Numerous studies support the use of N-acetylcysteine (NAC) for mood disorders and substance use cessation
N-acetylcysteine (NAC), well-known for its function as an antioxidant and anti-inflammatory,, is commonly used in the clinic as a mucolytic,, the treatment of choice for acetaminophen overdose, and to help prevent liver damage resulting from acetaminophen and other toxic substances., NAC provides cysteine, the rate-limiting amino acid for the synthesis of glutathione, the body’s main antioxidant and master detoxifier. As a precursor to glutathione, NAC also supports the normal immune response to viruses (much like selenium does), and has been studied as an adjunctive agent in conditions such as human immunodeficiency virus (HIV), where the glutathione levels are diminished in addition to the low levels of the protective immune cells which typifies the disease.
Studies have shown that NAC is neuroprotective, crossing the blood-brain barrier and accumulating in the central nervous system (CNS).
Studies have shown that NAC is neuroprotective, crossing the blood-brain barrier and accumulating in the central nervous system (CNS). NAC has been shown to improve mitochondrial function in the brain and reduce neuroinflammation in various animal models., This gives it great potential for use in diseases associated with CNS dysfunction and oxidative stress, including mental health conditions, neurodegenerative disease, and traumatic brain injury.
Although B vitamins are a primary therapy for hyperhomocysteinemia, NAC also has been shown to reduce homocysteine (HCY) levels, which are often high in individuals with depression and those who abuse substances, particularly alcohol., In the CNS, high HCY levels are also related to the development of dementia and Alzheimer’s disease, and it is a well-established cardiovascular disease risk factor.,, Levels of HCY in individuals with psychiatric disease may be high due to reduced clearance of this molecule by the kidneys – which is the very aspect of elimination that NAC helps improve. NAC also helps reduce the oxidative damage caused by HCY in the brain. Administration of NAC (or glutathione) to animals has been shown to reduce HCY levels by more than 50%. In humans, at a dosage of 1,800 mg daily for four weeks, NAC significantly reduced HCY levels, decreasing systolic and diastolic blood pressure as well.
Administration of NAC (or glutathione) to animals has been shown to reduce homocysteine levels by more than 50%.
In an animal model of obsessive-compulsive disorder (OCD), NAC was shown to reduce marble-burying behavior (a mouse “obsessive-compulsive” symptom), while another antioxidant, vitamin E, had no effect on this behavior, suggesting the mechanism was different than simply reducing oxidative stress or improving mitochondrial function, both of which vitamin E is also known to do. Indeed, NAC has been shown to reduce compulsive behavior via modulation of glutamate, a primary excitatory neurotransmitter that has been demonstrated to be dysregulated in mood disorders and addiction.,,, NAC appears to activate a cellular transporter that moves glutamate into the extracellular space, which inhibits further glutamate release, thereby improving compulsive behaviors. These and the other aforementioned findings have spurred many clinical studies investigating NAC as a treatment for a variety of neuropsychiatric conditions and to support cessation of addictive behaviors and substance use.,,
The use of NAC in psychiatry
Numerous animal and human studies suggest NAC may be a useful tool in mood disorders including depression, bipolar disorder, and OCD. The dose of NAC in these studies generally varies from 1,200 to 3,000 mg per day in divided doses, with some increasing from the initial dose after a month or so if improvements were not seen.
A 2016 systemic review and meta-analysis of the use of NAC for the treatment of depressive symptoms found that NAC ameliorated depressive symptoms, improved functionality, and was well tolerated. Since this review, another study found that NAC significantly improved anxiety and depression symptoms, but only in those with a high level of inflammation, as assessed by a parameter known as high-sensitivity C-reactive protein (hs-CRP). Individuals receiving NAC also had a significantly greater reduction in hs-CRP levels than those receiving placebo. Another study found that treatment with NAC significantly improved post-traumatic stress disorder symptoms and depression in veterans compared to placebo. A further study investigating NAC as an add-on agent for major depressive disorder refractory to treatment is ongoing.
