Lemborexant for Cannabis Use Disorder

• Lemborexant 10mg (Drug): 21 days of 10mg Lemborexant, taken nightly.
• Placebo (Drug): 21 days of visually-matched placebo, taken nightly.
• Brief Behavioural Intervention (Behavioral): Participants will receive a brief behavioural intervention at the in-person study visits aimed at helping participants identify ways to reduce their cannabis use.

Primary outcomes

• Feasibility: Participant Recruitment Rate [From first participant in until study closure (estimated 24 months).]: Measured by assessing the number of participants recruited into the study (28 anticipated) throughout study duration (24 months estimated).
• Feasibility: Participant Retention Percentage [From first participant in until study closure (estimated 24 months).]: Measuring the number of participants who complete the study compared to the total number of study participants, displayed as a percentage (%).
• Tolerability: Participant Drop-Out Rates [From first participant in until study closure (estimated 24 months).]: Measured by comparing frequency of participant drop-outs in treatment versus control groups.
• Safety: Adverse Event Frequency [Participants will have the opportunity to report adverse events daily during the study treatment phase (days 0-21).]: Measured by comparing the frequency of adverse events in the treatment versus control groups.
• Safety: MADRS-S Depression [The MADRS-S will be administered on days 0, 7, 14, and 21 during the study treatment phase (days 0-21).]: Measured using the Montgomery-Åsberg Depression Rating Scale - Self Report (MADRS-S) which scores depression from 0-54, with higher scores indicating worse depression.
• Safety: C-SSRS Suicidality [The C-SSRS will be administered on days 0, 7, 14, and 21 during the study treatment phase (days 0-21).]: Measured using the Columbia Suicide Severity Rating Scale (C-SSRS), which uses Yes/No answers to categorize into No, Low, Moderate, or High risk.

Secondary outcomes

• Sleep (Objective): Actigraphy Data [Measured continuously during the study treatment phase (days 0-21).]: Participants will wear actigraphy watches continuously during the study treatment phase in order to measure objective sleep data.
• Sleep (Subjective): PSQI [The PSQI will be administered at pre-screening and day 21.]: The Pittsburgh Sleep Quality Index (PSQI) will be used as a subjective measure of sleep. Scores can range from 0-21, with higher scores indicating worse sleep.
• Sleep (Subjective): LSEQ [Participants will take the LSEQ on days 0, 7, 14, and 21 throughout the study treatment phase (days 0-21).]: The Leeds Sleep Evaluation Questionnaire (LSEQ) is a subjective measure of sleep which uses a 100mm visual analog scale, with lower scores being indicative of worse sleep.
• Sleep (Subjective): Daily Diaries CSD [Daily diaries will be completed daily during the study treatment phase (days 0-21).]: Participants will complete daily diaries each morning via REDCap, which will include questions regarding their prior night's sleep from the Consensus Sleep Diary (CSD).
• Cannabis Use (Objective): Plasma THC and Metabolites [Blood draws will occur on days 0 and 21 during the study treatment phase (days 0-21).]: Blood draws will be performed in order to measure plasma THC and metabolite levels as an objective measure of cannabis use.
• Cannabis Use (Subjective): EC-TLFB [The EC-TLFB will be administered on days 0, 7, 14, and 21 during the study treatment phase (days 0-21).]: The Enhanced Cannabis Timeline Followback (EC-TLFB) will be administered during study visits in order to subjectively assess participant cannabis use.
• Cannabis Use (Subjective): Daily Diaries [Daily diaries will be completed daily during the study treatment phase (days 0-21).]: Participants will complete daily diaries each morning via REDCap, which will include questions regarding their cannabis use from the day prior.
• Cannabis Use (Subjective): DFAQ-CU [The DFAQ-CU will be administered on days 0 and 21 during the study treatment phase (days 0-21).]: The Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use (DFAQ-CU) measures multiple aspects of cannabis consumption in participants, and will be used as part of our subjective cannabis use measurements.
• Cannabis Withdrawal: Daily Diaries Modified MWC [Daily diaries will be completed daily during the study treatment phase (days 0-21).]: The Marijuana Withdrawal Checklist (MWC) asks participants to score their severity of 22 marijuana withdrawal symptoms. On a scale of 0-66, higher scores indicate worse marijuana withdrawal symptoms. We have adapted the MWC to ask participants about their prior day's symptoms, and included it as part of the REDCap daily diaries.
• Cognition: Divided Attention [Divided attention cognitive tasks will be administered on days 0 and 21 during the study treatment phase (days 0-21).]: Divided attention cognitive tasks assess participants' ability to focus on one task versus multiple tasks, with less difference between the them indicating better cognitive outcomes.
• Cognition: Working Memory [N-back and word memory tasks will be administered on days 0 and 21 during the study treatment phase (days 0-21).]: Working memory will be assessed via N-back and word memory tasks, with better scores being indicative of better cognitive function.
• Cognition: Planning via Tower of London [Tower of London will be administered on days 0 and 21 during the study treatment phase (days 0-21).]: The Tower of London task assesses participant planning ability, with higher scores indicative of better planning and cognition.

