Cannabinol Use in Patients With Insomnia Disorder (CUPID)

A Randomised, Double-blind, Placebo-controlled, Single-dose, Crossover, Pilot Study Investigating the Effects of Cannabinol (CBN) 30 mg and 300 mg on Sleep Architecture and Next-day Function in Insomnia Disorder

This study aims to investigate the acute effects of cannabinol (CBN) 30 mg and 300 mg, versus placebo, on sleep architecture and next-day functioning in adults aged 25-65 years with chronic insomnia disorder.

Study Overview

• Status: Completed
• Conditions: Insomnia Disorder
• Intervention / Treatment: Drug: 30 mg Cannabinol (CBN); Drug: 300 mg Cannabinol (CBN); Drug: Placebo

Detailed Description

This is a randomised, double-blind, placebo-controlled, three-arm, crossover, single-centre, proof-of-concept study in twenty participants with chronic insomnia disorder (as per clinician diagnosis and Insomnia Severity Index [ISI] Score ≥15). Across three overnight treatment sessions, participants will receive single dose oral liquid 30 mg cannabinol (CBN), 300 mg CBN, and matched placebo. Participants will undergo overnight sleep assessment using in-laboratory polysomnography (PSG) to examine CBN-related changes to sleep parameters; and various objective and subjective measures of sleep and next-day neurobehavioral function. Each treatment session will be separated by the two-week washout period.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Isobel Lavender, BPsycHons; Phone Number: +61 2 9114 0000; Email: isobel.lavender@sydney.edu.au
• Study Contact Backup: Name: Camilla Hoyos, MPH, PhD; Phone Number: +61 2 9114 0000; Email: camilla.hoyos@mq.edu.au

Study Locations

• Australia
  • New South Wales
    • Glebe, New South Wales, Australia, 2095
      • Woolcock Institute of Medical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Between 25 - 65 years of age
2. Insomnia Severity Index (ISI) score ≥ 15 at eligibility screening
3. Insomnia disorder (symptoms occurring at least 3 times per week and present for longer than 3 months) as determined by the study physician
4. Ability to take oral medication
5. Provision of signed and dated informed consent form
6. Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria:

1. Medical condition or medication that is the cause of the insomnia disorder as determined by the study physician
2. Known hypersensitivity to cannabis or cannabinoid products (including if this becomes evident during the trial)
3. Reported use of cannabis or cannabinoid products within the past 3 months as confirmed by at least one negative urine drug screen (UDS) (or at the study physician's discretion)
4. Sleep apnoea (defined as Apnoea Hypopnea Index [AHI] > 15 and Oxygen Desaturation Index [ODI]>10) as confirmed by polysomnography at screening
5. Sleep-related movement disorder as determined by the study physician
6. Delayed or advanced sleep phase syndrome (based on actigraphy and sleep diary) as confirmed during screening
7. Any medical condition that produces an abnormal EEG (i.e., epilepsy, brain injury)
8. Clinically relevant cardiovascular abnormalities as determined by the study physician and a 12-lead electrocardiogram (ECG) at screening
9. Shift work or trans meridian travel (two time zones) within the last month
10. History of major psychiatric disorder in the past 12 months at the study physician's discretion, except clinically managed mild depression and/or anxiety
11. History of suicide attempt or current suicide ideation (score greater than 1 on Q9 of the Patient Health Questionnaire [PHQ-9])
12. Pregnancy or lactating. Female participants are required to complete a urine pregnancy test at screening and treatment sessions and all participants are instructed to use a reliable form of contraception throughout the study duration
13. History of drug or alcohol dependency or abuse within approximately the past 2 years
14. Use of CNS-active drugs (cannabis, amphetamines, cocaine, antidepressants, opioids, benzodiazepines) in the past 3 months as confirmed by a positive urine drug test at screening or at the study physician's discretion
15. Use of medications that may have a clinically significant impact upon the metabolism and excretion of cannabinoids as determined by the study physician (e.g., CYP450 enzyme inducers/inhibitors
16. Excessive caffeine use that in the opinion of the study physician contributes to the participant's insomnia disorder, or the inability to abstain from caffeine use 24 hours prior to each overnight sleep study
17. Inability to refrain from alcohol consumption 24 hours prior to each overnight sleep study
18. Individuals with nicotine dependence (i.e., daily smokers)
19. Medical conditions that result in frequent need to get out of bed (e.g., sleep walking, nocturia)
20. Psychological or behavioural treatment for insomnia disorder, including cognitive behavioural therapy for insomnia, within 3 months before screening (excluding sleep hygiene advice)
21. Occupational or judicially ordered drug screening
22. Has held an unrestricted driving license < 1 year
23. Cannot speak English fluently

