Medical Research

Discovery of Anandamide-like Molecule that Regulates Fear Behavior

Written by Lydia Kariuki

Anandamide is an endogenous cannabinoid that is mostly associated with the cannabinoid 1 (CB1) receptor found in the brain and central nervous system.[1] It is also called the “bliss” molecule because it is a wellspring of joy, happiness, and good cheer. The psychotropic compound in cannabis, tetrahydrocannabinol (THC), binds to the same receptor as anandamide. It is no wonder that THC elicits a similar response when consumed, only that this effect can be magnified from mere happiness to euphoria.

This endocannabinoid belongs to a group of signaling lipids in the brain that are known as
N-acylethanolamines (NAEs). While researchers have known for a while about how the limbic system modulates emotions, there are still many avenues of further exploration into NAEs and how they might be involved in this pathway.

Recent research shed light on this issue with findings that could both transform our understanding of the anadamide and biological triggers of fear behavior.[2]

A study published in Nature Chemical Biology identified and characterized an anadamide-like molecule using a screening approach they named LEI-401.

Researchers used multiple methods to evaluate how LEI-401 affects the synthesis of NAEs. They found that this molecule inhibits the synthesis of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), an enzyme that creates NAEs. Consequently, this inhibition reduced NAE levels, including anadamide, in brain cells.

LEI-401 also had a negative effect on fear behavior, which is similar to what happens with CB1 receptor antagonists (agents that block receptor activity). The researchers believe these effects are exerted through the modulation of anandamide biosynthesis, as well as the activation of the hypothalamus-pituitary-adrenal axis fear behavior pathway.[2]

To summarize, this newly identified compound, LEI-401:

  • Reduced anandamide levels in the brain
  • Impaired fear behavior
  • Mimicked the effect of CB1 receptor antagonists

LEI-401 or similar molecules could prove important tools to use in further research to better evaluate how cannabinoids can be used to treat mood or fear-based disorders.

Image Source:


  1. Scherma M, et al. Brain activity of anandamide: a rewarding bliss? Acta Pharmacol Sin. 2019; 40(3):309-323.
  2. Mock ED, et al. Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice. Nat Chem Biol. 2020;16:667-675.

About the author

Lydia Kariuki