N-Acetyl Cysteine (NAC)
NAC is a dietary supplement derived from the essential amino acid L-cysteine. It is used medically for its liver-protective properties – primarily as an antidote for acetaminophen overdose – and to break up excess mucus in the lungs. It is an antioxidant, observed to reduce DNA damage and support healthy immune functioning, and serves as a precursor for glutathione, itself an important antioxidant. Depletion of cellular glutathione, indicating a decrease in the body’s antioxidant capacity, has been associated with aging, inflammation, and neurodegenerative diseases such as MS1. Supplementation with NAC has been suggested to be superior to glutathione in replenishing the body’s stores2.
In an EAE animal model of MS, NAC at a dose of 150 mg/kg was associated with improved antioxidant activity and decreased nitrosative and oxidative stress compared to controls. Further, there were fewer clinical signs of disease following NAC treatment3,4.
An animal model of nerve demyelination showed 50 mg/kg of NAC to be protective of brain cells, resulting in greater preservation of myelin5.
In a randomized, placebo-controlled study in RRMS and PPMS patients, two months of NAC at an oral dose of approximately 1000 mg/day for 6 days/week plus intravenous 50 mg/kg once/week was associated with significant increases compared to controls in brain metabolism and self-reported levels of cognition and attention based on standardized scoring. Other subjective measures such as pain, fatigue, anxiety, depression, and overall physical function showed trends toward improvement.
In a similarly designed study in RRMS and PPMS patients treated with the same dose, NAC was associated with significant improvements in brain blood flow and trends toward improvement in cognition and attention.
NAC at a dose of 3750 mg/day (1250 mg three times per day) was observed to be well-tolerated in patients with progressive MS, with side effects being mild and primarily digestive discomfort or headaches8.
NAC is considered to be poorly available to the body, about 9%, an issue believed to be responsible for inconsistent results in studies8. A form of NAC called N-acetylcysteine amide (NACA) has been shown to be significantly better utilized9,10, and has been successfully tested in animal models of MS. Doses of 160-500 mg/kg markedly reduced clinical signs, inflammation, and oxidant activity, and protected nerve fibers from demyelination damage11,12.
In a pregnant animal model (rats), NAC 300 mg/kg/day provided intravenously has consistently been associated with anti-inflammatory protection – particularly in the brain – to offspring from the effects of various physical and chemical insults13-15. In pregnant mice, intravenous NAC 100 mg/kg/day was shown to prevent the reproductive toxicity of zinc oxide particles (a common antibacterial substance), including maternal weight loss, abnormal development of offspring; and spontaneous abortion16. NAC 400 mg/kg/day given orally to pregnant and lactating mice was shown to not only be safe, but to protect offspring from impaired glucose tolerance due to a high-fat diet17.
An extensive review of human trials investigating NAC use in combination with conventional female infertility treatments concluded that NAC has an excellent safety profile in oral doses of 1200-1800 mg/day; overall, NAC was associated with fewer miscarriages and harmful side effects than the anti-inflammatory drug metformin or placebo, though with slightly more ectopic pregnancies than with placebo. Interestingly, NAC was associated with better ovulation and live pregnancy rate compared to no fertility treatment at all, but with more miscarriage18. These results may suggest that the lower doses suggested in studies could be better choices during the perinatal period.
NAC is the supplemental form, but regular L-cysteine is found in naturally in many high-protein foods, such as red meat, chicken, fatty fish, cottage cheese, whole grains, and legumes19.
