A detailed pharmacological review identified 13 probable endocannabinoids in mammalian tissue, including compounds that act as CB1 agonists, antagonists, and both positive and negative allosteric modulators.
Read this if you want a deep understanding of how the endocannabinoid system works at the molecular level.
13 endocannabinoids identified, including natural antagonists and modulators
What the researchers found
This comprehensive review catalogued 13 endogenous compounds that likely function as endocannabinoids based on being detected in mammalian tissue and binding to cannabinoid receptors.
Beyond the well-known anandamide and 2-AG, the review identified 11 additional endocannabinoids including noladin ether, virodhamine, oleamide, and docosahexaenoylethanolamide. Eight of these were found to activate CB1 and sometimes CB2 receptors.
Remarkably, the review also identified endogenous CB1 antagonists (sphingosine, haemopressin) and allosteric modulators. These include negative allosteric modulators (pepcan-12 and pregnenolone) and positive allosteric modulators (lipoxin A4), revealing that the body has built-in mechanisms to both amplify and dampen cannabinoid signaling.
Why it matters
The discovery that the endocannabinoid system has its own natural brakes (antagonists) and volume controls (allosteric modulators) transforms understanding of how the system maintains balance. This complexity has major implications for drug development.
The numbers in context
13 probable orthosteric endocannabinoids identified; 8 activate CB1 receptors; 1 CB1 antagonist (sphingosine); 1 CB1 antagonist/inverse agonist (haemopressin); 3 allosteric modulators identified
How the study worked
Comprehensive pharmacological review cataloguing all identified endocannabinoid compounds, their receptor binding properties, and functional effects based on in vitro evidence. Published in the Handbook of Experimental Pharmacology.
What this study cannot tell us
Based on in vitro evidence; in vivo relevance of some compounds is uncertain. Some putative endocannabinoids may be present at concentrations too low to be physiologically significant. Receptor binding does not always predict functional activity in living systems.
How to read the evidence
Authoritative pharmacological review in a reference handbook, comprehensively cataloguing in vitro evidence. Represents expert consensus on endocannabinoid pharmacology.
When this study was published
Published in 2015. Additional endocannabinoid compounds and signaling mechanisms continue to be discovered.
The bigger picture
The endocannabinoid system is far more complex than the simple "anandamide and 2-AG activate CB1 and CB2" model. The existence of endogenous antagonists and allosteric modulators suggests the system has evolved sophisticated self-regulation that external cannabinoids like THC may disrupt.
Questions still open
- Which of these 13 endocannabinoids are most physiologically relevant? Can allosteric modulators be developed as more nuanced therapeutics than direct receptor agonists? How does chronic cannabis use affect levels of all 13 compounds?
Common questions
How many endocannabinoids does the body make?
What are allosteric modulators?
Read the original research
Endocannabinoids and Their Pharmacological Actions.
Handbook of experimental pharmacology, 231, 1-37
Citation
Pertwee, Roger G. (2015). Endocannabinoids and Their Pharmacological Actions.. Handbook of experimental pharmacology, 231, 1-37. https://doi.org/10.1007/978-3-319-20825-1_1
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