Other outcomes

• Follow-Up Outcome (Safety): Adverse Event Frequency [Participants will have the opportunity to report adverse events daily during the study follow-up phase (days 22-35).]: Measured by comparing the frequency of adverse events in the treatment versus control groups.
• Follow-Up Outcome (Safety): Depression [The MADRS-S will be administered on day 35 during the study follow-up phase (days 22-35).]: Measured using the Montgomery-Åsberg Depression Rating Scale - Self Report (MADRS-S) which scores depression from 0-54, with higher scores indicating worse depression.
• Follow-Up Outcome (Safety): Suicidality [The C-SSRS will be administered on day 35 during the study follow-up phase (days 22-35).]: Measured using the Columbia Suicide Severity Rating Scale (C-SSRS), which uses Yes/No answers to categorize into No, Low, Moderate, or High risk.
• Follow-Up Outcome (Sleep): LSEQ [Participants will take the LSEQ on day 35 during the study follow-up phase (days 22-35).]: The Leeds Sleep Evaluation Questionnaire (LSEQ) is a subjective measure of sleep which uses a 100mm visual analog scale, with lower scores being indicative of worse sleep.
• Follow-Up Outcome (Sleep): Daily Diaries CSD [Daily diaries will be completed daily during the study follow-up phase (days 22-35).]: Participants will complete daily diaries each morning via REDCap, which will include questions regarding their prior night's sleep from the Consensus Sleep Diary (CSD).
• Follow-Up Outcome (Cannabis Use): EC-TLFB [The EC-TLFB will be administered on day 35 during the study follow-up phase (days 22-35).]: The Enhanced Cannabis Timeline Followback (EC-TLFB) will be administered during study visits in order to subjectively assess participant cannabis use.
• Follow-Up Outcome (Cannabis Use): Daily Diaries [Daily diaries will be completed daily during the study follow-up phase (days 22-35).]: Participants will complete daily diaries each morning via REDCap, which will include questions regarding their cannabis use from the day prior.
• Follow-Up Outcome (Withdrawal): Daily Diaries Modified MWC [The modified MWC will be completed daily during the study follow-up phase (days 22-35).]: The Marijuana Withdrawal Checklist (MWC) asks participants to score their severity of 22 marijuana withdrawal symptoms. On a scale of 0-66, higher scores indicate worse marijuana withdrawal symptoms. We have adapted the MWC to ask participants about their prior day's symptoms, and included it in the REDCap daily diaries.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Moderate to severe Cannabis Use Disorder.
* Ability to read/write in English.

Exclusion Criteria:

* Known allergies or hypersensitivities to Lemborexant.
* Use of any Orexin-Antagonist in the past 3 months.
* Current or recent (within the past 12 weeks) participation in a clinical trial involving medication administration.
* Narcolepsy, Complex sleep behaviors, sleep apnea, restless leg syndrome, and Periodic Limb Movement Disorder.
* Currently undergoing treatment for CUD.
* Any hospitalization or emergency department visit related to cannabis use.
* Moderate to severe hepatic impairment.
* Past or ongoing moderate to severe psychiatric disorders.
* Active suicidal ideation or serious attempt within the past 3 years.
* Epilepsy or history of seizures.
* Blood pressure over 160/95mmHg at the screening session.
* Current pregnancy or nursing, trying to become pregnant, or unwilling to use acceptable method of contraception during the study.

• David N Crockford, MD, Principal investigator, University of Calgary
• Leah M Mayo, PhD, Principal investigator, University of Calgary
• Stephanie L Borgland, PhD, Principal investigator, University of Calgary