Cbd studies 2019

Insomnia is a common sleep disorder that can present in isolation or comorbid to other medical or psychiatric conditions.1 Despite often emerging as a transient response to stress or change to one’s normal sleep–wake cycle,2 approximately 30% of individuals with insomnia display chronic symptoms.3 Chronic insomnia is characterised by sleep disturbances (difficulties with falling asleep, maintaining sleep, or inability to return to sleep on awakening) occurring at least three nights per week and for at least 3 months.4 5 The sleep disturbance is often coupled with clinically significant daytime impairments in social life, occupational function and/or educational achievement.4 5 It is often the perceived daytime impairments, as opposed to the noctural insomnia symptoms per se, that prompt patients to seek treatment.6 Chronic insomnia tends to either ‘wax and wane’ or persist over a lifetime, with the latter course predicted by more severe insomnia symptoms at baseline, female gender and older age.7 8There are emerging associations between chronic insomnia and increased health risks such as cardiovascular disease,9 depression10–12 and dementia,13 14 as well as high rates of absenteeism15 16 and healthcare utilisation.17 Indeed, longitudinal studies with follow-up period ranging from 1 to 34 years have found a substantial risk for developing depression (both first onset and recurrent major depressive disorder) in patients with insomnia, an association that is bidirectional.18 As such, there is a strong need for early clinical intervention.

The goal of treatment for insomnia is to improve sleep (both duration and quality) and alleviate daytime impairments. Psychological therapies such as cognitive behavioural therapy for insomnia (CBT-I) and psychoeducation regarding sleep hygiene can be effective.19 However, these often require access to a therapist and can involve substantial effort, time and financial commitment.20 Furthermore, the perceived benefits from these approaches are typically delayed. Thus, patients with persistent symptoms often seek strategies offering short-term relief to maintain normal daytime functioning; highlighting a specific role for adjunctive use of pharmacological treatments such as benzodiazepines, sedating antidepressants, and Z-drugs.21 However, these are associated with undesirable side effects such as cognitive impairment, tolerance/dependence and impaired driving due to sedative effects that can persist into the following day.22 Moreover, many of these medications disturb sleep architecture; increasing sleep fragmentation and one’s sense of having non-restorative sleep and ultimately impair the ability to undertake normal daily activities.23 Thus, novel approaches are needed to address the needs of people with chronic insomnia disorder.

Anecdotally, consumers of cannabis commonly report that the drug promotes uninterrupted sleep.24 The plant Cannabis sativa contains >100 different cannabinoids—the most abundant of which are the main psychoactive component, Δ 9 -tetrahydrocannabinol (THC), and the non-intoxicating cannabinoid, cannabidiol (CBD).25 Both CBD and THC affect components of the endogenous cannabinoid system which are involved in the regulation of the circadian sleep–wake cycle, including the maintenance and promotion of sleep.26 27 THC is a partial agonist of the cannabinoid 1 (CB₁) receptor, found primarily within the central nervous system28 and the cannabinoid 2 (CB₂) receptor, found primarily in the immune system and on peripheral organs.29 THC is known to have sedating properties via its action at the CB₁ receptor, which is notably dense in areas of the central nervous system such as the thalamus, hypothalamus, hippocampus, basal ganglia and cortex, suggesting a diverse role in the modulation of physiological functions including sleep.30 31 CBD is an indirect CB₁ and CB₂ receptor agonist, and has shown to increase concentrations of the major endogenous cannabinoid, anandamide, by inhibiting its degradative enzyme, fatty acid amid hydrolase (FAAH).32 33 Increasing endogenous anandamide via FAAH inhibition normalised deficits in stage N3 sleep in cannabis-dependent men experiencing withdrawal,34 consistent with preclinical data showing that anandamide promotes slow wave sleep, possibly through increases in extracellular adenosine concentrations.35–37 This effect can be blocked by administration of the CB₁ antagonist, rimonabant.38 Indeed, clinical trials of rimonabant have reported an increased risk of sleep disturbances,39 suggesting a role for the CB₁ receptor in mediating sleep. CBD is also a negative allosteric modulator of CB₁ receptor40 and may reduce the effects of THC and anandamide on the brain.41 42 There is an emerging viewpoint that coadministration of CBD with THC may enhance therapeutic outcomes by attenuating the adverse effects of THC (e.g., on emotion recognition,43 next-day memory performance,44 appetitive effects45 and acute psychotic symptoms46 47); however, findings are inconsistent with a recent study showing CBD exacerbating THC-induced impairment on driving and cognition, possibly via a pharmacokinetic interaction.48 Furthermore, CBD is a promiscuous molecule that exhibits activity on a wide array of molecular targets beyond CB₁ and CB₂ receptors such as inhibitory GABA_A receptors,49 which may also influence sleep. Administration of THC alone (15 mg) in the evening was associated with next-day changes in mood, sleepiness and memory in healthy adults,44 emphasising the need for careful consideration of dose and ratio of cannabinoids when administered in clinical insomnia populations.

