The ECS, Cannabis, & Sleep
JAKE F. FELICE, ND, LMP
Sleep is a dynamic and essential activity that involves a multitude of physiologic processes. Proper sleep assists the body with tissue repair, immune maintenance, memory storage, appetite, blood sugar control, blood pressure regulation, process learning, and so much more. Yet nearly half of the adult US population suffers with problems of sleep.1 Unfortunately, sleep disorders lead to chronic illness and increased costs to the healthcare system, and a chronic lack of sleep increases risks of cardiovascular disease, diabetes, and cancers, as well as immune imbalances including increased risk of infectious diseases such as pneumonia.2 After only a few days of sleep restriction, participants in controlled studies showed significant losses in neurocognitive functioning.2
Cannabis for Sleep
The recent explosion of scientific inquiry into the endocannabinoid system (ECS) has generated accumulating evidence that plant cannabinoids, including tetrahydrocannabinol (THC) and cannabidiol (CBD), have favorable subjective effects on sleep quality as well as produce objective changes on polysomnography. This is unsurprising, as the ECS is intimately involved in nearly all aspects of homeostasis and it functions as a self-regulating harm-reduction system.3 The ECS consists of cannabinoid receptors CB1 and CB2, endogenous ligands such as the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their transport mechanisms, and endocannabinoid-metabolizing enzymes. The ECS profoundly influences a plethora of physiologic processes, in the human body and in almost all other animals.
The usefulness of cannabis for sleep necessitates a comparison with its pharmacologic alternatives. Prescription drugs for sleep are associated with significant risks of dangerous drug interactions, as well as other side effects including withdrawal-insomnia.4 Most hypnotics are usually prescribed without valid indications, and even when indicated, they frequently produce little or no benefit and generally make patients sleepier the next day.5 Hypnotic medications are associated with substantially increased risk of all-cause mortality.5
A recent study comparing prescription records with medical examiner data showed that 76% of overdose patients had benzodiazepine prescriptions and 25% had a prescription for zolpidem.5 Even when fewer than 18 pills per year are prescribed, hypnotics have been associated with a greater than 3-fold increase in the risk of death.5 Benzodiazepines are involved in increasing numbers of emergency department visits.5 The frequency of unwanted and dangerous side-effects of conventional sleep agents results in dissatisfaction rates approaching 50%.4–7
Although no medication is risk-free, cannabis has a remarkably low toxicity profile. It is estimated that the average human would have to smoke the equivalent of 2000 to 4000 joints in 15 minutes to be fatal.8 This number translates to over 624 kg of cannabis inhaled in 15 minutes.8 The therapeutic ratio for commonly prescribed drugs is defined as the ratio of an effective dose compared to a toxic dose. The therapeutic ratio for many medications is 1:10, while the ratio for relatively low-toxic aspirin is 1:20. The therapeutic ratio for cannabis lies somewhere between 1:20 000 and 1:40 000, which is magnitudes lower than the toxicity for the vast majority of medications in the US pharmacopeia.8 Rates of cannabis dependence are more similar to those of coffee than of sedatives or alcohol, and cannabis withdrawal symptoms are typically limited to insomnia, anxiety, and sweating.9
With large numbers of patients using hemp, CBD, and THC-based products, it is important for clinicians to understand how plant cannabinoids affect sleep via the ECS. Knowing how the ECS functions under normal and pathologic conditions can provide clinicians with insights into sleep disorders, giving us windows into understanding how low-toxic approaches can improve sleep and sleep disturbances. Like any pharmacologic product intended for sleep, cannabis is far from perfect. However, due to its generally acceptable side-effect profile and extremely low toxicity, cannabis-based sleep aids can give clinicians an effective tool to address short-term sleeplessness.
This review highlights the potential of the ECS and cannabinergic therapy for sleep. At this time, the evidence shows great promise, though it remains in its infancy.