References
1.Tenorio M, Graciliano NG, Moura FA, Oliveira ACM, Goulart MOF. N-Acetylcysteine (NAC): Impacts on Human Health. Antioxidants (Basel). Jun 16 2021;10(6)doi:10.3390/antiox10060967
2.Grinberg L, Fibach E, Amer J, Atlas D. N-acetylcysteine amide, a novel cell-permeating thiol, restores cellular glutathione and protects human red blood cells from oxidative stress. Free Radic Biol Med. Jan 1 2005;38(1):136-45. doi:10.1016/j.freeradbiomed.2004.09.025
3.Ljubisavljevic S, Stojanovic I, Pavlovic D, et al. Suppression of the lipid peroxidation process in the CNS reduces neurological expression of experimentally induced autoimmune encephalomyelitis. Folia Neuropathol. 2013;51(1):51-7. doi:10.5114/fn.2013.34196
4.Ljubisavljevic S, Stojanovic I, Pavlovic D, Sokolovic D, Stevanovic I. Aminoguanidine and N-acetyl-cysteine supress oxidative and nitrosative stress in EAE rat brains. Redox Rep. 2011;16(4):166-72. doi:10.1179/1351000211Y.0000000007
5.El Sharouny SH, Shaaban MH, Elsayed RM, Tahef AW, Abd ElWahed MK. N-acetylcysteine protects against cuprizone-induced demyelination: histological and immunohistochemical study. Folia Morphol (Warsz). 2022;81(2):280-293. doi:10.5603/FM.a2021.0044
6.Monti DA, Zabrecky G, Leist TP, et al. N-acetyl Cysteine Administration Is Associated With Increased Cerebral Glucose Metabolism in Patients With Multiple Sclerosis: An Exploratory Study. Front Neurol. 2020;11:88. doi:10.3389/fneur.2020.00088
7.Shahrampour S, Heholt J, Wang A, et al. N-acetyl cysteine administration affects cerebral blood flow as measured by arterial spin labeling MRI in patients with multiple sclerosis. Heliyon. Jul 2021;7(7):e07615. doi:10.1016/j.heliyon.2021.e07615
8.Krysko KM, Bischof A, Nourbakhsh B, et al. A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine. Ann Clin Transl Neurol. Apr 2021;8(4):811-824. doi:10.1002/acn3.51325
9.Khayyat A, Tobwala S, Hart M, Ercal N. N-acetylcysteine amide, a promising antidote for acetaminophen toxicity. Toxicol Lett. Jan 22 2016;241:133-42. doi:10.1016/j.toxlet.2015.11.008
10.Sunitha K, Hemshekhar M, Thushara RM, et al. N-Acetylcysteine amide: a derivative to fulfill the promises of N-Acetylcysteine. Free Radic Res. May 2013;47(5):357-67. doi:10.3109/10715762.2013.781595
11.Gilgun-Sherki Y, Barhum Y, Atlas D, Melamed E, Offen D. Analysis of gene expression in MOG-induced experimental autoimmune encephalomyelitis after treatment with a novel brain-penetrating antioxidant. J Mol Neurosci. 2005;27(1):125-35. doi:10.1385/JMN:27:1:125
12.Offen D, Gilgun-Sherki Y, Barhum Y, et al. A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis. J Neurochem. Jun 2004;89(5):1241-51. doi:10.1111/j.1471-4159.2004.02428.x
13.Gutziet O, Iluz R, Ben Asher H, et al. Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model. Int J Mol Sci. Dec 20 2021;22(24)doi:10.3390/ijms222413629
14.Sharabi H, Khatib N, Ginsberg Y, et al. Therapeutic N-Acetyl-Cysteine (Nac) Following Initiation of Maternal Inflammation Attenuates Long-Term Offspring Cerebral Injury, as Evident in Magnetic Resonance Imaging (MRI). Neuroscience. Apr 1 2019;403:118-124. doi:10.1016/j.neuroscience.2018.01.013
15.Zmora O, Gutzeit O, Segal L, et al. Maternal N-acetyl-cysteine prevents neonatal brain injury associated with necrotizing enterocolitis in a rat model. Acta Obstet Gynecol Scand. May 2021;100(5):979-987. doi:10.1111/aogs.14054
16.Chen B, Hong W, Tang Y, Zhao Y, Aguilar ZP, Xu H. Protective effect of the NAC and Sal on zinc oxide nanoparticles-induced reproductive and development toxicity in pregnant mice. Food Chem Toxicol. Sep 2020;143:111552. doi:10.1016/j.fct.2020.111552
17.Michlin M, Argaev-Frenkel L, Weinstein-Fudim L, Ornoy A, Rosenzweig T. Maternal N-Acetyl Cysteine Intake Improved Glucose Tolerance in Obese Mice Offspring. Int J Mol Sci. Mar 13 2020;21(6)doi:10.3390/ijms21061981
18.Devi N, Boya C, Chhabra M, Bansal D. N-acetyl-cysteine as adjuvant therapy in female infertility: a systematic review and meta-analysis. J Basic Clin Physiol Pharmacol. Nov 19 2020;32(5):899-910. doi:10.1515/jbcpp-2020-0107
19.Vasdev S, Singal P, Gill V. The antihypertensive effect of cysteine. Int J Angiol. Spring 2009;18(1):7-21. doi:10.1055/s-0031-1278316