by Alan Gaspari Nutrient Journal
Acetylcysteine, also known as N-acetylcysteine or 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 dietary supplement which is claimed to exert antioxidant and liver protecting effects.
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 it 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 favorable cellular environment to achieve higher levels of performance.
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 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 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 behaviour , 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 reduced the desire for and interest in cocaine. More larger well designed trials are required to assert NAC’s efficiency in cocaine abusers.
All this data suggests that manipulation of glutamatergic system by NAC supplementation can target core symptoms of addictive behaviors 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 .
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