A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder

This was a randomized, double-blind, placebo-controlled pilot trial conducted in the United States. The NAC arm included 16 randomized participants who were medically healthy youth with autism spectrum disorder, aged 4 to 12 years, weighing at least 15 kg, and diagnosed with autistic disorder, PDD-NOS, or Asperger's disorder; all were judged moderately ill on the Clinical Global Impression Severity scale.

Oral N-acetylcysteine (NAC) was given as encapsulated powder capsules, titrated over the first 3 weeks to a target of 60 mg/kg/day in three divided doses, with a maximum dose of 4200 mg/day. Participants who weighed 15 to 30 kg started at 300 mg/day, and those above 30 kg started at 600 mg/day; the dose then stayed stable for the final 9 weeks of the 12-week trial.

NAC did not significantly improve core social impairment compared with placebo, although it was well tolerated and increased peripheral glutathione. On the primary CGI-I outcome, NAC response rates were 26.7% at week 4, 38.5% at week 8, and 50.0% at week 12, with no significant between-group differences at any time point (all p values > 0.60). Clinical secondary outcomes were also not significantly different between groups for ABC, SRS, or VABS-II change from baseline to week 12 (all ps > 0.13). In contrast, week 12 glutathione was higher in NAC than placebo (780.3 vs 640.4 uM; p < 0.05).

This was a small pilot study with limited power, and post-baseline analyses were based on completers rather than the full randomized sample. The 12-week duration was short, and the findings are limited to medically healthy, relatively high-functioning youth with ASD, which reduces generalizability. Peripheral oxidative stress markers were measured, but these are indirect biomarkers rather than direct measures of central nervous system effects.