Endocannabinoids: what they are, their types and functions

What are endocannabinoids and what do they do?

Endocannabinoids, or endogenous cannabinoids, are chemical substances produced by our own body that have an impact throughout the entire body, most notably in the brain. These molecules interact with the cells of our body to regulate their functions, and they do so through the endocannabinoid system. In particular, the function of endocannabinoids appears to be linked to the sense of well-being and happiness.

The 3 key ideas

• Endocannabinoids are the cannabinoids your own body produces (hence the prefix endo-, meaning “internal”); the two main ones are anandamide and 2-AG.
• Together with receptors and enzymes, they make up the endocannabinoid system, which regulates mood, stress, pain, sleep and appetite to keep the body in balance (homeostasis).
• You don't take them as a supplement: the body makes them. Sleeping well, exercise, a diet with omega-3 and omega-6, and reducing stress all help to maintain their levels.

Endocannabinoids and the endocannabinoid system

Endocannabinoids are part of the endocannabinoid system, along with cannabinoid receptors and cannabinoid enzymes (involved in their synthesis, metabolism, transport and degradation). Each and every part of this system is essential: none works without the others.

What does the term endocannabinoid mean?

The term endocannabinoid was coined by a group of Italian researchers in 1995 (1). The prefix “endo-” comes from Greek and means “inside”. Endo-cannabinoids are therefore the cannabinoids produced by the body.

The term “endocannabinoids” helps distinguish the cannabinoids produced by the body from other types of cannabinoid found in nature, such as those produced by plants, mainly in cannabis, known as phytocannabinoids. There are also synthetic cannabinoids.

Definition of endocannabinoids

Technically, endocannabinoids are endogenous substances able to bind to the body's cannabinoid receptors. Generally, endocannabinoids are derived from membrane phospholipids, mainly from arachidonic acid, although other types also exist.

Mechanism of action of endocannabinoids

Once synthesised in the body, endocannabinoids interact with their specific receptors, the cannabinoid receptors, which trigger a series of chemical processes in our body to help us stay in balance. Enzymes, receptors and cannabinoids are all interconnected to create what is known as the “endocannabinoid system”, allowing the body to regulate itself and stay healthy.

There are two main receptors: CB1, predominant in the nervous system, and CB2, more prevalent in the immune system. Unlike classic neurotransmitters, which are stored in the neuron, endocannabinoids are made “on demand” (de novo), exactly when the body needs them, and are quickly broken down by enzymes such as FAAH (9).

Types of endocannabinoids

There are several types of endocannabinoid in the body. The two most studied endocannabinoids are anandamide, or arachidonoylethanolamide (AEA), and 2-arachidonoylglycerol (2-AG), both present in high concentrations in the brain.

2-AG is the most abundant endocannabinoid in the brain, with concentrations almost 200 times higher than those of anandamide.

It is intriguing how these endocannabinoids carry out their functions in the brain. 2-AG is generated from a diacylglycerol, a lipid that comes from the phospholipids in the membrane of neurons, and its reuptake takes place through mechanisms similar to those used for anandamide. However, its degradation is mainly attributed to the enzyme monoacylglycerol lipase (MAGL).

Other types of endocannabinoid have also been identified, such as 2-arachidonyl glyceryl ether (noladin ether), O-arachidonoyl ethanolamine (virodhamine, which appears to be an endogenous antagonist of the CB1 receptor), and N-arachidonoyl dopamine (NADA, a vanilloid agonist with affinity for CB1).

There are two other endogenous compounds with a cannabimimetic effect, but with no affinity for cannabinoid receptors: oleoylethanolamide (OEA, studied for its potential role as an anti-obesity drug, due to its effect on appetite suppression) and palmitoylethanolamide (PEA, with anti-inflammatory and antiepileptic effects and the ability to inhibit intestinal motility).

Characteristics of endocannabinoids

Chemically, the main endocannabinoids are derived from polyunsaturated fatty acids, or essential fatty acids (the well-known omega-6 and omega-3), which sets them apart from phytocannabinoids.

More specifically, the main endocannabinoids studied are derivatives of arachidonic acid, conjugated with ethanolamine or glycerol. This chemical structure is reminiscent of eicosanoids (the body's inflammation mediators), such as leukotrienes and prostaglandins.

Interestingly, though, there are related compounds, such as palmitoylethanolamide and oleoylethanolamide, which are derived from fatty acids that are not polyunsaturated (palmitic and oleic acid) and which, as we have seen, do not bind to cannabinoid receptors.

Classification of endocannabinoids

Cannabinoids are a type of molecule that is relatively new to science: those from the plant were identified just over half a century ago (THC, in 1964), and endocannabinoids in the 1990s (anandamide, in 1992). Their effects on the body are highly diverse and cannot be classified within the other known systems.

If we wanted to classify them, we could refer to endocannabinoids as part of a neurotransmission system, which is why some authors describe the cannabinoid neurotransmitter system (2). However, that would not be entirely accurate either, because the effects of the endocannabinoid system go beyond the nervous system.

Functions of endocannabinoids

Endocannabinoids are part of a cell communication mechanism called the endocannabinoid system. Their function is to interact with other systems of the body by binding to cannabinoid receptors.

