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Abstract
The recent trend for legalization of medicinal cannabis and cannabinoid-containing products, together with their soporific effects, has led to a surge of interest of their potential therapeutic role in the management of some common sleep disorders, such as insomnia, sleep disordered breathing, and restless legs syndrome, and less common disorders such as narcolepsy and parasomnias. Although much of the pre-clinical and clinical data were derived from studies with relatively small sample sizes and limited by biases in assessment, and in clinical trials lack of allocation concealment, as a whole, the results indicate a potential therapeutic role for cannabinoids in the management of some sleep disorders. Clinical trials are underway for insomnia and obstructive sleep apnea management, but there remains a substantial need for rigorous large multi-center studies to assess the dose, efficacy, and safety of the various types of cannabinoids on sleep disorders. This review aims to summarize the modulatory effects of cannabinoids on sleep physiology and provide a critical evaluation of the research on their potential therapeutic benefit in various sleep disorders.
Introduction
Cannabinoids are psychoactive compounds found in the cannabis plant. With legalization, they have become the most frequently used psychoactive substance in the world. Around 104 cannabinoids have been identified, out of which delta-tetra-hydrocannabinol (THC) and cannabidiol (CBD) have been most widely studied [1]. Due to their psychotropic effects and somnolence, they have been frequently used for sleep induction and in conditions like post-traumatic stress disorder (PTSD)–related nightmares. We aim to provide a comprehensive review of the literature on effects on these cannabinoids on normal sleep architecture as well as various sleep disorders. Historical Significance of Cannabinoids
Marijuana, or cannabis, is recognized as a schedule I drug by the US Drug Enforcement Agency (DEA) with high potential for abuse. An exception to this is the cannabis-derived compound dronabinol which is classified as schedule III [2]. Marijuana is also one of the most widely cultivated drugs worldwide [3]. Historically, it may have been first utilized in the third millennium B.C. based on archeological evidence; however, the first evidence of its medicinal use is from around 400 AD [4]. In the USA, it is legalized for medicinal use in 33 states, four permanently inhabited territories, and the District of Columbia. Recreational use is legalized in 11 states, District of Columbia, Northern Mariana Islands, and Guam [5, 6].
There is growing data on the use of these compounds for medicinal purposes, such as treatment of pain and chemotherapy-related side effects. In addition, there has been a surge of interest of their use in other conditions [7]. Directly relevant to this review is their potential general sleep-promoting effects and effects on specific aspects of sleep physiology, which may be advantageous in the treatment of some sleep disorders.
Sleep Physiology
Sleep is an essential physiologic function that alternates with wakefulness. The structural organization of normal sleep is broadly organized into two alternating phases: non-rapid eye movement (NREM) and rapid eye movement (REM) Fig. 1a (normal sleep hypnogram).
The regulation of the sleep-wake cycle is a complex interplay between various neuroanatomical and neurochemical systems. REM sleep is regulated by neurons present in the pons and hypothalamus and NREM sleep is regulated by neurons in the preoptic areas (like the ventrolateral preoptic nucleus) that inhibit the ascending arousal systems [8]. These sleep-promoting regions are primarily regulated by inhibitory neurotransmitters like gamma-aminobutyric acid (GABA) or galanin. REM sleep is also promoted and maintained by cholinergic neurons located in the dorsolateral pons [9].
Wakefulness is mediated primarily by neurons in the reticular formation, especially the rostral half. These neurons send excitatory projections to areas of the thalamus, hypothalamus, and forebrain. Cholinergic, monoaminergic, and the orexin/hypocretin neurotransmitters are primarily involved in promotion of wakefulness [8, 10].
Along with changes in neuronal activity, there are dynamic fluctuations in physiology during sleep that involve the cardiovascular, autonomic, respiratory, and endocrine systems. Respiratory patterns vary during sleep with a regular respiratory pattern in NREM sleep and a more irregular pattern in REM sleep. The central and peripheral chemo- and mechanoreceptors respond to changes in oxygenation and ventilation, but this response also varies between sleep and wakefulness, becoming more pronounced during REM sleep. Sleep also decreases the tone of the pharyngeal muscles, which can be further exacerbated by certain positional changes. Further, there is reduction in the tone of other upper airway and intercostal muscles which leads to increased upper airway resistance, decreased thoracic movements, and ultimately hypoventilation which becomes especially pronounced during REM sleep [11]. This ventilatory load is normally counteracted by compensatory mechanisms in the awake state but is delayed during sleep [12]. This load compensation can be further pathologically reduced in conditions like obstructive sleep apnea (OSA) [13].
Cannabinoids and Sleep Architecture
The effects of these compounds on various stages of sleep with different modes of administration including inhalational or oral use have been evaluated in some small studies revealing variable effects on sleep stages. Most of the studies examining these effects were polysomnography-based primarily done in the early 1970s. These studies included several animal and small human studies. Most of these studies evaluated the effect of THC and cannabis; thus, data on effects of CBD are lacking [29].
Effects of Cannabis and THC on Sleep Architecture
- 1.Acute exposure/short-term use: With short-term use, it is suggested that there is more sleep consolidation, reduced sleep onset latency (SOL), increased total sleep time, and decreased wake after sleep onset (WASO). Acute administration of THC has also been associated with decreased REM sleep and increased slow wave sleep (SWS), similar to some animal studies [30, 31]. However, the effects on slow wave sleep and total sleep time are not persistent (Fig. 1b).
