N-Acetylcysteine in Cannabis Dependence

A Double-Blind Randomized Controlled Trial of N-Acetylcysteine in Cannabis-Dependent Adolescents.
Am J Psychiatry. 2012 Jun 15.
Gray KM, Carpenter MJ, Baker NL, Desantis SM, Kryway E, Hartwell KJ, McRae-Clark AL, Brady KT.


This trial used the over the counter supplement, N-Acetylcysteine.


The authors note that 

Animal models have demonstrated that chronic drug self-administration down-regulates the cystine-glutamate exchanger in the nucleus accumbens and that administration of NAC up-regulates this exchanger, normalizing a drug-induced pathology and reducing reinstatement of drug seeking

There were 116 patients, 13-21 years old, mostly older adolescents with average age of 18.
All used cannabis regularly (≥3 days/week on average) and presented requesting treatment


NAC was dosed at 1200 mg (or placebo) BID



This was combined with a twice-weekly contingency management intervention

participants were able to earn increasing contingent rewards over successive displays of desired behavior (adherence with appointments and procedures; cannabis abstinence as measured by instant urine cannabinoid testing)

For adherence and abstinence, the initial contingent reward was $5 (cash) for each. For each successive visit at which the participant was adherent or abstinent, the reward increased by $2 ($7, then $9, and so on). If a participant subsequently failed to adhere to study procedures or tested positive for cannabis use, he or she did not receive any reward at that visit, and the contingent reward value for the next session was reset to the baseline of $5. If, at a given visit, a participant tested positive but adhered to study procedures, he or she collected the adherence reward as scheduled but was not eligible for the abstinence reward.

The physician or physician assistant, in the context of medication management, provided nonmanualized brief (<10 minutes) cessation counseling at all clinic visits, incorporating educational, motivational, and cognitive-behavioral elements.

40.9% (190/464) of the urine cannabinoid tests in the NAC group were negative, compared with 27.2% (126/464) in the placebo group, per intent-to-treat analysis, assuming any missing urine test was positive



At the posttreatment follow-up visit, 19.0% (11/58) of the urine cannabinoid tests in the NAC group were negative, compared with 10.3% (6/58) in the placebo group. (not statistically significant, CI: 0.8–7.5)


The secondary efficacy measures, assessing time to first negative urine cannabinoid test (hazard ratio=1.5, 95% CI=0.9–2.5) and end-of-treatment abstinence (odds ratio=2.3, 95% CI=1.0–5.4), revealed a similar magnitude of estimates favoring NAC, but not statistically significant.


There was no significant difference in percentage of self-reported days of cannabis use throughout treatment.  Change in percentage of days using cannabis during treatment:
NAC -41, placebo -37 (CI -15.8 - 7.9)


No significant adverse effects were noticed.


This is an odd result: marked decrease in the number of positive urine tests, but no significant difference in reported use.  It is unclear to me whether this study can be considered to have proven efficacy.  None the less the medication appears to be quite safe and reasonable to consider.


The authors suggest NAC would work for other substance dependencies in the discussion

It appears that the neurobiological and behavioral effects of NAC may not be specific to a particular substance, suggesting that NAC may be a promising candidate medication for treatment of other substance use disorders, whether by modulation of glutamate or by other mechanisms.