Anandamide is an endocannabinoid that can help forget traumatic memories

Your body's cannabinoids can reduce traumatic memories

New research highlights the "bliss molecule" that is anandamide. An international team of researchers led by Mario van der Stelt from the University of Leiden in the Netherlands recently identified how anandamide modulates emotional behavior in mice. This article was published in the journal Nature Chemical Biology.

Although this research in mice is promising, more clinical research is needed to understand if and how the N-acylethanolamines (NAE), which make up the endocannabinoid called anandamide, can help humans minimize the impact of traumatic memories.

That being said, Van der Stelt's groundbreaking research on the biosynthesis of NAEs in the brain and how anandamide affects emotional behavior in mice draws on a wealth of evidence-based research (see below). ). His team's latest findings on anandamide (2020) could lead to new pharmaceutical treatments for generalized anxiety disorders, phobia-related disorders, panic disorders and post-traumatic stress disorder.

"This is a starting point for the development of new drugs," said Van der Stelt in a press release. "We have now shown that anandamide is responsible for forgetting anxiety; pharmaceutical companies can focus on a new target." And then you have two options: look for molecules that stimulate the production of anandamide or look for molecules that reduce its degradation. ”

Cannabis in the brain

When you smoke a joint, the active ingredient THC makes you feel relaxed. But there are also side effects, such as increased appetite or even "immediate" memory loss. What about our own body? Mario van der Stelt, professor of molecular physiology, asked himself the question five years ago. He decided to launch a research line to find out, and received a Vici grant from the Dutch Research Council in 2018. Two years later, in 2020, he and his team are the first in the world to inhibit the production of anandamide in the brain, revealing the true nature of this substance: it helps us to forget traumatic memories and reduces stress.

The research began in 2015, when Elliot Mock, first author of the publication and doctoral candidate at the time, and Anouk van der Gracht, master's student, managed to get their hands on the protein NAPE-PLD. This protein is responsible for the production of anandamide in the brain. The next step was to find a compound that stops this protein from working. Because the idea was that if you inhibit the production of anandamide, you can study its biological role.

Finding such a substance turned out to be a real feat. Mr. Van der Stelt then turned to the European plant in Oss, the Netherlands, which was co-founded by his research group in 2013 and which specializes in the rapid screening of hundreds of thousands of substances. He first had to get EU approval before a fully automated system could start looking for the compound that inhibits the protein. In fact, it required 350000 mini reactions, each with a different substance, ”explains Van der Stelt. They did this with the help of robotic arms from the automotive industry. It only took three days to screen 350 substances, which is very impressive. ”

At the end of the screening, a success appeared: a promising molecule to block the production of anandamide. But this molecule was not yet ready, ”says Van der Stelt. So Elliot got to work. Mock optimized the molecule and, with a number of students, spent two years synthesizing more than 100 analogs - molecules that differ slightly from each other. One of them finally revealed the function of anandamide in the body.

We then started working with Roche Pharmaceuticals to analyze whether our optimized molecule reached the brain, an essential condition. By that time, cell models had already identified the analogy that worked best and the researchers named it LEI-401. Roche then confirmed that LEI-401 does reach the brain. Next, researchers from the National Institutes of Health (NIH) in the United States and we investigated whether our substance actually worked in the brain. It turned out that this was the case, ”explains Van der Stelt.

After three years, the way was finally open to answer the burning question: what is the physiological role of anandamide? This time, Van der Stelt called on partners in Canada and the United States to study the physiological effects of reducing anandamide levels in the brain. In animal models, LEI-401 means that traumatic memories are no longer erased. In addition, the corticosteroid level was high and an area of ​​the brain responsible for coordinating the stress response was activated. We can deduce that anandamide is involved in reducing anxiety and stress ”.

Van der Stelt's research is paving the way for new methods to treat anxiety disorders such as PTSD. It is a starting point for the development of new drugs. As we have now shown that anandamide is responsible for forgetting anxiety, pharmaceutical companies can focus on a new target. And then you have two options: look for molecules that stimulate the production of anandamide or look for molecules that reduce its degradation. ”

What does scientific literature say?

Anandamide is an endocannabinoid (a version of chemicals also found in cannabis) that gets its name from the Sanskrit word ānanda, which means "bliss" or "happiness". In the Veda scriptures of Hinduism, ananda refers to a state of rapture which can accompany the cycles of rebirth of reincarnation. In The Power of Myth, Joseph Campbell discusses the archetypal symbolism of the ananda in the context of his famous maxim, "Follow your bliss".

In the daily life of many amateur joggers, anandamide works with endorphins and other neurotransmitters to create a "runner high". Over the past two decades, countless studies have shown that vigorous aerobic exercise stimulates the production of endocannabinoids in the brain.

In August 2002, an article published in Scientific American, " Cannabis-like brain chemical blocks bad memories", By Sarah Graham, reported groundbreaking research on endocannabinoids by the Max Planck Institute of Psychiatry in Germany. Giovanni Marsicano's article, " The endogenous cannabinoid system controls the extinction of aversive memories«, has been published in the journal Nature.

Graham summarizes in his article the results of this pioneering study on endocannabinoids:

“The researchers trained mice to associate a tone with the reception of a shock. Once the real shock was eliminated, normal mice ended up forgetting about their previous experience and realized that they shouldn't be afraid of sound anymore. Mice designed to have no receptors for cannabinoid chemicals in the brain, on the other hand, continued to fear sounds, suggesting that they were unable to forget their negative experiences. ”

In 2004, a summary article publié in the British Journal of Sports Medicine provided a comprehensive overview of the rapidly emerging interest in the XNUMXst century for a possible link between endocannabinoids and aerobic exercise. As the authors explain:

“The intense psychological experiences caused by the activation of endocannabinoid receptors are surprisingly similar to the experience of runner euphoria. For comparison, the mental changes that accompany long distance running include analgesia, sedation (post-exercise calm or radiance), reduced anxiety, euphoria, and difficulty estimating time. past ".

The title of the book, The Athlete's Way: Sweat and the Biology of Bliss (2007), was inspired by the connection between runner's euphoria and "the bliss molecule" (anandamide).

Anandamide is called "the bliss molecule" by neuroscientists and is the key to feeling good when you sweat. One day, I was cycling, when the idea of ​​sweat and anandamide suddenly found its way into the words "sweat and the biology of bliss." The sweat on the outside represents anandamide and other brain chemicals that pump inside. All I can imagine now when I see people sweat is the joie de vivre that comes from their bodies and the happy endocannabinoids that pump inside their brains, symbolized by the sweat that flows from their skin ” .

Wired article reveals a study led by scientists from the American firm Organix, who are striving to discover new pain-relieving molecules: these are also present in echinoderms, alias Urchins.

Le 2-arachidonoyl glycerol (2-AG) is another endocannabinoid that is produced naturally by the human body. And like anandamide, it has an effect on the CB receptors of the central and peripheral nervous system.

Scientists suggest that to clear an unpleasant memory, the body's innate cannabinoids flood the amygdala, the fear center of the brain, and inhibit the action of nerve cells. According to Pankaj Sah fromAustralian National University, " substances that target these molecules and their receptors could be useful new treatments for anxiety disorders".

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