The Endocannabinoid System (ECS) Basics
The ECS is an ancient signalling system which operates across many systems in the body. Its purpose is to maintain homeostasis (balance) within these systems.
Endocannabinoids Anandamide and 2-AG bind to various receptors, namely cannabinoid receptors CB1 and CB2 to convey messages which control bodily systems.
CB1 is found in abundance within the brain and nervous system. Different amounts of CB1 receptors can be found in various areas of the brain, which allow endocannabinoids to control sleep and circadian rhythm (body clock synchronisation).
The ECS is sensitive to changes within the environment (diet, exercise, day/night, stress), and has been found to be imbalanced in many diseases, including sleep disorders (*).
Endocannabinoids & Cannabinoids
The really neat thing about the ECS is that its messengers, 2-AG and Anandamide share very similar properties to cannabinoids from cannabis.
The most notorious cannabinoids are derived from C.Sativa, which you most likely know as THC and CBD.
2-AG, Anandamide (AEA) and THC activate CB1 and CB2 receptors which allow them to influence bodily function in similar ways. CBD acts on CB receptors indirectly, but can still support ECS function.
The fact that cannabinoids are similar compounds to endocannabinoids means that they can be used to control the function of the ECS. Sometimes the ECS can become imbalanced, making it less effective at preventing disease and dysfunction.
Finding and eradicating the root cause of ECS imbalance is the key to long-term health and longevity. But in the short term, cannabinoids can be used to restore ECS function and ensure homeostasis.
Endocannabinoids & The Sleep Wake Cycle
The sleep-wake cycle involves the amount, timing and architecture of sleep.
The sleep-wake cycle is regulated by ECS activity, which fluctuates according to what time of day/night it is.
Levels of 2-AG, Anandamide and CB1 vary throughout the day/night. These fluctuations control the initiation, duration, depth and quality of sleep.
Endocannabinoids & Getting To Sleep
The ECS plays a direct role in the promotion of sleep. The endocannabinoid Anandamide activates CB1 to induce sleep.
CB1 is found on all sorts of neurones which regulate neurotransmitter systems, such as GABA, Glutamate, Serotonin and Dopamine (*). This means that compounds that interact with CB1 can control diverse functions within the brain, including sleep.
Sleep is initiated by activating sleep promoting neurones (GABA) and inhibiting wake promoting ones (serotonin) via CB1 (*).
Mice with genetic deletion of CB1 also spent more time awake than their controls (*).
Endocannabinoinds also promote sleep by minimising evening cortisol spikes. Mice with genetic deletion of CB1 have significantly higher circulating corticosterone (cortisol) concentrations at bedtime (*). Elevated evening cortisol interferes with melatonin production, and sleep.
Endocannabinoids, Sleep Architecture & Duration
In addition to timing, quality sleep depends on the overall duration and time spent in various stages of sleep (sleep architecture).
Throughout the night, its typical to cycle between two main types of sleep.
1) Non-rapid eye-movement (NREM) sleep. These are sleep stages 1-4 and make up about 75 – 80% total sleep time. Deep sleep happens in stages 3-4, when you slip into slow wave sleep (SWS).
2) Rapid eye-movement (REM) sleep makes up around 20 – 25% of total sleep. Dreams occur, as well as memory consolidation (*).
Irregular cycling between REM and NREM, as well as missing sleep stages is associated with sleep disorders (*).
CB1 receptor activation is generally beneficial for sleep:
- CB1 activation increases release of acetylcholine to enhance REM sleep (*).
- CB1 activation at sunset caused a decrease in wakefulness and an increase in SWS and REM sleep (*).
- CB1 activation increases SWS duration and adenosine, which is sleep promoting (*).
- Increasing Anandamide enhanced NREM sleep and SWS potency compared to controls (*).
Blocking the CB1 receptor impairs sleep:
- Blocking CB1 4 hours after sunset increases wakefulness and decreases time spent in both SWS and REM sleep in mice (*).
- Blocking CB1 reduces the sleep promoting properties of Anandamide in rats (*).
In essence, CB1 activation promotes restful and restorative sleep, whereas blocking it promotes wakefulness and poor sleep quality. What this essentially means is that variations in 2-AG and Anandamide levels influence sleep quality.
Levels of 2-AG and Anandamide can vary according to your circadian rhythm, and other factors such as diet and stress.
Endocannabinoids & Circadian Rhythm
Staying in sync with the rhythms of night and day is important for getting quality sleep. This synchronisation is called a circadian rhythm. A rhythm that’s out of sync can disturb normal sleep cycles and health in general.
