The use of N-acetyl-cysteine (NAC) is an important and low-cost dietary supplement to include when treating a wide range of acute and chronic conditions. NAC has been used in medicine for years, mostly for supporting the treatment of excessive mucous production in respiratory conditions and for acetaminophen toxicity.1,2 NAC is derived from the amino acid L-cysteine. L-cysteine is considered a nonessential amino acid because it can be synthesized in the human body. It is considered a “conditionally essential” amino acid by some because the synthesis of L-cysteine may be compromised under stress of illness or in preterm infants.3 L-cysteine as a supplement has been shown to increase serum levels of glutathione. Levels of glutathione (GSH) in the human body are dependent on 3 conditionally essential amino acids, namely glycine, cysteine, and glutamic acid.4 NAC has been shown to increase serum levels of GSH, which accounts for its indirect antioxidant and anti-inflammatory properties.5 A quote from a summary published and read at the 42nd Annual Meeting of the American Association for Thoracic Surgery in St. Louis, Missouri, in 1962 provides a good example of historical use of NAC:
“Acetyl-cysteine, a derivative of the amino acid cysteine, has proved most efficacious in reducing the viscosity of mucoid and purulent secretions. Experience in over 285 patients during the operative period or with a variety of acute or chronic suppurative pulmonary diseases has revealed it to be extremely effective with almost no associated complications.”
In 1978, acetylcysteine became available for oral use in treating acetaminophen toxicity. The protocol called for 9,800 mg during an initial 4-hour period followed by 4,900 mg every 4 hours for 72 hours for a 70-kg person (140 mg/kg and 70 mg/kg, respectively). Studies have shown that this treatment prevents hepatotoxicity without elevating liver enzymes. Studies show that initiating NAC within 10 hours of acetaminophen overdose has the best chance of hepatoprotection, with less pronounced protection given after that 10-hour period.6
Besides the original use of NAC as a mucolytic and then for acetaminophen toxicity, we know now that the mechanism of action also includes anti-inflammatory, antioxidant, antimicrobial, and anticarcinogenic properties. The medical and dietary use of NAC is well-reviewed in an article published in the journal Antioxidants.7 The purpose of this article is to review the mechanism of action of NAC and the use of NAC in the treatment of respiratory, hepatological, neurological, and psychiatric conditions. Oral dosing, side effects, and toxicity of NAC are summarized at the end of this review.
Mucolytic Properties in Chronic Respiratory Disease
In humans, the immune system protects against harmful exposure to the body. This can occur on the skin, the intestinal lining, and to the lining of the airways. In the airways and intestinal lining, our own innate immune response releases peptides, called defensins. While mucus acts as a protective physical barrier, defensins, which are found in mucus, serve to protect against harmful pathogens and have antimicrobial, antifungal, and antiparasitic properties.8
The pathophysiology of respiratory conditions, such as chronic obstructive pulmonary disease (COPD) and chronic bronchitis, can occur as a result of irritation caused by irritants (eg, smoking, gas exposure, noxious particles, etc.). In response, the airways become inflamed, and hypersecretion of mucus occurs. Airway obstruction usually occurs more in the smaller airways and is caused by inflammation and narrowing of these smaller airways. Not all patients with, for example, chronic bronchitis, have airway obstruction, and not all patients with COPD have hypersecretion of mucus. Because NAC has both mucolytic and anti-inflammatory properties, it is ideal for multiple-symptom relief and improvement of lung function. COPD is characterized by poorly reversible airflow obstruction and an abnormal inflammatory response in the lungs. Acute bronchitis is often associated with hypersecretion of mucus as related to a cough and inability to expectorate the thick mucus. As a mucolytic agent, NAC breaks down disulfide bonds in the glycoproteins of mucus in the airways of individuals with conditions associated with overproduction of mucus such as cystic fibrosis, COPD, and bronchitis9 (Figure1).
