The Endocannabinoid System and Stress

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npp2017162f3How the Endocannabinoid System Interacts with the Hypothalamic-Pituitary-Adrenal Axis to Modulate the Stress Response by Dr Carrie Decker ND

With as much attention as the endocannabinoid system is receiving for its role in the modulation of pain,[1] mood,[2] inflammation, and immune system response,[3] a discussion of the body’s stress response would be incomplete without mention of the regulatory role the endocannabinoid system may have here as well. In addition to moderating pain pathways and inflammation, which can be contributors to hypothalamic-pituitary-adrenal (HPA) axis activation, direct signaling and feedback loops between the HPA axis and endocannabinoid system also exist.[4],[5] Although research on this continues to be expounded upon almost daily, certain observations pertaining to how the endogenous cannabinoids N-arachidonoylethanolamine (AEA), also known as anandamide, and 2-arachidonoylglycerol (2-AG) interact with the HPA axis are worthy of mention.

The cannabinoid receptors CB1R and CB2R are expressed throughout the body, CB1R primarily in the neurons (including the brain, spinal cord, and autonomic and enteric nervous systems) and CB2R primarily in circulating and tissue-specific immune cells (such as the microglia).[6] Both AEA and 2-AG bind CB1R and CB2R, although their affinity and efficacy vary.[7],[8] Although basal levels of AEA and 2-AG exist, both endocannabinoids can be synthesised and broken down locally on demand when certain signaling pathways are activated,[9],[10] and, as such, may further serve to control synaptic transmission and intracellular signaling.[11]

In multiple studies, reductions in circulating endocannabinoid levels have been observed in individuals with chronic stress. In humans subject to 520 days of social isolation (to mimic space travel to Mars), significantly lower levels of 2-AG, reduced positive emotions, and higher levels of catecholamines were seen.[12] In individuals who experienced post-traumatic stress disorder (PTSD) after the 9/11 World Trade Center attacks, significantly lower levels of 2-AG were observed compared to those who were in close vicinity to the attacks but did not meet the diagnostic criteria for PTSD.[13] Significantly lower levels of both AEA and 2-AG have been shown in medication-free women diagnosed with major depression compared to healthy controls.[14] Exercise, which often has positive effects on depression, has been shown to increase AEA levels,[15] giving possible explanation for the experience known as a “runner’s high.”

Under normal conditions, endocannabinoid signaling has been observed to act as a negative regulator of HPA axis activity. Deletion of CB1R (also expressed in the adrenal tissue[16]) leads to hyperactivation of the HPA axis,[17] while increased endocannabinoid signaling attenuates stress-induced HPA axis activity.[18] More recent findings suggest that CB1R may play a role in both inhibiting and potentiating activation of the HPA axis by stress, with the inhibitory arm being tonically active and promoting recovery to baseline after acute stress.4 CB1R has also been shown to mediate the effects of stress on bone health[19],[20] and gastrointestinal system function.[21]

Many studies continue to investigate the interactions between the HPA axis and endocannabinoid system. Although some discrepancies and new findings continue to challenge our knowledge of the exact mechanisms by which these systems interact, overwhelming evidence points to the role the endocannabinoid system plays in promoting homeostasis of our stress response mechanisms,[22] in addition to modulation of pain, mood, inflammation, and the immune system.


[1] Woodhams SG, et al. The role of the endocannabinoid system in pain. Handb Exp Pharmacol. 2015;227:119-43.

[2] Micale V, et al. Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther. 2013 Apr;138(1):18-37.

[3] Barrie N, Manolios N. The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease. Eur J Rheumatol. 2017 Sep;4(3):210-8.

[4] Hillard CJ, et al. Endocannabinoid Signaling and the Hypothalamic-Pituitary-Adrenal Axis. Compr Physiol. 2016 Dec 6;7(1):1-15.

[5] Evanson NK, et al. Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology. 2010 Oct;151(10):4811-9.

[6] Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008 May;20 Suppl 1:10-4.

[7] Hillard CJ. Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat. 2000 Apr;61(1-2):3-18.

[8] McAllister SD, Glass M. CB(1) and CB(2) receptor-mediated signalling: a focus on endocannabinoids. Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):161-71.

[9] Howlett AC, et al. Endocannabinoid tone versus constitutive activity of cannabinoid receptors. Br J Pharmacol. 2011 Aug;163(7):1329-43.

[10] Hashimotodani Y, et al. Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus. J Neurosci. 2007 Jan 31;27(5):1211-9.

[11] Kano M, et al. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009 Jan;89(1):309-80.

[12] Yi B, et al. Reductions in circulating endocannabinoid 2-arachidonoylglycerol levels in healthy human subjects exposed to chronic stressors. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jun 3;67:92-7.

[13] Hill MN, et al. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks. Psychoneuroendocrinology. 2013 Dec;38(12):2952-61.

[14] Hill MN, et al. Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress. Psychoneuroendocrinology. 2009 Sep;34(8):1257-62.

[15] Heyman E, et al. Intense exercise increases circulating endocannabinoid and BDNF levels in humans–possible implications for reward and depression. Psychoneuroendocrinology. 2012 Jun;37(6):844-51.

[16] Galiègue S, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995 Aug 15;232(1):54-61.

[17] Barna I, et al. The role of endogenous cannabinoids in the hypothalamo-pituitary-adrenal axis regulation: in vivo and in vitro studies in CB1 receptor knockout mice. Life Sci. 2004 Oct 29;75(24):2959-70.

[18] Gorzalka BB, Hill MN. Integration of endocannabinoid signaling into the neural network regulating stress-induced activation of the hypothalamic-pituitary-adrenal axis. Curr Top Behav Neurosci. 2009;1:289-306.

[19] Idris AI, et al. Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab. 2009 Aug;10(2):139-47.

[20] Samir SM, Malek HA. Effect of cannabinoid receptors 1 modulation on osteoporosis in a rat model of different ages. J Physiol Pharmacol. 2014 Oct;65(5):687-94.

[21] Zoppi S, et al. Endogenous cannabinoid system regulates intestinal barrier function in vivo through cannabinoid type 1 receptor activation. Am J Physiol Gastrointest Liver Physiol. 2012 Mar 1;302(5):G565-71.

[22] Steiner MA, Wotjak CT. Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis. Prog Brain Res. 2008;170:397-432.

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