Adolescents diagnosed with marijuana dependence were more than twice as likely to remain abstinent when they received N-acetylcysteine (NAC) versus placebo in addition to counseling, researchers said.
In an 8-week trial, about 44% of adolescents assigned to take 1,200 mg of NAC twice daily had negative urine test results for cannabinoids at the end of treatment, compared with 32% of those taking placebo, according to Kevin M. Gray, MD, of the Medical University of South Carolina in Charleston, S.C., and colleagues.
After adjusting for years of cannabis use, baseline urine test results, and major depressive disorder, the odds ratio for negative urine tests during the study period was 2.35 (95% CI 1.05 to 5.24, P=0.029), the researchers reported online in the American Journal of Psychiatry.
The effect did not appear to be durable, though. Four weeks after the end of treatment, only 19% of the NAC group and 10% of those assigned to placebo still had negative urine test results.
But the analysis was conducted on an intent-to-treat basis with a positive test result automatically assigned to participants not showing up for testing. Fewer than half of the original participants were tested at the post-treatment followup, so the finding may have underestimated the actual degree of abstinence.
In any event, the on-treatment benefit of NAC was sufficiently robust to warrant additional studies, Gray and colleagues wrote.
NAC is best known as an over-the-counter antioxidant supplement that also can serve as an antidote to acetaminophen overdoses, preventing acute liver failure. But it has neurological effects too, modulating glutamate activity in the nucleus accumbens, the researchers observed.
In particular, animal studies have shown that NAC upregulates a cysteine-glutamate exchanger that is suppressed with chronic self-administration of euphoric drugs, "reducing reinstatement of drug seeking," Gray and colleagues wrote.
For the randomized, double-blind trial, the researchers recruited 116 adolescents (13 to 21 years old) meeting standard criteria for cannabis dependence and who reported using cannabis an average of at least three days a week.
In addition to the study drugs, participants were enrolled in a twice-weekly "contingency management" program whereby escalating cash rewards were given for compliance with desired behaviors, such as keeping appointments and showing negative results on instant urine tests. The initial reward was $5 and could reach $37 if the participant was continuously compliant.
Regular clinic visits were scheduled weekly and included 10 minutes of cessation counseling by a physician or physician assistant.
The primary outcome measure was the percentage of urine tests performed at weekly clinic visits that were negative.
In the NAC group, 40.9% of tests were negative, compared with 27.2% of those in the placebo group (P=0.029 after adjustments).
Similar differences were seen in other endpoints, including the money paid out as rewards in the contingency management program.
Dropout rates in the study were substantial, with 60% of the original 116 participants retained through the 8-week treatment period and just under half providing samples at the 4-week followup. However, there were no significant differences in retention between the NAC and placebo groups.
Adverse effects were similar between treatment groups, with no serious events recorded. Only one participant withdrew from the study because of adverse effects -- a member of the NAC group who reported severe heartburn, which stopped after the drug was discontinued.
Gray and colleagues indicated that the study is the first placebo-controlled, double-blind trial to demonstrate that a drug-based treatment for cannabis dependence is effective in an intent-to-treat analysis.
However, noting that the drug therapy accompanied a psychosocial treatment, they expressed concern that the study "may prompt patients or providers to prematurely consider NAC as a standalone treatment."
The researchers also pointed to limitations of the study, which included its short duration, small size, and relatively healthy sample.
"Additional research is needed to replicate these findings in other settings and to explore the efficacy of NAC at varying doses, across different age groups, with longer treatment duration and posttreatment follow-up, with a direct test of the integrity of the blind, and with more stringent efficacy measures," Gray and colleagues wrote.
They also suggested that different psychosocial treatments be evaluated with NAC.
The study was funded by the National Institutes of Health.
Gray reported relationships with Merck and Supernus. Other authors reported relationships with Pfizer, Shire, and GlaxoSmithKline.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner