Trial of Tirzepatide for the Treatment of Cannabis Use Disorder

This is a double-blind, placebo-controlled, randomized clinical trial. 100 individuals with moderate to severe cannabis use disorder (CUD) will be randomized in a 1:1 ratio to receive either (1) weekly subcutaneous injections of tirzepatide or (2) weekly subcutaneous injections of matching placebo for 24 weeks. Tirzepatide will be initiated at 2.5 mg for 4 weeks (4 injections) and increased in 2.5 mg increments every 4 weeks as tolerated, up to a maximum dose of 15 mg.

The Primary Objective is to determine the maximum tolerated dose (MTD) of tirzepatide in individuals with CUD and to evaluate its efficacy in reducing cannabis use.

The primary Hypothesis is that tirzepatide will be well tolerated within the FDA-recommended dose range and compared with placebo, it will result in a significantly greater proportion of cannabis abstinent days as measured by the timeline follow-back (TLFB).

Secondary Objectives are to evaluate the effects of tirzepatide, relative to placebo, on (1) CUD severity based on DSM-5 criteria; (2) percentage of cannabis-negative weekly urine drug screens collected during the treatment period; (3) cannabis craving; (4) cannabis withdrawal severity; (5) retention in treatment; and (6) quality of life.

• Tirzepatide (Drug): Participants will receive weekly injections of tirzepatide 2.5 mg for 4 weeks. The dose is expected to increase by 2.5 mg every 4 weeks, however, the decision to increase the dose will be made based on the Dose Increase Checklist and shared decision between the site study physician (MD or DO) and the participant.
• Placebo (Drug): Participants will receive weekly masked injections of placebo.

Primary outcomes

• Maximum Tolerated Dose (MTD) [24 weeks (Treatment Phase)]: The maximum tolerated dose defined as the median dose within the FDA-recommended range, at which dose increase is not recommended (based on standardized and health care provider assessments).
• Days of Abstinence [24 weeks (Treatment Phase)]: Number of days per week with no cannabis use, as assessed by Timeline Follow Back (TLFB).

Secondary outcomes

• Severity of Cannabis Use Disorder (CUD) [24 weeks (Treatment Phase)]: Severity of CUD as determined by DSM-5 criteria for Cannabis Use Disorder Checklist and expressed as a number of reported symptoms
• Negative Urine Drug Screens (UDS) [24 weeks (Treatment Phase)]: Percentage of weekly urine drug screens testing negative for cannabis out of all scheduled weekly drug screens.
• Cannabis Craving [24 weeks (Treatment Phase)]: Cannabis Craving as assessed by the short form of the Marijuana Craving Questionnaire (MCQ) and expressed as a score. The score range is 12-84, and the higher score indicates a higher or more frequent level of craving.
• 1. Cannabis Withdrawal [24 weeks (Treatment Phase)]: Cannabis withdrawal as assessed by the DSM 5 Cannabis Withdrawal Checklist and expressed as a number of symptoms present (up to 7)
• Retention in Treatment [Week 24 (End of Treatment Phase)]: Percentage of randomized participants who receive study medication during the treatment phase.
• Quality of Life [24 weeks (Treatment Phase)]: Quality of life (physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, and pain intensity) as determined by PROMIS-29 questionnaire and expressed as a score. The domain scores (T-scores) range is 20-80 with higher scores representing better outcomes.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Between 18 and 70 years of age
* Meets DSM-5 criteria for moderate or severe CUD
* Interested in treatment for cannabis use disorder
* Able to understand the study procedures and written informed consent in English
* Willing to comply with all study procedures and medication instructions
* If female, is not pregnant, and agrees to use acceptable birth control methods

Exclusion Criteria:

* Body Mass Index (BMI) ≤ 23 kg/m²
* Presence of a medical or psychiatric disorder that contraindicates participation in the study
* Substance use disorder other than tobacco or mild alcohol-use disorder
* Known allergy or hypersensitivity to Tirzepatide, any GLP-1 or GIP receptor agonist, or any of the excipients in the product
* Current or recent (past 30 days) use of GLP-1 receptor agonists or other weight-loss drug
* Current or recent (past 6 months) enrollment in substance use disorder treatment
* Current or planned pregnancy and breastfeeding
* Living or medical situation that would interfere with adherence to the study protocol

• Jia Bei Wang, MD, PhD, Principal investigator, NIDA/NIH, Division of Therapeutics and Medical Consequences (DTMC)