N-acetylcysteine

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N-acetylcysteine

N-acetyl cysteine

N-acetylcysteine (NAC) also known as N-acetyl-cysteine, or acetylcysteine, is a powerful antioxidant with anti-inflammatory activity and a scavenger of reactive oxygen species (ROS) 1, 2. N-acetylcysteine (NAC) is a modified amino acid that is used as an antidote to treat acetaminophen (paracetamol) overdose to prevent acute liver injury 3, 4, 5. People commonly use N-acetylcysteine (NAC) for cough in idiopathic pulmonary fibrosis and as a mucolytic agent in cystic fibrosis and chronic obstructive pulmonary disease (COPD) 6, 7, 8, 9. N-acetylcysteine (NAC) is also used for flu, dry eye, contrast-induced nephropathy, Alzheimer disease and many other conditions, but there is no good scientific evidence to support many of these uses 10, 11, 12, 13. There is also no good evidence to support using N-acetylcysteine (NAC) for COVID-19 6. Although many dietary supplement products contain N-acetylcysteine (NAC), the United States Food and Drug Administration (FDA) states that it’s illegal for dietary supplements to contain N-acetyl cysteine since it’s technically an approved drug. Prescription N-acetyl cysteine products are available under the guidance of a healthcare provider. N-acetylcysteine is found mostly in plants of the Allium species, especially in the onion (Allium cepa, 45 mg NAC/kg) 14, 15

N-acetylcysteine (NAC) has also been used as an antioxidant precursor to glutathione (GSH), a tripeptide made up of cysteine, glycine, and glutamic acid that is found in relatively high concentrations inside many cells 16. Therefore, the human body requires all three amino acids (i.e, cysteine, glycine, and glutamic acid) and adequate enzymatic function to make sufficient quantities of glutathione 17. The availability of the amino acid cysteine is known to be rate-limiting for the synthesis of glutathione, and it is well documented, both clinically and in animal studies, that cysteine supplementation most practically achieved by administration of N-acetylcysteine (NAC) can boost glutathione synthesis and levels 18, 9, yet a review of research data indicates the use of N-acetylcysteine (NAC) to boost glutathione synthesis and levels may be inconclusive or equivocal 19. Cysteine is a sulfur amino acid, which might imply that consuming cysteine-rich foods such as meat, fish, grains, dairy, soybean, and egg products, may also support glutathione synthesis 20, 21. A systematic review 22 that included twelve clinical trials utilizing N-acetylcysteine (NAC) supplementation with a specific focus on cognitive markers indicated that there may be some benefit to using N-acetylcysteine in certain populations; however, the studies were too variable in design and outcome to make any definitive conclusion 19.

Although N-acetylcysteine (NAC) is promising as a supplement to both boost glutathione levels and has the potential to reduce some of the issues related to oxidative stress 23, 24, the research up till now is inconclusive 25, 26, 27, 28.  Furthermore, it is unclear if the effects of N-acetylcysteine (NAC) on oxidative stress are due to its antioxidant properties or due to increased glutathione synthesis 19. Moreover, it has been suggested that N-acetylcysteine (NAC) may work synergistically with other supplemental nutrients. For example, it has been postulated that glycine may be as important as cysteine when it comes to glutathione production, especially when concurrently supplemented with N-acetylcysteine 29. While further studies are required, it may be the better approach to supplement with both cysteine and glycine to see a boost in glutathione, especially among those who may not have adequate quantities of the amino acids or require higher levels of glutathione.

For example, in a small study 30 with eight healthy elderly adults and a control group of eight younger subjects, after measuring baseline glutathione synthesis in both groups, the older subjects were orally administered 0.81 mmol N-acetylcysteine per kg per day (around 132 mg/kg/day) and 1.33 mmol glycine/kg/day (roughly 100 mg/kg/day) for 14 days. Initially, the older subjects had 55.2% less glycine and 24.4% less cysteine in their red blood cells 30. They also had a 46.2% lower glutathione level than the controls 30. However, after N-acetylcysteine (NAC) supplementation, the glycine levels increased by 117.6% and the cysteine by 55.1%. Furthermore, they had a 94.6% higher glutathione concentration in their red blood cells, which also led to no statistical difference between the young controls and the elderly subjects in their glutathione levels 30. In addition, they experienced lower plasma oxidative stress and F2-isoprostanes 30. The researchers speculated that the typical reduction of glutathione in the elderly was due to a lower supply of glycine and cysteine, the precursors to glutathione synthesis, and that upon N-acetylcysteine (NAC) supplementation, they had the ability to stimulate synthesis and restore levels. Although impressive, it is important to recognize that this was a small study. It is worthwhile to note that there was also no translation to clinical benefit, as these subjects were healthy 19.

