NAC

Synonym(s): ACC, acetylcysteine, N-acetyl-L-cysteine

Nutrient group: Amino acids

Sources and physiological effects

Dietary sources
Acetylcysteine (NAC) is the N-acetyl derivative of the naturally occurring amino acid cysteine. NAC is only available in the diet in the form of supplements.
Physiological effects
Antioxidant	NAC is deacetylated to L-cysteine after oral administration and further metabolized to glutathione (GSH). Glutathione is one of the most potent antioxidants in the body.

Recommended intake

Nutrient safety
Preclinical studies	The active ingredient acetylcysteine has proven to be non-toxic in preclinical studies.
Clinical studies	A clinical study in humans showed that a daily dose of 11.6 g N-acetylcysteine orally over a period of three months did not lead to serious side effects.	<

Detailed information

Positive effect in tichotrillomania
L-cysteine – an integral component of L-glutathione
L-glutathione (GSH) is quantitatively the most important intracellular sulfur compound. Endogenous GSH formation depends largely on the availability of the non-essential amino acid L-cysteine (1). L-cysteine is a sulfur-containing amino acid which can be synthesized in the body from L-methionine and performs an important function in the formation and stabilization of proteins, as an antioxidant and in some enzyme systems (e.g. GSH peroxidase) (1) (2). As cysteine rapidly oxidizes, the acetylated and chemically more stable cysteine form, N-acetylcysteine (NAC), is generally used in therapeutic applications. After oral administration NAC is deacetylated to L-cyst(e)in and further metabolized to glutathione (GSH) (2). L-glutathione and GSH-dependent enzyme systems (GSH peroxidase, transferase, GSSG reductase) are of fundamental importance for to intracellular redox balance. Glutathione protects nucleic acids, cells, lipids and proteins from oxidative damage and also has detoxifying and immunological properties (1).
Adjuvant use in cardiovascular diseases
Increased lipoprotein(a) levels (>20 mg/dl) are now considered an independent risk factor for cardiovascular diseases. Human studies document the positive influence of NAC on elevated lipoprotein(a) levels. An 8-week administration of 2000 to 4000 mg/d NAC led to a dramatic reduction in lipoprotein(a) levels in patients by almost 70% (2). Lipoprotein(a) enhances the formation of foam cells, which are considered to be an early marker of arteriosclerosis (3). A recent study showed that NAC suppresses the formation of foam cells in oxidized LDL by downregulating the expression of a specific gene cluster and thus counteracts the development of arteriosclerosis (4). The level of HDL cholesterin is also optimized by NAC. In patients wiht hyperlipidemia, 1200 - 3600 mg NAC/d led to a significant dose-dependent increase in HDL cholesterol. Studies suggest that NAC could also play a role in the treatment of homocysteinemia. In some studies, the plasma homocysteine level was reduced by the administration of NAC. The suspected mechanism is the formation of NAC-homocysteine complexes and subsequently an increase in renal homocysteine clearance (2).
Effects on lung diseases
The anti-inflammatory effect of NAC and its effects as an antioxidant containing SH are well described (5) (6). Acute and chronic inflammatory lung diseases are characterized by an increased incidence of inflammatory cells such as neutrophilic granulocytes and macrophages in the lungs. The oxidative stress in the tissue increases and with it the GSH consumption, which can lead to an imbalance between oxidants and antioxidants (2).Chronic obstructive pulmonary disease can be particularly exacerbated in the cold season, characterized by increased coughing, respiratory problems and sputum. An imbalance in the oxidative-antioxidative balance is blamed for the exacerbations. A meta-analysis with double-blind and placebo-controlled long-term studies (≥ 5 months) confirmed the oral effectiveness of NAC in reducing acute exacerbations in COPD. The number of acute exacerbations decreased by 23 %. Antibiotic consumption and sick leave were also reduced. (10) (7).
Cysteine deficiency leads to a decrease in immune performance
Cysteine and glutathione are important for maintaining immune competence and fot the regulation of the nitrogen balance (1). Comparative studies by the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have found common immunological and biochemical differences in cyst(e)in, glutamine and GSH metabolism in patients with bronchial carcinoma, HIV infection and sepsis. The disorder, known as “CG deficiency syndrome“, is characterized by a significant decrease in cyst(e)in and glutamine plasma levels, a marked reduction in NK activity, excessive urea production and a progressive reduction in immunocompetent muscle mass. The plasma level of glutamate, on the other hand, increases, which leads to a competitive inhibition of cysteine uptake by macrophages and NK cells (2). When using NAC as a mucolytic (approx. 600 mg / d), sufficient fluid intake of approx. 2 l/d should be ensured (1).
Detoxification and Liver Protection
Cysteine and glutathione are significantly involved in the Phase II detoxification of toxic metabolites and in the detoxification of aflatoxins, xenobiotics and heavy metals within the scope of hepatocellular biotransformation. NAC can increase endogenous GSH biosynthesis and accelerate liver cell regeneration and detoxification (2) (8). NAC has been particularly successful in the treatment of paracetamol poisoning. When high doses of paracetamol are consumed, the hepatocellular GSH stores are exhausted and cannot be replenished quickly enough. This can lead to hepatogenic damage or even fatal liver cell necrosis. The administration of NAC as a "glutathione prodrug" replenishes the intracellular glutathione stores and counteracts liver cell necrosis (2). NAC also functions as an effective liver protector when used together with anti-tuberculosis drugs (isoniazid, rifampicin and pyrazinamide) (9).
Glutamate signaling plays a central role in various neuropsychiatric diseases. Thus, a therapeutic effect of NAC is presumed, as it influences glutamatergic neurotransmission. By regulating the glutamate level and on the other hand by modulating the cystine/glutamate antiporter. Studies in recent years have shown a possible positive effect of N-acetylcysteine in psychosomatic diseases. A smaller randomized double-blind, placebo-controlled study in 50 patients (average age 34.3 years) with trichotillomania treated for 12 weeks with either placebo or N-acetylcysteine showed a significant improvement in symptoms. After just 9 weeks, 56% patients treated with NAC indicated that the disease had improved well or very well. In the placebo group there was only a 16% improvement. The Massachusetts General Hospital Hair Pulling Scale also showed a significant improvement under therapy. The positive effect was due to reduced transport of glutamate into the synaptic cleft through NAC administration (11).
NAC facilitates nicotine withdrawal
Tobacco is one of the quickest substances to causes addiction. Nicotine, in combination with other substances, attacks the presynaptic and postsynaptic acetylcholine receptors (“nicotine receptors“) and leads to the release of neurotransmitters such as dopamine, serotonin, noradrenaline and endorphins. N-acetylcysteine could facilitate nicotine withdrawal by reducing smokers craving for tobacco and the rewards associated with cigarettes (12). A double-blind pilot study, in which participants received 3000 mg NAC daily or a placebo, showed a significant reduction in daily cigarette consumption. In the verum group 47.1% stoppe d smokingn after 12 weeks, while only 21.4% stopped in the placebo group (13).