Sleep Studies & Botanical Synergy in Cannabis
It is well known that cannabis products are not uniform and that countless variations and product types exist. Interestingly, due to variations in plant genetics and the environments in which they are grown, the cannabis plant produces products with considerably different chemical profiles.10 Studies suggest that utilization of isolated cannabinoids yields different experimental results compared to using whole plant. For example, whole-plant THC has been shown to have 2-4 times greater effect than THC isolate without the presence of other molecules in the plant.11
Unfortunately, the vast majority of sleep studies have examined only purified THC isolates, CBD isolates, or whole-plant cannabinoid preparations whose cannabinoid profiles have not been measured.12 Additionally, most studies on the sleep-promoting properties of cannabis have focused on either isolated THC or high-THC cannabis products12 rather than on CBD or other cannabinoids or terpenes that have known pharmacologic and pharmacokinetic effects.
Therefore, it goes without saying that the ideal scientific study of cannabis use in humans necessitates study designs based on an understanding of which botanical compounds are actually contained in the plants being used for experimental purposes. Unfortunately, few modern researchers are trained to develop experimental designs that accommodate this reality.
ECS & Sleep
ECS action influences sleep in multiple locations within the brain as well as in the periphery.12 Manipulations of the ECS alter sleep in terms of the time spent in various states of vigilance, as well as their effects on distinct sleep-linked brain rhythms and neurologically-related sleep architecture. For example, the endocannabinoid AEA promotes sleep when administered systemically.13-16 As well, other studies show that AEA uptake inhibitors and precursors reduce wakefulness and potentiate sleep.17-19 In a rat study, AEA circulation in cerebrospinal fluid demonstrated diurnal occilations.20 Additionally, in neural tissue, endocannabinoid signaling molecules exhibit brain region-specific circadian rhythms,21 and recent animal studies suggest that fluctuations in these molecules may influence internal circadian rhythms.22-24 In rats, AEA fluctuations in the pons were shown to correlated with sleep/wake cycles.20 At this early stage, the complex role of endocannabinoids in sleep warrants further clarification.
Cannabinoid Sleep Studies
The effectiveness of cannabis as a sleep aid has been described in the western medical literature since western scientists “discovered” its therapeutic properties in the 19th century after their encounters with traditional healers during the British colonization of India.25-28
In the modern era, experimental evidence for cannabis as a sleep aid began accumulating in the 1970s. Studies have suggested that THC increases slow-wave sleep while reducing rapid eye movement (REM) sleep, sleep onset latency, and waking after sleep.29,30
Studies of THC and/or CBD in multiple Phase I-III studies, including nearly 2000 subjects with 1000 patient years of exposure, have shown significant subjective improvements in sleep parameters in a wide variety of pain conditions, including intractable cancer pain, peripheral neuropathic pain, multiple sclerosis, and rheumatoid arthritis. All of these studies demonstrated an acceptable adverse-event profile.31
A 2008 review describes how both THC and inhaled cannabis helped with falling asleep and increasing the amount of time spent in Stage 4 sleep. Oral THC isolate was also found to reduce the time spent in REM sleep.32
A more recent review (2017) on cannabis, cannabinoids, and sleep suggests therapeutic potential for CBD in the treatment of insomnia, while THC may reduce the length of time to transition from full wakefulness to sleep.33 Importantly, this review also found that THC may impair sleep when used long-term.33
Long-term cannabis use can produce tolerance to its effects, including for sleep.29,34-38 Cannabis withdrawal can also disrupt sleep patterns,36,39-42 as a major problem with cannabis withdrawal includes altered sleep patterns; this can be observed in most cannabis users attempting to quit.33,43 Importantly, these features can lead to relapses following cannabis abstinence.40,41,44 Many patients attempting to quit cannabis cite sleep as a major reason for going back to cannabis use.37,43,45,46
It is well known that rebound insomnia can occur with almost any prescription sleep aid, also that sleep medications that impact sleep architecture have a high potential to affect the quality of normal sleep.47-50 Interestingly, a survey of 1500 cannabis patients showed that 76.7% of respondents were able to reduce their use of prescription sleep aids with cannabis.51 As mentioned above, a major benefit of cannabis as a sleep aid lies in its ultra-low toxicity. This enables patients to reduce potential harm from more toxic sleep medications such as hypnotics and benzodiazepines. As a clinician, this author has frequently seen large numbers of long-term medical cannabis patients successfully utilize CBD-dominant cannabis (<0.3% THC content) for treating THC-withdrawal insomnia.
