UH3 Varenicline for Cannabis Use Disorder

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).