In another study 31 on five people with mild to moderate Parkinson’s disease and three controls, a high dose of N-acetylcysteine (3000 mg taken orally twice daily) for a period of four weeks led to an increase of cysteine levels and antioxidant measures, with no commensurate improvement in oxidative stress measurements (4-hydroxynonenal and malondialdehyde) nor did it increase the level of glutathione in the brain 31. Additionally, some of the participants experienced a worsening of Parkinson’s symptoms that were alleviated upon stopping the N-acetylcysteine supplementation 19.

Another study 32 looking at those with neurodegenerative disorders found that a single intravenous (IV) dose of N-acetylcysteine led to an increase of the blood reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio and levels of glutathione in the brain 32. Those who had the greatest percent change in reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio also had a greater percent change in their levels of glutathione in their brain. While the study was too small and of too short duration to make any conclusions about the role of N-acetylcysteine in these conditions, what is notable is that through intravenous (IV) administration of N-acetylcysteine, brain levels could be altered 19.

In a 12-week clinical trial with children (n = 31) with autism spectrum disorder administered 60 mg/kg/day in three doses (maximum dose of 4200 mg/day) found that although there was no significant impact on the social impairment associated with autism, there was a significant impact on boosting the glutathione levels in the children 33. Similar to other studies, more needs to be explored as to how N-acetylcysteine influences glutathione levels, factors that modify individual response to supplementation and how symptomatology interrelates. Glutathione-S-transferase (GST) polymorphisms may play a role in the efficacy of N-acetylcysteine 19. In one study 34 investigating the impact of N-acetylcysteine on noise-induced hearing loss in men (n = 53) taking 1200 mg per day for 14 days led to a significant reduction of noise-induced temporary threshold shift, or the amount of hearing loss after a period of heightened noise exposure in a work setting relative to baseline, or pre-shift levels. When the participants were grouped according to their glutathione-S-transferase (GST) genotypes, the researchers found that only those with the null genotypes experienced a significant effect from taking N-acetylcysteine 19.

N-acetylcysteine can cause side effects such as dry mouth, nausea, vomiting, and diarrhea. One of the properties of N-acetylcysteine is that it has an unpleasant smell and taste that some people find hard to tolerate. Vomiting after intravenous use has been reported in about 11% at doses of 150 mg/kg and one anaphylactic reaction has been reported 35. N-acetylcysteine has anticoagulant and platelet inhibiting properties and the use in patients with bleeding disorders or blood thinners may be relatively counterindicated 36. The use of N-acetylcysteine with patients on nitroglycerine should be cautioned, since it may cause hypotension 37. Other more rare side effects may include inflammation of the mucous membrane of the mouth (stomatitis), drowsiness, runny nose (rhinorrhea), and coughing up blood (hemoptysis) 38.

Table 1. N-acetylcysteine (NAC) potential mechanisms of action

1Action on glutathioneN-acetylcysteine restores glutathione (cysteine is rate limiting) as seen in cell and animal studies and clinically in acetaminophen overdose 39.
2Stabilizes proteins/DNAProtects proteins by crosslinking cysteine disulfide molecules 40. Various mechanisms of DNA repair/protection as seen in animal studies and human cell studies 41.
3Scavenges free radicalsScavenging property via the redox potential of thiols as demonstrated in cell culture 42.
4Anti-inflammatory propertyReduces proinflammatory cytokines as seen in animal studies 43.
5Antioxidant propertyReduces oxidative damage as seen in cell cultures 44.
6Mucolytic propertySplits disulfide bonds in mucoproteins lowering viscosity demonstrated in purified mucus gels and tracheal explant systems and in vitro (in a pig tracheal pouch) models 45.
7Mitochondrial resilienceNeurogenesis-inducing ability 46 reduces apoptosis of mitochondria as demonstrated in human dental pulp cells 47.
8Metal chelationThiol groups provide binding sites for metals in animal studies 48.
9Glutamate/dopamine homeostasisModulates glutamate and dopamine extensive studies in humans 11.
10Antiviral propertiesImmune modulation, anti-NF-KB properties, and other unexplored mechanisms observed in vitro and in vivo 49.
11Vascular endothelial growth factorInhibition of vascular permeability as seen in human keratinocytes 50.
12Adenosine triphosphate (ATP) and nitric oxide (NO) productionIncreased ATP production in some cells like fibroblasts in vitro 51. Increased nitric oxide production as demonstrated in human studies 52.
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Figure 1. N-acetylcysteine structure

N-acetylcysteine

Figure 2. Glutathione structure

Glutathione

Footnote: Structure of the tripeptide glutathione (GSH) (reduced form). Glutamic acid (Glu) is linked in a gamma (γ) peptide linkage (via its gamma-carboxyl group) to cysteine (Cys), which in turn forms an alpah (α) peptide linkage with glycine (Gly).