To date, there have been no well-designed randomised controlled trials employing objective measures assessing the effects of cannabis on sleep duration and quality in a clinical insomnia population.50–52 Previous studies have shown potential benefits in the therapeutic use of nabiximols (Sativex), an oromucosal spray containing equal parts THC and CBD, in the relief of pain and other chronic symptoms including improved sleep, with the latter only assessed as a secondary outcome using subjective rating scales.53 Other studies using synthetic THC (nabilone) showed improvements in subjective sleep quality in patients with post-traumatic stress disorder (PTSD)54 55 and fibromyalgia,56 while CBD was found to be effective in reducing the frequency of rapid eye movement sleep behaviour disorder events in Parkinson’s disease.57 One case study showed that 25 mg CBD daily reduced anxiety symptoms and improved sleep disturbances in a young child with PTSD.58 Indeed, preclinical evidence has demonstrated anxiolytic effects of CBD, likely dependant on CB₁ and 5-HT_1A receptor action, with early human experimental evidence supporting preclinical findings.59 To address the lack of studies in a clinical insomnia population, we will investigate the acute effects of a plant-derived, pharmaceutical-grade, oral formulation containing 10 mg THC and 200 mg CBD relative to placebo on sleep and next-day function (cognitive function, alertness, simulated driving performance) in participants with physician-confirmed chronic insomnia disorder. This study will be the first to employ 256-channel high-density electroencephalography (EEG) coupled with structural MRI brain scans to examine and localise differences in sleep depth and brain activation during both sleep and wakefulness in this clinical population.

Methods and analysis

Study design

A double-blind, randomised, placebo-controlled, crossover study design will be used to evaluate the effects of 10 mg THC and 200 mg CBD on sleep and daytime function in participants diagnosed with chronic insomnia disorder. Participants will be recruited over an 18-month period commencing August 2019. The recruitment target is 20 participants, which will provide the proof-of-concept evaluation of the study drug to determine whether future larger studies in insomnia disorder are warranted. The study site and sponsor is the Woolcock Institute of Medical Research; a research institute and specialist sleep clinic in inner suburban Sydney, Australia. Participants will undergo two separate overnight study assessment visits. Each study assessment visit will be scheduled at least one week apart to avoid any carryover effects, as informed by previous studies of this nature.60 61 The protocol (Version 2.3, July 2019) has been prepared in accordance with the SPIRIT statement (see online supplementary file 1).62

Supplemental material

Recruitment and enrolment

The study population will be adults aged 35–60 years with chronic insomnia disorder as per International Classification of Sleep Disorders–Third Edition (ICSD-3) criteria.63 This age range was chosen to limit age-related variability in sleep architecture for better interpretation of EEG changes.64 Participation will be voluntary under conditions of informed consent. A list of the inclusion and exclusion criteria is presented in box 1. Participants will be recruited through the following strategies: (1) referral from sleep physicians and psychologists at the Woolcock Institute of Medical Research, Australia; (2) via two databases that host the details of people who have provided consent to be contacted about future clinical trials (”Woolcock Volunteer Database” and the “Lambert Initiative for Cannabinoid Therapeutics Expression of Interest database”); (3) physical study advertisements displayed around the local University area; and (4) study advertisements posted on social and news media. All participants will receive financial compensation for their time commitment to the study.

