The primary objective of this study is to evaluate the impact of N-acetylcysteine (NAC) 1200 mg versus matched placebo (PBO) twice daily, added to contingency management (CM), on cannabis use among treatment-seeking cannabis-dependent adults (ages 18-50).

The primary objective of this Phase 3 study is to evaluate the impact of NAC 1200 mg versus matched placebo (PBO) twice daily, added to contingency management (CM), on cannabis use among treatment-seeking cannabis-dependent adults (ages 18-50). After assessment and inclusion into the study, participants will be randomized to receive a 12-week course of NAC 1200 mg or matched placebo twice daily. All participants will concurrently participate in a twice-weekly contingency management (CM) intervention. Medication management will be conducted weekly throughout treatment by the medical clinician. Urine cannabinoid testing will occur at all visits, and will be used as the primary determinant of cannabis use. Participants will return approximately four weeks after treatment conclusion for evaluation of adverse events with medication discontinuation and sustained treatment effects.

Inclusion Criteria:

• Age 18-50 years
• Must be able to understand the study and provide written informed consent
• Must meet current DSM-IV criteria for cannabis dependence in the last 30 days
• Must express interest in treatment for cannabis dependence
• Must submit a positive urine cannabinoid test during screening
• Women of child bearing potential must agree to use appropriate birth control methods during study participation: oral contraceptives, contraceptive patch, barrier (diaphragm or condom), levonorgestrel implant, medroxyprogesterone acetate, complete abstinence from sexual intercourse, or hormonal contraceptive vaginal ring

Exclusion Criteria:

• Allergy or intolerance to N-Acetylcysteine
• Women who are pregnant or lactating
• Current use of NAC or any supplement containing N-Acetylcysteine (must agree not to take any such supplement throughout study participation)
• Use of carbamazepine or nitroglycerin within 14 days of randomization
• Current enrollment in treatment for cannabis dependence
• Any use of synthetic cannabinoids (such as K2/Spice) in the 30 days prior to screening or during the period between screening and randomization
• Current substance dependence, other than cannabis or nicotine
• Urine drug screen positive for any drug of abuse other than cannabis or amphetamines at the randomization visit (Only participants who have a valid prescription for amphetamines (e.g., for ADHD) may be included)
• Urine drug screen positive for amphetamines at the randomization visit without having a valid prescription for it
• Maintenance treatment with buprenorphine or methadone
• Recent history of asthma (within the last 3 years)
• History of seizure disorder, bipolar disorder, schizophrenia, or other significant or unstable medical or psychiatric illness that may place the participant at increased risk in the judgment of the medical clinician
• Significant risk of homicide or suicide

The lead investigator will submit coded individual level data on Clinical Trials Network (CTN) study participants to the Data Management Center contracted by NIDA Center for CTN. These data may include but are not limited to: demographic information, date of birth, medical history, substance use history, psychiatric history, objective measures of substance use and psychiatric status, HIV status and genetic information. Data will be submitted without information that could readily identify the study participant (i.e. We will not share medical record numbers, social security numbers or participant names or phone numbers with the Data Management Center). De-identified data will be made publicly available per the CTN's policies.

Evaluation of adverse events began after informed consent and continued at each weekly visit until the final 13 week follow up visit for all participants.

Participants were asked once a week