A Double-Blind Randomized Controlled Trial of N -Acetylcysteine in Cannabis-Dependent Adolescents
Open accessAbstract
OBJECTIVE: Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy. METHOD: In an 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. RESULTS: Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events. CONCLUSIONS: This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.
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CB1 agonists, gabapentin, and N-acetylcysteine have been shown to produce improvements in some symptoms of CUD in single studies.
“Some drugs, such as CB1 agonists, gabapentin, and N-acetylcysteine, have been shown to produce improvements in some symptoms of CUD in single studies”
From Psychosocial and pharmacological interventions for the treatment of cannabis use disorder (2018) · cites this paper as [68]
The Results > Efficacy section reports that adolescents receiving N-acetylcysteine had significantly greater odds of negative urine cannabinoid tests during treatment. Our copy does not report improvements from gabapentin or CB1 agonists; it lists a dronabinol trial in the References without giving its findings. The demonstrated outcome is cannabis use, rather than a specified CUD symptom. (LLM, conf=0.84)
Experimental — accuracy not yet measuredN-acetylcysteine produced positive results for cannabis use cessation and craving in past open-label and placebo-controlled trials among adolescents.
“a number of trials have evaluated N-acetylcysteine, a modulator of glutamatergic receptors, because of positive results for cannabis use cessation and subjective measures (craving) in past open-label and placebo-controlled trials among adolescents 68, 69.”
From Psychosocial and pharmacological interventions for the treatment of cannabis use disorder (2018) · cites this paper as [68]
The Discussion reports improved cannabis abstinence with N-acetylcysteine versus placebo in adolescents when added to contingency management and counseling. The Introduction calls an earlier open-label pilot trial encouraging, but the paper does not report a positive craving result for either trial; its stated efficacy outcomes concern cannabis use and abstinence. The indexed copy provides section labels but no page numbers. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPositive trials of N-acetylcysteine for cannabis use disorders among adolescents, smoking, and bipolar depression among adults suggest that N-acetylcysteine may benefit adolescents with comorbid bipolar and SUDs; however, studies examining this hypothesis have not yet been completed (level 4).
“Positive trials of N‐acetylcysteine for cannabis use disorders among adolescents,618 smoking,619 and bipolar depression among adults 281 suggest that N‐acetylcysteine may benefit adolescents with comorbid bipolar and SUDs; however, studies examining this hypothesis have not yet been completed (level 4).”
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- Authors
- Gray, K. M., Carpenter, M. J., Baker, N. L., DeSantis, S. M., Kryway, E., Hartwell, K. J., McRae-Clark, A. L., & Brady, K. T.
- Affiliations
- Medical University of South Carolina (US)
- From the Department of Psychiatry and Behavioral Sciences, the Hollings Cancer Center, and the Division of Biostatistics and Epidemiology, Department of Medicine, Medical University of South Carolina, Charleston; and the Ralph H. Johnson Veterans Affairs Medical Center, Charleston.
- Corresponding author
- Gray, Kevin M.
- Venue
- American Journal of Psychiatry
- Published
- 2012-08
- Volume
- 169
- Issue
- 8
- Pages
- 805-812
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3410961
- OpenAlex
- W2121945096
- Cited by
- 306
- References
- 37
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 19 · 2023: 27 · 2022: 23 · 2021: 20 · 2020: 16 · 2019: 20 · 2018: 34 · 2017: 23 · 2016: 30 · 2015: 18 · 2014: 32 · 2013: 11 · 2012: 7
- FWCI
- 16.28
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Pfizer
- GlaxoSmithKline
- Supernus Pharmaceuticals
- Shire
- National Institutes of Health (UL1TR000062)
- National Institute on Drug Abuse (K23DA020482, R01DA026777)
- National Center for Research Resources (UL1RR029882)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- N-acetylcysteine, cannabis use disorder, adolescents, cannabis cessation, pharmacotherapy, contingency management, glutamate modulation, nucleus accumbens, addiction treatment
- MeSH terms
- Acetylcysteine, Adolescent, Cannabinoids, Marijuana Abuse, Counseling, Double-Blind Method, Female, Humans, Male, Treatment Outcome, Excitatory Amino Acid Antagonists, Young Adult
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