The antioxidant N-acetylcysteine (NAC) has been found to reduce many types of habitual behavior, from gambling to drug use to compulsive hair-pulling. A recent study by researcher Gihyun Yoon and colleagues, which was presented at a 2015 scientific meeting, found that while NAC and placebo reduced days of heavy drinking by about the same rates, NAC significantly reduced alcohol cravings and quality of life compared to placebo among participants with alcohol dependence.
In the 8-week study, 44 participants aged 18–65 received either 3600mg/day of NAC or a placebo. This dose of NAC was higher than the 600mg–2400mg doses that have typically been used in research settings, and there were few side effects, confirming that NAC is a safe treatment.
The authors are not sure how NAC produces this effect, but it may be by regulating the neurotransmitter glutamate.
Glia are brain cells that surround neurons and synapses, protecting and insulating them. Chronic cocaine use and withdrawal changes the way certain glial cells, called astrocytes, interact with neurons. In particular, chronic cocaine use and withdrawal can shrink astrocytes and cause them to pull away from neurons. Cocaine use and withdrawal also interfere with the way the neurotransmitter glutamate is cleared from synapses and transported into astrocytes.
New research shows that certain medications that regulate and increase the movement of glutamate from the synapse into glial cells can reduce cravings for cocaine.
In studies of rats chronically exposed to cocaine and then denied access to it, treatment with these glutamate-targeting medications reduces the rats’ cocaine-seeking behaviors. The medications include N-acetylcysteine (NAC), an antioxidant that can reduce habitual behaviors, including addictive behaviors; riluzole, a treatment for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease; the antibiotic ceftriaxone; and propentofylline, which has been explored as a possible treatment for dementia and stroke.
The antioxidant N-acetylcysteine (NAC) has been found to be an effective treatment for a variety of habit-based behaviors—substance abuse, including cocaine, alcohol, marijuana, and nicotine; gambling; obsessive-compulsive behaviors; trichotillomania (compulsive hair-pulling), and repetitive behaviors among people with autism. Recent research by researcher Jon Grant and colleagues revealed that NAC can also treat skin-picking disorder.
At a 2015 scientific meeting, Grant reported that 1200–3000mg of NAC per day led to improvement in 47.1% of patients with a skin-picking disorder, compared to 19.2% improvement in patients who received placebo.
In addition to its positive effects in people with addictions and habit-based behaviors, NAC has also improved mood and anxiety in bipolar disorder and treated negative symptoms of schizophrenia, such as withdrawal and lack of motivation.
Editor’s Note: Given NAC’s effectiveness in such a wide range of disorders and behaviors, it could be a particularly useful treatment for people with major psychiatric disorders, such as bipolar disorder or schizophrenia, with co-occurring substance abuse.
N-acetylcysteine (NAC) is an anti-oxidant nutritional supplement that has been found to reduce a wide range of habitual behaviors, including drug and alcohol use, smoking, trichotillomania (compulsive hair-pulling), and gambling. It also improves depression, anxiety, and obsessive behaviors in adults, as well as irritability and repeated movements in children with autism. A new study suggests NAC may also be able to reduce non-suicidal self-injury, often thought of as “cutting,” in girls aged 13–21.
The open study, presented in a poster by researcher Kathryn Cullen at the 2015 meeting of the Society for Biological Psychiatry, compared magnetic resonance imaging (MRI) scans of 15 healthy adolescent girls to scans of 22 girls who had been engaging in self-injury, both before and after this latter group received eight weeks of treatment with N-acetylcysteine. Doses were 1200 mg/day for the first two weeks, 2400mg/day for the next two weeks, and 3600mg/day for the final four weeks. The girls also reported their self-injury behaviors.
Treatment with NAC reduced the girls’ self-injury behaviors. The brain scans showed that NAC also increased resting-state functional connectivity between the amygdala and the insula. Connectivity in this region helps people regulate their emotional responses. At baseline, the girls who engaged in self-harm had had deficient connectivity between the amygdala, the prefrontal cortex, insula, and the posterior cingulate cortices compared to the healthy girls, and this improved with the NAC treatment.
We reported in 2014 that researchers Ahmad Ghanizadeh and Ebrahim Moghimi-Sarani had found that the over-the-counter nutritional supplement n-acetylcysteine (NAC) added to the atypical antipsychotic risperidone reduced irritability in autism more than placebo added to risperidone.
A randomized, double-blind, placebo-controlled clinical trial published by M. Nikoo and colleagues in Clinical Neuropharmacology in 2015 replicated these results. Forty children with autism disorders aged 4–12 years were randomized to receive either risperidone plus NAC or risperidone plus placebo. Risperidone doses were between 1 and 2 mg/day, and NAC doses were 600 to 900 mg/day. By the end of the 10-week study, those children who received NAC had significantly greater reductions in irritability and hyperactivity/noncompliance than those who received placebo.