[Source 54 ]

Figure 3. Synthesis and recycling of glutathione

Synthesis and recycling of glutathione

Footnotes: One-carbon metabolism and glutathione (GSH) synthesis and metabolism. Folic acid is reduced to tetrahydrofolate (THF) and subsequently converted to 5-methyl THF. In a reaction catalyzed by methionine synthetase (MTR), the methyl group of 5‑methyl-THF can be transferred to homocysteine, generating methionine. Methionine is activated to form S‑adenosylmethionine (SAM), the universal methyl donor. The by-product of methylation reactions, S‑adenosylhomocysteine (SAH), is hydrolyzed to homocysteine. Homocysteine is either used to regenerate methionine or is directed to the transsulfuration pathway. Reduced glutathione (GSH) is a product of the transsulfuration pathway. Reduced glutathione (GSH) can serve as a continuous source of cysteine, which is extremely unstable, via the gamma‑glutamyl cycle. Reduced glutathione (GSH) is exported from the cell, and the enzyme gamma‑glutamyltransferase (GGT) transfers the gamma-glutamyl moiety of glutathione (GSH) to an amino acid, often cystine, producing cysteinylglycine and gamma-glutamyl amino acid. The gamma-glutamyl amino acid can be transported back into the cell and ultimately metabolized to glutamate. Cysteinylglycine is converted to cysteine and glycine by dipeptidase (DP). Cysteine is unstable extracellularly and can oxidize to cystine; both cysteine and cystine can be imported back into the cell for glutathione (GSH) production.

Abbreviations: B12 = vitamin B12; BHMT = betaine homocysteine methyltransferase; DMA = dimethylarsinic acid; InAs = inorganic acids; MMA = monomethylarsonic acid; GSSG = oxidized glutathione; GSH = reduced glutathione

[Source 55 ]

N-acetylcysteine health benefits

Even though N-acetylcysteine has been used for more than 50 years, there are still many controversies surrounding it as a medicine as well as a dietary supplement 35, 56, 57, 58, 59, 60, 61, 62, 48, 63, 9.

Much of the research on N-acetylcysteine has used an inhaled, liquid form of this compound. The inhaled N-acetylcysteine, which is classified as a drug, not a dietary supplement, is approved by the U.S. Food and Drug Administration (FDA) as a mucolytic agent and for decreasing respiratory secretion viscosity 64. Products containing N-acetylcysteine are also sold as dietary supplements, however, the FDA indicated that N-acetylcysteine cannot lawfully be marketed as a dietary supplement.

Figure 4. N-acetylcysteine health benefits

N-acetylcysteine health benefits
[Source 53 ]

N-acetylcysteine is effective for:

  • Acetaminophen (paracetamol) poisoning / acetaminophen overdosage 65, 66. Taking prescription N-acetyl cysteine by mouth or by IV reduces the death rate and prevents permanent harm caused by acetaminophen overdosage 67. Prescription products must be given by a healthcare provider. Optimal if given within 8 hours of acetaminophen ingestion; may be effective when given ≥24 hours after ingestion 68.
  • Complete or partial lung collapse (atelectasis). Inhaling a prescription form of N-acetyl cysteine helps treat collapsed lungs caused by mucus blockage. Prescription products must be given by a healthcare provider.
  • Mucolytic uses. N-acetylcysteine is used as an adjunctive treatment (add-on treatment used together with the primary treatment) for patients with abnormal, viscid, or inspissated mucous secretions associated with conditions such as acute and chronic bronchopulmonary disorders (e.g., pneumonia, bronchitis, emphysema, tracheobronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasis, primary amyloidosis of the lung); atelectasis caused by mucus obstruction; pulmonary complications of cystic fibrosis 69; pulmonary complications of thoracic and cardiovascular surgery; and post-traumatic chest conditions.
    • Cystic fibrosis. Cystic fibroses is a multiorgan genetic recessive disorder that affects 1/2500 births and is characterized by hyperviscoelastic sputum, neutrophilic inflammation, and infection. High-dose oral N-acetylcysteine was used safely in modulating inflammation, improving glutathione levels, and decreasing elastase activity 70. A recent study showed that lung function was maintained with oral N-acetylcysteine over 24 weeks, while there was deterioration on placebo; however, other markers of inflammation did not change 71. A 2013 Cochrane Review of nebulized N-acetylcysteine did not show significant benefit and nebulized N-acetylcysteine had a very bad taste and smell 72. Oral N-acetylcysteine studies were small and only showed minimal benefit 73. However, a recent study on nebulized N-acetylcysteine did show protection of lung function in children 74. Distal intestinal obstruction found in cystic fibroses patients may benefit from a nonsurgical alternative using N-acetylcysteine although further studies are warranted 75.
    • Chronic obstructive lung disease (COPD) and chronic bronchitis. As early as 1985, it was reported that, in chronic obstructive lung disease (COPD), polymorphonuclear leukocyte oxidative damage was reduced with the use of N-acetylcysteine in a controlled in vitro cell model 76. More recently, a meta-analysis looked at chronic bronchitis and COPD treated with N-acetylcysteine, and there were significantly fewer exacerbations in the treated group than in the placebo group 77, 78. For those with documented airway obstruction, recommendations are to take 1200 mg/day, as a preventative 79. A quantitative systematic review using N-acetylcysteine in chronic bronchitis showed significant benefit in preventing exacerbation and the number needed to treat to achieve benefit was 5.8 80. Recommendations as add-on therapy for COPD and chronic bronchitis is considered a reasonable approach 81.
  • Lung tests. Inhaling a prescription form of N-acetylcysteine is helpful to prepare people for diagnostic lung tests. Prescription products must be given by a healthcare provider.
  • Care of people with a tube placed in their windpipe (tracheostomy care). Inhaling a prescription form of N-acetylcysteine helps prevent crusting in people with a tube in the windpipe. Prescription products must be given by a healthcare provider.