In individuals with bipolar disorder, NAC, as an add-on therapy, has been shown to improve depressive symptoms in multiple studies, with two studies showing it improved manic symptoms as well.
In individuals with depression associated with bipolar disorder, a condition that often is difficult to treat due to the cycling between manic and depressive states, NAC, as an add-on therapy, has been shown to improve depressive symptoms in multiple studies,, with two studies showing it improved manic symptoms as well., Similar to the interaction effects shown with depressed patients having a higher level of inflammation, one study found that treatment with NAC was more advantageous in individuals who had other systemic cardiovascular or endocrine illness, pathologies that also often involve inflammation. Unfortunately, not all studies have duplicated these findings, however, a worsening of symptoms has not been reported.,
NAC has also been shown to reduce the severity of obsessive-compulsive symptoms in individuals with OCD.
Multiple clinical trials and case reports of the treatment of OCD using NAC have been reported, with doses ranging from 2,000 to 3,000 mg per day (in divided doses), usually for a period of about 12 weeks.,, Overall, NAC has been shown to reduce the severity of obsessive-compulsive symptoms and be well tolerated. Significant improvements have also been seen in adults with compulsive hair-pulling symptoms (a condition known as trichotillomania with many similarities to OCD), however in children with this same condition, improvements were not seen with NAC.
NAC, addiction, and substance use
Given the benefits seen with obsessive-compulsive behaviors and depression, it should not be surprising that numerous studies exist evaluating the potential use of NAC for the reduction of addictive behaviors and substance use. In an open-label outpatient study of cocaine-dependent patients, NAC at dosages of 2,400 or 3,600 mg/day was found to support the termination or reduced use of cocaine. In an additional small, double-blind study in cocaine-dependent patients, 2,400 mg/day of NAC significantly attenuated the reinforcing effects of cocaine use. In a systemic review of the research related to cocaine addiction, NAC was found in four of the six clinical trials to reduce craving, desire to use cocaine, cocaine-cue viewing time, and cocaine-related spending, with animal models showing a reversal of cocaine use-related disruption of glutamate homeostasis.
NAC was found in multiple clinical trials to reduce craving, desire to use cocaine, cocaine-cue viewing time, and cocaine-related spending.
In addition to cocaine-use disorder, NAC has also been investigated as a tool to support smoking cessation, and reduce pathological gambling, cannabis dependency, and alternate substance use during cannabis cessation. In a short-term pilot study of smoking cessation, compared to placebo, 3,600 mg/day of NAC significantly reduced the reward that smokers experienced with the first cigarette after a 3.5-day abstinence period. In an open-label study of 27 subjects being treated for gambling addiction, NAC was found to significantly reduce scores related to pathological gambling, with the mean effective dose being roughly 1,500 mg/day. The 16 responders to NAC then entered a double-blind placebo-controlled phase, and of those receiving NAC, 83.3% had improvement of behaviors, compared to 28.6% of those receiving placebo.
In the setting of cannabis cessation, treatment with 2,400 mg/day of NAC increased the odds of simultaneous alcohol abstinence, reduced weekly alcohol use, and decreased drinking days.
In treatment-seeking cannabis-dependent adolescents, 2,400 mg/day of NAC more than doubled the likelihood that participants would have a negative urine cannabis test result compared to placebo. A subsequent study found that adolescents with lower levels of pretreatment impulsivity and higher rate of adherence to NAC treatment increased the odds that participants would refrain from cannabis use. Notably, treatment adherence only was a factor that influenced abstinence in those taking NAC, and did not affect the amount of individuals taking placebo who were abstinent. Finally, in the setting of cannabis cessation in individuals not having an alcohol use disorder, treatment with 2,400 mg/day of NAC increased the odds of simultaneous alcohol abstinence, reduced weekly alcohol use, and decreased drinking days. Unfortunately, similar results were not seen with regards to the amount of cigarette smoking during cannabis cessation.