Deficiency symptoms

Impact on	Symptoms
Antioxidant status	Decreased antioxidative capacity Increased susceptibility to free radical associated diseases

Indications

Dosage	Indication	Dosage
Physiological effects at a low intake	Complementary therapy for hyperhomocysteinemia and hyperlipidemia	1500 - 2500 mg/d
	For dietary treatment with immune of deficiencies	1500 - 2500 mg/d
	For increasing the body's own glutathione synthesis in cases of low glutathione status determined by diagnostic means	1500 - 2500 mg/d
	To intensify cellular detoxification	1500 - 2500 mg/d
	As a mucolytic	1500 - 2500 mg/d

Administration

General mode of administration
When	NAC should be taken between meals. Hint: When taking a permanent therapeutic dose of NAC, the additional intake of double to triple the amount of vitamin C is recommended to prevent the formation of cystine stones (vitamin C inhibits the conversion of cysteine to cystine). If NAC and antitussives are taken at the same time, a limited cough reflex can cause dangerous congestion of secretion. When using NAC in for treatment, care must be taken to ensure adequate fluid intake (approx. 2 l/d). Oral antibiotic use should be delayed as NAC can lead to inactivation (take at least 2 hours apart).

Side effects
NAC can reduce platelet aggregation.
Contraindications
Simultaneous administration of antitussives, hypercystinuria, cystine stones, renal insufficiency

Interactions

Drug interactions
Antibiotics (penicillins, tetracyclines, cefalosporins)	Antibiotics may be inactivated by N-acetylcysteine if taken orally at the same time Exception: Doxycyclin
Antihypertensive drugs (nitrates)	In combinationcan increased efficacy of glycerol trinitrate due to increased vasodilatory and platelet aggregation inhibiting effects
Antitussiva (codeine derivatives)	Danger of congestion when used in combination
Analgetics (paracetamol)	Antidote, reduces liver toxicity of paracetamol
Nutrient interactions
Trace elements	Can form complexes with zinc

Description and related substances

Description

Synthetic derivative of the amino acid L-cysteine

References

1) Gröber, U. Mikronährstoffe. Metabolic Tuning – Prävention – Therapie. Wissenschaftliche Verlagsgesellschaft. 2011.
2) Gröber, U. Orthomolekulare Medizin. Wissenschaftliche Verlagsgesellschaft. 2008.
3) Gschwandt, P., Parhofer, K. Handbuch der Fettstoffwechselstörungen: Dyslipoproteinämien und Atherosklerose: Diagnostik, Therapie und Prävention. Schattauer Verlag. 2006.
4) Sung, H. J. et al. 2011. N-acetyl cysteine suppresses the foam cell formation that is induced by oxidized low density lipoprotein via regulation of gene expression. Mol Biol Rep.
5) Kerksick, C., Willoughby, D. 2005. The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr. 2:38-44.
6) Gillissen, A. 2011. Anti-inflammatory efficacy of N-acetylcysteine and therapeutic usefulness. Pneumologie.
7) Sadowska, A. M. et al. 2007. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD. Discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther. 20(1):9-22.
8) Breitbart, R. 2011. Intraperitoneal N-acetylcysteine for acute iron intoxication in rats. Drug Chem Toxicol.
9) Baniasadi, S. 2010. Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity. Eur J Gastroenterol Hepatol. 22(10):1235-8.
10) Sanguinetti, C. M. 2015. N-acetylcysteine in COPD: Why, how, and when? Multidiscip Respir Med. 11(1).
11) Grant, J. E. et al. 2009. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 66(7):756-763.
12) Knackstedt, L. A. et al. 2009. The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry. 65(10):841-5.
13) Prado, E. et al. 2015. N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study. Redox Rep. 20(5):215-22.

References Interactions
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.
Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.