Cannabinoids as a Treatment for Insomnia in Major Depression

Study Overview
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Brief Summary
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This single-site study is a pilot, three-armed, double-blinded, placebo-controlled randomized controlled trial (RCT) that will determine the feasibility of a definitive RCT investigating the use of cannabis oil as a treatment for insomnia in individuals with MDD. The study will also determine whether standard THC with higher CBD vs lower CBD has a differential impact on insomnia. The study will also analyze other important objective parameters of sleep including total sleep time and sleep efficiency from actigraphy data. Polysomnography data will also be analyzed. In addition, standardized, validated instruments will be used to collect data on severity of depressive symptoms, cognitive functioning biological rhythm disruption, daytime sleepiness, health-related quality of life (HRQoL), healthcare resource utilization, work productivity and activity impairment, as well as other side effects, in order to better understand the potential impact of the use of cannabis oil on these important health outcomes.

Detailed Description
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The study will be a three-arm, randomized, double-blind, placebo-controlled trial. The study population will include 60 males and females, ages 19 and older, who report chronic problems with insomnia at least three times per week for at least three months and have a diagnosis of co-morbid MDD. Eligible participants will complete a urine screen for drugs of abuse including opioids, cannabis, benzodiazepines and amphetamines before treatment randomization. Participants with a positive screen for any of these drugs of abuse will be excluded from the study. If the drug screen is negative, the principal investigator will assess patient health history and perform a physical examination. All study participants must be able to fully understand the study procedures and must sign a research ethics board (REB)-approved informed consent before study entry. A neuropsychological battery will be used to assess cognitive function in the domains of attention, verbal memory, psychomotor functioning, and executive functioning at baseline and at the end of the 4-week treatment in order to examine possible cognitive benefits or side effects from the treatment. These cognitive domains were chosen because these domains are known to be negatively affected by chronic insomnia and by cannabis use. Patients will also complete a series of clinician-rated and self-reported questionnaires. During the 4-week treatment period, participants will be instructed to start treatment with a single, dose of oil at bedtime. Each dose will have either 50 mg/ml CBD and 2 mg/ml THC (High CBD arm; MLP-001) or 10 mg/ml CBD and 2 mg/ml THC (Low CBD arm; MLP-002). Non-responding study participants will add 1 additional dose to their respective treatment after 2 weeks if a higher dosage is needed based on an Insomnia Severity Index (ISI) reduction of >8 points and tolerability (side effects). Responding participants will continue with 1 dose of their treatment after 2 weeks. This dose range is based on previous studies showing that the effective dosage of THC to improve sleep ranged, on average, between 5 and 15 mg daily.

Official Title
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A Pilot, Double-Blind, Randomized, Placebo-Controlled Trial Evaluating the Efficacy and Safety of a Cannabis-Infused Oil For Treatment of Insomnia in Major Depression

Conditions
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Insomnia, Depressive Disorder, Major, Sleep Disorder, Depression, Insomnia Chronic

Intervention / Treatment
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* Drug: 25:1 CBD/THC
* Drug: 5:1 CBD/THC
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age 19 or above (A minimal age of 19 was chosen in order to align with the cannabis legalization rules of the Province of Ontario, where the research participants will be recruited from: https://www.ontario.ca/page/cannabis-legalization#section-1) Diagnosis of MDD according to the Structured Clinical Interview for DSM-5 (SCID-5) 37 Diagnosis of Insomnia Disorder according to the Duke Structured Interview for Sleep Disorders 38 Patient Health Questionnaire (PHQ-9) 39 score of <10, indicating severity of mild-to-no depression (This criterion is important because a proper diagnosis of current co-morbid insomnia disorder cannot be accurately ascertained during acute major depressive episodes) Participant must be willing and able to complete self-reported assessments, including having sufficient fluency in English Participant must be willing to wear a wrist-worn actiwatch device Participants may be using psychotropic medications for treatment of depression, except benzodiazepines or any other sleep aids, as long as the dosage remains the same from a minimum of 2 months prior to study enrolment until the end of the study (This criterion is important because many individuals with MDD use antidepressant agents and this criterion would make the results more generalizable and useful in real life clinical practice) Exclusion Criteria Lifetime diagnosis of Schizophrenia, Bipolar Disorder or any other psychotic disorder, as well as current or recent (last 6 months) Alcohol or Substance Use Disorder according to the SCID-5 Individuals with current diagnosis of Generalized Anxiety Disorder, Panic Disorder, Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder or Eating Disorder will be excluded because these psychiatric disorders are associated with sleep disturbance; however, because of the high rates of co-morbid psychiatric conditions in MDD lifetime/past diagnosis will be allowed in order for the results to be generalizable and useful in real life clinical practice Current use of benzodiazepines or any other sleep aids Positive screening for drugs of abuse including but not limited to opioids, cannabis, benzodiazepines, cocaine, and/or amphetamines (except prescribed stimulants for comorbid ADHD) Presence of any sleep disorder other than insomnia that is considered the primary diagnosis, determined by the Duke Structured Interview for Sleep Disorders (e.g. Sleep Apnea, Limb Movement Disorder, or Circadian Rhythm Disorders) Presence of unstable medical conditions Pregnancy or breastfeeding (female participants will need to agree to use an acceptable contraceptive method during the study because of potential unknown teratogenic effects of cannabinoids Allergy to cannabis or any components of the cannabis treatment (including terpenes)

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will be a pilot, three-arm, randomized, double-blind, placebo-controlled trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High CBD [25:1]<br>1 dose (1 mL) of HIGH CBD 50 mg/ml CBD and 2 mg/ ml THC | Drug: 25:1 CBD/THC<br>* 1 dose (1 mL) of HIGH CBD 50 mg/ml CBD and 2 mg/ ml THC<br>* Other names: High CBD;|
| Experimental: Low CBD [5:1]<br>1 dose (1 mL) of LOW CBD 10 mg/ml CBD and 2 mg/ ml THC | Drug: 5:1 CBD/THC<br>* 1 dose (1 mL) of LOW CBD 10 mg/ml CBD and 2 mg/ ml THC<br>* Other names: Low CBD;|
| Placebo Comparator: Placebo<br>1 dose (1 mL) of PLACEBO No active ingredients | Other: Placebo<br>* 1 dose (1 mL) of PLACEBO No active ingredients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment Rate | Rates > 80% using descriptive statistics | 1 year, at the completion of the study | 
| Retention Rate | Rates > 80% using descriptive statistics | 1 year, at the completion of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sleep latency onset and wake after sleep onset | Change in time (minutes) as measured using actigraphy | through study completion, an average of 4 weeks | 
| Treatment compliance | Completion rate > 80% using descriptive statistics | through study completion, an average of 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mental Health, Cognition, Sleep Disorders, Major Depressive Disorder, Chronic Insomnia, Cannabis