AUTHORS' CHRONICLES

Effect of NAC on human cognition

Efectos de la NAC sobre la función cognitiva en los seres humanos

Andrew Marriot¹

¹ Deakin University, Geelong, Australia

Andrew Marriot describes for SIIC his article published in Neuroscience and Biobehavioral Reviews 78:44-56, Jul 2017.

Geelong, Australia (special for SIIC)

A systematic review of the published literature related to the clinical impact of N-acetylcysteine upon human cognition was performed. N-acetylcysteine (NAC) is a glutathione precursor with potent antioxidant, pro-neurogenic and anti-inflammatory properties, and a favourable safety profile. Results were promising regarding its efficacy in combination with other supplements. However, no firm conclusions could be drawn regarding its efficacy as monotherapy.

Oxidative stress and neuro-inflammation are pathophysiological processes common to a number of psychiatric and neurological disorders, including depression, anxiety, schizophrenia, traumatic brain injury, and neurodegenerative disease. The drivers of neuronal oxidative stress and neuro-inflammation vary across the diseases, but final common pathways involve disruption of the blood brain barrier and ingress of inflammatory cells and cytokines, local production of cytokines by astrocytes and microglia, and abnormal production of reactive oxygen species. Together, this results in a neurotoxic milieu which potentiates cognitive dysfunction, a symptom common to many disorders.

One of the body's protective mechanisms against this reactionary cascade is the production of the cellular antioxidant glutathione. Glutathione is the most highly expressed endogenous intracellular antioxidant, with key roles in ameliorating oxidative stress, facilitating posttranslational protein folding, and modulating inflammatory signaling. In vivo, glutathione is synthesised from sources of cysteine, glutamic acid, and glycine, with cysteine availability considered the rate-limiting factor. N-acetylcysteine (NAC) has been widely and effectively used as a source of bio-available cysteine in the treatment of paracetamol (acetaminophen) overdose. Numerous studies have demonstrated the capacity of NAC increase serum glutathione levels, with subsequent protective antioxidant and anti-inflammatory effects. Given the link between oxidative stress, neuro-inflammation and cognitive dysfunction, and the ability of NAC to modify the cellular insult, a number of clinical trials have examined the ability of NAC to provide cognitive protection in disorders that share similar pathophysiological processes. To date, no review has attempted to collate and quantify the cognitive effect of NAC.

We performed a systematic review of the evidence by searching through the PubMed and Medline databases, using broad Boolean search terms to capture as much of the field as possible. We included any studies of adults that included NAC supplementation and cognitive testing of participants; we included healthy and clinical samples and non-blinded studies. Our initial search yielded 2175 non-duplicate results, of which 2080 were excluded after a manual scan of titles. A subsequent review of the remaining 95 abstracts excluded all but 12 studies, which were in term subject to full-text examination. All of the final 12 studies were included in the final qualitative synthesis. Four of the included studies examined Alzheimer's disease; three examined healthy participants; two examined victims of physical trauma; and one each examined schizophrenia, bipolar disorder, and ketamine-induced psychosis.

Alzheimer's disease: Adair and colleagues (2001) found significant improvement in working memory and executive function after 6 months of NAC supplementation in early-stage Alzheimer's patients in comparison to controls. Further, Chan et al. (2008) and Remington et al. (2008) found that an antioxidant formulation with substantial NAC proportion was protective against cognitive deterioration in moderate-to-late stages of the disease.

Psychosis and psychotic disorders: Gunduz-Bruce et al. (2012) found that NAC supplementation did not mitigate the cognitive dysfunction associated with ketamine-induced psychosis, and Dean et al. (2012) observed comparable effects in a bipolar sample. In contrast, Rapado-Castro et al. (2016) observed significant cognitive improvements in a pooled sample of bipolar and schizophrenia patients after 6 months of supplementation in comparison to controls.

Physical trauma and TBI: Hoffer et al. (2012) compared NAC to placebo in the setting of mild traumatic brain injury associated with blast injury, and reported significantly fewer and less severe symptoms of TBI within the NAC group compared to the placebo group. In comparison, Amen et al. (2011) performed an open-label examination of an antioxidant formulation containing NAC in a sample of retired professional American football players with mild TBI, and found some minor improvements to cognitive function, though these were not sustained after statistical adjustment.

Healthy participants: Hauer et al. (2003), Chan et al. (2010), and Amen et al. (2013) all performed randomised double-blind placebo control trials in samples of healthy adults, with Chan and colleagues and Amen and colleagues testing antioxidant formulations with substantial NAC content and Hauer et al. using a small supplementation of NAC. All studies found significant pro-cognitive effects of the intervention, though Hauer et al. did not observe a significant improvement of NAC compared with a physical exercise-and-placebo group.

The infrequency of cognition as a primary outcome, heterogeneous methodologies (design, formulations and administration regimens, co-administered treatments and method of cognitive assessment) and under-powering of studies confounded the drawing of firm conclusions. Despite this, we found some promising evidence for the efficacy of NAC. As a monotherapy (where no other supplements or interventions beyond treatment-as-usual are utilised) NAC was relatively inconsistent as a cognitive modulator. In contrast, the use of NAC in combination with other supplements (such as in part of an "antioxidant cocktail") resulted in stronger evidence suggesting clinical efficacy for cognitive protection. The direct contribution of NAC was impossible to determine. In clinical conditions where cognitive dysfunction is thought to be associated with neuronal oxidative stress and inflammation, appropriately powered randomised placebo-controlled trials with cognitive assessment as a primary outcome are required to establish the efficacy of NAC as monotherapy.