The Emerging Role of the Endocannabinoid System in the Sleep-Wake Cycle Modulation

Abstract

The endocannabinoid system comprises amides, esters and ethers of long chain polyunsaturated fatty acids. Narachidonoylethanolamide (anandamide; ANA) and 2-arachidonoylglycerol (2-AG) are endogenous cannabinoids (endocannabinoids) ligands for the cannabinoid family of G-protein-coupled receptors named CB1 and CB2. Endocannabinoids are released upon demand from lipid precursors in a receptor-dependent manner and behave as retrograde signaling messengers, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters systems. The two principal enzymes that are responsible for the metabolism of ANA and 2-AG are fatty acid amide hydrolase and monoacylglycerol lipase, respectively. Pharmacological experiments have shown that the administration of endocannabinoids induce cannabimimetic effects, including sleep promotion. This review will focus on some of the current evidence of the pharmacological potential of the endocannabinoid system on sleep modulation.

Dose-dependent cannabis use, depressive symptoms, andFAAHgenotype predict sleep quality in emerging adults: a pilot study

“…Heavy cannabis use is associated with CB1 receptor downregulation, which decreases endocannabinoid signaling (73). Reduced endogenous cannabinoid activity is related to poorer sleep (4). Therefore, the observed sleep problems could be due to greater CB1 downregulation with increased cannabis use.…”

“…However, cannabis and two of its major components, Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are associated with disrupted sleep using objective measures (3). THC exerts its effects on the brain and body by binding to CB1 and CB2 receptors in the endocannabinoid system, which modulates the sleep-wake cycle (4). CB1 receptor antagonists increase wakefulness and reduce rapid eye movement (REM) time in animal studies (5–8).…”

Endocannabinoid signalling in reward and addiction

“…The contribution of these disruptions to cannabis use disorder and related physiological and behavioral disruptions is presently unexplored. However, as discussed below, ECs provide important homeostatic constraint over emotional state 86 and sleep function 87 , and it’s conceivable that Δ9-THC-induced impairment of endocannabinoid signaling contributes to negative emotional states and sleep disturbances present during protracted cannabis abstinence 88, 89 .…”

Weighing the balance: how analgesics used in chronic pain influence sleep?

“…[84][85][86] The place of endocannabinoids in the sleep-wake cycle has been described in recent reviews. 87,88 The endocannabinoid, anadamide is described as sleep promoting primarily through its action on the CB1 receptors. This may involve the stimulation of adenosine and acetylcholine release through activation of cholinergic neurons in the basal forebrain and brainstem (sites of CB 1 receptors) by endogenous anadamide or exogenous cannabinoids, which then promote sleep through their projections to the thalamus and resultant cortical de-synchronisation.…”