Insomnia Disorder
Conditions
Keywords
cannabinol, CBN, cannabinoid, medicinal cannabis, primary insomnia, chronic insomnia disorder, sleep architecture, wake after sleep onset, polysomnography, next-day function, randomised controlled trial, placebo-controlled, crossover, double-blinded
Brief summary
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.
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.
Interventions
DRUG30 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.
DRUG300 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.
DRUGPlacebo
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.
Sponsors
University of Sydney
Woolcock Institute of Medical Research
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind: Eligible participants will be assigned to one of six possible treatment orders using a pre-populated randomisation schedule. Study staff (including the study investigators, the clinical trials coordinator and the study medical officer) and the participants will be blinded. Allocation concealment will be managed by the trial epidemiologist and drug distributor who will not have any contact with participants or involvement in day-to-day trial activities. Traditional polysomnographic (PSG) measures will be scored by a PSG technician who will not be aware of participant treatment, nor will they meet the participant. The study drug and matched placebo are expected to be identical in their visual appearance, taste, or smell. A mint-flavoured lozenge will be administered immediately prior to the study drug to mask any possible differences in taste.
Intervention model description
Single site allocation: Randomised Intervention model: Crossover Masking: Double-blind (participant, investigator) Primary purpose: Pilot
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wake After Sleep Onset (WASO) | Night 1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Traditional sleep staging | Night 1 | 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. |
| Sleep Onset Latency (SOL) | Night 1 | 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. |
| Absolute Electroencephalographic (EEG) Power During Non-Rapid Eye Movement (NREM) Sleep. | Night 1 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Next day post-wake subjective sleep evaluation (RCSQ) (Tertiary outcome) | Morning after drug administration | 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). |
| Standard Deviation of Lateral Position (SDLP) During Next-day Post-Wake Simulated Drive (Safety outcome) | Morning after drug administration | 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). |
| Speed During Next-day Post-Wake Simulated Drive (Safety outcome) | Morning after drug administration | 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). |
| Distance Headway During Next-day Post-Wake Simulated Drive (Safety outcome) | Morning after drug administration | 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). |
| Subjective Mood Evaluation (Safety outcome) | Immediately after and morning after drug administration | 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). |
| Subjective Drug Effects (Safety outcome) | Immediately after and morning after drug administration | 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). |
| Postural sway (Safety outcome) | Immediately after and morning after drug administration | 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). |
| Behavioural Alertness and Reaction Time (Safety outcome) | Morning after drug administration | Psychomotor Vigilance Test (PVT) is administered twice the next-day (comparison between each CBN dose versus placebo). |
| Sleep Spindles During Non-Rapid Eye Movement (NREM) Sleep (Tertiary outcome) | Night 1 | 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. |
| Overnight Procedural Memory Consolidation (Safety outcome) | Morning after drug administration | 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). |
| Resting Wake Electroencephalography (EEG) Power After Sleep (Post-Wake Effects) (Safety Outcome) | Morning after drug administration | 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. |
| Subjective sleepiness after sleep | Morning after drug administration | 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. |
| Resting Wake Electroencephalography (EEG) Power Before Sleep (Acute Effects)(Exploratory outcome) | Immediately after drug administration | 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. |
| Subjective sleepiness after sleep (acute effects) (Exploratory outcome) | Immediately after drug administration | 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. |
| Plasma cannabinoid concentrations (Exploratory outcome) | Immediately after and morning after drug administration | 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. |
| Urinary cannabinoid concentrations (Exploratory outcome) | Immediately after and morning after drug administration | 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. |
| Salivary cannabinoid concentrations (Exploratory outcome) | Immediately after and morning after drug administration | Presence of cannabinoids (THC, CBN) and their metabolites (11-OH-CBN, 11-COOH-CBN, 11-OH-THC, 11-COOH-THC) in saliva samples. |
| Overnight Declarative Memory Consolidation (Safety outcome) | Morning after drug administration | 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). |
| Electroencephalogram (EEG) Arousal Index (Tertiary outcome) | Night 1 | 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. |
| Absolute Electroencephalography (EEG) Power During Rapid Eye Movement (REM) Sleep (Tertiary outcome) | Night 1 | 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. |
| Next day post-wake subjective sleep evaluation (LSEQ) (Tertiary outcome) | Morning after drug administration | 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). |
Countries
Australia
Outcome results
None listed