Editor’s Note: Three placebo-controlled studies have supported the efficacy of NAC in autism. One 2012 study, by A.Y. Hardan in Biological Psychiatry, evaluated monotherapy with oral NAC. In the other two, NAC was added to treatment with risperidone.
Nicotine addiction is highly cue-dependent, meaning that certain situations or places will make smokers crave a cigarette even if they’re trying to quit. Researchers working with rodents are exploring a combination of treatments that address different behavioral and neurobiological mechanisms to reduce nicotine addiction. In a recent study by Cassandra Gipson-Reichardt and colleagues, N-acetylcysteine reduced cue-induced nicotine seeking, while varenicline reduced nicotine self-administration. Together the drugs worked better to reduce nicotine relapse than either drug on its own.
In the study, rats were trained to self-administer nicotine (with 0.02mg/kg infusions), and cues were used to reinstate nicotine seeking. The rats were treated with 10 and 30 mg/kg injections of NAC and 1 and 3 mg/kg injections of varenicline.
Relapse is associated with rapid synaptic potentiation in the reward area of the brain, the nucleus accumbens. In addition to the positive behavioral changes noted, NAC also inhibited this synaptic potentiation, limiting rapid changes in the size of spines on dendrites and reducing the ratio of AMPA to NMDA (two different compounds that mimic glutamate) in the core of the nucleus accumbens.
Editor’s Note: The combination of NAC and varenicline has not yet been studied in humans, but because both compounds are effective in reducing smoking, it is likely that this animal research on nicotine will be replicated in humans who are addicted to the nicotine in cigarettes.
Cutting, or non-suicidal self injury, is a serious problem among adolescents, and few treatments are available. Researcher Kathryn Cullen and colleagues have found that N-acetylcysteine (NAC), an antioxidant nutritional supplement that has been effective in the treatment of depression and many addictions and habit-related behaviors, can reduce cutting.
The study included 25 participants with a history of non-suicidal self injury, aged 13–21, and 12 controls. They participated in brain scans before and after treatment. Compared to the controls, the self-injurers showed greater overall psychopathology, greater activation in a few brain regions (precuneus, posterior cingulate, insula, and temporal lobes), and reduced lower left frontal activation. Patients who received NAC up to 900mg twice daily in weeks 5–8 of the study reduced their cutting and also showed reduced psychopathology. An increase in frontal activation in response to negative emotion was linked to the reduction in cutting.
Editor’s Note: NAC improves mood in depression, many addictions, and many habits including trichotillomania (excessive hair-pulling), nail biting, and cutting. It may do this by increasing glial glutamate transporters in the nucleus accumbens, the brain’s reward center, which lessens the magnitude of the glutamate signal, mediating the compulsion to engage in the habitual behavior.
At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, Fung et al. presented a meta-analysis of treatments for autism that ranked them in terms of statistical effect size, ranging from 0.9 (large), to 0.5 to 0.8 (medium), to <0.4 (small). The only drug with a large effect size was risperidone, at 0.9. Most effect sizes were medium, including aripiprazole at 0.8 and N-acetylcysteine (NAC) at 0.7. Both clonidine and methylphenidate had effect sizes of 0.6, and tianeptine’s was 0.5.
Fung and colleagues noted that the first two on the list, the atypical antipsychotics risperidone and aripiprazole, often have problematic side effects (such as sedation, weight gain, and motor symptoms) that must be balanced against their effectiveness. In contrast, NAC is well tolerated with few side effects, and two placebo controlled studies showed that it was effective both alone and as an adjunctive treatment to the antipsychotic risperidone.
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Rieva et al. reported that 60% of bipolar patients with comorbid alcohol abuse have attempted suicide, and 48% of bipolar patients with cocaine abuse have attempted suicide. Thus, both of these comorbidities deserve specific attention and treatment. Unfortunately there are currently no Federal Drug Administration–approved drugs for bipolar patients with these comorbidities. The most promising treatments, based on data in patients with primary addictions, are the nutritional supplement N-acetylcysteine and topiramate, which have both performed better than placebo in studies of alcohol and cocaine abuse disorders.
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher N. Miyake described the effects of the nutritional supplement n-acetylcysteine (NAC) on clinical symptoms in subjects with subthreshold symptoms of psychosis.
N-acetylcysteine, a glutathione precursor, has neuroprotective effects. In this case series, four patients with subthreshold psychosis were given 2000mg/day of NAC for 12 weeks. The patients’ symptoms improved to the point that three of the four were no longer considered at risk for psychosis.
Editor’s Note: These promising anecdotal observations deserve careful follow up using a control group. Omega-3 fatty acids have been show to slow conversion to full psychosis and performed better than placebo in a controlled study. Both n-acetylcysteine and omega-3 fatty acids should definitely be studied for those with emerging symptoms of bipolar disorder.