Researchers at Vanderbilt University Medical Center have identified a natural signaling
molecule that activates cannabinoid receptors in the brain that play a critical role in
stress-resilience. The endocannabinoid family of signaling molecules that activate CB1
and CB2 cannabinoid receptors in the brain were investigated by Sachin Patel, M.D.,
Ph.D., the director of the Division of Addiction Psychiatry at Vanderbilt University
Medical Center. Patel indicated that finding ways to boost the signaling system could
represent a new treatment approach for many stress-linked disorders.
The endocannabinoids are endogenous ligands in the brain that activate CB1 and CB2.
While the endocannabinoids are a biochemistry topic too complex for this cursory look,
the effects of CB1 and CB2 have broad implications for the treatment and possible
prevention of disorders like major depression and PTSD. CB1 is found mostly in the
brain and central nervous system and to a lesser extent in other tissues. CB2 is mostly
found in peripheral organs and cells that service the immune system. CBD, which is now
generally available in several forms do not directly activated CB1 or 2; however, the
effects of CBD are foreshadowing the potential for treatment of not just mood disorders
but many other stress-related or stress-affected disorders, like diabetes, obesity,
memory, anxiety and neurodegenerative disorders.
Boosting this signaling system holds great promise. In fact, THC, the active compound
in marijuana, binds the CB1 receptor, which may explain why relief of tension and
anxiety is the most common reason cited by people who use marijuana chronically.
Patel and his colleagues previously have found CB1 receptors in the amygdala, a key
emotional hub in the brain involved in regulating anxiety and the fight-or-flight response.
They also showed in animal models that anxiety increases when the CB1 receptor is
blocked by a drug or its gene is deleted.
In the current study1 the researchers tested the effects of increasing or depleting the
supply of one endocannabinoid (2-AG) in the amygdala in two populations of mice: one
previously determined to be susceptible to the adverse consequences of acute stress,
and the other which exhibited stress-resilience. Augmenting the 2-AG supply increased
the proportion of stress-resilient mice overall and promoted resilience in mice that were
previously susceptible to stress, whereas depleting 2-AG rendered previously stressresilient mice susceptible to developing anxiety-like behaviors after exposure to acute
Taken together, these results suggest that 2-AG signaling through the CB1 receptor in
the amygdala promotes resilience to the adverse effects of acute traumatic stress
exposure and supports previous findings in animal models and humans suggesting that
2-AG deficiency could contribute to development of stress-related psychiatric disorders.
Marijuana use is highly cited by patients with PTSD as a way to control symptoms.
However, marijuana use in psychiatric disorders has obvious drawbacks including
possible addiction and cognitive side effects, among others. The Vanderbilt study
suggests that increasing production of natural cannabinoids may be an alternative
strategy to harness the therapeutic potential of this signaling system. For instance, once
levels of the endocannabinoids can be efficiently measured in humans, those identified
with low levels of the signaling system responsible for stress-related mood and anxiety
disorders could have their supply replenished without the complications of using
Rebecca J. Bluett, Rita Báldi, Andre Haymer, Andrew D. Gaulden, Nolan D. Hartley,
Walker P. Parrish, Jordan Baechle, David J. Marcus, Ramzi Mardam-Bey, Brian C. Shonesy,
Md. Jashim Uddin, Lawrence J. Marnett, Ken Mackie, Roger J. Colbran, Danny G. Winder,
Sachin Patel. Endocannabinoid signalling modulates susceptibility to traumatic stress
exposure. Nature Communications, 2017; 8: 14782