Given the low rate of adverse effects and promising results from many of these studies, NAC is worthy of consideration as an adjunctive therapy for those who experience mood disorders and for support in the cessation of addictive substances and patterns. Despite the safety seen with the use of NAC in these clinical studies, given the nature of each of these conditions, the use of this as a therapy should be under the care of a physician or psychotherapist, ideally one who also is aware of the research backing NAC.Click here to see References
 Samuni Y, et al. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 2013 Aug;1830(8):4117-29.
 Palacio JR, et al. Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages. Inflamm Res. 2011 Jul;60(7):695-704.
 Sadowska A, et al. Role of N-acetylcysteine in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2006 Dec;1(4):425-34.
 Kelly GS. Clinical applications of N-acetylcysteine. Altern Med Rev. 1998 Apr;3(2):114-27.
 Smilkstein MJ, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988 Dec 15;319(24):1557-62.
 Harrison PM, et al. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med. 1991 Jun 27;324(26):1852-7.
 Lee WM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64.
 Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014 Feb;141(2):150-9.
 Devasagayam TP, et al. Free radicals and antioxidants in human health: current status and future prospects. J Assoc Physicians India. 2004 Oct;52:794-804.
 De Rosa SC, et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest. 2000 Oct;30(10):915-29.
 Farr SA, et al. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem. 2003 Mar;84(5):1173-83.
 Cocco T, et al. Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine. Free Radic Biol Med. 2005 Mar 15;38(6):796-805.
 Fernandes J, Gupta GL. N-acetylcysteine attenuates neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat. Behav Brain Res. 2019 May 17;364:356-65.
 Bhatti J, et al. Systematic review of human and animal studies examining the efficacy and safety of N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) in traumatic brain injury: impact on neurofunctional outcome and biomarkers of oxidative stress and inflammation. Front Neurol. 2018 Jan 15;8:744.
 Kasperczyk S, et al. Effect of N-acetylcysteine administration on homocysteine level, oxidative damage to proteins, and levels of iron (Fe) and Fe-related proteins in lead-exposed workers. Toxicol Ind Health. 2016 Sep;32(9):1607-18.
 Nabi H, et al. Association of serum homocysteine with major depressive disorder: results from a large population-based study. Psychoneuroendocrinology. 2013 Oct;38(10):2309-18.
 Bleich S, et al. Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS). Alcohol Clin Exp Res. 2005 Mar;29(3):334-6.
 Ford AH, et al. Homocysteine, depression and cognitive function in older adults. J Affect Disord. 2013 Nov;151(2):646-51.
 Seshadri S, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83.
 Wald DS, et al. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23;325(7374):1202.
 Ipcioglu OM, et al. Reduced urinary excretion of homocysteine could be the reason of elevated plasma homocysteine in patients with psychiatric illnesses. Clin Biochem. 2008 Jul;41(10-11):831-5.
 Jara-Prado A, et al. Homocysteine-induced brain lipid peroxidation: effects of NMDA receptor blockade, antioxidant treatment, and nitric oxide synthase inhibition. Neurotox Res. 2003;5(4):237-43.
 Ovrebø KK, Svardal A. The effect of glutathione modulation on the concentration of homocysteine in plasma of rats. Pharmacol Toxicol. 2000 Sep;87(3):103-7.
 Hildebrandt W, et al. Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status. Am J Clin Nutr. 2015 Nov;102(5):1014-24.
 Egashira N, et al. N-acetyl-L-cysteine inhibits marble-burying behavior in mice. J Pharmacol Sci. 2012;119(1):97-101.
 Chakrabarty K, et al. Glutamatergic dysfunction in OCD. Neuropsychopharmacology. 2005 Sep;30(9):1735-40.
 Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007 Nov;12(11):988-1000.
 Terbeck S, et al. The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies. Front Neurosci. 2015 Mar 18;9:86.
