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Cannabis, Anxiety and Stress – What’s the Connection?

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A molecule, 2-arachidonoylglycerol, also referred to as “2-AG”, protects against stress by reducing “anxiety-causing” connections between two particular regions in the brain – 2-AG elicits its effect by activating the same receptors as cannabis. The researchers’ findings,1 published in Neuron, may help understand why some people find that cannabis successfully relieves anxiety and/or stress.

The endocannabinoid system and 2-arachidonoylglycerol

The endocannabinoid system (ECS) plays important role in the correct biological functioning of the human body – affecting the physiology and pathology of both the central and peripheral nervous systems. The ECS is composed of cannabinoid receptors (e.g. CB1 and CB2), endogenous cannabinoids (also known as endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids.2,3

2-AG is an endocannabinoid – it is an agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. Exogenous cannabinoids (such as those found in the cannabis plant) elicit their biological effects, similarly to endogenous cannabinoids, via interaction with the cannabinoid receptors. 3

Acute stress and 2-AG

The team found that when mice were subjected to acute stress, a break in the connection between the amygdala and frontal cortex disappeared, restoring the “circuit” between the two brain regions, causing them to exhibit anxiety-related behaviors. 2-AG is responsible for maintaining the disconnection between the two regions.

"The circuit between the amygdala and the frontal cortex has been shown to be stronger in individuals with certain types of anxiety disorders. As people or animals are exposed to stress and get more anxious, these two brain areas glue together, and their activity grows stronger together," says corresponding author, Sachin Patel, MD, PhD, in a recent press release.

Patel explains that it may be possible to predict whether there is a “collapse” in the endocannabinoid system, which includes 2-AG, in patients that go on to develop an anxiety or stress disorder.

However, not all patients go on to develop a psychiatric disorder post-trauma. So perhaps for those that don't develop a disorder, their body somehow finds a way to maintain “normal” functioning of the endocannabinoid system.

“Those are the things we're interested in testing next," explains Patel.

Endogenous cannabinoid signaling becomes compromised

The team also showed that the signaling between the amygdala and the frontal cortex can be increased through genetic manipulation which compromises endogenous cannabinoid signaling. This resulted in the mice becoming anxious – even in the absence of a stress stimulus. This manipulation suggests that the cannabinoid signaling system that suppresses the connection between the two brain regions is essential for regulating the level of anxiety in animals.

"We don't know how or why this cannabinoid signaling system disappears or disintegrates in response to stress, but it results in the strengthening of the connection between these two regions and heightened anxiety behaviors in mice. Understanding what's causing that compromise, what causes the signaling system to return after a few days, and many other questions about the molecular mechanisms by which this is happening are things we're interested in following up on," concludes Patel.

With a better understanding of the molecular mechanisms behind this process, in future, it may be possible to develop pharmacologic strategies to treat anxiety and stress – providing those using cannabis with an alternative way to alleviate symptoms.


1. Marcus, et al. (2020) Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening. Neuron. DOI: https://doi.org/10.1016/j.neuron.2019.12.024 

2. Aizpurua-Olaizola, et al. (2017) Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov Today. 22(1): 105–110. DOI: 10.1016/j.drudis.2016.08.005.

3. Lu & Mackie. (2016) An introduction to the endogenous cannabinoid system. Biol Psychiatry. 79(7): 516–525. DOI: 10.1016/j.biopsych.2015.07.028