In a rigorous trial of 192 youth with cannabis use disorder, N-acetylcysteine (NAC) performed no better than placebo when not paired with contingency management, despite prior positive findings.
Addiction medicine clinicians, youth substance use treatment programs, researchers studying CUD pharmacotherapy
What the researchers found
In a double-blind RCT of 192 treatment-seeking youth (ages 14-21) with CUD, N-acetylcysteine 1200 mg twice daily for 12 weeks showed no advantage over placebo on any cannabis use outcome. The proportion of negative urine tests did not differ (RR=0.93, p=0.80), nor did self-reported abstinence (RR=1.02, p=0.93). Both groups reduced cannabis use over time, but there was no between-group difference. NAC caused significantly more GI side effects (64% vs 39%).
Why it matters
A previous trial of NAC for youth CUD showed positive results, but that trial included contingency management (paying participants for negative drug tests). This follow-up demonstrates that NAC alone, without that behavioral platform, is not effective, fundamentally reframing what drove the earlier positive findings.
The numbers in context
192 youth randomized; ages 14-21; 12-week treatment; negative urine tests RR=0.93 (95% CI: 0.53-1.64, p=0.80); self-reported abstinence RR=1.02 (p=0.93); GI adverse events: 64% NAC vs 39% placebo (p<0.001)
How the study worked
Double-blind, placebo-controlled randomized trial. 192 treatment-seeking youth (ages 14-21) with CUD randomized to NAC 1200 mg or placebo twice daily for 12 weeks. All received weekly medical management and brief behavioral counseling. Primary outcome: proportion of negative urine cannabinoid tests during treatment.
What this study cannot tell us
Treatment-seeking youth may differ from the broader CUD population. Weekly medical management and counseling provided to both groups may have diluted any NAC effect. 12-week duration may be insufficient. High GI side effect rate may have functionally unblinded some participants.
How to read the evidence
Strong: well-powered double-blind RCT with objective primary outcome (urine testing) and pre-registered design.
When this study was published
2025 publication
The bigger picture
This negative result is actually informative: it suggests that contingency management, not NAC, was the active ingredient in prior positive studies. It redirects future CUD treatment research toward behavioral interventions and away from NAC as a pharmacological solution.
Questions still open
- Is contingency management the essential component for youth CUD treatment success?
- Are there other pharmacological candidates for youth CUD that should be tested with and without behavioral platforms?
Read the original research
N-acetylcysteine for youth cannabis use disorder: randomized controlled trial main findings.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(5), 731-738
Citation
Gray, Kevin M; Tomko, Rachel L; Baker, Nathaniel L; McClure, Erin A; McRae-Clark, Aimee L; Squeglia, Lindsay M. (2025). N-acetylcysteine for youth cannabis use disorder: randomized controlled trial main findings.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(5), 731-738. https://doi.org/10.1038/s41386-025-02061-y
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