madman
Super Moderator
Objective. To review the clinical usefulness of N-acetylcysteine (NAC) as treatment or adjunctive therapy in a number of medical conditions. Use in Tylenol overdose, cystic fibrosis, and chronic obstructive lung disease has been well documented, but there is emerging evidence many other conditions would benefit from this safe, simple, and inexpensive intervention.
Quality of Evidence. PubMed, several books, and conference proceedings were searched for articles on NAC and health conditions listed above reviewing supportive evidence. )is study uses a traditional integrated review format, and clinically relevant information is assessed using the American Family Physician Evidence-Based Medicine Toolkit. A table summarizing the potential mechanisms of action for N-acetylcysteine in these conditions is presented.
Main Message. N-acetylcysteine may be useful as an adjuvant in treating various medical conditions, especially chronic diseases. these conditions include polycystic ovary disease, male infertility, sleep apnea, acquired immune deficiency syndrome, influenza, parkinsonism, multiple sclerosis, peripheral neuropathy, stroke outcomes, diabetic neuropathy, Crohn’s disease, ulcerative colitis, schizophrenia, bipolar illness, and obsessive-compulsive disorder; it can also be useful as a chelator for heavy metals and nanoparticles.) there are also a number of other conditions that may show benefit; however, the evidence is not as robust.
Conclusion. The use of N-acetylcysteine should be considered in a number of conditions as our population ages and levels of glutathione drop. Supplementation may contribute to reducing morbidity and mortality in some chronic conditions as outlined in the article.
1. Introduction
N-acetylcysteine (NAC) is a sulfhydryl-containing compound, with mucolytic properties, originally patented in 1960, and its use in medicine was first reported in 1967 [1]. Its chemical structure and nomenclature are depicted in Figure 1. Clinically it has been used in cystic fibrosis since 1969 [2]. Since then, NAC use has been expanded to acetaminophen overdose and chronic obstructive lung disease and its role is ever-expanding clinically.
Cysteine is found naturally in meat, fish, grains, dairy, soybean, and egg products [3]. As a nutritional supplement, NAC is found in small amounts naturally in some fruits and vegetables [4]
The properties of NAC include enhancing glutathione S-transferase activity, repleting glutathione, scavenging free radicals, and stabilizing protein structures by crosslinking cysteine disulfide molecules along with its antioxidant, antiinflammatory, and mucolytic properties. A more complete list of mechanisms of action is given in Table 1.
The bioavailability of oral NAC in humans is between 4 and 9.1% in one study [20] and between 6 and 10% in another [21]; thus, studies using less than 1200 mg per day may show no significant benefit. The half-life of NAC is 6.25 hours, and clearance is both renal and nonrenal, with side effects of nausea, vomiting, and diarrhea [22].
Some have suggested that cysteine deficiency as we age is responsible for loss of youth and loss of health and quality of life and contributes to sarcopenia, especially since cysteine consumption is considered suboptimal [23].
There have been several systematic reviews of NAC in the literature over the past decade looking at various clinical trials in psychiatry and neurology [24], metabolic disease [25], pulmonary disease [26], infectious diseases including possible use in acute respiratory syndromes like coronavirus 2 (SARS-CoV-2) [27], and infertility [28] and as a chelator for metal toxicity [14].
