Impact of circadian rhythmicity and sleep restriction on circulating endocannabinoid (eCB) N-arachidonoylethanolamine (anandamide)

Psychoneuroendocrinology. 2020 Jan:111:104471. doi: 10.1016/j.psyneuen.2019.104471. Epub 2019 Oct 4.


Objective: The endocannabinoid (eCB) system is involved in diverse aspects of human physiology and behavior but little is known about the impact of circadian rhythmicity on the system. The two most studied endocannabinoids, AEA (ananamide) and 2-AG (2-arachidonoylglycerol), can be measured in peripheral blood however the functional relevance of peripheral eCB levels is not clear. Having previously detailed the 24-h profile of serum 2-AG, here we report the 24-h serum profile of AEA to determine if these two endocannabinoids vary in parallel across the biological day including a nocturnal 8.5-h sleep period. Further, we assessed and compared the effect of a physiological challenge, in the form of sleep restriction to 4.5-h, on these two profiles.

Methods: In this randomized crossover study, we examined serum concentrations of AEA across a 24-h period in fourteen young adults. Congeners of AEA, the structural analogs oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were simultaneously assayed. Prior to 24-h blood sampling, each participant was exposed to two nights of normal (8.5 h) or restricted sleep (4.5 h). The two sleep conditions were separated by at least one month. In both sleep conditions, during the period of blood sampling, each individual ate the same high-carbohydrate meal at 0900, 1400, and 1900.

Results: Mean 24-h concentrations of AEA were 0.697 ± 0.11 pmol/ml. A reproducible biphasic 24-h profile of AEA was observed with a first peak occurring during early sleep (0200) and a second peak in the mid-afternoon (1500) while a nadir was detected in the mid-morning (1000). The 24-h profiles for both OEA and PEA followed a similar pattern to that observed for AEA. AEA, OEA, and PEA levels were not affected by sleep restriction at any time of day, contrasting with the elevation of early afternoon levels previously observed for 2-AG.

Conclusions: The 24-h rhythm of AEA is markedly different from that of 2-AG, being of lesser amplitude and biphasic, rather than monophasic. These observations suggest distinct regulatory pathways of the two eCB and indicate that time of day needs to be carefully controlled in studies attempting to delineate their relative roles. Moreover, unlike 2-AG, AEA is not altered by sleep restriction, suggesting that physiological perturbations may affect AEA and 2-AG differently. Similar 24-h profiles were observed for OEA and PEA following normal and restricted sleep, further corroborating the validity of the wave-shape and lack of response to sleep loss observed for the AEA profile. Therapeutic approaches involving agonism or antagonism of peripheral eCB signaling will likely need to be tailored according to time of day.

Keywords: 24-h profile; Anandamide; Cannabinoid; Circadian rhythm.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amides
  • Arachidonic Acids / blood
  • Arachidonic Acids / metabolism*
  • Arachidonic Acids / physiology
  • Circadian Rhythm / physiology*
  • Cross-Over Studies
  • Endocannabinoids / analysis
  • Endocannabinoids / blood
  • Endocannabinoids / metabolism*
  • Endocannabinoids / physiology
  • Ethanolamines / analysis
  • Ethanolamines / blood
  • Female
  • Glycerides / blood
  • Glycerides / metabolism*
  • Glycerides / physiology
  • Humans
  • Male
  • Oleic Acids / analysis
  • Oleic Acids / blood
  • Palmitic Acids / analysis
  • Palmitic Acids / blood
  • Polyunsaturated Alkamides
  • Sleep / physiology
  • Young Adult


  • Amides
  • Arachidonic Acids
  • Endocannabinoids
  • Ethanolamines
  • Glycerides
  • Oleic Acids
  • Palmitic Acids
  • Polyunsaturated Alkamides
  • oleoylethanolamide
  • palmidrol
  • glyceryl 2-arachidonate
  • anandamide