Cannabis and psychosis: Are we closer to understanding the relationship?

Study highlights link between cannabis, anxiety and stress

A natural molecule produced by the brain activates endocannabinoid receptors, protecting against stress by reducing the anxiety-generating connections between the amygdala and the prefrontal cortex. The results may help explain why people turn to marijuana when they feel anxious or stressed.

This discovery, published today in Neuron , could help explain why some people use cannabis when they are anxious or stressed. It could also mean that pharmacological treatments that increase the levels of this molecule, known as "2-AG", in the brain could regulate anxiety and depressive symptoms in people with stress-related anxiety disorders. potentially avoiding addiction to medical marijuana or similar treatments.

A brain-produced molecule that activates the same endocannabinoid receptors reduces anxiety-causing connections between two regions of the brain, report researchers at the Vanderbilt University Medical Center.

Collapse of endocannabinoid signaling contributes to stress-induced amygdalo-cortical strengthening

“The circuit between the amygdala and the frontal cortex has been shown to be stronger in people with certain types of anxiety disorders. As people or animals are exposed to stress and become more anxious, these two areas of the brain stick together and their activity strengthens together, ”said Sachin Patel, MD, PhD, the journal's corresponding author and director of the General Psychiatry Division at Vanderbilt. University medical center.

When mice are exposed to acute stress, a breakdown in the anxiety-generating connection between the amygdala and the frontal cortex caused by the 2-AG temporarily disappears, causing the emergence of anxiety-related behaviors.

“We could predict that there is a collapse of the endocannabinoid system, which includes 2-AG, in patients who continue to develop the disorder. But, not everyone develops a psychiatric disorder after exposure to trauma, so maybe people who do not develop the disorder are able to maintain this system in some way or another. These are the things we want to test next. "

The study also found that signaling between the amygdala and the frontal cortex can be enhanced by genetic manipulations that compromise endogenous cannabinoid signaling in this pathway, making mice anxious even without exposure to stress in some cases. This finding demonstrates that the cannabinoid signaling system that suppresses the flow of information between these two brain regions is essential for setting the level of anxiety in animals.

“We don't know how or why this cannabinoid signaling system disappears or breaks down in response to stress, but it results in a strengthening of the connection between these two regions and an increase in anxiety behaviors in mice. Understanding what causes this trade-off, what causes the signaling system to come back after a few days, and many other questions about the molecular mechanisms by which this occurs are things we want to track, ”Patel said, also James G Blakemore Professor of Psychiatry and Behavioral Sciences, Molecular Physiology and Biophysics and Pharmacology.

David Marcus, graduate student in neuroscience and first author of the article, and S. Patel are also interested in how the system responds to more chronic forms of stress and want to determine if there are other environmental exposures that compromise or enhance this system to regulate behavior.

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How Cannabis Bypasses Brain Connections Related To Stress And Anxiety Disorders

In scientific terms : The functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the pre-limbic pre-limbic cortex of the mouse basolateral amygdala (BLA) (plPFC) is engaged by stress and activation of this pathway in the anxiogen. In addition, we demonstrate that exposure to acute stress results in a sustained increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG) mediated endocannabinoid signaling as a key mechanism limiting the release of glutamate at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to a persistent synaptic strengthening specific to the circuit and anxiety-like behaviors after exposure to stress. These data suggest that a circuit-specific alteration in 2-AG signaling could facilitate the functional coupling between BLA and plPFC and the translation of environmental stress into affective pathology.


  • The BLA-plPFC circuit is initiated by exposure to stress and its activation is anxiety-inducing
  • Stress improves glutamate release in a reciprocal BLA-plPFC-BLA subcircuit
  • BLA-plPFC glutamatergic entrainment is constrained by multimodal 2-AG signaling
  • Collapse of 2-AG signaling contributes to stress-induced circuit strengthening and anxiety
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While many users swear by the calming effects of weed, research like the new Vanderbilt study should help the drug earn the official seal of approval for treating additional conditions. 

On the one hand, their study offers an explanation for why weed might really be a key to reducing anxiety.

Tags : anxietyNeurosciencepsychiatrystressEndocannabinoid system
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