N-acetylcysteine possibly effective for:

  • Age-related macular degeneration (AMD). The addition of N-acetylcysteine to cell cultures of retinal pigment epithelium resulted in significant reduction of oxidative damage in cell studies 82. N-acetylcysteine also upregulates reduced glutathione production and also reverses lipid peroxidation in these cells 83. This has been suggested as a novel new treatment for macular degeneration and clinical studies are warranted.
  • Chest pain (angina). Taking N-acetyl cysteine by mouth or by IV seems to improve chest pain when used with the drug nitroglycerin. Taking N-acetyl cysteine by IV also seems to help prevent nitroglycerin tolerance, but it might increase the risk for headaches and low blood pressure. IV products can only be given by a healthcare provider.
  • Autism. Taking N-acetyl cysteine by mouth might improve irritability in children and adolescents with autism. But it doesn’t seem to help other autism symptoms.
  • Swelling (inflammation) of the main airways in the lung (bronchitis). Taking N-acetyl cysteine by mouth seems to reduce shortness of breath and coughing from chronic bronchitis. Also, taking N-acetyl cysteine by mouth for 3-36 months seems to prevent flare-ups.
  • Bronchiectasis. There is in vitro evidence that biofilms are disrupted and prevented with use of N-acetylcysteine potentially reducing infection 84. A recent long-term randomized controlled trial study using N-acetylcysteine 600 mg bid resulted in fewer exacerbations, less 24-hour mucous production, and a significant improvement in quality of life 85.
  • Bronchiolitis. Nebulized N-acetylcysteine used in children was found to be effective by reducing the clinical severity score within 3–5 days and resulted in earlier discharge 86. Further studies are in progress.
  • Idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease with limited options and poor prognosis. In 2011, the use of three medications Azathioprine, Prednisone, and N-acetylcysteine in combination was halted because of increased hospitalizations and deaths 87. The evidence against the use of these three medications together was strong 87. Evidence has been mixed over the years but more recently a systematic review and meta-analyses have provided more clarity in the clinical use of N-acetylcysteine in pulmonary fibrosis showing benefit in improving oxygenation and reduced the decline in lung function; however, complications and mortality have remained similar 88.
  • A lung disease that makes it harder to breathe (chronic obstructive pulmonary disease or COPD). Taking N-acetyl cysteine by mouth for at least 6 months seems to decrease flare-ups by about 40% in people with moderate to severe COPD. It seems to work best in people who are not already taking corticosteroids. In people with COPD who need to be hospitalized, taking N-acetyl cysteine in addition to regular treatment helps with recovery.
  • Kidney damage caused by contrast dyes (contrast induced nephropathy). Taking N-acetyl cysteine by mouth, with or without other drugs, might help to prevent kidney problems caused by dyes used during some X-ray exams. But it only seems to help in people who already have poor kidney function.
  • Non-acetaminophen-induced acute liver failure. The cause of non-acetaminophen-induced acute liver failure may include agents like viruses, drugs, toxins, herbal and traditional medications, and autoimmunity. Treatment includes removing the offending agent or specific treatments for the agent. N-acetylcysteine has been used in mushroom poisoning 89, herbicide (Paraquat) poisoning 90, chloroform poisoning 91, and protecting against polychlorinated biphenyls (PCB) induced steatosis 92 and other poisonings. N-acetyl cysteine has been used because of its antioxidant, anti-inflammatory, and vasodilating effects as seen in acetaminophen damage 93]. The use of N-acetylcysteine in non-acetaminophen-induced acute liver failure reduced mortality and average length of stay and improved survival 94, 95. A meta-analysis of prospective clinical trials reviewing N-acetylcysteine-treated and placebo-treated groups showed NAC to be safe and prolonged the survival of patients with native livers without transplantation but did not improve overall survival 96.
  • High levels of homocysteine in the blood (hyperhomocysteinemia). Taking N-acetyl cysteine by mouth seems to reduce homocysteine levels, a possible risk factor for heart disease.
    High levels of cholesterol or other fats (lipids) in the blood (hyperlipidemia). Taking N-acetyl cysteine by mouth seems to reduce levels of a blood fat called lipoprotein(a) in people with high levels of this blood fat.
  • Toxicity in people taking the cancer drug ifosfamide (Ifex). Taking N-acetyl cysteine by mouth seems to help prevent side effects of the cancer drug ifosfamide. But a drug called mesna seems to work better than N-acetyl cysteine.
  • Crohn’s disease. Crohn’s disease is characterized by marked systemic oxidative stress even in those in clinical remission 97. In a double-blind randomized controlled trial (N = 168), the relapse rate of those on N-acetylcysteine 400 mg twice daily was significantly reduced compared to placebo while tapering off prednisolone 98.
  • Ulcerative colitis. The use of antioxidant therapy in inflammatory bowel disease has been suggested in the past 99. In an randomized controlled trial, using 400 mg of N-acetylcysteine twice a day in ulcerative colitis patients who were on prednisolone taper, the relapse rate was significantly less in the treatment group. The endoscopic relapse rate, serum level of high-sensitivity C-reactive protein (hs-CRP), and fecal calprotectin level were all lower in the treatment group 100.
  • Diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy. N-acetylcysteine has been shown to benefit diabetic peripheral neuropathy in animals 101. Likewise, animal studies investigating diabetic retinopathy 102 and diabetic nephropathy 103 show promising results. Recently, a study in humans has shown significant benefit in painful peripheral neuropathy 104. Patients with painful neuropathy improved over 8 weeks with the use of N-acetylcysteine (600 mg bid) as adjuvant therapy to pregabalin. There was a >50% reduction in pain score compared to placebo.