As a result, endogenous cannabinoids influence the nervous, immune and reproductive systems, among others. They take part in the regulation of numerous bodily functions, including:

• Appetite, digestion and energy balance (metabolism)
• Mood, emotions and the stress response
• Pain perception
• Sleep and the sleep-wake cycle
• Memory, learning and other cognitive abilities
• The immune system and inflammation
• Motor coordination and body temperature
• Fertility, bone formation and hormonal control (3)

Endocannabinoids and the brain

These compounds appear to be particularly important in the brain, where they are thought to act as neuromodulators and have a tonic effect. For example, endocannabinoid levels have been found to be higher in the brain areas related to pain (the central or periaqueductal grey matter).

Endocannabinoids regulate various neurological functions, such as mood, stress, anxiety, pain and reward behaviours. Anandamide and 2-arachidonoylglycerol (2-AG) are the two main endocannabinoids released while we are experiencing something.

Endocannabinoids for mental health: a brain communication system

The endocannabinoid system plays an important role in the brain, as cannabinoids interact with multiple neurotransmitters to produce effects on learning and memory, locomotor activity, psychotropic properties and antiepileptic effects.

The system by which these cannabinoids work in the brain is key to developing pharmacotherapies aimed at treating these and other neurological disorders (4,5). In this regard, cannabinoids from the cannabis plant are currently being researched for their ability to stimulate the endocannabinoid system, in a similar way to how endocannabinoids would. In other words, some plant cannabinoids, such as THC, act on the same receptors as the cannabinoids produced by the body itself; others, such as CBD, barely bind to them and influence the system in other ways. This finding opens up a whole field of research and could help us better understand the role of endocannabinoids in maintaining health.

At Cannactiva you'll find CBD oil, CBD flower and CBD cream, hemp products with less than 0.3% THC that are studied precisely for their interaction with the endocannabinoid system. Each European country has its own rules: in some, such as the UK, hemp flower is controlled even when its THC content is low.

What are the differences between endocannabinoids and neurotransmitters?

Endocannabinoids differ from “classic” neurotransmitters in their neurotransmitter-modulating nature. In terms of function, endocannabinoids act as neuromodulators by inhibiting the release of primary neurotransmitters, such as GABA and glutamate, in order to regulate subsequent neuronal activity. It is as if endocannabinoids had been created specifically to accompany our emotions through the control of other neurotransmitters.

On a more technical level, their main feature as neuromodulators is that endocannabinoids are retrograde neurotransmitters released by postsynaptic neurons rather than presynaptic ones. In plain terms: between two neurons there is a synapse – a communication space – where presynaptic neurons release neurotransmitters and postsynaptic ones are activated by them. However, compared with the more common neurotransmitters, endocannabinoids travel in the opposite direction; instead, they are released by the postsynaptic neurons when these are activated and the calcium inside them rises. In this way, the endocannabinoid system interacts with acetylcholine, dopamine, GABA, histamine, serotonin, glutamate, noradrenaline, prostaglandins and opioid peptides. This mechanism is responsible for many of the pharmacological effects of cannabinoids that have been studied (antiepileptic and anxiolytic effects, etc.).

Thanks to their ability to move between presynaptic and postsynaptic cells, endocannabinoids can alter the flow of communication between neurons in a unique way.

Another unique feature that sets endocannabinoid activity apart from that of other neurotransmitter systems is its ability to maintain the body's homeostasis. All in all, the brain's endocannabinoids are such an intriguing signalling system that it almost invites us to learn more about it. What a fascinating mechanism!

How can you increase endocannabinoid levels in the brain?

As you would expect, good health, a balanced diet, physical exercise and general rest all contribute to the optimal functioning of our body. Use your common sense: rest, sleep enough hours, exercise and keep a good level of muscle mass, eat healthily and enjoy contact with nature and the sun. If you'd like to go further, we explain how to activate your endocannabinoid system with habits and cannabinoids.

In addition, it has been reported that some nutrients in the diet may increase endocannabinoid levels. For example, linoleic acid (the main omega-6 fatty acid in the diet) appears to raise endocannabinoid levels (6). Aromatic herbs and spices are also linked to this system because of their beta-caryophyllene content, a compound that does not increase endocannabinoids but acts directly on the CB2 receptor (7). The balance between dietary omega-6 and omega-3 fatty acids influences the levels of anandamide and 2-AG, which in turn are involved in regulating appetite and energy expenditure (8).

We hope this in-depth guide to endocannabinoids has been at least as interesting and exciting for you as it was for us. If you have any questions, take a look at the frequently asked questions below, or write to us and we'll try to help. See you next time!

Frequently asked questions about endocannabinoids

What are endocannabinoids?

Endocannabinoids are cannabinoids produced by the human body itself. They act as messengers that bind to cannabinoid receptors to regulate mood, pain, sleep or appetite, and help maintain internal balance (homeostasis).

What are the main endocannabinoids?

The two most studied are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). 2-AG is the most abundant in the brain, with concentrations almost 200 times higher than those of anandamide.

How do endocannabinoids differ from phytocannabinoids like CBD?

Endocannabinoids are made by the body; phytocannabinoids are produced by the cannabis plant. The best known is CBD: here you can read about what CBD is and what it's for. Both act on the endocannabinoid system.

How can you increase endocannabinoids naturally?

Healthy habits help maintain their levels: getting enough sleep, exercising and managing stress. Diet also plays a part: the balance between omega-6 and omega-3 fatty acids affects the levels of anandamide and 2-AG, which are also involved in appetite regulation.