N-Acetylcysteine - Little-Known Role in Mental Health

Over the last year or so, Naturopathic Currents covered several novel agents that are important with respect to mental health, including vitamin D, choline, and GABA. In this article, we discuss another up-and-coming agent: N acetylcysteine (NAC). There is a body of emerging evidence suggesting potent effects of NAC in a variety of psychiatric conditions, including depression, bipolar disorder, addiction, and schizophrenia.

NAC is an intriguing nutrient best known for its role in liver health and detoxification pathways. NAC functions as a cysteine donor (a sulfur-containing amino acid) and precursor for glutathione synthesis; glutathione (GSH) is a powerful antioxidant enzyme present within cells, including hepatocytes (liver cells), and is crucial for metabolizing heavy metals, toxins, and metabolic byproducts.^{[1, 2, 3]} Because of its hepatoprotective effects, NAC is the accepted antidote for acetaminophen (Tylenol) toxicity.^[4] Large amounts of glutathione are required to break down acetaminophen; in the event of overdose, glutathione is depleted, and the toxic metabolite of acetaminophen accumulates, resulting in permanent damage to liver cells.^[4] Because NAC increases glutathione synthesis, the treatment for Tylenol overdose is high-dose NAC administration. Glutathione is also critical in the detoxification of a host of other drugs, environmental toxins, and byproducts of cellular metabolism.^[5]

In the brain, increased levels of glutathione may help reduce oxidative stress. Researcher Ana Andreazza from the University of Toronto has published many studies on the role of oxidative stress in psychiatric illness.^[6] High levels of oxidative stress have been identified in the brains of patients with depression, bipolar disorder, and schizophrenia,^{[7, 8, 9]} and this has been associated with damage to specific mitochondrial proteins and transporters, leading to potentially impaired energy metabolism by these cells.^{[10, 11]} In a postmortem study using imaging techniques called immunohistochemistry and Forster resonance energy transfer (FRET), researchers found increased levels of protein oxidation and nitration in the dopamine-rich regions of the prefrontal cortex in patients with bipolar disorder and schizophrenia.^[7] Another study found that there were elevated levels of 4 hydroxynonenal (4 HNE), a major product of lipid peroxidation, in the brains of patients with bipolar disorder and schizophrenia.^[8] Finally, another study found that patients with psychiatric disorders including major depression, bipolar disorder, and schizophrenia had decreased brain levels of glutathione, which may increase their susceptibility to oxidative stress.^[9] NAC supplementation has been shown to increase brain glutathione levels,^[2] and may help protect neurons from oxidative damage.

A second mechanism for NAC in the brain is modulation of glutamate signaling. Glutamate is the primary excitatory neurotransmitter in the brain.^[12] Glutamate is important in mediating neuroplasticity and learning in the brain through its interaction with the N methyl-D aspartate (NMDA) receptor; however, when present at high levels, glutamate stimulation can lead to neurotoxicity through overstimulation of cells, and can even lead to neuronal and glial cell death through a process called excitotoxicity.^[12] A number of mood-stabilizing medications decrease excitotoxicity or target the glutamatergic system, such as lithium and valproate,^[12] and excess glutamate tone is now thought to have a role in psychiatric conditions including bipolar disorder and schizophrenia. For instance, a meta-analysis of studies using proton magnetic resonance spectroscopy imaging found that patients with bipolar disorder had significantly higher levels of glutamate and glutamine in all areas of the brain compared to healthy subjects, and this was irrespective of whether they were medicated or not.^[12]

Abnormal NMDA receptor stimulation, specifically NMDA hypofunction, has been proposed as a model for schizophrenia.^[13] Reduced NMDA receptor signaling is associated with reduced inhibition of glutamate release, so reduced NMDA receptor signaling leads to excess release of glutamate by neurons.^[13] Interestingly, the NMDA receptor is especially sensitive to oxidation: antioxidants (reducing agents) such as glutathione and lipoic acid increase NMDA activity, while pro-oxidants decrease activity. In addition, activation of presynaptic metabotropic glutamate receptors (mGluR2/3) leads to decreased glutamate release and thus inhibited excitotoxicity.^[13] NAC supplementation has been shown to stimulate mGluR activity, resulting in decreased excitotoxicity.^[13] As such, NAC may ameliorate underlying metabolic problems associated with psychiatric conditions through two mechanisms: generation of the antioxidant glutathione, as well as modulation of glutamate signaling. We will now examine some of the clinical research pertaining to NAC in these conditions.

Bipolar Depression

Several studies have examined the effects of NAC supplementation on bipolar depression. A study by Magalhães et al. examined the effectiveness of 2 g NAC daily for 24 weeks.^[14] A total of 17 patients with bipolar disorder experiencing major depressive episodes were randomized to receive NAC or placebo. The study reported “very large effect sizes in favor of NAC” for depressive symptoms: eight out of 10 patients treated with NAC were defined as having a treatment response, compared to only one out of seven who received placebo. A subgroup analysis of this study was done evaluating 14 patients with bipolar II, a variant characterized by dominance of depressive symptoms.^[15] Of these patients, six of seven patients receiving NAC achieved full remission of both depressive and manic symptoms, compared to only two of seven patients in the placebo group. While this is too small a study to draw conclusions from, it is encouraging and provides a strong basis for further investigation.