  • Flu (influenza). Taking N-acetyl cysteine by mouth seems to reduce flu symptoms. A double-blind randomized controlled trial in which 262 patients were given 600 mg of N-acetylcysteine or placebo for 6 months (during the winter) was conducted to determine the effect of long-term treatment on influenza 105. This study showed that only 25% of virus-infected patients in the N-acetylcysteine group were symptomatic compared to 79% of patients in the placebo group. There was a significant decrease in influenza-like episodes, severity, and length of time confined to bed and sharp reduction of both local and systemic symptoms in the N-acetylcysteine group. Replication of seasonal human influenza A viruses is inhibited by N-acetylcysteine along with inhibition of virus-induced proinflammatory responses 105.
  • Kidney failure. Taking N-acetyl cysteine by mouth seems to help prevent problems such as heart attack and stroke in people with kidney failure.
  • Heart attack. Giving N-acetyl cysteine by IV along with the drug nitroglycerin seems to help maintain heart function and reduce heart damage in people having a heart attack. Sometimes the drug streptokinase is also used along with N-acetyl cysteine and nitroglycerin. IV products can only be given by a healthcare provider.
  • Liver cancer (hepatocarcinoma). Liver cancer, most commonly known as hepatocarcinoma, is a common cancer and treatment of this cancer with interferon-alpha 2A (IFN-α) has a relatively poor response rate of about 30%. N-acetylcysteine acts synergistically to improve the efficacy of the drug by decreasing tumor viability, increasing apoptosis, and decreasing expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Inactivating the pathway of initiation, promotion, and progression of tumors by NF-kB can be done by using NAC as an adjuvant to IFN α 106.
  • Male infertility. In idiopathic male infertility, an randomized controlled trial using N-acetylcysteine showed improvement of oxidative status along with semen quality (improved motility, viscosity, and volume) 107. The dosage was 600 mg twice daily. In another randomized controlled trial using selenium and N-acetylcysteine together, there was significant improvement in semen quality 108.
  • Multiple sclerosis. A small randomized controlled trial study using intravenous N-acetylcysteine once weekly along with 500 mg twice a day for two months showed improvement in glucose metabolism in several areas of the brain as well as improved attention and cognition in self-reported scores in the treatment group 109. In a small study in progressive multiple sclerosis (MS), N-acetylcysteine at a dose of 1250 mg three times a day was well tolerated and resulted in sustained fatigue improvement 110. Glutathione levels are reduced in secondary progressive MS and N-acetylcysteine is able to improve this 111.
  • Sjogren’s syndrome. Oral N-acetylcysteine used in a double-blind study has shown improvements in daytime thirst, ocular soreness, ocular irritability, and halitosis in Sjogren’s syndrome 112.
  • Systemic lupus erythematosus. There is depletion of glutathione in patients with systemic lupus erythematosus as well as T-cell dysfunction. N-acetylcysteine replenishes glutathione and as an antioxidant in and of itself is able to inhibit mechanistic target of rapamycin (mTOR) in vitro 100. A double-blind randomized controlled trial pilot study using 2.4 gm of N-acetylcysteine daily safely and significantly improved lupus disease activity 113.
  • Nonalcoholic fatty liver disease (NAFLD). There is evidence that N-acetylcysteine may block hepatic lipid accumulation and provide therapeutic benefit against metabolic complications found in nonalcoholic fatty liver disease (NAFLD). This is primarily due to the antioxidant effects and attenuation of lipid peroxidation 114. This is supported by most preclinical studies and a few clinical studies, and there is an urgent need for larger clinical studies. Nonalcoholic fatty liver disease (NAFLD) affects up to 25% of the population, a condition which may lead to significant pathology such as fibrosis of the liver.
  • Parkinson’s disease. Dopamine may trigger apoptosis in neuronal cell cultures, which may initiate inappropriate loss of nigral cells in Parkinson’s disease. Thiols containing compounds like N-acetylcysteine are markedly protective by inhibiting dopamine-induced cell death in cell cultures 115. A clinical study using N-acetylcysteine both as a weekly intravenous infusion and 500 mg orally twice a day over three months significantly improved Parkinson symptoms and increased dopamine binding in the brain warranting further study 116.
  • Polycystic ovary disease, chorioamnionitis, and recurrent pregnancy loss. Treatment with N-acetylcysteine may improve insulin sensitivity in women with polycystic ovary disease 117. A systematic review of randomized controlled trials using N-acetylcysteine as a supplement in polycystic ovary disease resulted in improved fertility, ovulation, and odds of having a live birth although these results were not as robust as studies using Metformin 118. The dosage in studies varied from 1200 mg/day to 1800 mg/day. Chorioamnionitis, a devastating infection with increased risk of cerebral palsy and other neurological sequalae, may benefit from intravenous N-acetylcysteine (both antenatally and postnatally) by reducing neuroinflammation 119. The use of N-acetylcysteine as an adjunct in recurrent pregnancy loss has been shown to improve the take-home-baby rate as compared to folic acid alone 120.
  • Stroke. Acrolein-mediated damage after stroke has been implicated in the size of strokes in animal studies and N-acetylcysteine has been shown to reduce the size of the infarct 121. In a recent randomized double-blind placebo-controlled trial using N-acetylcysteine 4 grams four times a day for 72 hours at the onset (within 24 hours) of an ischemic stroke, the follow-up National Institute of Health Stroke Scale at 90 days resulted in a better outcome profile in both neurological deficit and disability 122.