Figure 4: NAC blocks hepatic lipid accumulation in preclinical models of NAFLD. NAC appears effective in improving liver function by reducing pro-inflammatory markers such as interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGFβ)-1 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This was primarily through the attenuation of lipid peroxidation, improvements in mitochondrial function, and enhancements in intracellular response antioxidants, particularly glutathione (GSH). Abbreviations: TG = triglycerides; DNL = de novo lipogenesis. Reprinted with permission from author and is from an open access article distributed under the terms and conditions of the Creative Commons Attribution license.
Hematopoietic stem cell transplantation (HSCT) is used in multiple myeloma and leukemia treatment but has complications associated with toxicity to the liver.36 In a placebo-controlled study using 100 mg/kg of NAC following HSCT, there was a significant reduction in AST and ALT in the group that used the NAC (P<0.0001) as well as a reduction in ALP (P<0.0002).37
As with NAFLD, liver damage is also very much a problem with people who regularly drink excess alcohol. Fatty liver and increased inflammation often occur with chronic alcohol intake. Ethanol is metabolized and oxidized in the liver and converted to acetaldehyde mostly by the enzyme alcohol dehydrogenase (ADH). Under normal conditions, the body converts acetaldehyde to acetate, and then to water and carbon dioxide. When excess alcohol is consumed, there is an increase in toxic levels of acetaldehyde, which can lead to irreversible damage and cancer.38 With excessive alcohol intake, the GSH/GSSG ratio is decreased.39 As a result of alcohol toxicity, especially in overweight individuals, there is an increase in ROS and increased inflammation. Glutathione is synthesized in the cytosol and can move into the mitochondria via carriers; however, mitochondrial GSH (mGSH) is not produced independently within the mitochondria.40 Alcohol consumption can cause mitochondrial dysfunction and decrease levels of glutathione. NAC can restore glutathione levels at a cellular level and potentially counteract the negative effects of increased levels of toxic substances such as acetaldehyde.41
Reduction of mGSH has been linked to various diseases, and replenishing these stores in the mitochondria is important. In addition, increased transport of cholesterol into the mitochondria can interfere with the normal physiologic protection against oxidative stress and is often found in patients with alcohol- and nonalcohol-induced fatty liver.42
Mitochondria exist within our cells and produce and maintain the necessary energy for normal cellular function. The number of mitochondria within cells varies depending on need. Muscle cells have a greater number of mitochondria due to increased energy needs. Mitochondria produce adenosine triphosphate (ATP) by a process called oxidative phosphorylation.43 As a normal part of aging, there is a decrease in oxidative phosphorylation and an increase in damage to cells via oxidative damage, causing mitochondrial dysfunction. The dysfunction has been associated with neurodegenerative conditions such as Alzheimer disease (AD) and Parkinson disease (PD).44 To benefit the mitochondria within brain cells, the antioxidant used needs to be able to cross the blood-brain barrier (BBB). Oral glutathione has not been shown to increase central nervous system (CNS) levels of GSH; however, it may reach the CNS if given intranasally.45 A reduction of GSH levels in the substantia nigra of Parkinson patients and increased oxidative stress may be associated with increased death of dopaminergic cells. NAC has been shown to cross the BBB in animal studies and decrease mitochondrial oxidative stress.46 In a small study involving 3 PD patients, levels of brain glutathione increased in all 3 subjects by 55%, 41%, and 34%, respectively, following an infusion of 150 mg/kg NAC.47 Another study gave a combination of intravenous and oral NAC to PD patients. One group was given intravenous NAC 50 mg/kg once weekly and 600 mg twice daily on the days infused NAC was not given. The clinical study showed significantly increased dopamine active transporter (DaT) binding in the caudate and putamen of PD patients (P=0.05). DaT is responsible for taking dopamine from the synaptic cleft of neurons and returning them to presynaptic neurons for later use. In addition, scores from the Unified Parkinson’s Disease Rating Scale (UPDRS), which measures clinical symptoms in patients with PD, showed significant improvement (P=0.01).48 Unfortunately, in this study, PD patients with major depression were not accepted into the trial. The reason this is important is because positive emotions are processed in the ventral portion of the striatum, while negative emotions are processed in the dorsal portion, as demonstrated using neuroimaging techniques. There is evidence from clinical observation that patients with early stages of PD have difficulty processing negative but not positive emotions.49 More research is needed on the use of NAC and other natural interventions in the adjunctive care of patients with neurodegenerative conditions. Without a cure for some of these conditions, adding quality of life for these patients follows the principle of “Treat the whole person.”50 The integrative practitioner understands well the interrelationship of the body, the environment, and the patient’s reaction to their situation on total health. It is only through this whole-person-based approach that we can seek to restore balance and health with our patients.