Inclusion and exclusion criteria

Inclusion criteria

Aged 35–60 years
Diagnosis of insomnia disorder made by a physician or a psychologist
Insomnia Severity Index (ISI) score≥15
Insomnia symptoms for >3 times per week and present longer than 3 months

Exclusion criteria

Shift worker
Medical condition (e.g., chronic pain) or medication that is the cause of the insomnia
Sleep apnoea (defined as Apnoea Hypopnoea Index (AHI)>15 and Oxygen Desaturation Index (ODI)>10) or sleep-related movement disorder based on in-laboratory polysomnography
Advanced or delayed sleep–wake phase disorder based on actigraphy
Used any modality of treatment for insomnia, including cognitive–behavioural therapy (CBT) and CNS-active drugs, within 3 months before screening or at the medical doctor’s discretion
Transmeridian travel (two time zones) in the past month
Use of medications that may influence cannabinoid metabolism (e.g. inhibitors/inducers of the CYP450 pathway)
Clinically relevant cardiovascular abnormalities (as determined by 12-lead ECG at screening)
Pregnancy or lactation (females)
History of a major psychiatric disorder within the past 12 months (except clinically-managed mild depression or anxiety) as per the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 or at the medical doctor’s discretion
History of attempted suicide or current suicidal ideation as determined by a score >0 on Q9 of the Patient Health Questionnaire (PHQ)-9
History of drug or alcohol abuse/dependency within the past 2 years
Urinary drug screen positive for drugs (benzodiazepines, opiates, cannabis, amphetamines, cocaine)
Known hypersensitivity to cannabis
Cannabis use within the past 3 months (confirmed by negative urine drug screen)
Unable to undergo brain MRI due to implanted device or other reason
Excessive caffeine use that, in the opinion of the medical doctor contributes to the participant’s insomnia, or is unable to abstain from caffeine use ≥24 hours prior to each overnight study assessment visit
Inability to refrain from alcohol consumption ≥24 hours prior to each overnight study assessment visit
Medical conditions that result in frequent need to get out of bed (e.g., nocturia)
Required to complete mandatory drug testing for cannabis (e.g., workplace testing, court order)

Study intervention

The investigational product (‘ETC120’) is a plant-derived oral formulation containing a 1:20 ratio of THC to CBD suspended in medium-chain triglycerides (MCT) oil. ETC120 will be purchased from Linnea (Ticino, Switzerland). Participants will be administered a single fixed dose of ETC120 (2 mL containing 10 mg THC and 200 mg CBD) or matched placebo (2 mL containing no cannabinoids). The 1:20 ratio of THC to CBD was chosen to harness the sedating properties of THC while including some of the potential anti-anxiety properties of CBD,65 given that anxiety is a very common comorbidity in people with insomnia disorder.66 67 As noted above, there is also possibility that this dose of CBD might reduce some of the possible adverse effects of THC (e.g., anxiety, memory impairment). The chosen ratio also mimics naturalistic findings in recent surveys where individuals reported using cannabis with higher CBD concentrations in addition to THC to effectively manage insomnia symptoms.68 69 The THC dose (10 mg) was chosen as being the maximum dose that is likely to induce subjective drug effects of feeling ‘sleepy/tired’ without impairing cognitive performance (e.g., reaction time tasks) or producing significant intoxication in naïve or occasional cannabis users.60 A significant intoxicating effect might inadvertently cause a stimulatory response and interfere with sleep induction.60 70

Randomisation and allocation concealment

Each participant will be randomly allocated to one of two treatment sequences: (1) ETC120–placebo, or (2) placebo–ETC120. As this is a blinded study, the participant, the study staff (including the medical doctor) and the outcome assessors will not be aware of which treatment order participants have been allocated to. Method of allocation concealment will involve central randomisation by computer prepared by the trial statistician (NSM) and identical containers numbered according to the randomisation sequence prepared by the drug distributor. Neither the drug distributer or the trial statistician will meet any prospective or enrolled participants or be involved in any day-to-day trial process. The sequence will be computer-generated using a simple 1:1 randomisation ratio by the trial statistician, and by the order of participant enrolment. The sequence will be stored in a password-protected data management system and cannot be accessed by blinded study staff who have contact with participants. The order of treatment will only be known by the drug distributer and the trial statistician. In the event of a serious adverse event (SAE) or reaction, the allocation list will be retrieved from the unblinded trial statistician or drug distributer to reveal the participant’s allocated treatment during the trial.

