N-acetyl-l-cysteine (NAC) is a derivative of the amino acid L-cysteine and is a by-product of glutathione. N-acetyl-l-cysteine is a nutritional supplement that has many uses in medicine. It is reported that it can counteract acetaminophen (or paracetamol) and carbon monoxide poisoning. This compound is also sold as a dietary supplement which is claimed to exert antioxidant and liver protecting effects. It is not considered an essential amino acid in adults as it can be synthesized from methionine (an essential amino acid).
Typical recommended dosage by manufacturers ranges from 500 to 600 mg taken 1 to 3 times daily. In studies doses as high as 2.400 g are used.
For antioxidant protection and general health take 500 mg daily to start; under doctor’s supervision dose may be increased.
NAC is not found in food, however, cysteine is found in most high-protein foods like :
- Cottage cheese
- Sausage meat
- Lunch meats
- Wheat germ
- Oat flakes
Reducing Exercise-Induced Stress Effect and Fatigue
It has been shown that intense exercise increases oxidative stress and free radical production inside our cells . N-acetyl-l-cysteine acts to augment the glutathione reserves in the body, which is an important antioxidant . Glutathione is responsible for maintaining the oxidative balance in the cell . Oral supplementation of glutathione, as well as L-cysteine, does not adequately restore glutathione levels . Oral N-acetyl-l-cysteine administration, on the other hand, results in increased plasma cysteine levels which leads to increase in plasma glutathione . Studies are exploring if N-acetyl-l-cysteine supplementation can actually improve performance due to its ability to provide a more favourable cellular environment to achieve higher levels of performance. L-citrulline and glutathione are known to further reinforce their effects.
Exercise causes cellular loss of potassium and gain of sodium . This effect can markedly impair muscle force development and is in part countered by sodium-potassium pump . Reactive oxygen species have been suggested to contribute to muscle fatigue in part via depressing maximal sodium-potassium pump activity . McKenna and associates  reported that intravenous infusion of antioxidant N-acetyl-l-cysteine halved the decline in skeletal muscle maximal sodium-potassium pump activity and improved plasma potassium regulation.
Intravenous infusion of N-acetyl-l-cysteine (150 mg/kg) has also been reported to increased force output by about 15% . Medved et al.  reported that infusion of NAC increased the time to fatigue by 26,3% at 92% peak VO2 compared to placebo group. A follow-up study by same researchers failed to alter time to fatigue at 130% peak oxygen consumption . However, NAC infusion did alter blood redox status during intense exercise . These studies suggest that oxidative stress plays a role in muscle fatigue.
Early pharmacokinetic studies report low oral bioavailability of N-acetyl-l-cysteine (only about 6 – 10%) . However, these studies did not account for the deacetylation of NAC to form cysteine during normal absorptive processes. Later studies suggest NAC has 100% bioavailability relative to cysteine when ingested orally . Therefore, benefits of oral NAC likely result from its ability to deliver cysteine safely and effectively.
It should be noted that there is much controversy around the concept of antioxidants due to reported inconsistencies by clinical trials.
Liver and Kidney Protection
Overdose with analgesic acetaminophen (paracetamol) results in hepatic necrosis due to the formation of highly toxic byproduct (N-acetyl-p-benzoquinone imine – NAPQI) which is metabolised from acetaminophen via cytochrome P-450 pathway . Glutathione detoxifies NAPQI but under overdose conditions, glutathione stores are depleted . As mentioned before, N-acetylcysteine enhances glutathione stores and thus acts as an antidote to acetaminophen poisoning . Alcohol abusers may be at higher risk of liver damage due to acetaminophen overdose as it has been shown that alcoholics are glutathione deficient .
N-acetyl-l-cysteine has also been shown to decrease plasma homocysteine levels via more efficient renal clearance of thiols . There is also some evidence that N-acetyl-l-cysteine may prevent alcoholic liver damage [16,17] and may be beneficial in the treatment of nonalcoholic fatty liver disease .
Intravenous infusion and oral supplementation of N-acetyl-l-cysteine is used to prevent kidney damage [19-22]. The mechanism behind N-acetyl-l-cysteines amelioration of renal function failure is not known but is suggested that it is due to its general properties as an antioxidant .
