Marijuana is the most commonly used illicit drug. There is high demand for effective interventions for cannabis use disorder, yet few specific treatments for have been developed. This study will evaluate the efficacy of varenicline for reducing marijuana use in people who use marijuana frequently.

Inclusion Criteria:

• Must meet DSM-5 criteria for cannabis use disorder and use cannabis at least 3 days per week in the last 30 days.
• Express interest in receiving treatment for cannabis use disorder and reducing use.
• Must be at least 18 years of age.
• If female and of childbearing potential, must agree to use acceptable methods of birth control for the duration of the trial.
• Must consent to random assignment, and be willing to commit to medication ingestion.
• Must be able to read and provide informed consent.
• Must have body weight >110lbs (50kg) and have BMI between 18 and 35kg/m2
• Must function at an intellectual level and have knowledge of the English language to sufficiently allow for accurate completion of assessments.

Exclusion Criteria:

• Women who are pregnant, nursing, or plan to become pregnant during the course of the study.
• Individuals with severe renal impairment (creatinine clearance less than 30 mL per minute).
• Lifetime history of DSM-5 Bipolar I or II Disorder, Schizophrenia or other psychotic disorder. Stably treated MDD, Dysthymia, GAD, Social Phobia, and Specific Phobia diagnoses are acceptable (i.e. same dose of medication has been prescribed for at least 2 months prior to screening and no changes in current medication expected during course of the trial).
• Past year or current posttraumatic stress disorder.
• Subjects who are actively suicidal, or who report suicidal ideation (SI) with intent or plan in the past year.
• Subjects who have a SBQ R total score ≥8, or for whom the investigator judges that a risk assessment by a qualified medical professional is required. Subjects answering 'yes' on questions 4 or 5 of C-SSRS will be referred to assessment by a qualified mental health professional.
• Suicidal behavior within the past 10 years or a lifetime history of serious or recurrent suicidal behavior.
• Concomitant use of psychotropic medications, with the exception of stable doses (defined as no dosing adjustments in the past two months) of non-MAO-I antidepressants, non-benzodiazepine anxiolytics, and ADHD medications.
• Current use of medications prescribed for mania or psychosis.
• Current use of buproprion or nortryptiline.
• Moderate or severe non-cannabis substance use disorders within the past 60 days with the exception of tobacco use disorder.
• Past year or current moderate or severe alcohol use disorder.
• Individuals taking an investigational agent within the last 30 days before baseline visit.
• Individuals with clinically significant medical disorders or lab abnormalities.
• Any individual at screening with SGOT (AST) or SGPT (ALT) greater than 3 times the upper limit of normal and/or total bilirubin greater than two times the upper limit of normal.
• Individuals with clinically significant cardiovascular disease in the past 6 months (e.g., myocardial infarction, CABG, PTCA, severe or unstable angina, serious arrhythmia, or any clinically significant ECG conduction abnormality.
• Individuals with clinically significant cerebrovascular disease in the past 6 months such as TIA, CVA, or stroke.
• Hypersensitivity to varenicline.
• Individuals who have participated in the clinical trial of any investigative compound within the last 60 days
• Individuals who are on probation or under a mandate to obtain treatment.
• Individuals with plans to initiate or change frequency of attendance at self-help meetings (e.g. AA, NA).

Adverse event data were collected from time of consent through last study visit (approximately 14 weeks).

Varenicline's efficacy for cannabis use disorder may vary by sex; however, this study was not powered to fully explore potential sex differences.