The master clock (SCN) in your brain keeps track of time internally. It runs between 23-25 hrs depending on your genetics. The master clock is reset each day by timekeepers, such as light and temperature, so that its in line with the rhythm of night and day (24hrs).
The master clock (SCN) controls the ECS
Timekeepers help the SCN synchronise the rhythm of night and day with your drive to sleep and wake, using the ECS as a middle man. Depending on what time of day it is, the SCN either turns ECS activity up or down to influence when you sleep and wake up.
For example, the number of cannabinoid receptors found in the brain varies according to what time of day it is.
The highest number of CB1 has been found at 9PM whereas the lowest was at 9AM in the brain of rats (*). More CB1 promotes sleep, whereas less promotes waking.
The concentration of endocannabinoids also varies according to time of day.
In humans, blood levels of Anandamide are higher at 10PM, whereas they are lowest at 07:30AM (*).
Essentially, Anandamide promotes sleep whereas 2-AG may be involved in promoting wakefulness (*).
The ECS controls the master clock (SCN)
On the flipside, endocannabinoids can also control the SCN’s sensitivity to light via the CB1 receptor. This also influences your sleeping and waking times.
CB1 receptor activation prevents wake up time shifting to earlier in the day, from exposure to light in the morning (*). However, activating CB1 can also prevent waking up later in the day by limiting sensitivity to light at night (*).
Blocking the CB1 receptor promotes waking up earlier in the day (*), by increasing sensitivity to light.
This basically means that endocannabinoids can control the SCN’s sensitivity to light, and influence the timekeeping effect of light on sleeping and waking patterns.
Endocannabinoids, Sleep Deprivation & Disorders
The ECS can become imbalanced from sleep deprivation. The ECS is also imbalanced in diseases accompanied by poor sleep.
Changes to the ECS occur as a result of sleep deprivation:
- Anandamide is lower at 17.30 the next day after sleep deprivation (*), which may make it harder to fall asleep the following night.
- However, CB1 receptor density increases in the brain following REM sleep deprivation (*), (*). More CB1 may help compensate for sleep loss by increasing SWS and REM sleep the following night.
- 2-AG increases after sleep deprivation, which increases hunger and temporarily elevates mood in humans the days following (*), (*). Too much 2-AG is linked to obesity and diabetes, which is why getting consistently good sleep is important.
Whilst the ECS attempts to compensate for sleep loss the following night, consistently bad sleep may interfere with this recovery process.
On the one hand, chronically bad sleep may increase the risk of disease via interfering with ECS balance.
On the other hand, diseases may also interfere with sleep by creating ECS imbalances.
Some irregularities in the ECS have been studied in several diseases where poor sleep is also an issue.
Anandamide and 2-AG are higher in Parkinson’s disease patients than in healthy subjects (*). Parkinson’s patients have trouble with excessive REM sleep. This may be due to overactivation of CB1, which promotes REMS.
In Alzheimer´s disease, FAAH gene expression is higher than in age-matched controls (*). This means there is less Anandamide to induce and maintain sleep.
Anandamide was 1-5x lower in brain of AD patients (*).
Anandamide is sleep inducing, which maybe why Alzheimer’s is associated with sleep disturbances (*).
A deficiency of Anandamide may be driving disruption in REM sleep in ADHD.
Anandamide is significantly higher, and FAAH is lower in the blood of schizophrenic patients than in healthy volunteers (*).
Anandamide is 3-8x higher in blood and CSF of patients (*).
Sleep disturbances are common in schizophrenics (*), including nightmares which may be a result of excessive REMS due to increased Anandamide.
Poor sleep and nightmares are common in PTSD. Nightmares are a result of REMS dysfunction in PTSD (*).
Endocannabinoids regulate REMS and sleep in general. PTSD is thought to be driven by endocannabinoid deficiency (*). There is a strong case for endocannabinoid imbalance to be a driving force behind sleep disturbance in PTSD.
Both reductions and elevations in 2-AG and Anandamide have been found in PTSD patients (*).
Is associated with trouble getting to and staying asleep, waking up feeling unrefreshed and circadian disruption (*).
IBS has also been associated with a clinical endocannabinoid deficiency (*).
Irregularities in 2-AG have been found in IBS patients compared to healthy controls (*).
The CB1 receptor controls many aspects of sleep, including duration, depth, quality, dreams and nightmares. It can also impact the synchronisation of the bodies internal clock to that of the external environment (24hr).
The density of CB1 receptors found in the brain and nervous system can be subject to genetic variation (*).
Specific genetic variations in the CB1 receptor are associated with sleep disorders (*).
In the case that endocannabinoids are imbalanced, cannabinoids can be helpful in picking up the slack to restore sleep and circadian (body clock) disruption.
