A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder.
BACKGROUND
Social impairment is a defining feature of autism spectrum disorder (ASD) with no demonstrated effective pharmacologic treatments. The goal of this study was to evaluate efficacy, safety, and tolerability of oral N-acetylcysteine (NAC), an antioxidant whose function overlaps with proposed mechanisms of ASD pathophysiology, targeting core social impairment in youth with ASD.


METHODS
This study was a 12-week randomized, double-blind, placebo-controlled trial of oral NAC in youth with ASD. Study participants were medically healthy youth age 4 to 12 years with ASD, weighing ≥15 kg, and judged to be moderately ill based on the Clinical Global Impressions Severity scale. The participants were randomized via computer to active drug or placebo in a 1:1 ratio, with the target dose of NAC being 60 mg/kg/day in three divided doses. The primary outcome measure of efficacy was the Clinical Global Impressions Improvement (CGI-I) scale anchored to core social impairment. To investigate the impact of NAC on oxidative stress markers in peripheral blood, venous blood samples were collected at screen and week 12.


RESULTS
Thirty-one patients were enrolled (NAC = 16, placebo = 15). Three participants were lost to follow-up, and three left the trial due to adverse effects. The average daily dose of NAC at week 12 was 56.2 mg/kg (SD = 9.7) with dose ranging from 33.6 to 64.3 mg/kg. The frequency of adverse events was so low that comparisons between groups could not be conducted. At week 12, there was no statistically significant difference between the NAC and placebo groups on the CGI-I (p > 0.69) but the glutathione (GSH) level in blood was significantly higher in the NAC group (p < 0.05). The oxidative glutathione disulfide (GSSG) level increased in the NAC group, however only at a trend level of significance (p = 0.09). There was no significant difference between the NAC and placebo groups in the GSH/GSSG ratio, DNA strand break and oxidative damage, and blood homocysteine levels at week 12 (ps > 0.16).


CONCLUSIONS
The results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD.


BACKGROUND
Clinicaltrials.gov NCT00453180.
Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue MLC 4002, Cincinnati, OH 45229 USA.
Logan K
LK
Wink
Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue MLC 4002, Cincinnati, OH 45229 USA.
Ryan
R
Adams
Investigative Toxicology and Pathology, School of Public Health, Indiana University, Bloomington, IN USA.
Zemin
Z
Wang
Investigative Toxicology and Pathology, School of Public Health, Indiana University, Bloomington, IN USA.
James E
JE
Klaunig
Department of Psychiatry, Christian Sarkine Autism Treatment Center, Riley Hospital for Children at Indiana University Health, Indiana University School of Medicine, Indianapolis, IN USA.
Martin H
MH
Plawecki
Indianapolis, IN USA.
David J
DJ
Posey
Lurie Center for Autism, Departments of Psychiatry and Pediatrics, Massachusetts General Hospital and MassGeneral Hospital for Children, Harvard Medical School, Boston, MA USA.
Christopher J
CJ
McDougle
Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue MLC 4002, Cincinnati, OH 45229 USA.
Craig A
CA
Erickson
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000067877:Autism Spectrum Disorder / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000097:blood; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010865:Pilot Projects; D015990:Placebo Effect; D012919:Social Behavior
D016166:Free Radical Scavengers; D006710:Homocysteine; D005978:Glutathione; D000111:Acetylcysteine
Autism; Autism spectrum disorder; N-acetylcysteine; Oxidative stress; Social impairment