Due to its effectiveness to protect and restore liver function NAC is often used by heavy steroid users in post-cycle therapy (along with other supplements).
Treating Addictions and Some Psychiatric Conditions
N-acetyl-l-cysteine is also an emerging agent in the treatment of psychiatric disorders. After 8 week treatment with 2000 mg per day of N-acetyl-l-cysteine, mismatch negativity in schizophrenia patients was shown to improve significantly . A more recent case report has also shown that NAC supplementation exerts beneficial effects in schizophrenia patients . Notable benefits were also reported in patients with obsessive-compulsive disorder . Furthermore, large decreases in depressive symptoms were also noted in 75 patients with bipolar disorder . Therefore, NAC appears to be promising in the treatment of several psychiatric disorders.
NAC’s ability to restore extracellular glutamate is showing promise for treating addictive behaviours , such as substance abuse and gambling. In a pilot study by Grant and colleagues , 27 pathological gamblers were supplemented with 1500 mg of NAC per day. At the end of the study, 60% of participants met the criteria for response. Two small-scale studies [28,29] also showed NAC may reduce the desire for and interest in cocaine. Larger well-designed trials are required to assert NAC’s efficiency in cocaine abusers.
All this data suggests that manipulation of the glutamatergic system by NAC supplementation can target core symptoms of addictive behaviours as well as several psychiatric disorders. Besides modulating glutamate levels, NAC has as also been shown to alter dopamine release [30,31].
N-acetyl-L-cysteine Side Effects and Precautions
N-acetyl-l-cysteine is considered a safe and effective precursor to L-cysteine . However, N-acetyl-l-cysteine, though antioxidant, can act as pro-oxidant when taken in high doses (1,2 – 2,4 grams)  and under certain conditions such as severe and acute inflammation caused by eccentric exercise . Therefore, it may increase oxidative stress and cell damage above levels induced by the injury alone . When N-acetyl-l-cysteine is used for treating paracetamol overdose, doses as high as 20 grams per day are administered which were reported to induce excessive zinc urinary excretion . However, no detectable influence on the metabolism of essential trace metals was reported with doses near 600 mg per day .
Very high doses (more than 7 grams) of cysteine may be toxic to human cells and may even lead to death .
(Other common names: L-Cysteine Hydrochloride, Acetylcysteine, N-acetylcysteine, NAC)
- Kerksick, Chad, and Darryn Willoughby. “The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress.” J Int Soc Sports Nutr 2.2 (2005): 38-44.
Dean, Olivia, Frank Giorlando, and Michael Berk. “N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action.” Journal of psychiatry & neuroscience: JPN 36.2 (2011): 78.
Holdiness, Mack R. “Clinical pharmacokinetics of N-acetylcysteine.” Clinical pharmacokinetics 20.2 (1991): 123-134.
Sejersted, Ole M., and Gisela Sjøgaard. “Dynamics and consequences of potassium shifts in skeletal muscle and heart during exercise.” Physiological Reviews 80.4 (2000): 1411-1481.
Cairns, Simeon P., John A. Flatman, and Torben Clausen. “Relation between extracellular [K+], membrane potential and contraction in rat soleus muscle: modulation by the Na+-K+ pump.” Pflügers Archiv 430.6 (1995): 909-915.
McKenna, Michael J., et al. “N‐acetylcysteine attenuates the decline in muscle Na+, K+‐pump activity and delays fatigue during prolonged exercise in humans.” The Journal of physiology 576.1 (2006): 279-288.
Reid, Michael B., et al. “N-acetylcysteine inhibits muscle fatigue in humans.” Journal of Clinical Investigation 94.6 (1994): 2468.
Medved, Ivan, et al. “N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals.” Journal of Applied Physiology 97.4 (2004): 1477-1485.
Medved, Ivan, et al. “N-acetylcysteine infusion alters blood redox status but not time to fatigue during intense exercise in humans.” Journal of Applied Physiology 94.4 (2003): 1572-1582.
- Olsson, B., et al. “Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine.” European journal of clinical pharmacology 34.1 (1988): 77-82.
