Review article
The effect of N-acetylcysteine (NAC) on human cognition – A systematic review

https://doi.org/10.1016/j.neubiorev.2017.04.013Get rights and content

Highlights

  • Oxidation and neuroinflammation modulate cognition through a variety of vectors.

  • NAC mitigates the cognitive effects of neuroinflammation in animals.

  • Evidence that NAC can modulate human cognition is promising but inconsistent.

  • Combined antioxidants are effective, but the specific contribution of NAC is unknown.

  • Further exploration of NAC’s ability to modify cognitive change is warranted.

Abstract

Oxidative stress, neuroinflammation and neurogenesis are commonly implicated as cognitive modulators across a range of disorders. N-acetylcysteine (NAC) is a glutathione precursor with potent antioxidant, pro-neurogenesis and anti-inflammatory properties and a favourable safety profile. A systematic review of the literature specifically examining the effect of NAC administration on human cognition revealed twelve suitable articles for inclusion: four examining Alzheimer's disease; three examining healthy participants; two examining physical trauma; one examining bipolar disorder, one examining schizophrenia, and one examining ketamine-induced psychosis. Heterogeneity of studies, insufficiently powered studies, infrequency of cognition as a primary outcome, heterogeneous methodologies, formulations, co-administered treatments, administration regimes, and assessment confounded the drawing of firm conclusions. The available data suggested statistically significant cognitive improvements following NAC treatment, though the paucity of NAC-specific research makes it difficult to determine if this effect is meaningful. While NAC may have a positive cognitive effect in a variety of contexts; larger, targeted studies are warranted, specifically evaluating its role in other clinical disorders with cognitive sequelae resulting from oxidative stress and neuroinflammation.

Introduction

Oxidative stress is a disturbance in the balance between the production of reactive oxygen species and antioxidant defences and may occur as a response to tissue damage, and may cause subsequent damage. It has been implicated in cognitive impairment in a variety of conditions including intrinsic neuropsychiatric disease processes (Berk et al., 2013), impact-related trauma (Abdul-Muneer et al., 2014, Amen et al., 2011a, Hoffer et al., 2013), neurodegenerative disorders (Cahill-Smith and Li, 2014, Schrag et al., 2013), and post-operative cognitive dysfunction (Mason et al., 2010, Newman et al., 2007, Zywiel et al., 2014). Given the putative effect of oxidative stress on cognitive function, it is theoretically plausible that the application of an antioxidant agent may to some degree mitigate this dysfunction. Previous studies of the efficacy of antioxidant intervention for cognitive dysfunction in humans have reported mixed results, such as those for vitamin E (Farina et al., 2012), Acetyl-l-Carnitine (Hudson and Tabet, 2003), and folic acid (Malouf et al., 2003). N-acetylcysteine (NAC) is a nutraceutical capable of replenishing brain glutathione and consequently protects against oxidative stress and is likely neuroprotective demonstrating pre-clinical efficacy in reducing markers of oxidative stress and the severity of cognitive dysfunction in animal models (Hsiao et al., 2012, Huang et al., 2010). Similar oxidative responses have been detected in humans (Moreira et al., 2007), though cognition has not been widely studied. To date, no review of the effect of the antioxidant N-acetylcysteine on human cognition has been conducted, and will form the focus of this systematic review.

Section snippets

Oxidative stress as a mechanism of cognitive change

Oxidative stress has been implicated as a critical pathophysiologic factor in numerous conditions, including neurodegenerative diseases. Oxidative stress can lead to cellular dysfunction, increased rates of apoptosis, neuroinflammation, and alter the permeability of the blood brain barrier (BBB) to neuropathic proteins, aggregate mechanisms which theoretically contribute to cognitive dysfunction (Enciu et al., 2013, Erickson et al., 2012).

Trauma has been regularly implicated as a precipitating

How NAC might work to mitigate oxidative stress

NAC has been examined in a wide range of chronic neuropsychiatric disorders, including bipolar disorder, schizophrenia, trichotillomania, depression and addiction among others (Berk et al., 2013). NAC functions as a precursor to glutathione which is the principal antioxidant produced by the body. Glutathione assists in maintaining oxidative homeostasis by removing reactive oxygen species, reactive nitrogen species, and peroxides (Samuni et al., 2013, Berk et al., 2013).