N-acetylcysteine possibly ineffective for:

  • Lou Gehrig’s disease (amyotrophic lateral sclerosis or ALS). Taking N-acetyl cysteine by IV doesn’t seem to improve ALS symptoms. IV products can only be given by a healthcare provider.
  • Alzheimer’s disease. Alzheimer’s disease is the most common form of dementia among older people. Dementia is a brain disorder that seriously affects a person’s ability to carry out daily activities. Results of different studies showed that lipoic acid and N-acetylcysteine decreased levels of oxidative and apoptotic markers via protection of mitochondrial function 123, 124. Combination of both lipoic acid and N-acetylcysteine maximizes this protective effect suggesting that this may prevent mitochondrial decay associated with aging and age-related disorders such as Alzheimer’s disease.
  • Dementia. Animal studies have shown significant promise improving cognitive function even though beta-amyloid pathology was unchanged 125. There is some evidence that N-acetylcysteine as an adjuvant may slow the progression of dementia; however, this effect was seen clinically in a nutraceutical containing several ingredients including N-acetylcysteine 126.
  • Heart damage caused by certain cancer drugs (anthracycline cardiotoxicity). Taking N-acetyl cysteine by mouth doesn’t seem to prevent or treat heart damage caused by doxorubicin.
  • A lung disease that affects newborns (bronchopulmonary dysplasia). Giving N-acetyl cysteine through a hole in the windpipe does not seem to prevent breathing problems in premature infants. This can only be given by a healthcare provider.
  • Acute asthma. Studies at present do not support the use of N-acetylcysteine in acute asthma attacks because of lack of improvement of cough, wheezing, dyspnea, sputum expectoration, or night sleep 127. However, in animal models, steroid-resistant acute exacerbation of asthma did benefit from NAC 128. To date, there have been no long-term studies using N-acetylcysteine in prevention of recurrent asthma attacks by reducing inflammation and mucous plugging. NAC has been shown to reduce the allergen-induced nasal inflammatory cascade in allergic rhinitis in animal models 129. Topical application of N-acetylcysteine prior to ragweed exposure resulted in attenuation of the late phase allergic response mediated nasal symptoms 130.
  • Cannabis use disorder. Taking N-acetyl cysteine by mouth doesn’t seem to improve depression or help reduce cannabis use in teens and adults with cannabis use disorder.
  • Cystic fibrosis. Taking N-acetyl cysteine by mouth or inhaling it doesn’t seem to improve lung function in people with cystic fibrosis.
  • Diabetes. Animal studies show that N-acetylcysteine may inhibit hepatic steatosis and development of glucose intolerance and improve lipid profiles 131, 132. In type 2 diabetic humans, there does not appear to be any benefit in improving glucose tolerance or ß-cell function with the addition of N-acetylcysteine in short-term trials (2 weeks) 133. Long-term trials are warranted.
  • An inherited disorder marked by sensitivity to light (erythropoietic protoporphyria or EPP). Taking N-acetyl cysteine by mouth doesn’t seem to reduce light sensitivity in people with EPP.
  • A digestive tract Helicobacter pylori (H. pylori) infection that can lead to ulcers. Taking N-acetyl cysteine by mouth along with usual treatments for H. pylori infection doesn’t help eliminate the infection any better than usual treatment 134.
