NAC for Schizophrenia

Dec 26, 2015

Jacob Schor ND, FABNO


Several recent studies suggest that n-acetyl-cysteine (NAC) taken orally may provide benefit to people suffering from schizophrenia.  One of these studies, Rapado-Castro et al, published in March 2015 reported intriguing findings.  The longer a patient has suffered from schizophrenia, the more NAC appears to help them.[1]   Data analyzed in this paper actually came from a randomized clinical trial that was published in 2008.[2]    This time the data was analyzed to see if duration of illness influenced degree of benefit.


In the initial 2008 study 121 participants were randomized in a double fashion to 24 weeks (placebo=62; NAC=59).  Participants had been previously diagnosed with schizophrenia. Participants took 500 mg of NAC per day, 200 mcg of selenium per day, or 500 IU of Vitamin E per day. The subjects treated with NAC improved more than placebo-treated subjects over the study period. Effect sizes at end point were consistent with moderate benefits.


This new Rapado-Castro paper found a significant interaction between duration of the illness and response to treatment.  The longer a patient had been ill, the stronger the positive response to the NAC, that is, the better NAC worked.


These changes were not what the investigators had predicted. Their assumption was that NAC impact would be greater in patients with more recent disease onset.  The results were the opposite, the longer the history of illness, the greater the response.


The response was much greater in those participants with a 20 or more history of illness than in participants with a shorter history. NAC may be more useful in those with more chronic disease than acute illness. [I realize I’m repeating this over and over.  These results are so surprising I think I need to repeat myself so this sinks in.]


About 1.1% of the general population suffers from schizophrenia [3] but it is long known that schizophrenia runs in families. Risk of the disease increases to 10% of people who have a first-degree relative with schizophrenia and for an identical twin of a person with schizophrenia, the risk increases to 40-65%. [4]   


NAC is derived from the amino acid cysteine and is widely available over-the-counter as a nutritional supplement promoted for its antioxidant properties.  NAC is well tolerated and safe; it has been widely used internationally for decades. [5]    NAC is used to antidote acetaminophen overdose and has been approved for this purpose by the FDA since 1985, given either orally or by IV.[6]  


NAC is also used as a mucolytic agent in chronic obstructive pulmonary disease [7] and cystic fibrosis [8], to protect the kidneys from damage from the contrast-agents used in imaging studies [9]  and as a preventive agent for atrial fibrillation.[10]      NAC can be used to prevent and treat seasonal influenza virus infection.[11]  


There has been growing evidence over the past ten years that NAC is also useful in treating psychiatric and neurological disorders; it appears to moderate pathophysiological processes that are involved in a range of psychiatric and neurological disorders, including oxidative stress, neurogenesis and apoptosis, mitochondrial dysfunction, neuroinflammation and dysregulation of glutamate and dopamine. [12] NAC reverses the neuroadaptation and metaplasticity induced by cocaine addiction.[13]    The neuroadaptation theory of addiction suggests that exposure to drugs of abuse induces adaptive molecular and cellular changes in the brain that mediate addiction-related memories. Compared to other types of memories, addiction-related memories develop fast and last extremely long; the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient. [14]


In the last few years numerous reports have been published on using NAC to treat a range of psychiatric or neurological conditions including schizophrenia, bipolar disorder, skin picking, trichotillomania, obsessive-compulsive disorder, autism and addiction to nicotine, cannabis, cocaine, methamphetamine, gambling [15]  as well as epilepsy, amyotrophic lateral sclerosis, neuropathy and traumatic brain injury.[16]  


In a systematic review of NAC use in psychiatry and neurology published in August 2015, Deepmala et al evaluated and graded the level of evidence for the use of NAC in treating psychiatric and neurological disorders as it stood at the time.  For now Deepmala’s paper and in particular the summary tables should stand as our go to reference in these matters.[17]    The amount of NAC used in these trials was usually from 2.0 to 2.4 grams of NAC per day administered orally divided into two doses.


For those of us trained in naturopathic medicine back when NAC was used solely as a mucolytic agent, this new range of applications is quite fascinating.


This current paper by Rapado-Castro now suggests NAC may be of even greater utility after long-term psychiatric debility. This is even more fascinating as NAC may provide benefit in conditions that we once might have thought too long standing and too deeply ingrained to be ameliorated. 





1. Rapado-Castro M, Berk M, Venugopal K, Bush AI, Dodd S, Dean OM. Towards stage specific treatments: effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Mar 3;57:69-75.


2.   Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008 Sep 1;64(5):361-8.

Full text:






5.  LaRowe SD, Mardikian P, Malcolm R, Myrick H, Kalivas P, McFarland K, Saladin M, et al. Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict. 2006 Jan-Feb;15(1):105-10.


6.  Yarema MC, Johnson DW, Berlin RJ, Sivilotti ML, Nettel-Aguirre A, Brant RF, Spyker DA, et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med. 2009 Oct;54(4):606-14.


7.  Sadowska AM. N-Acetylcysteine mucolysis in the management of chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2012 Jun;6(3):127-35.


8.  Dauletbaev N, Fischer P, Aulbach B, Gross J, Kusche W, Thyroff-Friesinger U, Wagner TO, Bargon J. A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis. Eur J Med Res. 2009 Aug 12;14(8):352-8.


 9. Quintavalle C, Donnarumma E, Fiore D, Briguori C, Condorelli G. Therapeutic strategies to prevent contrast-induced acute kidney injury. Curr Opin Cardiol. 2013 Nov;28(6):676-82.


10.  Liu XH, Xu CY, Fan GH. Efficacy of N-acetylcysteine in preventing atrial fibrillation after cardiac surgery: a meta-analysis of published randomized controlled trials. BMC Cardiovasc Disord. 2014 Apr 16;14:52.


  Geiler J, Michaelis M, Naczk P, Leutz A, Langer K, Doerr HW, Cinatl J Jr. N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus.

Biochem Pharmacol. 2010 Feb 1;79(3):413-20.


11.  Samuni Y, Goldstein S, Dean OM, Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 2013 Aug;1830(8):4117-29.


12.  Moussawi K, Pacchioni A, Moran M, Olive MF, Gass JT, Lavin A, Kalivas PW. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci. 2009 Feb;12(2):182-9.


13.  Lee BR, Dong Y. Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond. Neuropharmacology. 2011 Dec;61(7):1060-9.


14.  Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013 Mar;34(3):167-77.


15.  Hoffer ME, Balaban C, Slade MD, Tsao JW, Hoffer B. Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study. PLoS One. 2013;8(1):e54163.


16.  Deepmala, Slattery J, Kumar N, Delhey L, Berk M, Dean O, Spielholz C, Frye R. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015 Aug;55:294-321.   Full text: