N-acetylcysteine: A Promising Treatment of Many Disorders

N-acetylcysteine (NAC) is an amino acid widely used in emergency rooms to treat people who overdose on acetaminophen (Tylenol™). Studies have investigated the effectiveness of NAC both as a stand-alone and adjunctive treatment of depressed mood, bipolar disorder, schizophrenia, and trichotillomania, as well as nicotine, Cannabis, and cocaine abuse and dependence. This post is offered as a concise summary of research highlights.

How NAC is beneficial for brain function

NAC is a necessary precursor of glutathione, a molecule that reduces the cell damage caused by "free radicals." NAC also decreases blood levels of molecules that cause inflammation in the body and brain, such as interleukin-6, which may play a role in the pathogenesis of schizophrenia, bipolar disorder, and depressed mood (Drexhage et al 2010). A third proposed mechanism of action has to do with the stimulation of the increased synthesis and release of the neurotransmitters glutamate and dopamine (Gere-Paszti & Jakus 2009).

NAC as a treatment of particular psychiatric disorders — what the evidence suggests

A meta-analysis and systematic review of placebo-controlled studies on NAC as a stand-alone treatment of depressed mood in individuals diagnosed with major depressive disorder, bipolar disorder, and other psychiatric disorders (Fernandes et al 2016) found evidence for moderately improved depressed mood and improved global functioning.

In a four-month, double-blind study, individuals treated with NAC plus their usual antidepressant improved more than individuals taking a placebo with their antidepressant medication (Berk et al 2014). Individuals with bipolar disorder may also have relatively higher oxidative stress, especially during acute mania, compared to the healthy population. NAC supplementation at doses of 2 gm/day may be beneficial for bipolar depressed mood; however, the findings of placebo-controlled studies are inconsistent (Berk et al 2008a; Berk et al 2011; Berk et al 2012; Berk et al 2019).

It has been suggested that individuals with schizophrenia—as in those with bipolar disorder—may also have greater oxidative stress that may predispose them to changes in neuronal cell membranes and mitochondrial function that manifest as symptoms of schizophrenia (Carter 2006). NAC supplementation may reduce the severity of psychotic symptoms by reducing overall oxidative stress and increasing CNS glutamate levels (Carlsson 2006).

In a large, six-month, double-blind study, individuals with schizophrenia who had failed to respond to multiple trials on antipsychotics (including clozapine) were treated with NAC 1,000 mg twice daily or a placebo while taking their usual antipsychotic medication (Berk et al 2008b). Importantly, individuals taking NAC experienced moderate improvements in symptoms of apathy and social withdrawal (i.e., so-called "negative" symptoms), improvements in day-to-day functioning, and fewer abnormal involuntary movements caused by their antipsychotic.

NAC as a treatment of substance abuse

NAC has been investigated as a treatment of substance use disorders with promising results. As in mood disorders, the beneficial effects of NAC may be related to its role in restoring neurotransmitter activity affected by chronic substance abuse (Madayag et al 2007). The findings of small, placebo-controlled studies suggest that NAC in total daily doses of 1,200 to 3,600 mg help heavy Cannabis users to reduce their use (Gray et al 2010) and may reduce the intensity of withdrawal and craving in individuals in the early stages of recovery following cocaine use (La Rowe et al 2007).

NAC for trichotillomania and other impulse control disorders

In addition to its mood-enhancing benefits, there is evidence that NAC may reduce compulsive hair pulling, nail-biting, skin picking, and pathological gambling (Grant, Odlaug & Kim 2009; Berk et al 2009). Over 80 percent of individuals with pathological gambling who responded to NAC 1,800 mg/day in an eight-week, open-label study and who were subsequently enrolled in a six-week, placebo-controlled trial continued to report significant reductions in gambling (Grant et al 2007).

Bottom line

Depressed mood, schizophrenia, impulse control disorders, and substance use disorders may be caused or exacerbated by harmful consequences of increased oxidative stress on brain function. Research findings support that NAC supplementation has beneficial effects on these disorders because of its role in restoring the body’s principal "free radical scavenger," glutathione, decreasing blood levels of pro-inflammatory molecules and enhancing the synthesis and release of neurotransmitters. Large placebo-controlled studies are needed to confirm the beneficial effects of NAC in mental health care and to determine safe, optimal dosages of NAC as a standalone or adjunctive treatment of specific psychiatric and substance use disorders.