The endocannabinoid system (ECS) is a signaling network your body uses to keep other systems in balance. It has three parts: cannabinoids your body makes on its own, the receptors they bind to and the enzymes that make and break them down. Scientists found it while trying to understand how THC works, which is how a plant ended up naming a part of human biology. Here's how it was discovered, how its parts fit together and how plant cannabinoids interact with it.
Discovery: from THC to receptors to the body's own cannabinoids
The story runs backward from the plant to the body. Researchers first learned what THC was, then went looking for what it acted on, and only then found the molecules the body makes for itself.
| Year | Milestone |
|---|---|
| 1964 | Raphael Mechoulam and Yechiel Gaoni work out THC's structure in Israel |
| 1988 | Researchers identify a cannabinoid receptor in rat brain |
| 1990 | The CB1 receptor is cloned |
| 1992 | The first endocannabinoid, anandamide, is isolated |
| Early 1990s | A second receptor, CB2, is cloned |
| 1995 | A second endocannabinoid, 2-AG, is discovered |
Anandamide's name comes from the Sanskrit word ananda, which means bliss. The discovery showed that the brain makes its own cannabinoid-like messengers, and that THC works by borrowing their receptors.
What is the endocannabinoid system for, and which animals have one?
The central idea is balance, or homeostasis. A 2019 review described the ECS as a system that helps keep the nervous and immune systems, along with many other organ systems, in balance. It doesn't run any one function. Instead, it fine-tunes signals in tissues all over the body.
It works differently from most messengers. Endocannabinoids are made on demand from fats in cell membranes rather than stored for later. In the brain, a receiving nerve cell releases them, and they travel backward to the sending cell, where they turn down its signals. Think of them as a dimmer switch on nerve traffic.
The ECS isn't unique to people. It has been found in mammals, birds, reptiles and fish, and in invertebrates such as sea urchins, leeches, mussels and roundworms. Insects appear to be the notable exception. It's one important regulatory system among many, not the body's master switch.
Endocannabinoids: anandamide and 2-AG
The two best-studied endocannabinoids are:
- Anandamide, chemically arachidonoyl ethanolamide (AEA)
- 2-AG, or 2-arachidonoyl glycerol
Both are built from fats and both can bind CB1 and CB2. They're made and broken down by different pathways, which gives them different roles in the body. They also differ in strength at the receptor: 2-AG switches CB1 and CB2 on fully, while anandamide switches them on only partway, much as THC does.
Receptors: CB1, CB2 and other targets such as TRPV1
Receptors are the docking points that turn a chemical signal into a response.
- CB1 is the most abundant cannabinoid receptor. It sits mainly on nerve endings in the brain and spinal cord, with high levels in the amygdala, hippocampus, cerebral cortex and cerebellum. It also appears in tissues such as the gut and the cardiovascular system.
- CB2 is found mostly on immune cells, in places such as the spleen and tonsils, and on the brain's support cells, called astrocytes and microglia.
- Other targets. Some cannabinoids also act on transient receptor potential (TRP) channels, including TRPV1, and on proteins called PPARs. Endocannabinoids themselves bind and act at several TRP channels.
Enzymes that break them down: FAAH and MAGL
Because endocannabinoids are made on demand, the body also needs a way to switch them off. Two enzymes do most of that work:
- FAAH (fatty acid amide hydrolase) breaks down anandamide, and to a lesser degree 2-AG.
- MAGL (monoacylglycerol lipase) breaks down 2-AG.
The balance between how fast endocannabinoids are made and how fast these enzymes clear them sets what researchers call endocannabinoid tone, which varies from tissue to tissue.
Body processes linked to the ECS
Researchers have tied CB1 and CB2 receptors to a wide range of processes, including:
- how connections between nerve cells strengthen or weaken over time
- pain signaling
- anxiety and stress responses
- inflammation, including inflammation in the brain
- immune function
- metabolism
- bone growth
- brain development
Linked to doesn't mean controlled by, and it doesn't mean a cannabis product can fix a problem in any of these areas. Most of this work comes from cell and animal studies.
How THC, CBD, CBG, CBC and THCV interact with it
Plant cannabinoids, or phytocannabinoids, act on the system in very different ways. Our guide to what cannabinoids are covers the whole family.
| Cannabinoid | What research shows |
|---|---|
| THC | Partly switches on CB1 and CB2; its action at CB1 produces the high |
| CBD | Barely binds CB1 or CB2 directly; in lab cells it can blunt compounds that activate them, and more than 65 other targets have been reported |
| CBG | Weakly activates CB1 and CB2; also acts on TRP channels and on serotonin 5-HT1A and alpha-2 adrenergic receptors |
| CBC | First identified as a CB2 activator, later found to bind both receptors; strongly activates the TRPA1 channel and may slow anandamide's removal |
| THCV | Blocks CB1 at low doses and may activate it at high doses in animal studies; partly activates CB2 in lab tests |
Our guide to how THC works in the body goes deeper on the main cannabinoid. For the minor ones, see our guides to CBG, CBC and THCV. A 2021 review noted that none of the minor cannabinoids has been shown in clinical studies to act as a psychotropic drug. Some researchers also think these compounds may work together, though firm experimental evidence is still lacking. That idea is explored in our piece on the entourage effect.
Research ahead: what is and isn't proven
Some things about the ECS are well established: its main parts, where its receptors sit and the fact that THC produces its high through CB1. A 2015 review of CBD's many reported targets concluded that CBD is very unlikely to produce its effects in neurological diseases through the ECS, and that it doesn't interact with the system directly except at very high concentrations in lab tests. That shows how much the details still matter.
Other ideas are far less settled. "Endocannabinoid deficiency," the notion that low endocannabinoid tone causes certain illnesses, is a hypothesis, not an established diagnosis. Products that promise to "balance" or "boost" your ECS are making marketing claims that go beyond the evidence.
If you're considering cannabis for a health reason, talk with a clinician first, especially if you're pregnant, take medications or have a heart or mental health condition. Keep THC products away from children and pets, too. Cannabis is for adults 21+, or patients 18+ with a Michigan medical card. Please consume responsibly.
