What do a simple three-layered worm, a sea squirt, and you have in common? 

Your genes. Long before humans were walking upright or carving tools out of stone, the first glimpses of the endocannabinoid system were developing in simple, efficient creatures.

Reminder: The endocannabinoid system is made up of enzymes, cannabinoids, and receptors. 

After the discovery of anandamide in 1992 by Lumir Hanus (1), research into endocannabinoid signaling began to explode. If our bodies produce endogenous cannabinoids, then how and why are they used in relaying messages? Where did these signaling molecules come from? How do we know when this started happening? 

To answer these questions, we turn to the field of science called Orthology. Orthology is the study of genes present in different species that evolved from a common ancestor. Think ancestry.com but for your protein sequences. Researchers take protein and nucleotide sequences, and use a tool called BLAST (Basic Local Alignment Search Task) to compare the genes of organisms, ultimately to find out where the splits in evolution occurred. By comparing orthologs such as FAAH, CB1, GPR55, etc (all parts of the endocannabinoid system), scientists were able to estimate that the endocannabinoid system evolved in mammals over 600 million years ago. 

600 million years ago, simple organisms began showing signs of bilateral symmetry (2). About 40 million years later, another evolutionary split occurred, and these new creatures form a front, a back, and a distinct top and bottom. This formed two different types of organisms:  Protostomes and Deuterostomes. Surprisingly, both the protostomes and deuterostomes have parts of a modern-day endocannabinoid system. CiCBR, an intermediary of our present day receptors CB1 and CB2, is found in deuterostomes. 

The most primitive organism that put all the pieces of an endocannabinoid system together is the humble sea squirt, or as he’s known to his academic friends, the Tunicate (4). This discovery was a breakthrough for endocannabinoid signaling, because it meant that receptors were present in common ancestors that date back much further than previously thought. (3) 

Fast forward to March 29th, 2001, when three landmark experimental papers were published that transformed our understanding of endocannabinoid signalling in the mammalian nervous system. Independently, three research groups obtained evidence that endocannabinoids act as signals for neurotransmitter release. While endocannabinoids acting as signaling molecules had been hypothesized earlier, the publishing of these three papers changed endocannabinoid signaling theory from a hypothesis, to a textbook principle. 

This is just the start of our exploration of endocannabinoid’s effects on the body. Follow us on Instagram as we break this down in a virtual textbook!


Extra Credit Resources: 

1) Sourcing the Code: Searching for the Evolutionary Origins of Cannabinoid Receptors, Vanilloid Receptors, and Anandamide

2) Curious about Cannabis Podcast - A Brief history of the endocannabinoid system 

3) Evolution of Dance

1) How the Endocannabinoid System was discovered: Cannabis Sciences. (2018, April 05). Retrieved October 08, 2020, from https://www.labroots.com/trending/cannabis-sciences/8456/endocannabinoid-system-discovered

2) Chen, J., Bottjer, D., Oliveri, P., Dornbos, S., Gao, F., Ruffins, S., . . . Davidson, E. (2004, July 09). Small Bilaterian Fossils from 40 to 55 Million Years Before the Cambrian. Retrieved October 08, 2020, from https://science.sciencemag.org/content/305/5681/218

3) Phylogeny of Endocannabinoid Receptors in the Brain. (n.d.). Retrieved October 08, 2020, from https://www.reed.edu/biology/professors/srenn/pages/teaching/web_2006/Ryan.Courtney.Website/phylogeny.html 

4) Stoned sea-squirts. (2004, April 01). Retrieved October 08, 2020, from https://www.innovations-report.com/life-sciences/report-27683/

5) Elphick M. R. (2012). The evolution and comparative neurobiology of endocannabinoid signalling. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367(1607), 3201–3215. https://doi.org/10.1098/rstb.2011.0394