Scientists from Leiden University in the Netherlands have shown that anandamide — a natural cannabinoid produced by the brain — could help people to forget traumatic memories and reduce stress levels.

Cannabinoids are chemical compounds found in the cannabis plant. One of the most notable of these is THC, an active ingredient responsible for the psychoactive effects of the drug. Another is cannabidiol oil (CBD), which can have a calming effect. Researchers are actively researching CBD for its benefits in anxiety and pain.

However, the body also produces cannabinoids called endocannabinoids. These bind to receptors throughout the nervous system to exert effects on functions, including memory, appetite, and stress.

Scientists from Leiden University in the Netherlands have now shown that one such endogenous cannabinoid produced in the brain — called anandamide — could help people to forget traumatic memories.

The findings are available in Nature Chemical Biology.

Scientists first discovered anandamide in 1922. Its name derives from the Sanskrit word ‘ananda’ and means bliss or happiness. Scientists have been very interested in it since its discovery, and some studies have already implicated it in the modulation of pain, stress, anxiety, and appetite.

One way that scientists can study the role of anandamide is by changing its levels in the brain. Reducing the amount of a particular compound or chemical and monitoring its effect on behavior is a powerful way to understand its function.

However, up until now, there have been few clinical trials or pharmacological tools for scientists to do this.

The team behind this study designed a new tool, starting from a protein called NAPE-PLD. This protein is responsible for producing anandamide in the brain.

Inhibiting NAPE-PLD would effectively reduce the levels of anandamide in the brain. This would help the researchers to understand, biologically, what anandamide does.

The researchers screened thousands of different substances. To find a molecule that did this.

“This involved 350,000 mini reactions, each with a different substance,” explains the senior author of the study, Prof. Van der Stelt.

With the help of robotic arms from the automotive industry, they were able to screen the 350,000 different substances in just 3 days.

The next stage of the process required intensive human input, which took a little longer to complete.

After identifying a promising inhibitor, the team set to work optimizing the molecule and spent 2 years creating over 100 different versions of the inhibitor.

After finding a promising compound called LEI-40 and working with Roche Pharmaceuticals to confirm that it crosses the blood-brain-barrier into the brain, they began to collaborate with the National Institutes of Health (NIH) to test whether it worked in the brain.

To do this, they used animal models. They gave mice the equivalent of a human traumatic memory in the form of a startling shock to the foot, which they paired to a sound.

Over time, the researchers stopped administering the shocks but continued to play the sound. Healthy animals lose the memory of the shock as time passes.

However, when the mice received the inhibitor LEI-401 and, therefore, had less anandamide in their brains, these fearful memories remained, and the mice continued to be scared when hearing the sound.

The mices’ stress levels increased (measured by corticosteroid levels), and a region of the brain responsible for coordinating the stress response, called the HPA axis, became active.

“From this, you can infer that anandamide is involved in reducing anxiety and stress,” says Prof. van der Stelt.

The findings suggest that anandamide could be important in regulating stress and anxiety in people.

Although scientists will need to carry out much more research, these findings could eventually lead to new treatments for anxiety disorders, including post-traumatic stress disorder (PTSD), say the researchers.

“As we have now shown that anandamide is responsible for forgetting anxieties, pharmaceutical companies can focus on a new target. And you then have two options: looking for molecules that stimulate the production of anandamide or looking for molecules that reduce its degradation,”

– Prof. van der Stelt.

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