The low cost of supplemental NAC, added to the evidence that it crosses the BBB, makes this supplement a valuable therapeutic intervention for psychiatric conditions such as depression, addiction, bipolar disease, and schizophrenia. This is of particular importance because NAC has been shown to increase levels of glutathione in the brain. Oxidative stress can play a role in psychological conditions, and reduced levels of brain glutathione have been found in patients suffering from psychiatric conditions. This is important because GSH is 1 of the main antioxidants in the brain.51 Bipolar disease has been associated with reduced levels of brain GSH.52 As mentioned in the previous section, NAC has been shown to have positive effects on the dopaminergic system through the enhancement of the DaT system. This mechanism also plays a role in the treatment of obsessive-compulsive disorder and addiction.53 Dopamine 2 (D2) receptors are reduced in individuals who take addictive drugs, such as opioids or nicotine. These receptors play a critical role in transporting dopamine in areas of the brain, such as in the striatum.
It may be that the benefits of NAC in psychiatric disorders are related to what is referred to as glutamate homeostasis modulation54—in other words, the body’s attempt to regulate the amount of glutamate release in the brain. Too much glutamate and too little have negative consequences. As in neurodegenerative conditions, excess glutamate is associated with excitotoxicity and dysfunction in release of calcium (Ca2+), which in turn increases oxidative stress and even leads to cell death.55 Research related to Huntington disease (HD) suggests that reduced levels of glutamate are associated with symptoms of depression and with reduced activity in glutamate transporter-1 (GLT-1) and system Xc- or (xCT). These 2 transporter systems are responsible for establishing a homeostasis of glutamate. Increased levels of glutamate, specifically in the hippocampus region of patients with HD, can improve symptoms of depression. In animal studies, injection of NAC has been shown to enhance the transporter systems GLT-1 and xCT and increase levels of glutamate.56
Depression and Bipolar Disorder
Studies involving the use of NAC in depression are limited, and more research needs to be done in this area. In a systematic review involving 574 individuals diagnosed with depression, the use of NAC had a significant positive effect on depression scales as well as global functionality (P<0.001).57 The dosage used in these studies is consistent with typical doses found in other studies. The dosage ranged from 2 to 3 g daily in 2 divided doses.
There was an interesting study lasting 32 weeks and involving the use of 2 g per day of NAC as an adjunct to pharmaceutical medications used for maintenance of bipolar disorder. During the first 8-week phase of “open label” use of NAC, there was some improvement in symptoms; however, during the final 24 weeks during the randomized, double-blinded phase of the study, no significant difference was found in the NAC and placebo groups (P=0.451).58
Schizophrenia is a very complex condition, with genetic and environmental factors associated with the development of this disorder.59 An oversimplified way to think about schizophrenia is to approach it from the aspect of the “positive” and “negative” symptoms represented in individuals afflicted with this medical problem. The pharmaceutical treatment for schizophrenia centers around the use of antipsychotic medications that inhibit dopamine.60 These antipsychotic medications, such as trifluoperazine and risperidone, focus on the reduction of “positive” symptoms such as hallucinations and delusions.61 Unfortunately, these types of medications carry side effects similar to the symptoms of patients who suffer from Parkinson disease such as tremors, rigidity, shuffling gait, and reduced facial expressions.