- Fishbane, Steven, et al. “N-acetylcysteine in the prevention of radiocontrast-induced nephropathy.” Journal of the American Society of Nephrology 15.2 (2004): 251-260.
- Alsalim, Walid, and Mohamed Fadel. “Oral methionine compared with intravenous n-acetyl cysteine for paracetamol overdose.” Emergency Medicine Journal 20.4 (2003): 366-367.
- Smilkstein, Martin J., et al. “Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose.” New England Journal of Medicine 319.24 (1988): 1557-1562.
- Yuan, Liyun, and Neil Kaplowitz. “Glutathione in liver diseases and hepatotoxicity.” Molecular aspects of medicine 30.1 (2009): 29-41.
- Ventura, Paolo, et al. “N-acetyl-cysteinereduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excertion.” Pharmacological research 40.4 (1999): 345-350.
- Ozaras, Resat, et al. “N-acetylcysteine attenuates alcohol-induced oxidative stress in the rat.” World Journal of Gastroenterology 9.1 (2003): 125-128.
- Nguyen-Khac, Eric, et al. “Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis.” New England Journal of Medicine 365.19 (2011): 1781-1789.
- Mehta, Kapil, et al. “Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants.” Nutrition reviews 60.9 (2002): 289-293.
- DiMari, J. O. H. N., et al. “N-acetyl cysteine ameliorates ischemic renal failure.” American Journal of Physiology-Renal Physiology 272.3 (1997): F292-F298.
- Tepel, Martin, et al. “Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine.” New England Journal of Medicine 343.3 (2000): 180-184.
- Shyu, Kou-Gi, Jun-Jack Cheng, and Peiliang Kuan. “Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure.” Journal of the American College of Cardiology 40.8 (2002): 1383-1388.
- Alonso, Alvaro, et al. “Prevention of radiocontrast nephropathy with< i> N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials.” American Journal of Kidney Diseases 43.1 (2004): 1-9.
Lavoie, Suzie, et al. “Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.” Neuropsychopharmacology 33.9 (2008): 2187-2199.
Bulut, Mahmut, et al. “Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia.” World Journal of Biological Psychiatry 10.4_2 (2009): 626-628.
Lafleur, Daniel L., et al. “N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder.” Psychopharmacology 184.2 (2006): 254-256.
Berk, Michael, et al. “N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial.” Biological psychiatry 64.6 (2008): 468-475.
Grant, Jon E., Suck Won Kim, and Brian L. Odlaug. “N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study.” Biological psychiatry 62.6 (2007): 652-657.
LaRowe, Steven D., et al. “Safety and Tolerability of N‐Acetylcysteine in Cocaine‐Dependent Individuals.” The American Journal on Addictions 15.1 (2006): 105-110.
LaRowe, Steven, et al. “Is cocaine desire reduced by N-acetylcysteine?.” American Journal of Psychiatry 164.7 (2007): 1115-1117.
Janáky, Réka, et al. “Modulation of [3H] dopamine release by glutathione in mouse striatal slices.” Neurochemical research 32.8 (2007): 1357-1364.
Hashimoto, Kenji, et al. “Effects of N‐Acetyl‐l‐Cysteine on the Reduction of Brain Dopamine Transporters in Monkey Treated with Methamphetamine.” Annals of the New York Academy of Sciences 1025.1 (2004): 231-235.
Dilger, R. N., and D. H. Baker. “Oral N-acetyl-L-cysteine is a safe and effective precursor of cysteine.” Journal of animal science 85.7 (2007): 1712-1718.
Kleinveld, H. A., P. N. M. Demacker, and A. F. H. Stalenhoef. “Failure of N-acetylcysteine to reduce low-density lipoprotein oxidizability in healthy subjects.” European journal of clinical pharmacology 43.6 (1992): 639-642.
Childs, A., et al. “Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise.” Free Radical Biology and Medicine 31.6 (2001): 745-753.
Brumas, V., et al. “Can N-acetyl-L-cysteine affect zinc metabolism when used as a paracetamol antidote?.” Agents and actions 36.3-4 (1992): 278-288.
- University of Maryland Medical Center (UMMC) – http://www.r2ms.net/health/medical/altmed/supplement/cysteine – Retrieved Marc 2018