The endocannabinoid system explained: CB1, CB2 and CBD

The endocannabinoid system (ECS) is a signalling network found in humans and other mammals. It has three parts: receptors (mainly CB1 and CB2), messengers the body makes itself (anandamide and 2-AG), and enzymes that break those messengers down. It helps nerve, immune and skin cells adjust their activity, and it is where plant cannabinoids such as THC and CBD act.

What is the endocannabinoid system?

The endocannabinoid system is one of the body's communication networks. Reviews describe it as three parts working together (Lu & Mackie, 2016):

• Receptors on the surface of cells. The two best known are CB1 and CB2.
• Endocannabinoids, fat-based messengers the body makes itself. The two best studied are anandamide and 2-AG.
• Enzymes that build these messengers and break them down again once they have done their job.

What makes the system unusual is timing. Most messengers in the nervous system are made in advance and stored. Endocannabinoids are made on demand from building blocks in the cell membrane, released within moments and then broken down quickly (Lu & Mackie, 2016).

In the brain they also travel "backwards". A nerve cell that receives a signal releases endocannabinoids, which drift back to the sending cell and tell it to ease off. Researchers call this retrograde signalling, and it acts like a volume control on communication between nerve cells.

Scientists describe the ECS as a regulator that helps many tissues keep their processes in balance, a state called homeostasis (Tóth et al., 2019). It doesn't do one single job. Its effect depends on where the receptors are and what the cell is doing at the time.

How was the endocannabinoid system discovered?

The system is named after the cannabis plant because researchers found it while trying to work out how THC acts on the body. The receptors came first, and the body's own messengers were found afterwards.

Where are CB1 and CB2 receptors in the body?

CB1 is the most common cannabinoid receptor. It is found at very high levels in parts of the brain involved in memory, thinking and movement, such as the hippocampus, basal ganglia and cerebellum (Herkenham et al., 1990), and at lower levels throughout the body (Mackie, 2008). Outside the brain it occurs in nerves, the gut, liver, fat tissue, skeletal muscle, bone, skin and the eye (Zou & Kumar, 2018). CB1 is the receptor through which THC produces its high.

One detail from the first brain maps is often quoted. The brainstem areas that control breathing and heart rate carry very few CB1 receptors, which the researchers suggested may explain why high doses of THC are not lethal (Herkenham et al., 1990).

CB2 was first found in immune cells in the spleen (Munro et al., 1993). It is mainly an immune-cell receptor, with moderate levels in the gut, liver, fat tissue, bone and the heart and blood vessels (Zou & Kumar, 2018). The brain has much less CB2 than CB1, mostly on its immune cells (microglia), but levels can rise sharply after injury or inflammation (Lu & Mackie, 2016).

Endocannabinoids and plant cannabinoids also act on other targets, including the TRPV1 channel (which senses heat and pain), GPR55 and the PPAR family. Some researchers therefore speak of an extended "endocannabinoidome" (Di Marzo & Piscitelli, 2015).

What are anandamide and 2-AG?

Anandamide and 2-AG are the body's two main endocannabinoids. Both are made from arachidonic acid, a fatty acid in cell membranes, but they are built and broken down by different enzymes. That is why they have different roles (Lu & Mackie, 2016).

Sources for the table: Devane 1992, Mechoulam 1995, Stella 1997 and Lu & Mackie 2016.

2-AG is the workhorse. It is the most abundant endocannabinoid and a full activator of both receptors, (Stella et al., 1997). It is also the main messenger in the retrograde "ease off" signal between nerve cells (Lu & Mackie, 2016).

Anandamide is a partial activator. Where receptors are scarce, it can even dampen the effect of stronger activators. It also switches on TRPV1, the same channel that responds to the heat of chilli. FAAH breaks it down quickly, and blocking FAAH raises its level. In a 2020 trial in healthy adults, an experimental FAAH-blocking drug increased anandamide about tenfold (Mayo et al., 2020).

The body makes several smaller endocannabinoid-like messengers too, such as virodhamine, noladin ether and N-arachidonoyl dopamine (NADA). Their roles are less well understood.

Endocannabinoids and plant cannabinoids: what's the difference?