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 30 mg Cannabinol (CBN); Single fixed dose administered 2 hours prior to habitual sleep onset.	Drug: 30 mg Cannabinol (CBN); Participants will receive a 2 mL oral dose of 'ECS 310' (1.5%), an oral formulation of CBN (15 mg/mL) suspended in medium chain triglycerides (MCT) oil.; Other Names: ECS 310 (1.5%)
Experimental: 300 mg Cannabinol (CBN); Single fixed dose administered 2 hours prior to habitual sleep onset.	Drug: 300 mg Cannabinol (CBN); Participants will receive a 2 mL oral dose of 'ECS 310' (15%), an oral formulation of CBN (150 mg/mL) suspended in medium chain triglycerides (MCT) oil.; Other Names: ECS 310 (15%)
Placebo Comparator: Placebo; Single fixed dose administered 2 hours prior to habitual sleep onset.	Drug: Placebo; Participants will receive a 2 mL oral dose of placebo. Placebo contains the same excipient, medium chain triglycerides (MCT) oil, as the investigational products but does not contain cannabinoids.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wake After Sleep Onset (WASO)	WASO measured in minutes using in-laboratory overnight polysomnography, from the first epoch after lights out until the last epoch, scored as any stage of sleep by an experienced polysomnographic technician in accordance with American Academy of Sleep Medicine (AASM) 2020 Sleep Scoring criteria (Version 2.6). Comparisons between each CBN dose versus placebo.	Night 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Traditional sleep staging	Proportion of the sleep opportunity scored at the 5 stages (wake, and N1, N2, N3, and REM sleep) between lights out and lights on, measured using overnight in-laboratory polysomnography, scored by a polysomnography technician in accordance with AASM Sleep Scoring criteria. Comparisons between each CBN dose versus placebo.	Night 1
Sleep Onset Latency (SOL)	SOL measured in minutes using in-laboratory polysomnography, calculated from the time of lights out to the first sleep epoch as scored by a polysomnographic technician in accordance with AASM Sleep Scoring criteria. Comparisons between each CBN dose versus placebo.	Night 1
Absolute Electroencephalographic (EEG) Power During Non-Rapid Eye Movement (NREM) Sleep.	Spectral power of delta (1-4.5 Hz), theta (4.5-8 Hz), alpha (8-12 Hz), sigma (12-15 Hz), beta (15-25 Hz), and gamma (25-40 Hz) frequency ranges between treatment arms. Power spectral analysis will be applied to EEG signals from polysomnography after artefacts are detected and removed. Comparisons between each CBN dose versus placebo.	Night 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Spindles During Non-Rapid Eye Movement (NREM) Sleep (Tertiary outcome)	Sleep spindle and slow oscillation events in NREM sleep from in-laboratory overnight polysomnography. A sleep spindle and slow oscillation detection algorithm will be applied to electroencephalography (EEG) signals from polysomnography after artefacts are detected and removed. Comparisons between each CBN dose versus placebo.	Night 1
Electroencephalogram (EEG) Arousal Index (Tertiary outcome)	Number of cortical arousals captured via the electroencephalogram per hour of sleep scored by the polysomnographic technician on the polysomnogram in accordance with AASM Sleep Scoring criteria. Comparisons between each CBN dose versus placebo.	Night 1
Absolute Electroencephalography (EEG) Power During Rapid Eye Movement (REM) Sleep (Tertiary outcome)	Spectral power of delta (1-4.5 Hz), theta (4.5-8 Hz), alpha (8-12 Hz), sigma (12-15 Hz), beta (15-25 Hz), and gamma (25-40 Hz) frequency ranges between treatment arms. Power spectral analysis will be applied to EEG signals from polysomnography after artefacts are detected and removed. Comparisons between each CBN dose versus placebo.	Night 1
Next day post-wake subjective sleep evaluation (LSEQ) (Tertiary outcome)	LSEQ score. LSEQ scores range from 0-100, with higher scores indicating better subjective experience. Assessed within 1 h after wake (comparison between each CBN dose versus placebo).	Morning after drug administration
