The endocannabinoid system, explained

What is the endocannabinoid system?

Every person, whether they’re a medicinal cannabis patient or not, has an endocannabinoid system. 

The endocannabinoid system (ECS) is a biological retro-grade signalling  system made up of a vast network of lipid-based chemical signals, cellular receptors and enzymes located throughout our CNS and body. These help regulate and balance many processes in the body – including immune responses, communication between cells, sleep, pain, appetite, hormone levels, metabolism, memory, and more. 

The endocannabinoid system is made up of:

1. Endogenous cannabinoids (endocannabinoids)
2. Cannabinoid receptors
3. Enzymes responsible for the synthesis and degradation of the endocannabinoids (we’ll unpack all of these terms below!)

Unlike the nervous system or cardiovascular system, the endocannabinoid system is not an isolated structural system located in a specific region of the body. Instead, the ECS is a receptor system broadly distributed throughout the body which is acted upon by cannabinoids and enzymes. Endocannabinoids and cannabinoid receptors can be found throughout the brain, organs, connective tissues, glands, and immune cells.

Let’s unpack the endocannabinoid system further.

What is the role of the endocannabinoid system?

The ECS plays a vital role in the central nervous system and immune systems. Researchers have linked the endocannabinoid system to at least 15 internal processes in the body.¹

These include:

• Appetite and digestion
• Bone remodelling and growth
• Cardiovascular system function
• Chronic pain
• Inflammation and other immune responses
• Learning and memory
• Liver and function
• Metabolism
• Mood
• Motor control
• Muscle formation
• Reproductive system function
• Skin and nerve function
• Sleep
• Stress

All of these functions contribute to the stability and balance of a person’s internal environment. The role of the endocannabinoid system is to ensure that when external force – such as an injury, illness, or stressors – throws the body off balance, the ECS can kick in to help return the body to a state of homeostasis.  

The endocannabinoid system is made up of those three core components mentioned above: endocannabinoids, cannabinoid receptors, and enzymes. Each of these components play an important role in helping internal functions run smoothly, and are constantly working together to keep a wide range of bodily processes in balance. Let’s look at each component individually:

1. Endogenous cannabinoids (endocannabinoids) 

Endocannabinoids are naturally occurring lipid-based molecules found in the body. They exist to mediate our normal physiological functions, and appear to have evolved in the brain to maintain biological harmony while also playing a role in neuronal plasticity (how the brain adapts to change).

The two major endocannabinoids that have been discovered are:

• Anandamide (AEA) (ananda is the Sanskrit word for bliss)
• 2-Arachidonoyl glycerol (2-AG)

Both of these endocannabinoids help our internal functions run smoothly, and a healthy human body produces them as needed. When there is a deficiency or imbalance in our endocannabinoid production, then we may need to look at external ways to upregulate our endocannabinoid system (more on this below).

Endogenous cannabinoids (endocannabinoids) are not to be confused with Phytocannabinoids which are found in plants. Phytocannabinoids naturally occur in a range of plant species, but are most commonly associated with the cannabis plant. You’ve probably heard of the popular cannabinoids, CBD and THC, however there are hundreds of cannabinoids. 

2. Cannabinoid receptors

Cannabinoid receptors are found on the surface of cells throughout the body. When endocannabinoids bind to these receptors, this signals to the ECS to kick-start a response.  Researchers have identified two primary cannabinoid receptors within the body:¹ 

• CB1 receptor (cannabinoid receptor type 1) – predominantly found in the central nervous system, brain, connective tissues, gonads, glands, and organs. CB1 receptors can also be considered a THC receptor due to the way THC directly binds to CB1 receptors (more about this later).
• CB2 receptor (cannabinoid receptor type 2) – predominantly found in the immune system, specifically within organs and cells responsible for some sort of response.

Many tissues contain both CB1 receptors and CB2 receptors, and each is linked to a different action. Both endocannabinoids (like Anandamide (AEA) and 2-arachidonoyl glycerol (2-AG)) and phytocannabinoids (like THC and CBD) interact with our two primary cannabinoid receptors to produce varying effects on the mind and body. More about how cannabis interacts with our CB1 receptors and CB2 receptors below.

3. Enzymes

Enzymes are molecules that accelerate chemical reactions in the body. Enzymes in the ECS are responsible for the synthesis and degradation of endocannabinoids.² This means that certain enzymes will help produce endocannabinoids on demand, and once they have carried out their functions in the body, other enzymes will then just as quickly break the endocannabinoids down again.

