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.
It appears that the nutritional supplement n-acetylcysteine (NAC) may be useful for people who want to quit smoking. Researcher Eduardo S. T. Prado et al. reported that compared to placebo, NAC decreased the number of cigarettes a patient smoked per day and the amount of carbon monoxide they exhaled. Participants in the study took 1,500mg of NAC twice a day.
Editor’s Note: It looks as though NAC is effective in most addictions, including gambling, cocaine, heroin, marijuana, alcohol, and now smoking. Since it also helps depressed mood and anxiety in patients with bipolar illness (a finding first reported by researcher Michael Berk et al. in 2008), and can improve trichotillomania and obsessive compulsive disorder (OCD), it could be an important adjunctive treatment for many patients with bipolar illness who also suffer from many of these comorbidities. The usual dose in most of these studies was 500mg twice a day for one week, then 1,000mg twice a day thereafter, as opposed to the doses of 1,500mg twice a day that were used in the smoking study.
Combination of N-acetylcysteine and Risperidone Improves Irritability in Autistic Disorders More Than Placebo and Risperidone
In a 2013 study of 40 children and adolescents with autism spectrum disorders published by Ahmad Ghanizadeh and Ebrahim Moghimi-Sarani in the journal BMC Psychiatry, the combination of the over-the-counter nutritional supplement n-acetylcysteine (NAC) and the atypical antipsychotic risperidone alleviated irritability more than the combination of placebo and risperidone. Side effects were mild. The data extend 2012 observations by A.Y. Hardan et al. in which NAC improved irritability and stereotypy (repeated behavior) in autism more than placebo did.
The two studies taken together support the effectiveness of NAC prescribed either alone or in conjunction with an atypical antipsychotic for the treatment of autism.
New discoveries in neuroanatomy are helping clarify what addiction looks like in the brain. Peter Kalivas of the Medical University of South Carolina reported at the 2013 meeting of the Society of Biological Psychiatry that most drugs of abuse alter glutamate levels and the plasticity of synapses in the nucleus accumbens, the reward area of the brain. Glutamate is the main excitatory neurotransmitter in the brain, and compulsive habits may be associated with increased release of glutamate in this brain area.
During chronic cocaine administration, for example, the neurons in the nucleus accumbens lose their adaptive flexibility and their ability to respond to signals from the prefrontal cortex. Normally, low levels of stimulation would induce long-term depression (LTD) while high levels of stimulation would induce long-term potentiation (LTP). These are long-term changes in the strength of a synapse, which allow the brain to change with learning and memory. When long-term potentiation and long-term depression are no longer possible, memory and new learning in response to messages from the prefrontal cortex are diminished.
Given this absence of flexible responding, animals extinguished from cocaine self-administration (when a lever they had pressed to receive cocaine ceases to provide cocaine) are highly susceptible to cocaine reinstatement if a stressor is presented or if a signal appears that suggests the availability of cocaine. This cocaine reinstatement is associated with high levels of glutamate in the nucleus accumbens, so Kalivas reasoned accurately that lowering these levels would be associated with a lesser likelihood of cocaine reinstatement.
The drug N-acetylcysteine (NAC), which is available from health food stores, decreases the amount of glutamate in the nucleus accumbens by inducing a glutamate transporter in glial cells that helps clear excess synaptic glutamate. In Kalivas’ research, NAC prevented cocaine reinstatement, cocaine-induced anatomical changes in spine shape (bigger, stubby spines), and the loss of long-term potentiation and long-term depression in the nucleus accumbens.
The findings on NAC in animal studies led to a series of important small placebo-controlled clinical trials in people with a variety of addictions, and positive results have been found using NAC in people addicted to opiates, cocaine, alcohol, marijuana, and gambling. It also decreases hair-pulling in trichotillomania and reduces stereotypy and irritability in children with autism.
NAC also appears to be effective in the treatment of unipolar and bipolar depressed patients in placebo-controlled trials by Australian researcher Michael Berk. Thus, NAC could be useful for patients with affective disorders who are also having difficulties with comorbid substance use.
Some antibiotics (that are not commonly available) also induce the glutamate transporter and glial cells of the nucleus accumbens, offering a potential new approach to treating some addictions.
Michael E. Hoffer et al. reported in the journal PLosOne in 2013 that veterans with blast-induced mild traumatic brain injury had a better acute outcome when they were given the antioxidant N-acetylcysteine (NAC) within the first 24 hours after the trauma versus when they were given placebo during the same period. Forty-two percent of those receiving placebo had a good acute outcome, while 86% of those receiving N-acetylcysteine had a good acute outcome. Memory loss, sleep disturbance, dizziness, and headaches all improved more in the N-acetylcysteine group. NAC’s benefits diminished when it was given 3 or 7 days after the trauma.