  • Swelling (inflammation) of the liver (hepatitis). Taking N-acetyl cysteine by mouth doesn’t seem to help treat viral hepatitis. It also doesn’t seem to improve response to interferon therapy in people with hepatitis C. But it might help prevent relapses in people with hepatitis C.
  • HIV and AIDS. Taking N-acetyl cysteine by mouth doesn’t seem to improve immune function or reduce the amount of virus in the body in most people with HIV. In a double-blind placebo-controlled trial using 800 mg of N-acetylcysteine, there was a reduction in the decline of the CD4 count (number of a type of white blood cell) seen in the placebo group and tumor necrosis factor-alpha (TNF-alpha) levels were also reduced 135. Glutathione levels are improved with N-acetylcysteine, inhibiting actions of inflammatory cytokines and slowing cachexia and wasting 136.
  • Low blood pressure (hypotension). Taking N-acetyl cysteine by mouth doesn’t seem to reduce the risk of kidney failure in people with long-term low blood pressure.
  • Inability to become pregnant within a year of trying to conceive (infertility). Taking N-acetyl cysteine by mouth doesn’t seem to improve pregnancy rate or miscarriage rate in females with fertility problems.
  • Liver transplant. Giving N-acetyl cysteine by IV during liver donor surgery doesn’t seem to prevent transplant rejection in liver transplant recipients. IV products can only be given by a healthcare provider.
  • Swelling (inflammation) of the pancreas (pancreatitis). Taking N-acetyl cysteine by mouth doesn’t prevent pancreatitis in people having a certain procedure that can cause pancreas swelling. Also, taking N-acetyl cysteine by IV along with selenium and vitamin C doesn’t seem to improve pancreas function in people with serious pancreatitis. IV products can only be given by a healthcare provider.
  • Recovery after surgery. Taking N-acetyl cysteine by mouth or by IV doesn’t seem to reduce the risk of heart attack, stroke, kidney injury, or death after heart surgery. IV products can only be given by a healthcare provider.

N-acetylcysteine likely ineffective for:

  • Head and neck cancer. Taking N-acetyl cysteine by mouth doesn’t prevent new tumors or improve survival in people with head and neck cancer.
  • Lung cancer. Taking N-acetyl cysteine by mouth doesn’t prevent new tumors or improve survival in people with lung cancer.
  • Multiple organ failure. Giving N-acetyl cysteine by IV might increase the risk of death in people with multiple organ failure. IV products can only be given by a healthcare provider.

There is interest in using N-acetyl cysteine for a number of other purposes, but there isn’t enough reliable information to say whether it might be helpful.

Is N-acetylcysteine safe?

N-acetylcysteine is likely safe for most adults. N-acetylcysteine is an FDA-approved prescription drug.

When inhaled: N-acetylcysteine is likely safe for most adults, when used as a prescription medication. It can cause swelling in the mouth, runny nose, drowsiness, clamminess, and chest tightness.

Special precautions and warnings

Pregnancy

N-acetylcysteine is possibly safe when taken by mouth or inhaled during pregnancy. N-acetyl cysteine crosses the placenta, but there is no evidence that it harms the unborn child. But N-acetyl cysteine should only be used when medically needed.

