A Comprehensive Map of 13 Endocannabinoids and Their Actions
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.
Quick Facts
What This Study 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.
Key Numbers
13 probable orthosteric endocannabinoids identified; 8 activate CB1 receptors; 1 CB1 antagonist (sphingosine); 1 CB1 antagonist/inverse agonist (haemopressin); 3 allosteric modulators identified
How They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- 13 endocannabinoids identified, including natural antagonists and modulators
- Evidence Grade:
- Authoritative pharmacological review in a reference handbook, comprehensively cataloguing in vitro evidence. Represents expert consensus on endocannabinoid pharmacology.
- Study Age:
- Published in 2015. Additional endocannabinoid compounds and signaling mechanisms continue to be discovered.
- Original Title:
- Endocannabinoids and Their Pharmacological Actions.
- Published In:
- Handbook of experimental pharmacology, 231, 1-37 (2015)
- Authors:
- Pertwee, Roger G(17)
- Database ID:
- RTHC-01038
Evidence Hierarchy
Summarizes existing research on a topic.
What do these levels mean? →Frequently Asked Questions
How many endocannabinoids does the body make?
This review identified 13 probable endocannabinoids, though anandamide and 2-AG remain the best studied. The others include noladin ether, virodhamine, oleamide, and several others with varying levels of evidence for physiological relevance.
What are allosteric modulators?
They are compounds that bind to a receptor at a different site than the main active site, either increasing or decreasing the receptor's response to its normal signals. The body produces its own allosteric modulators of cannabinoid receptors, providing a fine-tuning mechanism.
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Cite This Study
https://rethinkthc.com/research/RTHC-01038APA
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
MLA
Pertwee, Roger G. "Endocannabinoids and Their Pharmacological Actions.." Handbook of experimental pharmacology, 2015. https://doi.org/10.1007/978-3-319-20825-1_1
RethinkTHC
RethinkTHC Research Database. "Endocannabinoids and Their Pharmacological Actions." RTHC-01038. Retrieved from https://rethinkthc.com/research/pertwee-2015-endocannabinoids-and-their-pharmacological
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.