- 2.Long-term use: In contrast to the above, chronic administration of THC has been shown to decrease SWS, suggesting the possibility of tolerance with its long-term use. Effects of the chronic use of THC on REM stage are non-uniform, unlike SWS effects seen in various human and animal studies [32,33,34]. There is also suggestion of increased sleep disruption due to increased SOL, increased WASO, and reduced TST [35]. A polysomnography-based study demonstrated these effects by evaluating objective and subjective measures of sleep in current cannabis users. The majority of participants showed decreased overall sleep time (78%), with increased SOL (>30 min), poor sleep efficiency (<85%), and increased WASO (54.7). Increased REM sleep latency (average 114.5 min) as well as decreased percentage of REM sleep (17.7%) were also noted (Fig. 1c).
- 3.Withdrawal effects: With cannabis withdrawal, there are associated sleep disturbances and vivid dreams. A study comparing different PSG characteristics in prior heavy marijuana users demonstrated lower total sleep time (TST), decreased SWS and decreased REM latency as compared to controls (Fig. 1d). This group also had longer sleep onset and worse sleep efficiency than the control group, though the study was limited by lack of baseline PSG data in both groups [36]. Another study also showed an increase in periodic limb movements (PLMs) after abrupt cessation of heavy marijuana use [37,38,39]. Withdrawal-related sleep disturbances have been found to be worse among heavy users and usually occur in about 24–72 h after discontinuation and can persist up to 6–7 weeks. Given these duration-dependent variable effects on sleep architecture, the role of cannabinoids in sleep disorders remains under investigation.
Effect of CBD on Sleep Architecture
Data regarding effects of cannabidiol or CBD on sleep are limited. Studies in rats injected with increasing dosages of CBD showed an increase in total percentage of sleep, with a decrease in REM latency at lower doses and an increase in REM latency at higher doses [40, 41]. At this time, there are a lack of human studies collaborating these findings. A recent controlled trial did show increased sleepiness based on subjective assessment in subjects who used CBD-dominant cannabis, but it is unclear if this was due to the small amount of THC in it [42]. Chronic effects of CBD are yet to be studied. Thus, studies on the isolated effects of CBD on sleep architecture are limited and mostly have mixed results.
Effects of Combined THC and CBD on Sleep Architecture
Studies of CBD in combination with THC have shown that CBD has more alerting effects and tends to counteract the sedative effects of THC especially at higher doses, as shown in a double-blinded, placebo-controlled four-armed crossover study using EEG monitoring [28].
In summary, most of these studies evaluating effects of cannabis and cannabinoids are limited by differences in study designs, sample sizes, and procedures, as well as the ratios of THC to CBD used. These effects are summarized in Fig. 1 with various hypothetical hypnograms depicting effect of cannabinoids on stages of sleep.
Therapeutic Role of Cannabinoids on Sleep Disorders
Insomnia
Insomnia is a prevalent problem in the population with several recognized health consequences. Given limited therapeutic drug options and the potential deleterious health effects of available pharmacological agents, investigation of additional therapeutics is warranted. Due to their anxiolytic effect, cannabinoids have been historically used as sleeping aids [48]. Cannabinoids (CBD and THC) have variable effects on different sleep stages (as demonstrated by the hypnogram in Fig. 1). While some studies have demonstrated decreased insomnia severity with their use, most have shown mixed results. Applicability is also limited due to lack of assessment of dose-related effects.
CBD use has been shown to increase total sleep percentage with mid to high doses in rat models [40]. There is a dose-dependent effect on REM sleep latency—with higher doses causing an increase in latency while mid-range doses yield a decrease [60]. Another study found that CBD had a positive effect on anxiety-related REM sleep suppression but no effect in the NREM phase. CBD used in combination with THC has been shown to decrease N3 sleep [28]. THC alone has been shown to decrease sleep latency but with long-term use it can decrease total sleep, likely due to tolerance of effect [61]. There is also increased evidence of improvement in insomnia symptoms secondary to chronic conditions. Patients with chronic conditions such as fibromyalgia frequently report insomnia. A study comparing the effect of synthetic THC (nabilone) versus amitriptyline on sleep in fibromyalgia patients with chronic insomnia demonstrated superiority of nabilone over amitriptyline in insomnia severity index and some improvement in restfulness [62]. It is unclear if this is due to the effect of marijuana on sleep quality or better pain control [63]. Recently, some randomized controlled trials (RCTs) are underway evaluating the effect of various cannabinoid products on chronic insomnia, which includes use of various combinations of CBD, THC, and cannabinol (CBN) or CBD alone [64,65,66]. One of these proposed trials, the CANSLEEP trial (cannabidiol and Δ9-tetrahydrocannabinol for chronic insomnia disorder), is a proof-of-concept trial evaluating safety and efficacy of single dose of ETC120 oil (a product containing THC and CBD) in chronic insomnia patients based on PSG data, EEG, and source modeling (using brain MRI) [67].
In summary, the effect of cannabinoids on sleep and insomnia is not only dose dependent, but also heavily influenced by type and combinations used. Before it can be reliably considered a choice for insomnia treatment, larger controlled studies are needed to better evaluate optimal doses as well as effects on various sleep stages.
Conclusion
The recent trend for legalization of medicinal cannabis and cannabinoid-containing products, together with their soporific effects, has led to a surge of interest of their potential therapeutic role in the management of some common sleep disorders, such as insomnia, sleep disordered breathing, and restless legs syndrome, and less common disorders such as narcolepsy and parasomnias. However, the science of cannabinoids in various sleep disorders is still in infancy. Our review summarizes the mechanism, role, and current body of literature on cannabinoids in various sleep disorders. Though widely utilized historically and legally in many parts of the world, robust knowledge about the effects of these substances, especially long term, is lacking. Most studies are pre-clinical or have small sample sizes which limit their applicability. Currently, some placebo-controlled trials are underway for evaluation of the effects on sleep apnea and insomnia [99].
Overall, synthetic derivatives in their purest form with known mechanism of action, route of administration, and thoroughly studied pharmacology have a greater potential of revolutionizing their therapeutic role in sleep disorders.