Breastfeeding

There isn’t enough reliable information to know if N-acetylcysteine is safe to use during breast-feeding. Stay on the safe side and avoid use.

Children

N-acetyl cysteine is likely safe when taken by mouth in doses of 900-2700 mg daily for up to 12 weeks.

Allergy

Don’t use N-acetylcysteine if you are allergic to acetyl cysteine.

Asthma

N-acetylcysteine might cause bronchospasm in people with asthma if inhaled or taken by mouth. If you take N-acetyl cysteine and have asthma, you should be monitored by your healthcare provider.

Bleeding disorder

N-acetyl cysteine might slow blood clotting. N-acetyl cysteine might increase the risk of bruising and bleeding in people with bleeding disorders.

Surgery

N-acetylcysteine might slow blood clotting. This might increase the risk of bleeding during and after surgery. Stop taking N-acetyl cysteine at least 2 weeks before a scheduled surgery.

N-acetylcysteine interactions with medications and supplements

Major interactions

Do not take this combination

  • Nitroglycerin. Nitroglycerin can dilate blood vessels and increase blood flow. Taking N-acetyl cysteine seems to increase the effects of nitroglycerin. This could increase the risk for side effects including headache, dizziness, and lightheadedness.

Moderate interactions

Be cautious with this combination.

  • Activated charcoal. Activated charcoal is sometimes used to prevent poisoning in people who take too much acetaminophen (Tylenol) or other medications. Taking N-acetyl cysteine at the same time as activated charcoal might decrease how well it works for preventing poisoning.
  • Chloroquine (Aralen). Chloroquine is a drug used to treat malaria. N-acetyl cysteine might reduce the effects of chloroquine against malaria.
  • Medications for high blood pressure (antihypertensive drugs). N-acetyl cysteine might lower blood pressure. Taking N-acetyl cysteine along with medications that lower blood pressure might cause blood pressure to go too low. Monitor your blood pressure closely.
  • Medications that slow blood clotting (anticoagulant / antiplatelet drugs). N-acetyl cysteine might slow blood clotting. Taking N-acetyl cysteine along with medications that also slow blood clotting might increase the risk of bruising and bleeding.
  • Herbs and supplements that might lower blood pressure. N-acetyl cysteine might lower blood pressure. Taking it with other supplements that have the same effect might cause blood pressure to drop too much. Examples of supplements with this effect include andrographis, casein peptides, L-arginine, niacin, and stinging nettle.
  • Herbs and supplements that might slow blood clotting. N-acetyl cysteine might slow blood clotting and increase the risk of bleeding. Taking it with other supplements with similar effects might increase the risk of bleeding in some people. Examples of supplements with this effect include garlic, ginger, ginkgo, nattokinase, and Panax ginseng.

N-acetylcysteine dosage

N-acetylcysteine dose varies significantly with various clinical studies and doses of 1200 mg daily or more are usually required to be clinically relevant 53. Studies in metabolic diseases show that 500 to 600 mg orally per day may be sufficient to reduce fatty liver disease. For Crohn’s disease and ulcerative colitis, doses of 800 mg per day seemed sufficient. Doses as high as 1250 mg orally three times a day have been used safely in multiple sclerosis (MS) and showed benefit in reducing fatigue. Doses of 8000 mg/day orally did not cause clinically significant reactions in HIV patients 137. Clearly dosing is still debated and much needs to be learned in this area.

N-acetylcysteine side effects

N-acetylcysteine can cause side effects such as dry mouth, nausea, vomiting, and diarrhea 57, 9. One of the properties of N-acetylcysteine is that it has an unpleasant smell and taste that some people find hard to tolerate. Vomiting after intravenous use has been reported in about 11% at doses of 150 mg/kg and one anaphylactic reaction has been reported 35. N-acetylcysteine has anticoagulant and platelet inhibiting properties and the use in patients with bleeding disorders or blood thinners may be relatively counterindicated 36. The use of N-acetylcysteine with patients on nitroglycerine should be cautioned, since it may cause hypotension 37. Other more rare side effects may include inflammation of the mucous membrane of the mouth (stomatitis), drowsiness, runny nose (rhinorrhea), and coughing up blood (hemoptysis) 38.

Get emergency medical help if you have signs of an allergic reaction to N-acetylcysteine:

  • hives;
  • difficult breathing;
  • swelling of your face, lips, tongue, or throat.

N-acetylcysteine may cause serious side effects. See your doctor at once if you have:

  • severe or ongoing vomiting;
  • coughing up blood or vomit that looks like coffee grounds; or
  • signs that the medicine may not be working–upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects of N-acetylcysteine may include:

  • nausea, vomiting, upset stomach;
  • rash;
  • fever.

This is not a complete list of side effects and others may occur. See your doctor for medical advice about side effects.

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