N-acetyl-cysteine monograph

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Background

N-acetyl-cysteine, commonly abbreviated to NAC, is a precursor of the amino acid L-cysteine and the antioxidant glutathione (GSH). One of NAC’s most important roles involves maintaining cellular GSH levels and minimising the damaging effect of reactive oxygen species (ROS).[1] As oxidative stress is involved in the pathophysiology of numerous disease states, NAC supplementation may play a key role in both the prevention and treatment of these conditions.

NAC has a history of use as a mucolytic agent in chronic respiratory diseases, and also as an antidote to acute paracetamol-induced hepatotoxicity.[2]

Key benefits[3-5]

  • Anti-inflammatory
  • Antioxidant
  • Chemoprotective 
  • Hepatoprotective 
  • Improves parameters of both male and female fertility
  • Lowers homocysteine levels
  • Modulates the glutamatergic system
  • Mucolytic 
  • Precursor to L-cysteine
  • Promotes detoxification
  • Promotes glutathione synthesis

Clinical applications[4-10]

  • Cancer
  • Cardiovascular diseases, e.g. angina, hyperhomocysteinaemia, hyperlipidaemia, myocardial infarction 
  • Chronic fatigue syndrome 
  • Compulsive and impulsive behaviours, e.g. nail biting, skin picking, trichotillomania (hair pulling), gambling 
  • Conditions associated with increased oxidative stress, e.g. infertility, heart disease, cancer, lung diseases, cataracts, diabetes, Parkinson’s disease
  • Drug addictions, e.g. cocaine, marijuana 
  • Exercise and sports performance
  • Female reproductive health, e.g. polycystic ovarian syndrome (PCOS), miscarriage prevention, infertility
  • Fibromyalgia 
  • Heavy metal detoxification
  • Helicobacter pylori infection (to increase the effectiveness of triple therapy)
  • HIV infection 
  • Inflammatory diseases
  • Influenza
  • Liver detoxification
  • Male reproductive health
  • Neurological and neurobehavioural disorders, e.g. schizophrenia, bipolar disorder, depression, autism, attention deficit hyperactivity disorder (ADHD)
  • Paracetamol poisoning and associated hepatotoxicity 
  • Respiratory diseases, e.g. chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis 

Mechanisms of action

NAC is a thiol, a sulfhydryl containing compound with widespread activity in the body and diverse clinical applications. The sulfhydryl group of NAC provides important metabolic activity including stimulating GSH synthesis, enhancing glutathione-S-transferase activity, promoting detoxification and acting directly on free radicals. The acetyl-substituted amino group is also key to NAC’s clinical effectiveness, reducing its susceptibility to oxidation and enhancing its overall absorption.[3]

Glutathione synthesis

Perhaps NAC’s most documented and important action is its ability to enhance GSH synthesis. GSH is a ubiquitous antioxidant, synthesised endogenously in the majority of the body’s cells and regarded as one of the most important antioxidants. GSH maintains the redox state of the cell and plays a pivotal protective role against the damaging effects of oxidative stress.[1] Reactive oxygen species reduce both intracellular and extracellular glutathione and may influence or initiate disease progression.  

GSH is synthesised from the amino acids glutamate, glycine and cysteine. Its synthesis is regulated by gamma-glutamylcysteine synthetase activity, cysteine availability and glutathione feedback inhibition.[1,11] Cysteine is the rate limiting amino acid in glutathione synthesis, with reduced cysteine availability limiting glutathione synthesis during times of increased oxidative stress.

NAC crosses the cell membrane where it is converted to cysteine then GSH.[4]  Supplementation with NAC may replenish GSH levels, increasing the body’s antioxidant defences. This occurs most effectively when GSH demand is increased during times of heightened oxidative stress or during certain disease processes.[3]

Antioxidant

In addition to stimulating GSH synthesis, NAC has shown direct antioxidant activity against ROS.[12] The direct and indirect antioxidant activity of NAC may account for its ability to prevent adverse effects due to toxic chemicals and drug reactions.[3]

Mucolytic

NAC has been employed as a successful mucolytic agent for a range of respiratory conditions including COPD. The sulfhydryl group of NAC provides mucolytic activity by hydrolysing the mucoprotein disulfide bonds, causing the mucus to split into smaller, less viscose pieces.[13] NAC may also clear mucus from respiratory airways by stimulating ciliary action and the gastro-pulmonary vagal reflex, resulting in expectorant activity.[2]

In addition, NAC has a mucoregulatory effect, whereby it inhibits mucus secretory cell hyperplasia and enhances expression of the MUC5AC gene.[14]

Anti-inflammatory

Research has shown that NAC down-regulates the production of pro-inflammatory mediators and transcription factors including tumour necrosis factor-alpha (TNF-alpha), nuclear factor κappaB (NFkB) and interleukins.[4] These compounds are often induced by oxidative stress, and support the hypothesis that NAC’s anti-inflammatory properties are due to its antioxidant activity.[15]

NAC’s anti-inflammatory effect has been demonstrated in a number of clinical trials, were it has shown to reduce interleukin-6 (IL-6), IL-8 and C-reactive protein (CRP) in a variety of patients including those with COPD and renal disease.[16,17]

Detoxification

One of the earliest and most established uses of NAC is in the treatment of paracetamol poisoning. When ingested in excess, paracetamol forms a toxic metabolite that diminishes GSH levels, causing hepatic injury and even death. Oral or intravenous administration of NAC restores hepatic glutathione levels and prevents hepatic injury.[15]