2.1. N-Acetylcysteine in Lung Disorders
2.2. Cystic Fibrosis (LOE = A)
2.3. Chronic Obstructive Lung Disease and Chronic Bronchitis (LOE = A, C)
2.4. Asthma and Allergy (LOE = B)
2.5. Bronchiectasis (LOE = A)
2.6. Bronchiolitis (LOE = A)
2.7. Idiopathic Pulmonary Fibrosis (LOE = A)
3. Liver and Bowel Diseases
3.1. Acetaminophen Overdose (LOE = A)
3.2. Non-Acetaminophen-Induced Acute Liver Failure (LOE = A)
3.3. Hepatocarcinoma (LOE = B)
3.4. Crohn’s Disease (LOE = A)
3.5. Ulcerative Colitis (LOE = A)
3.6. Systemic Lupus Erythematosus (LOE = A)
4. Metabolic Syndrome including Nonalcoholic Fatty Liver Disease, Diabetes, and Polycystic Ovary
4.1. Nonalcoholic Fatty Liver Disease (LOE = B)
4.2. Diabetes
4.3. Diabetic Neuropathy, Retinopathy, and Nephropathy (LOE = A)
4.4. Polycystic Ovary Disease, Chorioamnionitis, and Recurrent Pregnancy Loss (LOE = A, B)
4.5. Male Fertility (LOE = A)
4.6. Hypertension (LOE = B)
4.6.1. Pulmonary Hypertension.
4.7. Chemotherapy
4.8. Breast Cancer, Prostate Cancer, Lung Cancer, Glioblastoma, and Chronic Lymphocytic Leukemia
4.9. Sleep Apnea (LOE = B)
5. Infectious Disease
5.1. Overview
5.2. Acquired Immune Deficiency Syndrome (LOE = A)
5.3. Tuberculosis (LOE = A)
5.4. Influenza, Respiratory Syncytial Virus, and SARS-CoV-2 (LOE = A, B)
5.5. H. pylori (LOE = B)
6. Neurodegenerative Disorders
6.1. Overview
6.2. Parkinson’s Disease (LOE = B)
6.3. Dementia (LOE = B)
6.4.NeuropathicPain (LOE= A, B)
6.5. Stroke (LOE = A)
6.6. Multiple Sclerosis (LOE = B)
7. Eye Conditions
7.1. Age-Related Macular Degeneration
7.2. Glaucoma (LOE = B)
7.3. Sjogren’s Syndrome (Dry Eyes) (LOE = A)
8. Psychiatric Conditions
8.1. Schizophrenia (LOE = A)
8.2. Obsessive-Compulsive Disorder (LOE = A)
8.3. Bipolar Illness (LOE = A)
8.4. Trichotillomania, Pathologic Nail Biting, and Skin Picking (LOE = A, B)
8.5. Addiction Behaviour (LOE = B)
8.6. Use as Chelator for Metal Toxicity (LOE = A, B)
8.7. Nanoparticle-Induced Reduction of Deoxyribonucleic Acid Methylation (LOE = B)
8.8. Side Effects
8.9. Dosing of NAC
9. Discussion and Conclusion
N-acetylcysteine appears to be well tolerated with minimal side effects when used as a supplement or in the treatment of various disorders. As stated above, the dosage required for this medication is not always clear, and there is much work needed to provide this information. A number of mechanisms of its actions are listed in Table 1. These actions provide reasoning for some of the results that are seen in so many different conditions. Many other conditions not listed in this document are emerging as understanding about NAC grows. As seen with other antioxidants in the past, there is some caution as expressed above with lung cancer models, where there may be an increase in proliferation as a result of p53 inhibition or likewise a possible increase in pulmonary hypertension.
As seen above, the benefit has been shown with pulmonary, psychiatric, neurologic, metabolic, and infectious diseases, fertility issues, and some cancers. For most of these conditions, NAC can be used as an adjuvant, which may improve quality of life, morbidity, and mortality.
The use in metal toxicity and recent evidence in protecting DNA are also important. Much needs to be learned and more in vivo studies need to be performed to give us more confidence in using this simple compound.
Quality of Evidence. PubMed, several books, and conference proceedings were searched for articles on NAC and health conditions listed above reviewing supportive evidence. )is study uses a traditional integrated review format, and clinically relevant information is assessed using the American Family Physician Evidence-Based Medicine Toolkit. A table summarizing the potential mechanisms of action for N-acetylcysteine in these conditions is presented.
Main Message. N-acetylcysteine may be useful as an adjuvant in treating various medical conditions, especially chronic diseases. these conditions include polycystic ovary disease, male infertility, sleep apnea, acquired immune deficiency syndrome, influenza, parkinsonism, multiple sclerosis, peripheral neuropathy, stroke outcomes, diabetic neuropathy, Crohn’s disease, ulcerative colitis, schizophrenia, bipolar illness, and obsessive-compulsive disorder; it can also be useful as a chelator for heavy metals and nanoparticles.) there are also a number of other conditions that may show benefit; however, the evidence is not as robust.
Conclusion. The use of N-acetylcysteine should be considered in a number of conditions as our population ages and levels of glutathione drop. Supplementation may contribute to reducing morbidity and mortality in some chronic conditions as outlined in the article.
1. Introduction
N-acetylcysteine (NAC) is a sulfhydryl-containing compound, with mucolytic properties, originally patented in 1960, and its use in medicine was first reported in 1967 [1]. Its chemical structure and nomenclature are depicted in Figure 1. Clinically it has been used in cystic fibrosis since 1969 [2]. Since then, NAC use has been expanded to acetaminophen overdose and chronic obstructive lung disease and its role is ever-expanding clinically.
Cysteine is found naturally in meat, fish, grains, dairy, soybean, and egg products [3]. As a nutritional supplement, NAC is found in small amounts naturally in some fruits and vegetables [4]
The properties of NAC include enhancing glutathione S-transferase activity, repleting glutathione, scavenging free radicals, and stabilizing protein structures by crosslinking cysteine disulfide molecules along with its antioxidant, antiinflammatory, and mucolytic properties. A more complete list of mechanisms of action is given in Table 1.