Next day post-wake subjective sleep evaluation (RCSQ) (Tertiary outcome)	RCSQ score. RCSQ scores range from 0-100, with higher scores indicating better subjective experience. Assessed within 1 h after wake (comparison between each CBN dose versus placebo).	Morning after drug administration
Standard Deviation of Lateral Position (SDLP) During Next-day Post-Wake Simulated Drive (Safety outcome)	SDLP ("weaving") is measured across the 'standard', 'car following', and 'divided attention' sub-sections of a ~30 minute simulated driving task. Assessed within 2 h after wake (comparison between each CBN dose versus placebo).	Morning after drug administration
Speed During Next-day Post-Wake Simulated Drive (Safety outcome)	Average speed and standard deviation of speed is measured across the 'standard' and 'divided attention' sub-sections of a ~30 minute simulated driving task. Assessed within 2 h after wake (comparison between each CBN dose versus placebo).	Morning after drug administration
Distance Headway During Next-day Post-Wake Simulated Drive (Safety outcome)	Average distance headway (i.e., distance between the driver's vehicle and vehicle immediately in front) and standard deviation of distance headway is measured across the 'car following' sub-section of a ~30-minute simulated driving task. Assessed within 2 h after wake at both treatment sessions (comparison between each CBN dose versus placebo).	Morning after drug administration
Subjective Mood Evaluation (Safety outcome)	The Abbreviated Profile of Mood States (POMS) consists of 40 items measuring domains of 'tension', 'depressed', 'anger', 'vigour', 'fatigue', and 'concentration'. Participants respond to each item using 5-point Likert scales ranging from 0 (Not at all) to 4 (Extremely). A total mood disturbance score is calculated by summing negative domains and subtracting positive domains. Administered pre and post drug administration, as well as next-day (comparison between each CBN dose versus placebo).	Immediately after and morning after drug administration
Subjective Drug Effects (Safety outcome)	The Drug Effects Questionnaire (DEQ) assesses the extent to which participants feel a drug effects, feel high, like the effects, dislike the effects, want more of the substance, and feel sedated, on self-rating 100mm visual analogue scales. A total mood disturbance score is calculated by summing negative domains and subtracting positive domains. Administered pre and post drug administration, as well as next-day (comparison between each CBN dose versus placebo).	Immediately after and morning after drug administration
Postural sway (Safety outcome)	Centre-of-pressure (COP) during computerised static posturography. Administered pre and post drug administration, as well as next-day (comparison between each CBN dose versus placebo).	Immediately after and morning after drug administration
Behavioural Alertness and Reaction Time (Safety outcome)	Psychomotor Vigilance Test (PVT) is administered twice the next-day (comparison between each CBN dose versus placebo).	Morning after drug administration
Overnight Declarative Memory Consolidation (Safety outcome)	Word pair recall scores measured using the computerised Word Pairs Task (WPT). Administered pre-drug administration and next-day (comparison between each CBN dose versus placebo).	Morning after drug administration
Overnight Procedural Memory Consolidation (Safety outcome)	Motor sequence learning measured using the computerised Finger Tapping Task (FTT). Administered pre-drug administration and next-day (comparison between each CBN dose versus placebo).	Morning after drug administration
Resting Wake Electroencephalography (EEG) Power After Sleep (Post-Wake Effects) (Safety Outcome)	Resting wake EEG power during the Karolinska Drowsiness Test (KDT) upon wake: delta (1-4.5 Hz), theta (4.5-8 Hz), alpha (8-12 Hz), sigma (12-15 Hz), beta (15-25 Hz), and gamma (25-40 Hz) frequency ranges. Power spectral analysis is applied to EEG signals from polysomnography, after artefacts are detected and removed. Comparison between each CBN dose versus placebo.	Morning after drug administration