NAC has also been used for heavy metal poisoning including gold, silver, copper, mercury, lead and arsenic.[2] NAC may form complexes with these metals, e.g. methylmercury (MeHg)-NAC complex, which are then actively transported across renal tubule cells.[15]

Addictions and compulsive behaviours

Growing evidence supports the use of NAC in the treatment of addictions and compulsive behaviours. Changes in glutamatergic neurotransmission have recently been implicated in the pathophysiology of addiction, with glutamate dysregulation associated with drug and pleasure-seeking behaviour.[6

Animal studies demonstrate reduced basal glutamate levels in rodents chronically treated with cocaine which occurs via the down-regulation of the cystine-glutamate exchanger in the nucleus accumbens.[6]

Basal extracellular glutamate levels are maintained through the exchange of extracellular cysteine for intracellular glutamate, which occurs via the cystine–glutamate exchange system. NAC administration has been shown to up-regulate this exchange, increasing extracellular levels of glutamate and stimulating glutamate receptors to regulate dopamine and glutamate release.[15] This reduces compulsive and drug-seeking behaviours.[4,18]

Fertility

Oxidative stress may negatively impact both reproductive health in both male and females.[19,20] A growing body of evidence supports the use of NAC in enhancing both male and female fertility.

In men, NAC supplementation improves semen parameters including volume, motility and viscosity, while improving serum antioxidant capacity and reducing oxidative stress.[21,22] In women, NAC has been shown to improve pregnancy rates and live births in women with recurrent unexplained pregnancy loss, and improve ovulation and pregnancy rates in women with PCOS.[23,24]

Clinical studies

NAC improves ovulation and pregnancy rates in PCOS patients

Background: To review the safety and efficacy of NAC in women with PCOS.

Subjects/Method: Literature review of 8 studies involving 910 women with PCOS.

Results: Women receiving NAC had higher odds of ovulation, becoming pregnant and having a live birth, compared to placebo. The reviewers concluded that NAC supplementation significantly improves pregnancy and ovulation rates as compared to placebo.  

Thakker D, Raval A, Patel I, et al. N-acetylcysteine for polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Obstet Gynecol Int 2015;2015:817849.

NAC reduces cannabis use in cannabis-dependent adolescents

Background: Preclinical research suggests NAC may reduce substance dependence via glutamate modulation in the nucleus accumbens.

Subjects/Method: Randomised double-blind, placebo-controlled trial involving 116 cannabis-dependent adolescents. 

Intervention: Patients received either 1200mg NAC or placebo twice daily for 8 weeks in addition to a contingency management intervention and brief weekly cessation counselling.

Results: Patients in the NAC group were more likely to abstain from cannabis, which was determined through a higher rate of negative urine cannabinoid tests during the treatment period. The results support the use of NAC to complement psychosocial treatment for cannabis dependence in adolescents.

Gray KM, Carpenter MJ, Baker NL, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry 2012;169(8):805-812. 

NAC stimulates GSH synthesis in workers exposed to lead

Background: To investigate the efficacy of NAC in restoring erythrocyte GSH content in workers exposed to lead and its effect on oxidative stress intensity.

Subjects/Method: Randomised, controlled trial involving 171 healthy males with occupational lead exposure. 

Intervention: Patients were randomised into 4 groups: Group 1 acted as the control group and did not receive any antioxidants, drugs, vitamins or dietary supplements; Group 2 received 200mg NAC per day; Group 3 received 200mg NAC twice a day; Group four received 400mg NAC twice a day. All patients continued to work during the 12 week treatment period.

Results: All three NAC groups experienced significant decreases in blood lead levels compared to baseline readings. Erythrocyte GSH concentrations were significantly elevated in workers receiving 400mg and 800mg of NAC compared to those at baseline. Lipofuscin (LPS) levels (a measure of oxidative stress intensity) decreased significantly in all three NAC groups, with 400mg and 800mg showing the most significant changes. The researchers concluded that NAC supplementation decreases oxidative stress in workers exposed to lead by stimulating glutathione synthesis.

Kasperczyk S, Dobrakowski M, Kasperczyk A, et al. The administration of N-acetylcysteine reduces oxidative stress and regulates glutathione metabolism in the blood cells of workers exposed to lead. Clin Toxicol (Phila) 2013;51(6):480-486.

Dosage range according to clinical studies

Cautions and contraindications

  • At dosages of 1200mg twice day, NAC is well tolerated with very few side effects. 
  • Safety in pregnancy and breastfeeding has not been established, although no adverse effects to the foetus or mother have been found according to current research.[4]
  • Very high doses of NAC (as used in paracetamol poisoning) may result in side effects including gastrointestinal disturbances, headaches, tinnitus, rashes, chills and fever, although their occurrence is rare.[3,9]
  • Contraindicated in acetyl cysteine allergy.[4]

References

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  22. Safarinejad MR, Safarinejad S. Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. J Urol 2009;181(2):741-751. [Abstract]
     
  23. Amin AF, Shaaban OM, Bediawy MA. N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss. Reprod Biomed Online 2008;17(5):722-726. [Abstract]
     
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Alinda_Boyd's picture
Alinda Boyd
Alinda holds a Bachelor of Naturopathy and has over a decade of experience in the natural medicine industry, having worked both in Australia and overseas. Alinda has a special interest in gastrointestinal and children’s health, as well as a passion for writing. Alinda is a regular contributing writer for magazines, websites and leading Australian nutraceutical brands covering a diverse range of health topics.