INL Education - N-Acetyl Cysteine

The Versatility of N-Acetyl Cysteine

Pubmed published their first article on “reactive oxygen species” in 1945. Since then, using the same keyword or its abbreviation ROS there have been more than 117,000 articles written in English, with around 12,000 review articles!

Most of these studies have linked ROS to the progression or aetiology of diseases such as insulin resistance, cancer, diabetes, coronary artery disease and aging. (1)

ROS, a natural by-product of normal metabolism by the mitochondria, have long been implicated in the induction of apoptosis. The most abundant non protein thiol, glutathione (GSH) plays an important role in the regulation of apoptosis via its role in scavenging ROS.

N-Acetyl Cysteine (NAC), with its cysteine content, is the rate limiting amino acid in glutathione production. Deficiencies of cysteine can cause liver and kidney GGT enzyme upregulation in an attempt to recycle more of the acid for glutathione production.

Originally highlighted for its antioxidant properties and action on increasing intracellular GSH levels, as research has unfolded, NAC has become a versatile intervention that covers inflammation, mental health, detoxification and the management of respiratory infections.

Whilst a lot of NAC’s success has been related to its antioxidant and mucolytic qualities in this article, we will be exploring some of the wider uses of its application.

NAC and its role in heavy metal removal and protection from toxin-induced damage

NAC demonstrated reduced blood lead levels in workers exposed to lead with doses between 400mg and 800mg. In the group who supplemented with NAC, lower levels of oxidative stress intensity were also seen. (2)

Further to this, NAC has been found to promote methylmercury urinary excretion along with animal studies showing a protective effect against the complications of methylmercury exposure.

In one trial specifically, rats purposely exposed to methylmercury experienced a pronounced decrease in DNA synthesis of brain neurons and neuron precursors, lower hippocampal synthesis along with an increase in immunoreactive cells.

Treatment with NAC was stated to completely attenuate the toxicity effects of mercury, seeing increases in DNA synthesis and hippocampal size together with a reduction of the immunoreactive cells. (3)

NAC and its varied role in the management of mental health conditions

Once again, the focus on NAC within the mental health space is for its antioxidant role, which in this case, has been shown to have a dramatic effect on the reduction of neuroinflammation and the buffering of local mitochondrial function. Both of which are well-known contributing factors in many mood disorders and neurodegenerative disorders.

Disordered glutamatergic neurotransmission is understood to be one of the origin factors behind the development of addiction. NAC acts to harmonise glutamatergic neurotransmission adding to its potential and application within the mental health sphere.

In fact, NAC has been successfully trialed for delivering benefits in the following conditions:

  • Pathological gambling (average dose 1500mg/day for 8 weeks) (4)
  • Pathological gambling with nicotine dependence (3000mg/day for 12 weeks) (5)
  • Cannabis dependence in adolescents (1200mg/day for 8 weeks) (6)
  • Cocaine desire in cocaine-dependent patients (7)
  • Obsessive Compulsive disorder (2400mg-3000mg/day for 12 weeks) (8)
  • Trichotillomania (hair pulling) (1200mg-2400mg/day for 9 weeks) (9)

In a more specific application, the use of NAC as an adjunctive measure with mood stabilisers was assessed in bipolar patients in a randomized controlled trial. The group administered the NAC simultaneously at a dose of 2000mg/day demonstrated a significant improvement in depression, mania, quality of life and social and occupational functioning when compared with the placebo group. (10)

NAC and action on inflammatory mediators

Inflammatory compounds that are often induced by oxidative stress have been shown to be well-managed by NAC’s antioxidant activity. (11)

A variety of clinical trials have investigated NAC’s anti-inflammatory action, most notably its ability to reduce interleukin-6 (IL-6), IL-8 and C-reactive protein (CRP) in a selection of different settings including patients with COPD and renal disease. (12) (13)

NAC and amelioration of complications of obesity and metabolic syndrome

Uncontrolled adiposity in obesity is understood to drive the onset of dysregulations with the metabolic pathways, mostly involving oxidative stress and chronic immune activation. This prolonged inflammation and oxidative stress have been linked to the development of metabolic syndrome and its often-associated coronary artery disease outcomes.

Literature investigating NAC’s role in attenuating these complications have found that NAC could inhibit lipid accumulation by targeting peroxisome proliferator-activated receptor gamma (PPARy) as well as improving insulin sensitivity through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. (14)

Together with these significant actions, research into the role of NAC and its attenuation of the oxidative damage caused by small dense LDLs is beginning to surface. In a in vivo study NAC was shown to reduce atherosclerotic plaque formation in hyperlipidemic mice, suggesting its role not only in coronary artery disease but in the concomitant fatty liver presentations seen in metabolic syndrome. (15)

Interestingly in a study released comparing NAC and Metformin use on the metabolic parameters of PCOS, NAC was found to be equally efficacious as metformin in improving indicators of insulin resistance and metabolic syndrome with minimal occasional side effects ensuring a better compliance for a long-term therapy. (16)

NAC and improvement of fertility outcomes

A developing body of research is pointing to the negative effects of oxidation on both the male and female reproductive systems. (17)

In women, NAC was demonstrated to improve pregnancy rates and live births in women with recurrent unexplained pregnancy loss along with improved ovulation and pregnancy rates in women with PCOS. (18)

NAC and the attenuation of fatty liver

Nonalcoholic fatty liver disease (NAFLD) has surfaced as the most prevalent chronic liver disease worldwide and is heavily associated with the presence of oxidative stress. Disturbances in the metabolism of lipids leads to hepatic accumulation, which affects different ROS generators, including mitochondria, endoplasmic reticulum, and NADPH oxidase. (19)

NAC and its role in the protection of the liver from injury, especially in the case of NAFLD has been well-researched. One particular study comparing NAC with Vitamin C saw the NAC group result in a significant decrease in serum alanine aminotransferase (ALT) after 3 months of treatment along with a marked decrease in the span of the spleen and increases in general liver function. (20)

The collection of evidence pointing to the multiple different ways that NAC can assist in patient outcomes is not only a testament to its versatility but also a testament to the importance of maintaining oxidative and ROS processes within all the different systems of the body.

N-Acetyl Cysteine (NAC) is the main amino acid required to create glutathione, one of the most important antioxidants in the body.

Originally highlighted for its antioxidant properties, NAC has become a versatile intervention that covers inflammation, mental health, detoxification, fertility, metabolic syndrome and obesity amongst others (See Product)!