The bioavailability of oral NAC in humans is between 4 and 9.1% in one study [20] and between 6 and 10% in another [21]; thus, studies using less than 1200 mg per day may show no significant benefit. The half-life of NAC is 6.25 hours, and clearance is both renal and nonrenal, with side effects of nausea, vomiting, and diarrhea [22].
Some have suggested that cysteine deficiency as we age is responsible for loss of youth and loss of health and quality of life and contributes to sarcopenia, especially since cysteine consumption is considered suboptimal [23].
There have been several systematic reviews of NAC in the literature over the past decade looking at various clinical trials in psychiatry and neurology [24], metabolic disease [25], pulmonary disease [26], infectious diseases including possible use in acute respiratory syndromes like coronavirus 2 (SARS-CoV-2) [27], and infertility [28] and as a chelator for metal toxicity [14].
2.1. N-Acetylcysteine in Lung Disorders
2.2. Cystic Fibrosis (LOE = A)
2.3. Chronic Obstructive Lung Disease and Chronic Bronchitis (LOE = A, C)
2.4. Asthma and Allergy (LOE = B)
2.5. Bronchiectasis (LOE = A)
2.6. Bronchiolitis (LOE = A)
2.7. Idiopathic Pulmonary Fibrosis (LOE = A)
3. Liver and Bowel Diseases
3.1. Acetaminophen Overdose (LOE = A)
3.2. Non-Acetaminophen-Induced Acute Liver Failure (LOE = A)
3.3. Hepatocarcinoma (LOE = B)
3.4. Crohn’s Disease (LOE = A)
3.5. Ulcerative Colitis (LOE = A)
3.6. Systemic Lupus Erythematosus (LOE = A)
4. Metabolic Syndrome including Nonalcoholic Fatty Liver Disease, Diabetes, and Polycystic Ovary
4.1. Nonalcoholic Fatty Liver Disease (LOE = B)
4.2. Diabetes
4.3. Diabetic Neuropathy, Retinopathy, and Nephropathy (LOE = A)
4.4. Polycystic Ovary Disease, Chorioamnionitis, and Recurrent Pregnancy Loss (LOE = A, B)
4.5. Male Fertility (LOE = A)
4.6. Hypertension (LOE = B)
4.6.1. Pulmonary Hypertension.
4.7. Chemotherapy
4.8. Breast Cancer, Prostate Cancer, Lung Cancer, Glioblastoma, and Chronic Lymphocytic Leukemia
4.9. Sleep Apnea (LOE = B)
5. Infectious Disease
5.1. Overview
5.2. Acquired Immune Deficiency Syndrome (LOE = A)
5.3. Tuberculosis (LOE = A)
5.4. Influenza, Respiratory Syncytial Virus, and SARS-CoV-2 (LOE = A, B)
5.5. H. pylori (LOE = B)
6. Neurodegenerative Disorders
6.1. Overview
6.2. Parkinson’s Disease (LOE = B)
6.3. Dementia (LOE = B)
6.4.NeuropathicPain (LOE= A, B)
6.5. Stroke (LOE = A)
6.6. Multiple Sclerosis (LOE = B)
7. Eye Conditions
7.1. Age-Related Macular Degeneration
7.2. Glaucoma (LOE = B)
7.3. Sjogren’s Syndrome (Dry Eyes) (LOE = A)
8. Psychiatric Conditions
8.1. Schizophrenia (LOE = A)
8.2. Obsessive-Compulsive Disorder (LOE = A)
8.3. Bipolar Illness (LOE = A)
8.4. Trichotillomania, Pathologic Nail Biting, and Skin Picking (LOE = A, B)
8.5. Addiction Behaviour (LOE = B)
8.6. Use as Chelator for Metal Toxicity (LOE = A, B)
8.7. Nanoparticle-Induced Reduction of Deoxyribonucleic Acid Methylation (LOE = B)
8.8. Side Effects
8.9. Dosing of NAC
9. Discussion and Conclusion
N-acetylcysteine appears to be well tolerated with minimal side effects when used as a supplement or in the treatment of various disorders. As stated above, the dosage required for this medication is not always clear, and there is much work needed to provide this information. A number of mechanisms of its actions are listed in Table 1. These actions provide reasoning for some of the results that are seen in so many different conditions. Many other conditions not listed in this document are emerging as understanding about NAC grows. As seen with other antioxidants in the past, there is some caution as expressed above with lung cancer models, where there may be an increase in proliferation as a result of p53 inhibition or likewise a possible increase in pulmonary hypertension.
As seen above, the benefit has been shown with pulmonary, psychiatric, neurologic, metabolic, and infectious diseases, fertility issues, and some cancers. For most of these conditions, NAC can be used as an adjuvant, which may improve quality of life, morbidity, and mortality.
The use in metal toxicity and recent evidence in protecting DNA are also important. Much needs to be learned and more in vivo studies need to be performed to give us more confidence in using this simple compound.