Subjective sleepiness after sleep	The Karolinska Sleepiness Scale (KSS) is a 10-item measure of subjective drowsiness. Participants respond to each item using a 9-point Likert scale ranging from 1 (Extremely alert) to 9 (Extremely sleepy). Higher scores are indicative of increased drowsiness. The KSS will be collected in accordance with the KDT protocol but will not be analysed due to insufficient statistical power.	Morning after drug administration
Resting Wake Electroencephalography (EEG) Power Before Sleep (Acute Effects)(Exploratory outcome)	Resting wake EEG power during the KDT prior to sleep: delta (1-4.5 Hz), theta (4.5-8 Hz), alpha (8-12 Hz), sigma (12-15 Hz), beta (15-25 Hz), and gamma (25-40 Hz) frequency ranges. Power spectral analysis is applied to EEG signals from polysomnography, after artefacts are detected and removed. Comparison between each CBN dose versus placebo.	Immediately after drug administration
Subjective sleepiness after sleep (acute effects) (Exploratory outcome)	The KSS is a 10-item measure of subjective drowsiness. Participants respond to each item using 9-point Likert scales ranging from 1 (Extremely alert) to 9 (Extremely sleepy). Higher scores are indicative of higher drowsiness. The KSS will be collected in accordance with the KDT protocol but will not be analysed due to insufficient statistical power.	Immediately after drug administration
Plasma cannabinoid concentrations (Exploratory outcome)	Presence of cannabinoids (CBN, delta-9-tetrahydrocannabinol [THC], and cannabidiol [CBD]) (e.g., 11-OH-CBN, 11-COOH-CBN, 11-OH-THC, 11-COOH-THC, 7-OH-CBD, 7-COOH-CBD), and endocannabinoids and related molecules (e.g., 2-Arachidonoylglyceroland anandamide) and their metabolites in plasma samples.	Immediately after and morning after drug administration
Urinary cannabinoid concentrations (Exploratory outcome)	Presence of cannabinoids (CBN, THC, and CBD) and their metabolites (11-OH-CBN, 11-COOH-CBN, 11-OH-THC, 11-COOH-THC, 7-OH-CBD, 7-COOH-CBD) in urine samples.	Immediately after and morning after drug administration
Salivary cannabinoid concentrations (Exploratory outcome)	Presence of cannabinoids (THC, CBN) and their metabolites (11-OH-CBN, 11-COOH-CBN, 11-OH-THC, 11-COOH-THC) in saliva samples.	Immediately after and morning after drug administration

Collaborators and Investigators

• Sponsor: Woolcock Institute of Medical Research
• Collaborators: University of Sydney
• Investigators: Principal Investigator: Camilla Hoyos, MPH, PhD, Woolcock Institute of Medical Research; Principal Investigator: Brendon Yee, MBChB, FRACP, FCCP, PhD, Woolcock Institute of Medical Research

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2022
• Primary Completion (Actual): August 29, 2023
• Study Completion (Actual): September 5, 2023

Study Registration Dates

• First Submitted: April 12, 2022
• First Submitted That Met QC Criteria: April 19, 2022
• First Posted (Actual): April 25, 2022

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: polysomnography; randomised controlled trial; placebo-controlled; crossover; sleep architecture; cannabinoid; primary insomnia; cannabinol; CBN; medicinal cannabis; chronic insomnia disorder; wake after sleep onset; next-day function; double-blinded
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders
• Other Study ID Numbers: 112/2021-08-907

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Non-identifiable IPD will be shared upon reasonable request to the Chief Investigators.
• IPD Sharing Time Frame: Non-identifiable IPD will become available one year after the Actual Study Completion Date and will be available for 10 years.
• IPD Sharing Access Criteria: Individual participant level meta-analyses of congruent studies
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No