Study objectives

The primary outcome of the study is to assess the effect of 10 mg THC and 200 mg CBD on sleep continuity (wake after sleep onset) and quantity (total sleep time) assessed using attended overnight full polysomnography in participants with chronic insomnia disorder.

To determine changes in sleep microarchitecture metrics measured using high-density EEG and source modelling in participants with chronic insomnia disorder treated with ETC120 relative to placebo.
To assess next-day neurobehavioural functioning (cognition, alertness and simulated driving performance) in participants with chronic insomnia disorder treated with ETC120 relative to placebo.
To demonstrate feasibility of a cannabinoid study in chronic insomnia and establish clinical trial procedures for future trials in this area.

The ANZCTR trial registry has a comprehensive list of the trial’s primary and secondary outcomes. See online supplementary file 2 for WHO Trial Registration Data Set.

Supplemental material

Study visits and procedures

Screening

A flowchart of the study is depicted in figure 1. Initial suitability assessment via a brief online questionnaire and a follow-up telephone screen will be conducted by the study investigator. Written informed consent will be obtained by the study medical doctor before conducting an interview to ascertain sleep difficulties and diagnose ICSD-3 chronic insomnia disorder (Visits 1–2). Individuals will then undergo comprehensive screening to be completed within one month of study entry, which will include a diagnostic sleep study at the Woolcock Clinic to exclude sleep disorders other than insomnia disorder (unless one has already been conducted in the past 12 months). The Insomnia Severity Index71 (ISI; measure of nature, severity, and impact of insomnia), the Pittsburgh Sleep Quality Inventory72 (PSQI; measure of sleep quality and sleep habits), the Epworth Sleepiness Scale73 (ESS; measure of daytime sleepiness), the Hospital Anxiety Depression Scale74 (HADS; measure of anxiety and depression) and the Patient Health Questionnaire75 (PHQ-9; multi-purpose tool for assessing severity of depression) will be administered to phenotype insomnia symptoms and to assess suitability for study inclusion. All participants will be screened for prior cannabis use history (ie, whether they have consumed cannabis in the past, the form(s) in which it was consumed, and frequency of use) as well as for past or present cannabis use disorder as per the ICD-10 criteria.76 A urine specimen will be screened (DrugCheck NxStep OnSite Drug Test, Minnesota, USA) to rule out recent drug use. Participants testing positive for any drug (cannabis, cocaine, benzodiazepines, opiates or amphetamines/MDMA/methamphetamines) will result in exclusion or rescheduled at the studymedical doctor’s discretion. A standard 12-lead electrocardiogram (ECG) will be recorded to screen for any clinically relevant cardiovascular abnormalities. Rapid urine pregnancy test (Alere HCG Combo Cassette, Massachusetts, USA) will be administered to female participants, and identification of pregnancy will result in exclusion. Participants will then be instructed to maintain a sleep diary and wear a wrist-worn commercially available device (Actiwatch 2, Philips Respironics) to monitor sleep and wake periods for one week. These data will allow the study team to estimate the participant’s individual typical sleep-onset and wake-onset times for the study assessment visits as well as rule out advanced or delayed sleep-wake phase syndrome.

Following screening, the participants will undergo a structural brain MRI at a medical imaging clinic (Visit 3). Then, participants will attend the sleep clinic for an orientation session (Visit 4) to practise wearing the high-density EEG sensor cap during a short nap opportunity as well as complete a familiarisation and practice drive on the driving simulator. Participants will then be asked to maintain consistent sleep-onset and wake-onset times, confirmed by at-home sleep diary and actigraphy for one week prior to each study assessment visit. Participants will be instructed to abstain from illicit drug use for the duration of the study (ie, from pre-enrolment until after the final study assessment visit) and to refrain from consuming alcohol and caffeine for 24 hours prior to and during the study assessment visits, but to continue use of any regular prescribed medications (except those listed in the exclusion criteria). Standardised meals and snacks will be provided for participants at each study assessment visit. Table 1 depicts the schedule of visits and procedures from pre-enrolment to study completion.

Schedule of study visits and procedures