There are two main enzymes responsible for this:

• fatty acid amide hydrolase (FAAH) – which breaks down the endocannabinoid anandamide (AEA)
• monoacylglycerol acid lipase (MAGL) – which typically breaks down the endocannabinoid 2-arachidonoyl glycerol (2-AG)

Modulation of these two enzymes can up-regulate or down-regulate the endocannabinoid system by increasing or decreasing endocannabinoid levels within the body.

How does the endocannabinoid system work?

The endocannabinoid system works by relying on each of its components – endocannabinoids, cannabinoid receptors and enzymes – to create balance within the body. 

A typical endocannabinoid system function works via postsynaptic retro-grade signalling. Endocannabinoids are produced on demand from the body, this is a little different to typical neurotransmitters which are synthesised and usually stored in vesicles. Once the endocannabinoids have been produced they are released from a postsynaptic neuron and bind to cannabinoid receptors on the presynaptic neuron, modulating neurotransmitter release and resulting in regulatory feedback.

This signalling occurs throughout the CNS and various organs and tissues which aids in the regulation of a vast number of bodily functions including mood, pain, inflammation, digestion and sleep.

Essentially, when a system or function in the body is out of balance, cannabinoids bind to receptors to help correct the problem. Once the endocannabinoid system brings the body back into balance, enzymes will break down the cannabinoids to prevent overcorrecting the problem.

The endocannabinoid system and pain in patients

If a patient is experiencing pain, then a signal may be sent to enzymes to synthesise (produce) the endocannabinoid 2-AG. The 2-AG may then bind with and activate the CB1 receptors and/or the CB2 receptors³ to relieve the sensation of pain⁴ without interrupting other important bodily functions, such as temperature regulation, digestion and more. Once the body has been brought back into balance, the enzyme MAGL will then rapidly degrade the endocannabinoid 2-AG to avoid overcorrecting the problem and creating an imbalance in the body. 

It is this process that helps other functions of the body run smoothly even when the body is experiencing disruptions such as pain, inflammation or a fever.

When it comes to conditions like chronic pain, anxiety, or inflammatory diseases where the endocannabinoid system has not managed to bring the body back into balance and reduce symptoms, then it may be worth investigating whether an endocannabinoid deficiency or ECS dysregulation is contributing to your patient’s symptoms and looking at ways you can support them in upregulating the ECS to provide relief.

How does medicinal cannabis interact with a patient’s endocannabinoid system? 

There are hundreds of cannabinoids found in cannabis. The most popular and well-known cannabinoids are CBD and THC, followed by CBN, CBC and CBG. Because these phytocannabinoids have a similar chemical structure to our endocannabinoids, they have the potential to aid internal processes and mediate physiological functions in some patients when taken correctly and responsibly.

Phytocannabinoids like THC, CBD and CBN interact with a patient’s endocannabinoid system in varying ways:

THC and the endocannabinoid system

THC has been shown to work directly with the ECS by activating the CB1 receptors in the brain, producing a psychoactive effect. This may help relieve symptoms of pain, reduce nausea and vomiting, increase appetite, improve sleep, and more in some patients. 

It’s important to note that because THC works so directly upon the endocannabinoid system via the CB1 receptor, using too much THC can actually flood the CB1 receptors, potentially leading to increased anxiety, impaired memory and slow reaction times. By creating a tailored treatment plan for all of your medicinal cannabis patients, you help to ensure that a patient’s exact needs and symptoms are being addressed. 

CBD and the endocannabinoid system

CBD works indirectly with the ECS to interact with the opioid, dopamine, and serotonin receptors, giving it the potential to reduce pain, depression, and anxiety in some patients while boosting the immune system and helping with addiction. 

CBD is more likely to bind to the CB2 receptor, but it does not bind to the CB1 receptor like THC does. CBD is believed to be an allosteric modulator both of CB1 and CB2, this means it does not bind directly to the active site of the receptor, instead it attaches to another part of the receptor changing its shape which in turn modulates the receptors activity.

Because the stimulation of the CB1 receptors is what causes the ‘high’ associated with cannabis (an unwanted side effect for some), CBD taken without THC does not cause this effect. CBD may also work by preventing endocannabinoids from being broken down, allowing them to have a greater effect on your body. For example, CBD has been found to inhibit the activity of the fatty acid amide hydrolase enzyme,⁵ which breaks down the endocannabinoid anandamide (AEA). Because anandamide levels play a key role in memory, mood, appetite, sleep, and pain relief, CBD’s inhibition of the enzyme that breaks it down may aid these functions while stimulating a sense of happiness and mental wellness in some patients.

CBN and the endocannabinoid system

One of the lesser known (but no less important) cannabinoids found in the cannabis plant is CBN, short for ‘cannabinol.’ CBN is known to have anticonvulsant, sedative, and other pharmacological activities⁶ that are still being explored. CBN is created during the breakdown of the psychoactive cannabinoid THC.

