of production so that the compound is not used as a cloak for cancer or viral development.
References:
1) JCI Insight. 2019 Oct 3;4(19). pii: 127647. doi: 10.1172/jci.insight.127647.
2) Sci Transl Med. 2014 Jan 29;6(221):221ra15. doi: 10.1126/scitranslmed.3007653.
3) Rejuvenation Res. 2014 Jun;17(3):306-11. doi: 10.1089/rej.2014.1577.
4) Sci Transl Med. 2015 Oct 7;7(308):308re8. doi: 10.1126/scitranslmed.aad3740.
5) https://oukosher.org/…/consumer-kosher/what-could-be-wrong…/
6) N-Acylation of Cysteine Tellis A. Martin, John R. Corrigan, and Coy W. Waller
The Journal of Organic Chemistry 1965 30 (8), 2839-2840 DOI: 10.1021/jo01019a509
7) https://www.sigmaaldrich.com/catalog/product/sial/a7250…
8) Oxid Med Cell Longev. 2018; 2018: 2835787.
9) Pharmacol Ther. 2014 Feb;141(2):150-9. doi: 10.1016/j.pharmthera.2013.09.006. Epub 2013 Sep 28.
10) Sci Transl Med. 2015 Feb 25; 7(276): 276ra27. doi: 10.1126/scitranslmed.3010525
11) Br J Clin Pharmacol. 2006 Jan; 61(1): 5–15.
12) J Cardiovasc Pharmacol. 2009 Oct;54(4):319-26. doi: 10.1097/FJC.0b013e3181b6e77b.
13) Korean J Physiol Pharmacol. 2010 Dec;14(6):391-7. doi: 10.4196/kjpp.2010.14.6.391.
14) Int J Oncol. 2011 Feb;38(2):485-92. doi: 10.3892/ijo.2010.878.
15) J Steroid Biochem Mol Biol. 2011 Jan;123(1-2):85-9. doi: 10.1016/j.jsbmb.2010.11.010.
16) Basic Clin Pharmacol Toxicol. 2011 Jan;108(1):14-20. doi: 10.1111/j.1742-7843.2010.00619.x.
17) J Trace Elem Med Biol. 2003;17(1):19-26.
18) Anticancer Agents Med Chem. 2014;14(8):1146-53.
19) Am J Respir Cell Mol Biol. 2013 Nov; 49(5): 855–865.
20) Biochem Pharmacol. 2011 Sep 1;82(5):548-55. doi: 10.1016/j.bcp.2011.05.014. Epub 2011 May 25.
21) J Negat Results Biomed. 2011 May 9;10:5. doi: 10.1186/1477-5751-10-5.
22) Eur Respir J. 1997 Jul;10(7):1535-41.
23) Cell Death Dis. 2013 Mar 28;4:e562. doi: 10.1038/cddis.2013.89.
24) Front Microbiol. 2014; 5: 296.
Published online 2014 Jun 17. doi: 10.3389/fmicb.2014.00296.
25) Blood. 2007 Feb 1;109(3):1131-7. Epub 2006 Sep 19.
26) J Virol. 2007 Aug; 81(16): 8692–8706.
27) JCI Insight. 2016 Dec 8; 1(20): e88255.
28) Clin Infect Dis. 2003 Sep 15;37(6):857-9. Epub 2003 Aug 28.
29) Intensive Care Med. 2020 Mar 3. doi: 10.1007/s00134-020-05991-x. [Epub ahead of print].
30) Semin Immunopathol. 2017; 39(5): 529–539.
31) Exp Ther Med. 2020 Feb;19(2):1511-1521. doi: 10.3892/etm.2019.8383.
32) Int J Mol Sci. 2020 Feb 6;21(3). pii: E1090. doi: 10.3390/ijms21031090.
33) Int Immunopharmacol. 2019 Apr;69:19-26. doi: 10.1016/j.intimp.2019.01.026. Epub 2019 Jan 18.
34) J Neurochem. 1999 Aug;73(2):859-66.
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