Review articleThe effect of N-acetylcysteine (NAC) on human cognition – A systematic review
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)
- et al.
N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial
Biol. Psychiatry
(2008) - et al.
N-acetyl cysteine for depressive symptoms in bipolar disorder – a double-blind randomized placebo-controlled trial
Biol. Psychiatry
(2008) - et al.
The promise of N-acetylcysteine in neuropsychiatry
Trends Pharmacol. Sci.
(2013) - et al.
N-acetylcysteine reverses existing cognitive impairment and increased oxidative stress in glutamate transporter type 3 deficient mice
Neuroscience
(2012) - et al.
Thiram-induced cytotoxicity is accompanied by a rapid and drastic oxidation of reduced glutathione with consecutive lipid peroxidation and cell death
Toxicology
(2001) - et al.
Oxidative balance, homocysteine, and uric acid levels in older patients with late onset Alzheimer's disease or vascular dementia
J. Neurol. Sci.
(2014) - et al.
A vitamin/nutraceutical formulation improves memory and cognitive performance in community-dwelling adults without dementia
J. Nutr. Health Aging
(2010) - et al.
Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system
Brain Behav. Immun.
(2008) - et al.
Effects of N-acetyl-cysteine treatment on glutathione depletion and a short-term spatial memory deficit in 2-cyclohexene-1-one-treated rats
Eur. J. Pharmacol.
(2010) - et al.
Antioxidant vitamins reduce acute meal-induced memory deficits in adults with type 2 diabetes
Nutr. Res.
(2008)
Total antioxidant capacity of diet in relation to cognitive function and decline
Am. J. Clin. Nutr.
Glutathione relates to neuropsychological functioning in mild cognitive impairment
Alzheimers Dement.
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.
N-acetylcysteine prevents memory deficits, the decrease in acetylcholinesterase activity and oxidative stress in rats exposed to cadmium
Chem. Biol. Interact.
N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study
Biol. Psychiatry
Is antioxidant use protective of cognitive function in the community-dwelling elderly?
Am. J. Geriatr. Pharmacother.
High-dose antioxidant supplements and cognitive function in community-dwelling elderly women
Am. J. Clin. Nutr.
Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease
Neurobiol. Aging
Glutamatergic modulation of auditory information processing in the human brain
Biol. Psychiatry
Amelioration of social isolation-triggered onset of early Alzheimer's disease-related cognitive deficit by N-acetylcysteine in a transgenic mouse model
Neurobiol. Dis.
Changes in skeletal muscle proteolytic gene expression after prophylactic supplementation of EGCG and NAC and eccentric damage
Food Chem. Toxicol.
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.
A prospective randomized trial of N-acetyl cysteine administration during cold preservation of the donor liver for transplantation
Ann. Hepatol.
Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment
Am. J. Clin. Nutr.
Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study
Lancet. Neurol.
N-acetyl-cysteine against noise-induced temporary threshold shift in male workers
Hear. Res.
N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial
J. Affect. Disord.
Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder
Prog. Neuropsychopharmacol. Biol. Psychiatry
Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine
Brain Behav. Immun.
Blood–brain barrier breakdown in the aging human hippocampus
Neuron
Effect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study
Reprod. Biomed. Online
Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome
Eur. J. Obstet. Gynecol. Reprod. Biol.
Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury
Mol. Neurobiol.
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)
Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease
Neurology
A key role for an impaired detoxification mechanism in the aetiology and severity of autism spectrum disorders
Behav. Brain Funct.
N-acetyl-cysteine prevents toxic oxidative effects induced by IFN-alpha in human neurons
Int. J. Neuropsychopharmacol.
Effect of N-acetylcysteine on inflammation biomarkers in pediatric acute pyelonephritis: a randomized controlled trial
Iran. J. Kidney Dis.
Effects of brain-directed nutrients on cerebral blood flow and neuropsychological testing: a randomized, double-blind, placebo-controlled, crossover trial
Adv. Mind Body Med.
Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation
J. Psychoact. Drugs
Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans
Neuropsychopharmacology
What causes Alzheimer's disease?
Folia Neuropathol.
A prospective randomized study using N-acetyl-l-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation
Bone Marrow Transpl.
Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats
J. Neurosci.
Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial
BMC Med.
Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting
CNS Spectr.
Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Arteriel
J. Am. Geriatr. Soc.
Oxidative stress, redox signalling and endothelial dysfunction in ageing-related neurodegenerative diseases: a role of NADPH oxidase 2
Br. J. Clin. Pharmacol.
Oxidative stress and β-amyloid protein in Alzheimer's disease
Neuromol. Med.
Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial
PLoS ONE
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