The primary purpose of this study is to investigate the effect of guanfacine-ER on reductions in cannabis use and explore its effects on impulsivity and withdrawal through a hybrid in-person and virtual trial of treatment-seeking individuals with Cannabis Use Disorder (CUD), and assessing the feasibility of the virtual components of the study.

This will be a 12-week randomized, double-blind, placebo-controlled trial, of guanfacine-ER compared to placebo for CUD. Participants will start on guanfacine-ER 1mg nightly for 1-week (week 1) and slowly increase by 1mg/per week to a max dose of 4mg or maximum dose as tolerated through week 4. Patients will be maintained on the medication through week 11. During week 11, they will begin a taper to discontinuation, decreasing the dose of guanfacine by 1mg every 4 days until stopped during the last week of the study (week 12). The primary purpose of this study is therefore to investigate the effect of guanfacine-ER on reductions in cannabis use and explore its effects on impulsivity and withdrawal through a hybrid in person and virtual trial of treatment-seeking individuals with CUD. In light of COVID-19 viral transmission mitigation policies, we will make use of the technological applications of virtual visits, remote administration of urine drug testing and medication, and ecological momentary assessments (EMA) in conjunction with once monthly in person visits to the clinic during weeks 1, 4, 8, 12.

Inclusion Criteria:

• Meets DSM-V criteria for a current cannabis use disorder
• Seeking treatment for cannabis use disorder with goal to reduce or stop use
• THC-positive drug screen
• Capable of giving informed consent and complying with study procedures
• Access to internet and devices capable of completing study procedures
• capability of receiving mailed packages for study supplies

Exclusion Criteria:

• Lifetime history of DSM-V diagnosis of schizophrenia or schizoaffective disorder
• Current DSM-V criteria for a psychiatric disorder supported by the MINI that in the investigator's judgment is unstable, would be disrupted by the study medication, or is likely to require new pharmacotherapy or psychotherapy during the study period. Individuals who are currently stable on psychotropic medication for at least 2 months may be included if in the investigator's opinion the psychotropic medication is compatible with the study medication (guanfacine-ER). Any medical or psychiatric conditions that in the investigator's judgment would interfere with safe participation in the study will be exclusionary.
• Individuals who meet DSM-V criteria for any moderate to severe substance use disorder other cannabis, caffeine or nicotine use disorders
• Pregnancy, lactation, or failure to use adequate contraceptive method in female patients who are currently engaging in sexual activity that can result in pregnancy
• Legally mandated to participate in a substance use disorder treatment program
• Current or recent history of significant violent or suicidal behavior, risk for suicide or homicide
• Known history of allergy, intolerance, or hypersensitivity to guanfacine
• Bradycardia (< 50 beats/minute), hypotension (sitting or standing BP < 90/50), or symptoms attributable to hypotension (i.e. lightheadedness or dizziness on standing)
• Individuals currently being treated with the antihypertensive medications, including the class of alpha 2 agonists that have a potential drug-interaction with guanfacine based on adrenergic modulation
• Individuals currently taking medications that may interact adversely with guanfacine and deemed not clinically safe by study physician at consent, such as rifampicin, ketoconazole, St. John's Wort, and amitriptyline.

Individual participant data that underlie the results published in this report (after de-identification) (text, tables, figures)

beginning twelve months and ending 5 years after article publication

to researcher who provides a methodologically sound proposal to achieve aims in approved proposal