Like THC, CBN also binds to the CB1 receptor, but not as strongly in comparison to THC.⁷ This technically makes it a psychoactive compound, but it doesn’t produce much of a ‘high’ sensation that some patients may experience with THC. CBN has a stronger affinity towards the CB2 receptors, which are mostly associated with immune system regulation.⁷

Can some patients experience an endocannabinoid deficiency? 

Clinical Endocannabinoid Deficiency⁸ (CECD) is a term coined by neuropharmacologist Dr Ethan Russo in the early 2000s in an attempt to explain the potential therapeutic effects of cannabis in treating certain treatment-resistant conditions. 

The theory suggests that a low functioning endocannabinoid system – which may look like low endocannabinoid levels, an overabundance of metabolic enzymes or some other ECS dysfunction – could contribute to the development of certain chronic conditions such as:

• Irritable bowel syndrome⁹
• Fibromyalgia⁹
• Chronic migraines⁹
• Endometriosis¹⁰
• Anxiety¹¹
• Depression¹²
• PTSD¹³
• Autism spectrum disorder¹⁴

A 2016 article reviewing over 10 years of research on the endocannabinoid system and its relationship with IBS, fibromyalgia and chronic migraines, suggests that endocannabinoid deficiency may explain why some people develop some of these conditions.⁹ However, much more research is needed before we can come to a definitive conclusion.

What are the possible signs of endocannabinoid deficiency?

If a patient is demonstrating issues with sleep, chronic pain, menstrual pain, unmanageable stress, IBS symptoms, migraine, depression or any other issues relating to bodily functions that are regulated by the endocannabinoid system, this may be a sign of endocannabinoid deficiency or dysregulation. 

Unfortunately, there is no definitive cause of CECD and the concept is still very much a theory that requires more robust research to be better understood. 

Is medicinal cannabis the right treatment option for my patient? 

If your patient has a chronic condition with symptoms that are resistant to other types of treatment, such as pain or anxiety, medicinal cannabis can be explored as a potential treatment option.

Medicinal cannabis may be beneficial for patients who have some kind of endocannabinoid dysfunction, which has been seen in endometriosis patients, fibromyalgia patients and more.

Working with your patients to understand their symptoms, their ideal type of cannabis treatment (flower, oil, or topical treatments), their preferred method of consumption, and the optimal dose will help you as a healthcare professional to determine which cannabinoids and other cannabis compounds would best benefit them. 

6 ways to balance your endocannabinoid system

There are a number of ways that patients can naturally regulate their endocannabinoid systems in order to achieve balance in the body and treat potential endocannabinoid deficiencies. 

Some of these methods include: 

1. Eating more omega-3 fatty acids: fatty acid precursors – like those found in omega-3 – are known to produce endocannabinoids.¹⁵ Encourage your patients to consume more omega-3 rich foods like wild-caught fish, nuts and seeds and pasture-raised eggs.
2. Diversifying the gut microbiome: eating a wide range of fruits and vegetables (all of which contain microbacteria feeding prebiotics) can boost endocannabinoid levels.¹⁶
3. Trying terpenes: terpenes are the aromatic compounds found in plants – including cannabis. The terpene Beta-caryophyllene (BCP) which is found not only in cannabis but in basil, black pepper, cloves, cinnamon and more activates the CB2 receptor¹⁷ and has anti-inflammatory, anxiety and pain reducing and neuroprotective effects.
4. Moving more: exercise has been shown to increase endocannabinoids¹⁸ to help maintain homeostasis within the body, with moderate aerobic activity¹⁹ having a greater benefit than light or intense exercise. 
5. Reducing stress: prolonged periods of stress can impair the development of new cannabinoid receptors, and increased amounts of the stress hormone cortisol interfere with the function of our CB1 cannabinoid receptors. Finding ways to reduce stress is another good way for patients to regulate the ECS.²⁰
6. Consuming cannabinoids: When there is a potential endocannabinoid deficiency,⁹ or a condition like chronic pain that is resistant to standard treatments (such as medications, therapies and lifestyle changes), phytocannabinoids in medicinal cannabis treatments can potentially help boost our endocannabinoid system function.

The bottom line

Although there is still much research to be done, studies to date strongly suggest that the endocannabinoid system plays a vital role in our central nervous system and immune systems. This means that maintaining a balanced and functioning endocannabinoid system is essential for good health. Lifestyle changes like diet, exercise, stress reduction techniques and herbal medicines can be used to help upregulate the endocannabinoid system and drive a range of health benefits in patients, while cannabinoids like THC and CBD can be useful in helping to correct potential endocannabinoid deficiencies where other treatments have failed.

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