CBD Sleep Studies
Interestingly, despite a growing body of evidence showing the sleep efficacy of CBD products, CBD isolate by itself appears to be a wake-inducing agent.52 In contrast, studies show that CBD products containing whole-plant cannabis effectively promote sleepiness.53 The sleep inducing effects of CBD-dominant cannabis may very well be due to additive and synergistic effects from the small amounts of THC contained in these products, as well as other cannabinoids and bioavailable terpenes in these preparations.53 In one long-term retrospective case series, patients using CBD in hemp-based products reported improved sleep.54 Surprisingly, many “full-spectrum” hemp-based CBD products may still contain enough THC to have clinical significance.55
Another study, which examined the effects of a low-dose 1:1 ratio of THC and CBD on sleep in pain-related insomnia patients, reported enhanced sleep without any evidence tolerance development.31
Many available cannabis formulations certainly support sleep; however, because of their distinct chemical compositions, some formulations may not support sleep. It is unfortunate that most study designs do not keep this in mind during the design phase of cannabis studies.
Pain, PTSD & Sleep
The primary goals of quality sleep include both increasing the quantity of sleep and enhancing daytime functioning. A fairly large and growing body of evidence indicates that cannabis offers relief for pain patients having trouble with sleep,56-60 as well as for PTSD patients with poor-quality sleep.61-65 Of particular note for pain patients, the use of cannabis as a treatment for pain has the added advantage of potentially enhancing mood and daily functioning.66 A 2019 cross-sectional study of older adults with chronic pain and insomnia concluded that, despite the potential development of tolerance, cannabis use may have an efficacious impact on maintaining sleep throughout the night.67
Recent evidence demonstrates the role of the ECS and cannabinoids in the extinction of fear-based memories in PTSD.68 Additionally, a recent systemic review examining cannabis and PTSD concluded that, although further investigations should be conducted, cannabis reduces PTSD-related insomnia and night terrors.69 In a rat study, modulation of the ECS was shown to influence how emotions are stored in memory, suggesting that ECS-altering agents may be helpful complements to cognitive therapy for PTSD.70
A number of psychiatric disorders, including PTSD, involve poor adaptation to environmental conditions as well as atypical memory processing at the CB1 receptor.71 A 2013 study suggests that abnormal AEA signaling, mediated by CB1 receptors, is involved in PTSD. This research now provides scientists an evidenced-based model with which to approach this condition.72 Through modulation of memory processing, cannabinergic therapies may decrease the formation and entrenchment of traumatic memories as well as improve sleep.68
ECS networks in the hypothalamus and amygdala indicate the importance of the ECS in the body’s responses to stress and memory, allowing the unique inhibitory circuits of the ECS to forget or deprioritize the entrenchment of trauma and the recall of traumatic memories.69,73
The ECS & Jetlag
One approach to sleep that clinicians should be aware of is the potential for cannabinoids to alter diurnal sleep rhythms. Cannabis may be used as a zeitgeber, acting to reset the body’s circadian rhythyms23,24,74; ie, it represents a possible chrono-biotic treatment for jetlag.75 The authors of this review suggest that “precise administration of these (cannabinoid) compounds may bidirectionally entrain central and peripheral circadian clocks and benefit multiple aspects of aging physiology.”75
Cannabis and cannabinoids offer clinicians safe and effective low-toxic solutions for short-term sleep issues. Evidence points to particular efficacy and usefulness for patients with pain and/or PTSD with concomitant sleep issues. Cannabis is generally well tolerated and, though its side-effect profile is very favorable, like most sleep medications, a common side-effect of long-term cannabis use in some patients is rebound insomnia. In addition to utilizing cannabinoid-based, botanically-derived molecules to influence sleep, the body’s own ECS offers potential insight into how various current and future non-cannabinoid-based CAM therapies may potentially benefit sleep through their actions and influence on the endocannabinoid system.
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Jake F. Felice, ND, LMP is a cannabis author, clinician, educator, and consultant whose vision is to advance the science and practical application of cannabis for medical and recreational markets around the world. Dr Felice provides world-class educational experiences by speaking authentically about hemp and cannabis. He consults with healthcare providers, industry, and the general public. His Category 1 CME courses for doctors, nurses, and pharmacists has been translated into 4 languages. Dr Felice is the founder of Cannabis Matrix Consulting, LLC, and he maintains a regular cannabis blog at drjakefelice.com.