.png)
Introduction
Chronic insomnia disorder, characterized by difficulty initiating or maintaining sleep at least 3 nights per week for at least 3 months, is present in 6%–15% of the population [1, 2], and is associated with poor health outcomes and reduced productivity. Cognitive behavioral therapy for insomnia (CBTi) is the first-line treatment, with improvement reported in approximately 60% of patients [3]. In cases where treatment is ineffective or access to CBTi is limited or delayed, then pharmacological therapies can be useful. However, adverse effects from conventional pharmacological treatments for insomnia are common [4] and include dependence, abuse potential, tolerance, daytime sedation, psychomotor impairment manifesting as falls and cognitive impairment [5] and increased risk of head injury or fracture [6]. These undesirable side-effects drive an ongoing search for alternative therapies. Cannabinoids have emerged as a possible alternative therapy for patients with insomnia who are considering therapeutic options.
Cannabis use in the United States was prohibited from 1937 until it was legalized for medical use in the late 1990s. Similar legislative changes have followed in many countries, prompting increased availability and use for medical purposes. Insomnia (or “sleep disorder”) is a common symptom for which people use cannabis [7]. However, few studies have examined the efficacy of cannabinoid formulations in treating insomnia [8], and a placebo-controlled randomized trial has yet to be undertaken. Improvements in sleep quality have been reported with delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone or in combination. However, when taken in combination CBD is known to attenuate the potential psychotropic effects of THC [9] although high doses of CBD have been reported to have potential alerting properties [10]. Greater drowsiness has been reported with the addition of cannabinol (CBN) and THC than with THC alone [11].
This study therefore employed a double-blind, randomized, placebo-controlled, crossover design to evaluate the safety and efficacy of a cannabinoid formulation which included THC, CBD, and CBN (ZTL-101), for treating insomnia symptoms in patients with chronic insomnia disorder.
Discussion
This Phase 1b study demonstrated that nightly sublingual administration of a novel cannabinoid formulation for 2 weeks improved insomnia symptoms without significant adverse events in participants with chronic insomnia symptoms. This study used the ISI, a reliable, valid, and widely used instrument, to quantify perceived insomnia severity and its impact on daily function [17]. The ISI was lower while taking ZTL-101 relative to placebo. Consistent with this positive treatment response, improvements in self-reported sleep diary and objective actigraphic measures of sleep quality and quantity were also documented.
The novel formulation, ZTL-101, was well tolerated with only one participant withdrawal, due to a nonserious adverse event. Seventeen of the 24 participants experienced at least one adverse event while taking ZTL-101, with dry mouth and dizziness being most frequently reported. Although the number of adverse events is somewhat greater than that commonly reported for contemporary hypnotics [20], it is comparable to other trials using medicinal cannabis [21]. Furthermore, all adverse events were classified as mild and all but one (xerostomia, oral hypesthesia, swollen tongue, nausea in the participant who withdrew) had resolved upon waking or soon afterwards. The occurrence of dizziness and hallucinations are the most concerning and suggest caution is required in populations such as the elderly or those with psychiatric disorders. Although the occurrence of adverse events may be reduced with a more gradual dose titration [22], it is clear that further research is required to more comprehensively assess benefits and harms of medicinal cannabis use for the treatment of insomnia.
The effects of ZTL-101 on sleep were assessed from self-report, actigraphy, and PSG. Each of these methods is widely used to assess sleep, although none are without limitations in individuals with insomnia. For example, while self-reported sleep difficulty is the basis of the clinical diagnosis of insomnia, self-reported measures of total time spent asleep and time taken to fall asleep at the start of the night are known to be under and overestimated, respectively [23]. Actigraphy can objectively and unobtrusively measure sleep over multiple nights in the home environment. However, it tends to overestimate sleep time and underestimate wake time because the method designates periods of no motion as sleep, whether asleep or not. PSG is considered the “gold-standard” method of defining sleep, wake, respiration, and movement, and can therefore provide an objective measure of sleep quality, quantity, and identify other sleep disorders. It is typically performed in a laboratory or clinic on a single night and is more intrusive than actigraphy. However, its use in individuals with insomnia is limited by first night effects (i.e. patients sleeping worse or better than usual) and an inability to capture night-to-night variability in sleep behavior with a single night measurement. To enable a thorough evaluation of the impact of ZTL-101 on sleep, the present study utilized all three methods.
