Cannabinoids, Endocannabinoids and Sleep

Abstract

Sleep is a vital function of the nervous system that contributes to brain and bodily homeostasis, energy levels, cognitive ability, and other key functions of a variety of organisms. Dysfunctional sleep induces neural problems and is a key part of almost all human psychiatric disorders including substance abuse disorders. The hypnotic effects of cannabis have long been known and there is increasing use of phytocannabinoids and other formulations as sleep aids. Thus, it is crucial to gain a better understanding of the neurobiological basis of cannabis drug effects on sleep, as well as the role of the endogenous cannabinoid system in sleep physiology. In this review article, we summarize the current state of knowledge concerning sleep-related endogenous cannabinoid function derived from research on humans and rodent models. We also review information on acute and chronic cannabinoid drug effects on sleep in these organisms, and molecular mechanisms that may contribute to these effects. We point out the potential benefits of acute cannabinoids for sleep improvement, but also the potential sleep-disruptive effects of withdrawal following chronic cannabinoid drug use. Prescriptions for future research in this burgeoning field are also provided.

Keywords: 2-AG; AEA; CB1; CBD; THC; cannabis; marijuana; polysomnography.

Figure 1

General effects of cannabinoid type 1 (CB1) activity on slow-wave sleep (SWS) and paradoxical sleep (PS) in rodents and humans. Top and bottom rows show trends related to SWS and PS, respectively. The rodent panel illustrates trends extrapolated from Pava et al. (2016). The human trends are illustrated using arrows showing the direction, i.e., overall increase or decrease, of change in SWS and PS associated with initial cannabis use, extended use and associated tolerance, and cessation of use.

Figure 2

The number of scientific publications in PubMed containing sleep and either cannabis, Δ-9-tetrahydrocannabinol (THC), cannabidiol CBD, or cannabinoid from 1963 to 2019. Data collected from PubMed in March 2020. Notice lull in research publications during the 1980s–1990s between prior interest in the 1970s stemming from initial findings on hypnogenic properties of cannabis and its distillates, and later interest after the discovery of the endocannabinoid system and identification of sleep effects during cannabis use, abuse, and withdrawal.

Figure 3

Molecular mechanisms of central cannabinoid action. Schematic diagram of the endocannabinoid (eCB) system perturbations that have been used in experiments and have altered sleep. eCBs, either anandamide/N-arachidonoylethanolamine (AEA) or 2-arachidonoylglycerol (2-AG), generated and then released from the postsynaptic neuron typically act on presynaptic CB1 receptors to reduce presynaptic neurotransmitter release via several intracellular signaling cascades. AEA and 2-AG are then typically catabolized and removed from the system by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. See Figure 1 for trends in sleep that can occur from the two scenarios further illustrated on the right side of the schematic.