May 4, 2016

N-acetylcysteine as Adjunctive Treatment for Schizophrenia

Study finds benefits greater for participants with long-term illness
Study finds N-acetylcysteine improves symptoms of schizophrenia, with an unexpected answer to the question: Is it more effective for early or longstanding illness?


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;3(57):69-75. 


A double-blind, placebo-controlled trial to investigate whether duration of illness was a factor in modulating the response to N-acetylcysteine (NAC). 


The study included 121 participants who were randomized to receive placebo (n=62) or N-acetylcysteine (NAC; n=59) for 24 weeks. Participants were required to meet diagnostic criteria for schizophrenia (DSM-IV) and have either a Positive and Negative Symptom Score (PANSS) of ≥55 (range is 30 to 100) or a Clinical Global Impression-Severity (CGI-S) score ≥3 (range is 1 to 7). Both inpatients and outpatients were eligible. Participants needed to be currently taking an antipsychotic agent. Individuals who were taking a mood stabilizer (eg, lithium, valproate, carbamazepine) were excluded, as were those currently taking drugs known to prevent glutathione depletion (500+ mg of NAC per day, 200+ μg of selenium per day, or 500+ IU of vitamin E per day). 

Study Medication and Dosage

Participants received 2 NAC (500 mg) capsules 2 times a day (for a total of 2 g a day) or matching placebo capsules. 

Outcome Measures

Participants were assessed at baseline using a structured clinical interview (Mini International Neuropsychiatric Interview [MINI], DSM-IV) using various psychological assessment tools. Blinded investigators, who were all experienced clinicians, performed the assessments. 
Efficacy measures were repeated every 2 weeks for the first 8 weeks or on the day of study termination if the participant withdrew prior to 8 weeks. After 8 weeks, evaluations were every 4 weeks until 24 weeks, when the treatment was stopped. Postdiscontinuation follow-up was held 4 (±2) weeks after completion to determine any change in participant status.
Duration of the illness at baseline was grouped into <10 years, 10-20 years, and >20 years and compared with outcome measures. Data from this same study cohort was first published in 2008.1

Key Findings 

Initial analysis of these data in 2008 reported that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total (P=0.009), PANSS negative (P =0.018), and PANSS general (P=0 035). Improvements were also reflected in CGI-S (P=0.004), and CGI-Improvement (P=0.025) scores. No significant change on the PANSS positive subscale was seen. NAC treatment also was associated with an improvement in akathisia (P=0.022) in the first published study. Effect sizes at endpoint were consistent with moderate benefits. 
In this current paper analyzing the same data but comparing duration of illness with outcome, “an interaction between treatment group and duration was consistently found for positive symptoms [PANSS positive subscale: F2, 60=6.578; P=0.003 and PANSS total: F2, 60=4.308; P=0.018) and functional variables (CGI): F2, 58=4.647; P=0.013], Global Assessment of Functioning Scale (GAF): F2, 59=5.848; P=0.005 and the Social and Occupational Functioning Assessment Scale (SOFAS): F2, 21=3.964; P=0.035].” In other words, the longer the patients had suffered from schizophrenia, the more improvement they experienced taking NAC.
Participants who had been ill for 20 years or more gained the greatest advantage from the treatment. 
Participants who had been ill for 20 years or more gained the greatest advantage from the treatment.
These changes were not what the investigators had predicted. Their assumption was that the effects of NAC 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. 

Practice Implications

These results are a pleasant and welcome surprise. 
The hypothesis of this study was that people with early stages of schizophrenia would derive more benefit from NAC; this idea was proven wrong. Instead, it seems that the longer participants had suffered from schizophrenia, the greater their benefit from taking NAC. We should note that these benefits only apply to the symptoms of the illness. NAC did not change the “extrapyramidal adverse events associated with treatment” (ie, the movement disorders from long-term use of treatment medications); it only improved the symptoms of schizophrenia itself.  
About 1.1% of the general population suffers from schizophrenia2, but it is long known that schizophrenia runs in families. Risk of the disease increases to 10% for people who have a first-degree relative with schizophrenia. For an identical twin of a person with schizophrenia, the risk increases to 40% to 65%.3
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.4 NAC is used as an antidote for acetaminophen overdose and has been approved for this purpose by the FDA since 1985, given either orally or intravenously.5
NAC is also used as a mucolytic agent in chronic obstructive pulmonary disease6 and cystic fibrosis,7 to protect the kidneys from damage from the contrast agents used in imaging studies,8 and as a preventive agent for atrial fibrillation.9 NAC can be used to prevent and treat seasonal influenza virus infection.10 It is also used to favorably affect ovulatory dysfunction in women with PCOS.
There has been growing evidence over the past 10 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.11 NAC reverses the neuroadaptation and metaplasticity induced by cocaine addiction.12 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 quickly and last for an extremely long time; the cellular and molecular processes that mediate addiction-related memories are exceptionally adept and efficient.13
In the last few years numerous reports have been published regarding the use of NAC to treat a range of psychiatric or neurological conditions, including schizophrenia; bipolar disorder; skin picking; trichotillomania; obsessive-compulsive disorder; autism; gambling; addiction to nicotine, cannabis, cocaine, and methamphetamine; epilepsy; amyotrophic lateral sclerosis; neuropathy; and traumatic brain injury.14-15
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, this review article, particularly the summary tables, should stand as our go-to reference in these matters.16 The amount of NAC used in these trials typically ranged from 2.0 to 2.4 grams of NAC per day, administered orally and divided into 2 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 longstanding and too deeply ingrained to be ameliorated. 

Categorized Under


  1. Berk M, Copolov D, Dean O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008;64(5):361-368. 
  2. National Institute of Mental Health. Schizophrenia. Accessed May 2, 2016.
  3. National Institute of Mental Health. Schizophrenia. Accessed May 2, 2016.
  4. LaRowe SD, Mardikian P, Malcolm R, et al. Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict. 2006;15(1):105-110.
  5. Yarema MC, Johnson DW, Berlin RJ, 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;54(4):606-614. 
  6. Sadowska AM. N-Acetylcysteine mucolysis in the management of chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2012;6(3):127-135. 
  7. Dauletbaev N, Fischer P, Aulbach B, et al. A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis. Eur J Med Res. 2009;14(8):352-358.
  8. Quintavalle C, Donnarumma E, Fiore D, Briguori C, Condorelli G. Therapeutic strategies to prevent contrast-induced acute kidney injury. Curr Opin Cardiol. 2013;28(6):676-682.
  9. 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;14:52. 
  10. Geiler J, Michaelis M, Naczk P, et al. 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;79(3):413-420. 
  11. Samuni Y, Goldstein S, Dean OM, Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 2013;1830(8):4117-4129. 
  12. Moussawi K, Pacchioni A, Moran M, Olive MF, Gass JT, Lavin A, Kalivas PW. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci. 2009;12(2):182-189. 
  13. Lee BR, Dong Y. Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond. Neuropharmacology. 2011;61(7):1060-1069. 
  14. Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013;34(3):167-177. 
  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, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294-321.