 Kalivas PW, et al. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci. 2009 Aug;10(8):561-72.
 Grant JE, et al. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2009;66:756-63.
 Ooi SL, et al. N-acetylcysteine for the treatment of psychiatric disorders: a review of current evidence. Biomed Res Int. 2018; 2018:2469486.
 Dean O, et al. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011;36(2):78-86.
 Minarini A, et al. N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects. Expert Opin Drug Metab Toxicol. 2017 Mar;13(3):279-92.
 Fernandes BS, et al. N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry. 2016 Apr;77(4):e457-66.
 Porcu M, et al. Effects of adjunctive N-acetylcysteine on depressive symptoms: modulation by baseline high-sensitivity C-reactive protein. Psychiatry Res. 2018 May;263:268-274.
 Back SE, et al. A double-blind, randomized, controlled pilot trial of N-acetylcysteine in veterans with posttraumatic stress disorder and substance use disorders. J Clin Psychiatry. 2016 Nov;77(11):e1439-46.
 Yang C, et al. N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial. BMC Psychiatry. 2018 Sep 4;18(1):279.
 Magalhães PV, et al. N-acetylcysteine for major depressive episodes in bipolar disorder. Braz J Psychiatry. 2011 Dec;33(4):374-8.
 Berk M, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder–a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008 Sep 15;64(6):468-75.
 Magalhães PV, et al. A preliminary investigation on the efficacy of N-acetyl cysteine for mania or hypomania. Aust N Z J Psychiatry. 2013 Jun;47(6):564-8.
 Magalhães PV, et al. N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial. J Affect Disord. 2011 Mar;129(1-3):317-20.
 Magalhães PV, et al. Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012 Apr 27;37(1):132-5.
 Ellegaard PK, et al. The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study. J Affect Disord. 2019 Feb 15;245:1043-51.
 Panizzutti B, et al. Mediator effects of parameters of inflammation and neurogenesis from a N-acetyl cysteine clinical-trial for bipolar depression. Acta Neuropsychiatr. 2018 Dec;30(6):334-41.
 Oliver G, et al. N-acetyl cysteine in the treatment of obsessive compulsive and related disorders: a systematic review. Clin Psychopharmacol Neurosci. 2015 Apr 30;13(1):12-24.
 Couto JP, Moreira R. Oral N-acetylcysteine in the treatment of obsessive-compulsive disorder: a systematic review of the clinical evidence. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30;86:245-54.
 Paydary K, et al. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2016 Apr;41(2):214-9.
 Grant JE, et al. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009 Jul;66(7):756-63.
 Bloch MH, et al. N-Acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial. J Am Acad Child Adolesc Psychiatry. 2013 Mar;52(3):231-40.
 Mardikian PN, et al. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):389-94.
 Levi Bolin B, et al. N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order. Drug Alcohol Depend. 2017 Sep 1;178:452-60.
 Nocito Echevarria MA, et al. N-acetylcysteine for treating cocaine addiction – a systematic review. Psychiatry Res. 2017 May;251:197-203.
 Schmaal L, et al. Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addict Res. 2011;17(4):211-6.
 Grant JE, et al. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry. 2007 Sep 15;62(6):652-7.
 Gray KM, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 2012 Aug;169(8):805-12.
 Bentzley JP, et al. Low pretreatment impulsivity and high medication adherence increase the odds of abstinence in a trial of N-acetylcysteine in adolescents with cannabis use disorder. J Subst Abuse Treat. 2016 Apr;63:72-7.
 Squeglia LM, et al. The effect of N-acetylcysteine on alcohol use during a cannabis cessation trial. Drug Alcohol Depend. 2018 Apr 1;185:17-22.
 McClure EA, et al. Cigarette smoking during an N-acetylcysteine-assisted cannabis cessation trial in adolescents. Am J Drug Alcohol Abuse. 2014 Jul;40(4):285-91.