When taking ZTL-101 participants reported an improvement in the time taken to fall asleep, time spent asleep, and feelings of being more rested/refreshed on waking. These self-reported improvements were supported by actigraphy-derived measures of the mean total time spent asleep each night, which increased by 33.5 min; SE, which increased by 2.9%–84.8%; and the time spent awake during the night, which decreased by 10 min. The mean total time spent asleep across the 2-week period was over 7 h while taking ZTL-101, which is the recommended minimum sleep duration for adults [24], and above average for individuals of comparable age without insomnia [25]. Despite this, the average time spent awake during the night remained high at greater than 70 min, possibly reflecting a persisting tendency to disturbed sleep in individuals with chronic insomnia or that sufficient sleep had been achieved given the other improvements. Notably, the time taken to fall asleep was unchanged by ZTL-101. This has been reported in other studies [26] and could reflect a “floor effect” given the relatively short aSOL values at baseline in the study participants; or the inability of actigraphy to differentiate motionless wakefulness from sleep.
The improvements in self-reported and actigraphy-based measures of sleep with ZTL-101 were not seen in any PSG measure of sleep quantity or quality. This is likely due, at least in part, to the inclusion criteria being based on self-reported diagnostic criteria for insomnia [12] rather than PSG-defined insomnia, as well as the limitations of a single night PSG measure described previously. The main purpose of PSG was to identify and exclude participants with other sleep disorders such as sleep apnea and periodic limb movement disorder, which can coexist with insomnia and potentially confound interpretation of any sleep-related changes ascribed to ZTL-101. It is important to also note that ZTL-101 did not induce these sleep disorders, nor did it alter the proportion of time spent in the different sleep stages. By contrast, alteration of the proportion of sleep stages is common with many hypnotic medications; benzodiazepines, for example, are known to significantly decrease the proportion of REM sleep [27].
Insomnia is characterized by self-reported difficulties initiating or maintaining sleep [2]. As such, any globally effective pharmacological therapy for it should be capable of targeting either characteristic. To explore this, the pharmacokinetic properties of ZTL-101 overnight were determined after a standardized evening meal, thereby obtaining measurements of drug metabolism under conditions pertaining to its use in the clinical setting. Following a single dose of ZTL-101, peak plasma levels of the major constituents were reached at approximately 4–6 h. A similar profile was observed following ingestion of a double dose of ZTL-101, albeit with greater maximum plasma levels. Although it is possible that accumulation of cannabinoids might occur with dosing over multiple nights, this has not been demonstrated in dosing with THC/CBD = 21.6/20.0 mg out to 9 days. These data suggest that for patients with sleep onset insomnia dosing 2–4 h before desired bedtime might be optimal, while those with sleep maintenance insomnia should dose 1 h before desired bedtime.
Limitations
Due to the possible risk of exacerbating preexisting conditions, individuals with a history of significant cardiovascular disease or known major psychopathology were excluded. The safety and efficacy of ZTL-101 in these populations remains to be established. Likewise, the possible drug–drug interaction between ZTL-101 and cytochrome P450 inhibitors requires further investigation. Maintenance of blinding is challenging in hypnotic [28] and cannabinoid trials [29] and this study is one of the first randomized, placebo-controlled medicinal cannabis trials to assess efficacy of blinding. The results of the blinding questionnaire suggest that despite considerable efforts to ensure ZTL-101 and placebo were similar in appearance, odor, and taste, effective blinding for a beneficial treatment effect was unable to be achieved; thus the data should be interpreted with this in mind. This is the first study to demonstrate acceptable safety and promising efficacy of a cannabinoid therapy in a randomized, double-blind, placebo-controlled manner, although it was limited to 2 weeks and included a relatively small sample of participants. Similarly, the pharmacokinetic component of the study used a subset of participants (n = 9), which although small is not unusual for pharmacokinetic studies [30, 31].
We undertook a multifaceted study of the influence of ZTL-101 on sleep and wakeful function, examining for a consistent trend across many measures beyond the ISI, the co-primary outcome measure. Adjustment for multiple comparisons was not performed as we did not want to artificially discount any of the exploratory analyses, which are all presented [32]. Further dedicated studies are needed to confirm the promising findings of this preliminary investigation of a novel pharmacological approach to a very common and vexing health issue.
Conclusions
This study has demonstrated that ZTL-101, a novel cannabinoid therapy, is well tolerated and improves insomnia symptoms and sleep quality in individuals with chronic insomnia symptoms. These improvements, observed over a 2-week dosing period, are encouraging and support further investigation of ZTL-101 for the treatment of insomnia in studies with larger sample sizes.
