Reference
A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012;71(11):956-961.
Design
Double-blind, randomized, placebo-controlled trial of 12-week duration
Participants
33 subjects were randomized to the trial, 25 completed the study, and 29 were included in study data, with (N-acetylcysteine) NAC (n=14) and placebo (n=15). Participants were healthy males (n=31) and females (n=2) between the ages of 3.2 and 10.7, diagnosed with autism, with a Clinical Global Impressions Score (CGI-S) of 4 or greater on a scale of 1 to 7. These subjects all had stable care providers and medications with no planned changes for the duration of the trial. None of these had done a previous trial of NAC or were currently taking other antioxidants or glutathione prodrugs.
Study Medication and Dosage
NAC (Bioadvantex, Inc, manufacturer) 900 mg per day for the first 4 weeks, 900 mg twice per day for the next 4 weeks, then 900 mg three times per day for the final 4 weeks (or as tolerated).
Outcome Measures
Participants were evaluated at 0, 4, 8, and 12 weeks on the medication. This study focused on changes in irritability levels in patients with autism. Primary outcome measures included the Aberrant Behavior Checklist (ABC) irritability subscale and the Dosage Record and Treatment Emergent Symptom scale, which evaluates side effects. Secondary outcome measures included the ABC stereotypy subscale, Social Responsiveness Scale (SRS), Repetitive Behavior Scale-Revised (RBS-R), and the Clinical Global Impressions-Improvement Scale.
The ABC is a standardized scale with five subscales that is assigned by a clinician; this evaluates behavior problems. The SRS is a parent questionnaire that helps to assess social behavior and autistic preoccupations. The RBS-R is a clinician-assigned scale that measures restricted, repetitive behavior in autism. The CGI-S is a clinician-assigned scale that rates the severity of symptoms.
Key Findings
Primary Outcomes: NAC treatment showed significant improvement in ABC irritability subscales over placebo (P<0.001). Improvement was evident at week 4 and increased through week 12. Minimal adverse effects were observed with the exception of 1 participant whose symptoms worsened.
Secondary Outcomes
A trend toward significance in improvement was shown on the ABC stereotypic/repetitive behavior subscale, and significant improvement was shown on the RBS-R stereotype subscale. Although there was no effect on SRS total scores, improvement was shown on SRS social cognition and autism mannerisms subscales. No significant effects were shown for other SRS or ABC subscales, though a large reduction in ABC hyperactivity scores was shown at week 12. For CGI-I scales, 11 participants in the NAC group showed improvement, versus 7 in the placebo group.
Practice Implications
This study is of potential clinical relevance for treatment of autism spectrum disorders (ASDs) and other mental health issues. Two theories that have been presented as to why NAC may have clinical benefit in ASD are its effect on glutamatergic neural pathways and its use as an antioxidant.
Glutamate is well known as a primary excitatory neurotransmitter in the body. It is also important in neural and cognitive development and has been shown to modulate functions such as memory and learning. The exact role of glutamate in ASD and other mental health issues, however, is unclear. Although glutamate dysregulation has been implicated in ASD, there is controversy as to whether this is due to excessive or deficient levels. Animal models have shown behaviors associated with ASDs as a result of hypo-glutamatergia; however, excessive glutamate signaling has also been shown to cause behavioral changes consistent with ASDs.1 Animal studies have also shown a decrease in ASD behaviors with glutamate receptor blockers.2 Some models are now indicating that the expression of ASD traits are associated with glutamate receptor dysregulation, rather than absolute glutamate levels.3
Some models are now indicating that the expression of ASD traits are associated with glutamate receptor dysregulation, rather than absolute glutamate levels.
In this study, it is postulated that NAC may be effective in modifying irritability via the glutamatergic pathway by increasing extracellular cystine, the oxidized form of cysteine. Ultimately, extracellular cystine leads to lowering the concentration of glutamate at the synapse.
Cystine causes an increase in nonvesicular transport of glutamate to the extracellular space. This stimulates inhibitory type 2 and 3 metabotropic glutamate receptors, which reduces the synaptic vesicular release of glutamate. This in turn reduces the excitatory-to-inhibitory ratio, which theoretically results in decreased irritability. A similar increase in extracellular glutamate from taking NAC has been seen in the nucleus accumbens, the part of the brain associated with pleasure, reward, and addiction. Studies on gambling, cannabis, and cocaine dependency have shown a decrease in these addictive behaviors with the administration of NAC.4,5,6 NAC has also been shown to improve symptoms of obsessive-compulsive disorder (OCD) via what is postulated to be glutamatergic pathway manipulation.7
The cocaine-dependent patients in the study mentioned above had significantly higher glutamate levels in the anterior cingulate cortex than healthy control subjects; these higher baseline levels were associated with more impulsive behavior. Interestingly, administration of NAC decreased glutamate levels in the cocaine-dependent group but did not affect the healthy controls.8 This supports the assertion that the concern isn’t necessarily glutamate excess or deficiency, but rather the inability to properly use glutamate via transport between the neuron and the extracellular space.
Another possibility for NAC’s mechanism of action is increasing antioxidant capacity. NAC has been shown to increase glutathione, a dominant redox reduction system within cells. Redox imbalance and possible impairment of antioxidant status may play a role in ASD. Studies have looked at substances such as vitamin C and omega-3 fatty acids, but these showed less benefit than NAC.9,10 The possible difference between NAC and other antioxidants in this case is that cysteine is a precursor to glutathione and thus will increase the size of the glutathione pool. Other antioxidants such as vitamin C will only reduce oxidized glutathione and will not affect the overall amount available, which is the postulated difference in efficacy between vitamin C and glutathione
It is however possible that the theories of glutamate manipulation versus antioxidant status as contributing factors for ASD are 2 pieces of the same puzzle. One trial found NAC had significant benefit on depression. In this case, the authors note “oxidative stress processes might play a relevant role in the pathogenic mechanisms underlying many major psychiatric disorders … reactive oxygen and nitrogen species have been shown to modulate levels and activity of noradrenaline, serotonin, dopamine and glutamate.”11 Whereas glutamate imbalance may be associated with symptoms of ASD, that imbalance may be the result of oxidation.
NAC has shown clinical benefit in ASD, as well as other mental health issues, including depression, OCD, and addiction. Whether as an antioxidant or by manipulating glutamate, it seems to be able to help balance neurotransmitter levels. It can improve symptoms of irritability, depressed mood, and impulsivity. Given its very low potential for side effects, NAC could be a useful adjunct to other therapies for these conditions.