In a study using NAC in conjunction with risperidone (dopamine-2 and serotonin-2 receptor antagonists) in patients with schizophrenia, there was improvement of total and negative symptoms compared to the placebo group. The study used 1,000 mg of NAC for the first week and 2,000 mg for the last 7 weeks of the trial (P<0.001).62
Characteristics, as demonstrated by electroencephalography (EEG), have been proposed as a biomarker for schizophrenia. One of these is mismatch negativity (MMN) deficits in schizophrenia, first reported in 1991.63 The EEG can register event-related potentials (ERP) in response to sensory and cognitive stimuli. Improvement in MMN is associated with improved brain functioning. In a study using 2 grams of NAC per day for 60 days, there was clinically significant improvement in MMN generation in schizophrenic patients compared with placebo (P=0.025).64
As we move into the last topic to be discussed in this review article, it is interesting that individuals with schizophrenia have a higher rate of addiction, and epidemiological studies have reported up to 50% of this population suffer from drug and alcohol addiction.65 As mentioned previously in this article, oxidative stress and deficient antioxidant status are associated with psychiatric conditions, including obsessive-compulsive disorder and addiction. Addiction represents a serious medical challenge, and a particularly difficult challenge for primary care physicians. When addiction treatment is discussed, it is important to consider using interventions to counteract withdrawal symptoms, including cravings and urges, as well as detoxification methods and prevention of relapse.
In a pilot study involving a group of veterans, NAC was used at a dose of 1,200 mg twice daily for 8 weeks and compared to placebo participants with substance abuse disorder (SUD) and post-traumatic stress disorder (PTSD). Both groups participated in weekly cognitive therapy during the study and were screened for use of drugs and alcohol. Methods of evaluation used in the study included the Clinician Administered PTSD Scale (CAPS), PTSD Checklist-Military, the craving scale (Visual Analogue Scale), and the Beck Depression Inventory-II (DBI-II). Those in the NAC group (n=18) showed significant reduction in number and frequency of cravings (P<0.05) and, in addition, a reduced DBI-II score (P<0.05).66
Administration, Side Effects, and Toxicity of NAC
Acetylcysteine is rapidly absorbed, with peak plasma concentrations reached approximately 1 to 2 hours after oral administration67; however, oral bioavailability is very low (approximately 4% to 9 %).68 Typical dose in the research discussed in this article ranged from 1,200 mg to 2,400 mg. Due to the short half-life, it is recommended to divide dosing to twice daily.
Most of the side effects related to the oral intake of NAC are associated with gastrointestinal symptoms, including increased gas, diarrhea, and nausea. There have been reports of severe anaphylactoid reactions occurring with the use of intravenous NAC; however, the effects subsided after discontinuation of the infusions. In a study of the use of NAC on human immunodeficiency virus (HIV) infections, oral doses up to 8,000 mg demonstrated no side effects.69 There are reports in the research showing that NAC may have anticoagulant properties. These findings were associated with infusions of NAC at a dose of 100 mg/kg (bolus) followed by infusion of 20 mg/kg/hr for 4 hours. This study was associated with patients undergoing cardiac surgery, and all the individuals had renal insufficiency.70,71
The low cost of supplemental NAC, added to the evidence that it crosses the BBB, makes this supplement a valuable therapeutic intervention for psychiatric conditions such as depression, addiction, bipolar disease, and schizophrenia. NAC appears to be an excellent choice for acute upper respiratory and sinus problems, and the mucolytic properties of NAC make it an important adjunct for treatment. The use of NAC as a direct and indirect antioxidant is well-established in clinical trials. When the desired outcome is to increase glutathione in the brain, NAC has more research than oral glutathione and is much more inexpensive.
As far as using NAC for more complicated medical conditions such as Parkinson disease, bipolar disorder, and schizophrenia, it is essential to regard this supplement as an important adjunct to any medical intervention when using medications as a first-line therapy. Using NAC to enhance quality of life or make even slight improvements in physical symptoms (eg, fatigue, muscle weakness, movement dysfunction, tremors) in patients with neuromuscular diseases is welcomed by patients and their families.
As evidence-based research into the clinical uses of NAC in practice continues and NAC remains available at a low cost, integrative practitioners need to consider this supplement as an essential option in day-to-day clinical practice.