Editor’s Note: These data add to the growing list of neuropsychiatric syndromes in which NAC has shown efficacy. These include schizophrenia, bipolar depression, unipolar depression, cocaine and heroin addiction, gambling addiction, trichotillomania (compulsive hair-pulling), obsessive-compulsive disorder (as an adjunctive treatment to SSRIs), and improvement in irritability and stereotypy (repetitive behaviors) in children with autism.
Given what appears so far to be a relatively benign side effects profile for NAC, and the potential for severe consequences from traumatic brain injury (TBI), a case for wider use of NAC (for example in emergency rooms) might be made.
The mechanisms of action of NAC in different syndromes remains to be clarified. Researcher Michael Berk used NAC in schizophrenia and bipolar disorder and more recently in unipolar depression because it has antioxidant properties. Peter Kalivas found that NAC can normalize glutamate in the reward area of the brain through actions on the cystine-glutamate exchanger, and it also increases clearance of glutamate by increasing the glutamate transporter in glial cells. NAC decreases the amount of cued glutamate release in a part of the brain called the nucleus accumbens, which may be helpful in recovery from pathological habits. NAC also has anti-inflammatory and perhaps neuroprotective effects, and it increases brain-derived neurotrophic factor (BDNF), which protects neurons and is important for long-term learning and memory. Which of these many actions is important in the treatment of PTSD is not yet known.
N-acetylcysteine (NAC) is a drug available over-the-counter in health food stores that is effective in a variety of disorders, including trichotillomania (compulsive hair-pulling) in adults. Researcher Michael Block of Yale University reports that, in contrast to NAC’s robust effects in adults, the drug was not effective in children with trichotillomania aged 8 to 17. However, behavior therapy has been reported to be effective in both adults and children.
Editor’s Note: Why a drug that is so effective for trichotillomania in adults does not work well or at all in children is not clear. It is even more perplexing given that NAC has shown robust effects on some other childhood disorders, such as irritability and stereotypy in children with autism. However, if this discrepancy and other differences in pharmacological response across demographics are replicated, the reasons for differential response should be investigated.
As many researchers have emphasized, kids are not just shorter adults, but might have entirely different brains that are in a different stage of development. Extrapolating the therapeutic effects that occur in adults to children may not always be a valid strategy.
The antioxidant N-acetylcysteine (NAC), which can be found in health food stores, seems to be effective for irritability and repetitive behaviors in children with autism. In a small controlled study that was published by Hardan et al. in the journal Biological Psychiatry in 2012, 33 mostly male children with autism (aged 3-12 years) received either placebo or NAC at doses of 900mg daily for 4 weeks, followed by 900mg twice daily for 4 weeks, then 900mg three times a day for 4 weeks. Beginning in week 4, the children receiving NAC showed significantly improved irritability scores, and a trend for improvement in repetitive behaviors.
Social responsiveness did not improve significantly, but the children receiving NAC did show some improvement in some areas of social behavior, such as social cognition and autism mannerisms.
There were few side effects associated with NAC. The most significant were gastrointestinal side effects, but these were mild, especially when compared with the side effects associated with FDA-approved treatments for autism, such as the atypical antipsychotics risperidone and aripiprazole.
The authors of the study plan to expand their research in a study of more than 100 children with autism.
Editor’s Note: It should we previously summarized this study in the BNN based on research presented by Fung et al. at a meeting of the American Academy of Child and Adolescent Psychiatry two years ago. The study has now been published.
N-acetylcysteine (NAC) is a drug available over-the-counter in health food stores that seems to be effective for a variety of disorders, including depression and many different habits and addictions. Preventing relapse of cocaine abuse is one of its uses. Researcher Kathryn Reissner at the Medical University of South Carolina found that NAC increases the expression of a glial glutamate transporter (GLT-1) that helps clear excessive glutamate in the nucleus accumbens, and that this mechanism is critical to preventing the reinstatement of cocaine self-administration in rodents.
As we have previously described in the BNN, NAC also decreases cued release of glutamate in the nucleus accumbens by potentiating the cystine-glutamate exchanger. This initially increases extrasynaptic glutamate, but subsequently downregulates glutamate release in the nucleus accumbens through actions at an inhibitory presynaptic metabotropic glutamate receptor.
However, the new data indicate that this action at the cystine-glutamate exchanger is not required for NAC’s effects on cocaine reinstatement, but the induction of GLT-1 is. Furthermore, another compound, propentofylline, which increases glutamate GLT-1, is also effective in suppressing cocaine reinstatement. Cocaine decreases a marker of glial activity, glial fibrillary acidic protein (GFAP), in the nucleus accumbens, suggesting that deficient glial functioning and uptake of glutamate could be another target of therapeutics in cocaine addiction.
Editor’s Note: There are also glial deficits in depressed patients, so it is conceivable that NAC’s effect on GLT-1 glutamate clearance is also involved in the antidepressant effects of NAC.