The prefix "endo" means "from within". Endocannabinoids are made by the body; phytocannabinoids ("phyto" = plant) come from hemp and cannabis. The two groups meet at the same system but behave differently.

Sources: Lu & Mackie 2016 and Pertwee 2008. For more on the plant side, see what cannabinoids are and which cannabinoids are psychoactive.

How does CBD interact with the endocannabinoid system?

CBD doesn't simply "bind to" cannabinoid receptors, as is often claimed. A systematic review found that CBD is a very low-affinity CB1 ligand that still affects CB1 activity indirectly in living systems (McPartland et al., 2015). Research points to several routes:

• It changes how CB1 responds. In cell studies, CBD acted as a negative allosteric modulator: it attached to a different site on CB1 and reduced the effect of THC and 2-AG, instead of switching the receptor on (Laprairie et al., 2015).
• It slows the clearance of anandamide. In laboratory tests CBD weakly inhibited FAAH and the uptake of anandamide into cells (Bisogno et al., 2001). In a 2012 hospital trial in which CBD was taken by mouth at a medicinal dose (800 mg a day), blood anandamide levels rose (Leweke et al., 2012).
• It acts on other targets. In the same 2001 study, CBD activated the TRPV1 channel with an effect similar to capsaicin. It also interacts with CB2 in ways that differ from THC (Pertwee, 2008).

This indirect action is why CBD doesn't produce a high: it doesn't switch on CB1 the way THC does. Most of these findings come from cell and laboratory studies, and research on how much each route matters in people is still developing. Read more in what CBD is and what THC is.

Does the skin have an endocannabinoid system?

Yes. Skin cells make endocannabinoids and carry CB1 and CB2 receptors, along with the enzymes that make and break down endocannabinoids. Reviews describe the skin's ECS as involved in the growth and renewal of skin cells, the skin barrier, hair follicles and sebaceous glands, and the skin's local immune balance (Bíró et al., 2009; Tóth et al., 2019).

In a laboratory model using human skin cells, CBD raised the cells' own anandamide levels (Petrosino et al., 2018). This was a cell study, and research on what it means for skin care is still developing.

This is relevant to how we sell our products: our CBD oils and creams are cosmetics, notified for use on the skin (CPNP in the EU, SCPN in the UK).

Do animals have an endocannabinoid system?

Yes. The ECS is found across mammals, and receptor mapping in animals other than humans is an active research field (Silver, 2019). Some of the key discoveries came from animals: 2-AG was first isolated from dog intestine (Mechoulam et al., 1995). In a treadmill study, endocannabinoid signalling rose after intensive running in both humans and dogs, but not in ferrets (Raichlen et al., 2012).

What has our Bologna research found about receptors in cats and horses?

To use cannabinoids well in animals, researchers first need to know where the receptors are. Formula Swiss funded a project led by Professor Roberto Chiocchetti at the University of Bologna's Department of Veterinary Medical Sciences. His university record lists it as a 2019–2021 project on CBD receptors in the digestive tract of cats and horses and in horse spinal ganglia. The team stained tissue samples to see which cells carry cannabinoid receptors. Each of the five papers below names Formula Swiss as a funder.

In the cat mouth study, receptor levels were much higher in the inflamed tissue of cats with chronic gingivostomatitis, a painful mouth disease. The authors concluded that the ECS may play a role in keeping the mouth lining healthy (Polidoro et al., 2021). The horse nerve studies found receptors in the cells that carry touch and pain signals, giving a basis for future research on pain in horses. The team also mapped the horse small intestine (Galiazzo et al., 2021), one of the topics in the project's university record.

These are tissue studies. They show where cannabinoids may act, but no animal was given CBD, no product was tested and no dose was studied. The Bologna team's receptor research also covers dogs; see CBD for dogs and CBD for cats. Our scientific research page describes the collaboration.

Can you support your endocannabinoid system naturally?

Exercise is the best-studied example. In trained young men, 50 minutes of moderate running or cycling activated the endocannabinoid system (Sparling et al., 2003), and researchers link this to the "runner's high". A 2014 systematic review listed diet, exercise, massage and several medicines among the factors that can change endocannabinoid activity. It concluded that human trials are needed to confirm these promising approaches (McPartland et al., 2014).

Cosmetics for use on the skin, made in Switzerland: our CBD oils