Cannabinoids & Getting to Sleep
Cannabinoids are a way of inducing sleep and entraining your internal body clock, through interacting with the CB1 receptor.
Exposure to light after sunset can make it harder to get to sleep. When light hits the SCN, this hinders the production of melatonin (our sleep inducing hormone), which increases wakefulness.
There are CB1 receptors throughout the SCN. Like Anandamide, THC activates CB1 in the SCN reducing its sensitivity to light. This enhances the production of the sleep inducing hormone melatonin from the pineal gland.
Evening melatonin production has been found to increase after 8 healthy individuals were given THC (*).
THC has also been found to reduce the time it takes to get to sleep in 8 other healthy individuals (*).
Cannabinoids & The Sleep Wake Cycle
Cannabinoids can also help the ECS regulate the amount, timing and quality of sleep you get.
THC & its pharmacological siblings directly activate the CB1 receptor in the brain to control sleep.
Although THC can induce sleep, it can also reduce REM sleep, which is a deep restorative stage of sleep important for emotional memory, learning and problem solving.
However, in some cases this is beneficial, for example in PTSD, schizophrenia and parkinsons, where there is commonly nightmares as a result of excessive REM sleep.
Another THC sibling Dronabinol, improves circadian disruption in dementia patients (*).
THC reduced nightmares and improved sleep quality in PTSD patients (*).
THC can also increase slow wave sleep in the short term (*) which is important for memory consolidation, and the brains recovery from daily activities.
However, long term THC use can reduce slow wave sleep (*).
THC improved the ability to fall asleep (easier, faster, more drowsy) and improved quality of sleep (less wakefulness) in patients with neuropathic pain (*).
Whilst short term THC use may improve sleep, long term use may actually hinder it. However, this depends on the activity of your own endocannabinoid system and your own balance of REM and NREM sleep.
Everyone is different. To optimise sleep, one might consider playing around with different doses of THC, frequency of use and duration.
There are two mechanisms by which CBD influences sleep, and they act in different ways.
Low doses of CBD have been found to be stimulating (*), increase wakefulness in humans (*) and decrease REM sleep (*). This could be due to CBD blocking the CB1 receptor (*), which increases alertness (*).
In contrast, high doses of CBD have been shown to aid sleep. CBD boosts Anandamide levels, by inhibiting FAAH (the enzyme that breaks Anandamide down). Anandamide aids sleep by activating CB1 (*).
High dose CBD increases total sleep time and slow wave sleep in rats (*).
160mg CBD increased total sleep time and reduced arousal during sleep in individuals with insomnia (*).
High doses of CBD also increased REM sleep (*), which may improve sleep quality.
18-24mg CBD reduced insomnia and PTSD symptoms in a case report (*).
CBD reduced symptoms of REM sleep disorder in 4 Parkinson’s disease patients (*).
Although more research with CBD is needed, higher doses appear to be favourable for sleep quality and duration in general.
Although REM sleep is beneficial, too much can also contribute to sleep disorders. The reduction in REM sleep is beneficial in PTSD patients, who experienced less nightmares as a result.
Cannabis also improved time spent asleep in addition to ratings of sleep quality in 10 HIV patients compared to dronabinol (THC) alone (*).
Sativex (1:1 THC/CBD combo) improved sleep quality scores in 58 rheumatoid arthritis patients compared to placebo (*).
A 1:1 THC/CBD combo significantly reduced sleep disturbance ratings in 66 patients with multiple sclerosis compared to placebo (*).
17 chronic cannabis users (> 1 year daily smoking) body clocks were more closely synchronised with the natural 24 hour cycle than 13 non-smokers (*).
Perhaps cycling cannabis use, or using lower doses of THC (and higher CBD) over the long term may offset the negative effects on sleep long term for healthy individuals. However, in chronic diseases which interfere with sleep, cannabis use may be of benefit for sleep regardless.
The effect cannabis has on sleep seems to depend on a few factors:
- The initial state of your endocannabinoid system (over or under-active), and how this affects cycling between REM and NREM sleep stages.
- Cannabinoid combinations
- How long you use it for
- Your genetic make-up dictating your chronotype (early bird or night owl)
Different people may benefit from cannabis in different ways:
- Excessive REM sleepers may benefit from using THC (or higher THC : CBD cannabis)
- Those who lack REM sleep may benefit from using CBD (at high doses)
- Those who are sleepy during the day may benefit from using low doses of CBD
- Those who struggle to get to, and stay asleep may benefit from a low THC : high CBD combo.
- A low THC : high CBD combo may be beneficial for sleep quality and duration in general.