An study by Berk et al. examined 149 individuals with moderate depression who received 2 g NAC or placebo in a randomized controlled trial assessing NAC as a maintenance treatment for bipolar.^[16] The estimated mean Bipolar Depression Rating Scale (BDRS) score at baseline was 19.7, while at the end of the 8-week open-label phase, the score had decreased to 11.1. There were improvements in functioning and quality of life. Berk et al. also report a randomized controlled trial examining 75 patients with bipolar disorder.^[17] Two grams (2 g) NAC or placebo was given for 24 weeks, as an adjunct to usual medications. At the end of 24 weeks of treatment, the group receiving NAC showed significant improvements in the Montgomery Asberg Depression Rating Scale (MADRS), global functioning, as well as social and occupational functioning. Patients then underwent a four-week washout, where NAC was not given; after this time, observed improvements were lost, confirming the causal role of NAC treatment. In general, the improvements seen were rated as “medium to high”.^[17]

In addition to clinical research, which suggests the safety and additive benefit from adding NAC to conventional treatments, there have been preliminary animal studies into the way NAC may interact with conventional antidepressant medications.^[18] One study examined the impact of NAC when added to antidepressant therapy in mice.^[18] The study found that “a subeffective dose of NAC reduced the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion”.^[18] The same subeffective dose of NAC increased the minimum effective dose of fluoxetine, which may indicate a need for further human level research in this area.

In addition to depression, there has also been research into the mood-stabilizing effects of NAC in bipolar mania or hypomania.^[19] A total of 15 patients participated in a randomized, controlled trial, receiving 2 g NAC for 24 weeks during mania or hypomania, or placebo, in addition to their usual medications, which included lithium, mood stabilizers, atypical antipsychotics, antidepressants, and benzodiazepines. Results showed that there was a significant improvement in manic symptoms measured on the Young Mania Rating Scale (YMRS) in the NAC group over this period of time, while during the same period, there was no significant change in mania and a worsening of depressive symptoms (depressive switch) in the placebo group. At the end of the 24-week treatment period, 60% of NAC-treated patients were in remission, compared to only 15% of placebo patients. As this study is limited in size, further research is needed to confirm these effects.

Schizophrenia

Several studies indicate that NAC may be of benefit in schizophrenia, acting both as a glutathione precursor and modulator of glutamate. In a proof-of-principle study, Carmeli et al. found that supplementation with NAC was able to modulate electroencephalogram (EEG) synchronicity, a measure of electrical activity within the brain, in patients with schizophrenia.^[20] Another study examined the effect of NAC 3 g on auditory processing in the brain.^[21] This study found that while NAC did not inhibit the effects of ketamine on brain function, it did reduce auditory mismatch negativity (MMN) amplitude and increased P3 amplitudes, indicating potential cognitive enhancing effects. A randomized, double-blind, placebo-controlled trial analyzed data from 84 patients with schizophrenia on maintenance antipsychotic medication.^[22] The study found that supplementation with 2 g NAC daily led to improvements in negative symptoms associated with schizophrenia, clinical global impression of disease severity, and akathisia. Negative symptoms of schizophrenia include flat affect (lack of facial expressiveness or a monotonous voice, lack of pleasure in everyday life, lack of ability to begin or sustain planned activities, and lack of speech or interaction). Akathisia refers to feelings of inner restlessness, and constant urge to be moving; it may occur as a result of antipsychotic medications. The study found no impact on positive symptoms of schizophrenia, which include hallucinations, delusions, movement disorders (agitation), or thought disorders (disorganized thinking). The effect sizes were consistent with “moderate” effects.^[22] Another randomized, double-blind, placebo-controlled trial examined the effect on NAC on mismatch negativity, which is an indicator of deficits in auditory sensory processing and occurs in patients with schizophrenia.^[23] Treatment with NAC was shown to significantly improve MMN generation, compared with placebo, indicating improvements in cognitive processing. Finally, a recent 2013 study found that NAC was a safe and effective adjunct to risperidone in the treatment of schizophrenia.^[24] Among 42 patients with chronic schizophrenia, supplementation with 2 g NAC was able to significantly lower negative symptom scores compared to placebo. There was no difference in the rate of adverse events compared to placebo, indicating that NAC is a safe add-on therapy to risperidone.

Addiction

The last area we will discuss is addiction. Use of NAC has shown promise in the treatment of substance-use disorders, including marijuana and cocaine, as well as gambling behaviour. One randomized trial found that treatment with 1200 mg NAC twice daily, versus placebo, led to increased success in marijuana cessation in cannabis-dependent adolescents, when used in addition to weekly counseling (both groups).^[25] Another study found that use of NAC during 3-day hospitalization for cocaine dependence resulted decreased desire to use and less interest in response to being shown cocaine slides, compared to placebo.^[26] Finally, another study of 27 pathological gamblers found a reduction of almost 50% in ratings on the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) scale after treatment with NAC. Almost 83% of NAC-treated participants had a treatment response at the end of 14 weeks, compared to only 28% of placebo-treated subjects.^[27]

In conclusion, these data show the promise of NAC in the treatment of a range of psychiatric conditions. NAC acts by improving glutathione status as well as by modulating glutamate transmission. NAC is safe and enhances the effectiveness of psychiatric medications used in the treatment of bipolar and schizophrenia, and deserves further research in larger clinical studies.