NAC has been shown to

Animal models of cognitive dysfunction

There is considerable evidence that NAC is effective in mitigating cognitive dysfunction in a variety of animal models. In particular, NAC has shown striking pro-cognitive effects in multiple models in which oxidative or inflammatory damage is a feature of the pathological process. This includes models of metabolic dysfunction such as diabetes and other less common disorders of metabolism (Prakash et al., 2015, Rodrigues et al., 2013, Scaini et al., 2012, Kamboj et al., 2008), metal toxicity (

Search strategy

A PubMed database search and a Medline database search using the terms: n acetyl cysteine OR “NAC” OR antioxidant AND cognit* was conducted. Only studies examining human cognition were included. No time limit was imposed upon the search, up until the final search date of November 14th, 2014. Additionally, the reference lists of applicable studies were manually examined for additional articles for inclusion. In total, 2175 articles were screened for inclusion, and a subset of 95 was selected for

Results

The characteristics of the included studies can be seen in Table 1. The sample size ranged from 12 to 106. The mean age of included participants across all studies ranged from 18 years to 85 years. The variability between studies, including dosage, design, participant demographics and pathologies, and intervention formulation demonstrated that the available evidence was not suitable for quantitative meta-analysis, and so a systematic review of the research was performed.

Discussion

The results of the review revealed enormous variability across studies investigating the impact NAC has on cognition. Participant demographics, research design, sample size, treatment regimen, dosage strength and duration of invention all varied across studies. The examined studies suggest that the administration of NAC alone may be beneficial in some circumstances but the sum of the evidence must be described as equivocal. In combination with other substances, in conjunction with other

Conflicts of interest

Biomedica Australia is providing NAC and placebo capsules for a clinical trial being conducted by the authors investigating the ability of NAC to modulate cognitive trajectories in elderly patients undergoing major surgery.

Acknowledgements

DRS is supported by the Sydney Parker Smith Scholarship from Barwon Health. MB is supported by a NHMRC Senior Principal Research Fellowship1059660.

References (152)

  • E.E. Devore et al.

    Total antioxidant capacity of diet in relation to cognitive function and decline

    Am. J. Clin. Nutr.

    (2010)
  • S.L. Duffy et al.

    Glutathione relates to neuropsychological functioning in mild cognitive impairment

    Alzheimers Dement.

    (2014)
  • M.A. Erickson et al.

    Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood–brain barrier: protection by the antioxidant N-acetylcysteine

    Brain Behav. Immun.

    (2012)
  • J.F. Gonçalves et al.

    N-acetylcysteine prevents memory deficits, the decrease in acetylcholinesterase activity and oxidative stress in rats exposed to cadmium

    Chem. Biol. Interact.

    (2010)
  • J.E. Grant et al.

    N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study

    Biol. Psychiatry

    (2007)
  • S.L. Gray et al.

    Is antioxidant use protective of cognitive function in the community-dwelling elderly?

    Am. J. Geriatr. Pharmacother.

    (2003)
  • F. Grodstein et al.

    High-dose antioxidant supplements and cognitive function in community-dwelling elderly women

    Am. J. Clin. Nutr.

    (2003)
  • I. Guidi et al.

    Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease

    Neurobiol. Aging

    (2006)
  • H. Gunduz-Bruce et al.

    Glutamatergic modulation of auditory information processing in the human brain

    Biol. Psychiatry

    (2012)
  • Y.-H. Hsiao et al.

    Amelioration of social isolation-triggered onset of early Alzheimer's disease-related cognitive deficit by N-acetylcysteine in a transgenic mouse model

    Neurobiol. Dis.

    (2012)
  • C.M. Kerksick et al.

    Changes in skeletal muscle proteolytic gene expression after prophylactic supplementation of EGCG and NAC and eccentric damage

    Food Chem. Toxicol.

    (2013)
  • E. Kesse-Guyot et al.

    French adults’ cognitive performance after daily supplementation with antioxidant vitamins and minerals at nutritional doses: a post hoc analysis of the Supplementation in Vitamins and Mineral Antioxidants (SU.VI.MAX) trial

    Am. J. Clin. Nutr.

    (2011)
  • A.W. Khan et al.

    A prospective randomized trial of N-acetyl cysteine administration during cold preservation of the donor liver for transplantation

    Ann. Hepatol.

    (2005)
  • A. La Rue et al.

    Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment

    Am. J. Clin. Nutr.

    (1997)
  • S.W. Levin et al.

    Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

    Lancet. Neurol.

    (2014)
  • C.-Y. Lin et al.

    N-acetyl-cysteine against noise-induced temporary threshold shift in male workers

    Hear. Res.

    (2010)
  • P.V. Magalhaes 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)
  • P.V. Magalhaes et al.

    Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2012)
  • M. Möller et al.

    Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine

    Brain Behav. Immun.

    (2013)
  • A. Montagne et al.

    Blood–brain barrier breakdown in the aging human hippocampus

    Neuron

    (2015)
  • A. Nasr

    Effect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study

    Reprod. Biomed. Online

    (2010)
  • G. Oner et al.

    Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome

    Eur. J. Obstet. Gynecol. Reprod. Biol.

    (2011)
  • P.M. Abdul-Muneer et al.

    Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury

    Mol. Neurobiol.

    (2014)
  • H. Abu Hashim et al.

    N-acetyl cysteine plus clomiphene citrate versus metformin and clomiphene citrate in treatment of clomiphene-resistant polycystic ovary syndrome: a randomized controlled trial

    J. Women's Health (2002)

    (2010)
  • J.C. Adair et al.

    Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease

    Neurology

    (2001)
  • A. Alabdali et al.

    A key role for an impaired detoxification mechanism in the aetiology and severity of autism spectrum disorders

    Behav. Brain Funct.

    (2014)
  • S. Alboni et al.

    N-acetyl-cysteine prevents toxic oxidative effects induced by IFN-alpha in human neurons

    Int. J. Neuropsychopharmacol.

    (2013)
  • Z. Allameh et al.

    Effect of N-acetylcysteine on inflammation biomarkers in pediatric acute pyelonephritis: a randomized controlled trial

    Iran. J. Kidney Dis.

    (2015)
  • D.G. Amen et al.

    Effects of brain-directed nutrients on cerebral blood flow and neuropsychological testing: a randomized, double-blind, placebo-controlled, crossover trial

    Adv. Mind Body Med.

    (2013)
  • D.G. Amen et al.

    Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation

    J. Psychoact. Drugs

    (2011)
  • S.L. Amen et al.

    Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans

    Neuropsychopharmacology

    (2011)
  • R.A. Armstrong

    What causes Alzheimer's disease?

    Folia Neuropathol.

    (2013)
  • L. Barkholt et al.

    A prospective randomized study using N-acetyl-l-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation

    Bone Marrow Transpl.

    (2008)
  • R.M. Barrientos et al.

    Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats

    J. Neurosci.

    (2012)
  • M. Berk et al.

    Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial

    BMC Med.

    (2012)
  • M. Berk et al.

    Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting

    CNS Spectr.

    (2009)
  • C. Berr et al.

    Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Arteriel

    J. Am. Geriatr. Soc.

    (2000)
  • S. Cahill-Smith et al.

    Oxidative stress, redox signalling and endothelial dysfunction in ageing-related neurodegenerative diseases: a role of NADPH oxidase 2

    Br. J. Clin. Pharmacol.

    (2014)
  • Z. Cai et al.

    Oxidative stress and β-amyloid protein in Alzheimer's disease

    Neuromol. Med.

    (2011)
  • C. Carmeli et al.

    Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial

    PLoS ONE

    (2012)
  • Cited by (86)

    • Targeting mitochondrial dysfunction with nutrients: challenges and opportunities

      2023, Molecular Nutrition and Mitochondria: Metabolic Deficits, Whole-Diet Interventions, and Targeted Nutraceuticals
    • N-acetyl-L-cysteine ameliorates hepatocyte pyroptosis of dog type 1 diabetes mellitus via suppression of NLRP3/NF-κB pathway

      2022, Life Sciences
      Citation Excerpt :

      Research showed that liver damage will activate inflammasome [22]. It is made up of NLRP3, apoptosis-associated speck-like protein containing (ASC) and an effector caspase-1 (caspase-1) associated to convey innate immunity and adaptive immunity [23]. NLRP3 inflammation activated command two signaling molecular including pathogen-related molecular patterns (PAMPs, for example virus) and damage-associated molecular patterns (DAMPs, for example hyperglycemia), at the same time activating NF-κB signaling pathway [24].

    View all citing articles on Scopus
    View full text