Pleiotropy of the Endocannabinoid System, Part 1

When I first started as a medical cannabis pharmacist, I knew little about cannabis and the endocannabinoid system. When I was learning about the myriad of disease states that cannabis was supposed to affect, I was deeply skeptical. I said to myself,  “this sounds like a cure-all.” And, if there's one thing we in medicine know about cure-alls, is that they cure nothing. But when I began a deep dive into the medical literature, I found pieces of the larger picture that led me to reconsider this assessment. 

Why cannabis seems to be a cure-all, is because that it does, in fact, treat multiple conditions because it manipulates the Endocannabinoid system (ECS), which is a major feedback system impacting a large number of physiological functions. The ECS operates in almost every system in the body and wherever it operates, it is as a “return to homeostasis” signal-  a switch that says, “Hey, you're getting out of balance, return to baseline.”

The body's natural endocannabinoids (EC) are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The interesting thing is that AEA and 2-AG are not just two EC that do the same thing- they commonly do the opposite thing in each system they operate in. For example, in bone homeostasis, 2-AG acts on the CB2 receptor in the bone marrow to increase osteoblast (bone building cells) differentiation while it suppresses osteoclast (cells that break bone down) differentiation. AEA, on the other hand, does the opposite actions of increasing osteoclast production and suppressing osteoblast production. Thus, the ECS operates a homeostasis loop in bone reproduction that we can take advantage with using cannabinoids.

Similar ECS feedback systems are present all over the body in organ repair systems (deciding what proportion of scar tissue vs healthy cells are made), the immune system (how aggressive the immune system should behave),  and the brain (overall electric activity and the distribution of the signals either along heavily trafficked lines or along less trafficked neural paths). Because the ECS operates so widely in the body and can modulate changes in both directions, cannabis can be a very useful medicinal tool to prod systems in a particular direction. This means that we can use cannabinoid compounds like THC, CBD, CBG, CBC, CBN, THCv and others to prod the ECS to behave in specific ways, and this is only the tip of the iceberg. The complexity of the ECS is far deeper and more interesting than even this- and terpenes are keys to that story.

Ethan Carruthers