The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders

FAB RESEARCH COMMENT:

This comprensive, detailed open-access review, by leading researchers in this area, provides an excellent summary of the research to date into the possible benefits of dietary supplementation with N-acetyl cysteine as an adjunctive treatment for many different psychiatric disorders.

Some promising results have been found in clinical trials to date, but as usual for nutritional treatments, studies have been small and short-term. The authors flag the particular need for future trials to take into account both

• the high co-occurrence between different psychiatric disorders (which adds to the heterogeneity of populations studied)
• the relatively long time period that may be needed for benefits from NAC to become apparent   

As they conclude:

"NAC currently has the most evidence for its use in the treatment of negative symptoms of schizophrenia (if treatment continues for at least 24 weeks), severe autism spectrum disorder, OCD, and obsessive-compulsive-related disorders."


And the following excerpt from the introduction provides an excellent summary of the rationale for considering NAC as a potential adjunctive treatment in conditions involving excessive oxidative stress.

This is a characteristic feature of many psychiatric disorders (particularly autism and schizophrenia spectrum conditions, and neurodegenerative conditions such as dementia) and is both excerbated by, and contributes to inflammation - a well documented feature in many patients with clinical depression, anxiety and/or substance use disorders.



"NAC has multiple relevant actions including antioxidant effects, reduction of cytokine activity, modulation of dopamine release, reversal of mitochondrial dysfunction, reductions in apoptosis and ferroptosis, anti-inflammatory activity, increased neurogenesis, and increased glutamate release [1–10]. Perhaps the most important of these for the treatment of psychiatric disorders is its antioxidant activity, which it achieves through multiple mechanisms.

NAC functions as an antioxidant through stimulating the synthesis of glutathione, enhancing glutathione-S-transferase activity, scavenging free radicals, and stimulating group II metabotropic glutamate receptors to decrease glutamate transmission [2]. Glutathione is the primary endogenous antioxidant in the brain. Its production rate is limited by L-cysteine availability, so increasing the supply of L-cysteine via NAC supplementation leads to an increase in brain glutathione [3].

Antioxidants reduce oxidative stress, which is implicated in the pathogenesis of many psychiatric disorders [11]. Oxidative stress represents a state in which there is an imbalance between reactive oxygen species, such as hydrogen peroxide, superoxide, and peroxynitrite, and tissue redox defenses. It can be the result of having increased reactive oxygen species, decreased antioxidant defenses, or unrepaired oxidative damage [12].

Reactive oxygen species cause cellular lipid peroxidation, inactivation of important enzymes, malfunction of the respiratory chain, and DNA modification [11, 12]. Antioxidant enzymes, such as superoxide dismutase, glutathione reductase and peroxidase, metabolize reactive oxygen species into less toxic molecules, protecting the brain from harms caused by oxidative stress [12].

Severe prolonged oxidative stress can lead to glutathione depletion via the increase in glutathione disulfide formation and accumulation, leading to export and extracellular hydrolysis, protein S-glutathionylation, and formation of glutathione adducts [13]. Oxidative stress is linked to mitochondrial dysfunction, which NAC has been shown to prevent [4, 5]."