Endocannabinoid System 101: All Your Questions About the Endocannabinoid System & CBD Answered

Over 25 years ago, scientists studying the effects of cannabis made several groundbreaking discoveries. Firstly, they identified the active compound in Cannabis sativa—tetrahydrocannabinol (THC). Secondly, when investigating the psychotropic effects of THC on the human brain, they discovered an entirely new system, which they called the endocannabinoid system (ECS). Yes, we have an entire system named after marijuana.

Endocannabinoid System

Let’s start with an endocannabinoid system overview.

What is the Endocannabinoid System?

The endocannabinoid system (ECS) plays a fundamental role in regulating almost every process within the human body. It’s comprised of endocannabinoids, cannabinoid receptors, and the enzymes responsible for synthesizing and degrading endocannabinoids. 

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Cannabinoid Receptors

Twotypes of cannabinoid receptors have been identified within the human body, including CB1 and CB2 receptors. Although both types are scattered throughout all tissues, CB1 receptors are abundant in the central nervous system (CNS), particularly within regions of the brain like the cortex, basal ganglia, hippocampus, and cerebellum. CB2 receptors, on the other hand, are primarily found in immune tissues and digestive cells. [1]

Endocannabinoids

Endocannabinoids are essentially cannabinoid-like molecules that bind to and activate cannabinoid receptors. Except, unlike phytocannabinoids (such as CBD and THC), which are found naturally within the cannabis plant, endocannabinoids are produced by cells in the human body (‘phyto’ means ‘plant’ whereas ‘endo’ means ‘within’ the body).

While the cannabis plant contains over 100 different phytocannabinoids, which are responsible for the plant’s psychoactive and therapeutic effects, scientists have only identified two major endocannabinoids: anandamide and 2-arachidonoyl glycerol (2-AG). These endocannabinoids are synthesized on-demand from lipids within cell membranes of nerve cells.

Both phytocannabinoids and endocannabinoids are chemical “messengers” called neurotransmitters. They both bind to cannabinoid receptors through the ‘lock-and-key’ method to produce a certain response. You can think of cannabinoids as ‘keys’ and cannabinoid receptors as ‘locks.’ When the key fits the lock, a response occurs. 


What Does the Endocannabinoid System do?

Although scientists are still piecing together exactly what the ECS does, we do know that it plays a crucial role in maintaining homeostasis. Basically, homeostasis is the existence of a stable internal environment. Maintaining homeostasis is vital to our health. Our body has developed various mechanisms to restore this inner balance — and the ECS is just one of these. 

In fact, all humans and animals are born with an ECS, which exists throughout the lifespan regardless of whether or not you have tried cannabis. [2]The cannabis plant, is, therefore, not the reason our ECS exists. But rather, it exists to aid in our development and calibrate almost all our biological systems to keep our body in a state of homeostasis. 

For example, research shows that the ECS plays a key role in brain development during neonatal and fetal growth. [3] In particular, a process that is known as synaptogenesis, which is the formation of synapses. Synapses are electrical junctions between individual nerve cells (called neurons) that allow chemicals (called neurotransmitters) to transmit information from one neuron to the next.

The ECS is also involved in another crucial process called synaptic pruning, which removes unnecessary synaptic connections to improve the efficiency of neurotransmission. What's even more interesting is that endocannabinoids facilitate the formation of memories, particularly within our “working memory.” This is part of our short-term memory, which is involved in the rapid processing of information such as numbers, dates, and names. 

But, as mentioned earlier, the ECS doesn’t just look after our brain and memory; it helps to regulate many important processes throughout the entire body, such as: 

  • Immune response
  • Appetite
  • Digestion
  • Cognition 
  • Emotion
  • Wake/Sleep cycle
  • Memory
  • Pain and inflammation
  • Reproduction and fertility
  • Body temperature

How Does the Endocannabinoid System Maintain Homeostasis?

The human body produces endocannabinoids in response to specific situations that threaten our internal balance (such as hunger, stress, or exercise). For instance, when your energy levels are low, your body begins producing endocannabinoids that stimulate your appetite. Studies show that the endocannabinoid anandamide stimulates the release of ghrelin, a hormone responsible for promoting hunger, as well as certain gastrointestinal hormones, which slow gastric emptying.

In another example, when we experience a stressful event, such as public speaking, an important exam, or a toddler tantrum at the grocery store, the stress hormone (cortisol) rises within our blood helping to prepare us for danger in what’s known as the “fight or flight” response. However, scientists have recently revealed that the endocannabinoid system actually learns from these stressful situations, and with repeated exposures, begins to block the release of cortisol, resulting in a progressively smaller stress response. 

Once the endocannabinoids have restored homeostasis, certain enzymes degrade them and prevent them from taking any further action that could upset the balance. The two major enzymes are MAGL, which breaks down 2-AG, and FAAH, which breaks down anandamide. This distinguishes endocannabinoids from other signaling molecules, including regular neurotransmitters and hormones, which usually persist for much longer or are stored for later use. It’s a very precise system, which is under tight control. 


Why are Endocannabinoids Different to Other Neurotransmitters?

Endocannabinoids are different from regular neurotransmitters in many other ways too. Regular neurotransmitters are pre-made within presynaptic terminals of neurons (nerve cells) and upon stimulation are released from the presynaptic terminal, travel across the synapse (the small gap between individual neurons), and then attach to receptors on the postsynaptic terminal of another neuron. This is how our nervous system communicates. 

The endocannabinoid system actually works in reverse. When a postsynaptic neuron is stimulated, endocannabinoids are produced “on demand” from lipids (fat cells) present within the postsynaptic neuron. The endocannabinoids then diffuse back across the synapse and bind with CB1 receptors on the presynaptic neuron. 

Why is this important? Because endocannabinoids act on presynaptic neurons, they can regulate the release of other neurotransmitters. Ultimately, this gives them the ability to act as “dimmers” and fine-tune physiological functions within the body. 


How Does CBD Interact With the Endocannabinoid system? 

Cannabidiol (CBD) is one of over 100 different phytocannabinoids present in cannabis. It’s well-known for its therapeutic properties, including anti-anxiety, anticonvulsant, and anti-inflammatory, just to name a few. Unlike tetrahydrocannabinol (THC), CBD does not cause psychoactive effects. Medical researchers have thus shown great interest in the potential of CBD in the treatment of various chronic diseases; however, scientists are yet to pinpoint precisely how the endocannabinoid system and CBD work together. 

While THC has a high affinity for CB1 and CB2 receptors, CBD appears to have a weak affinity for both. Nonetheless, various studies have shown that CBD acts as an agonist to CB2 receptors. In other words, when CBD bonds with CB1 and CB2 receptors through the ‘lock-and-key’ method mentioned earlier, it enhances the capabilities of that receptor. In fact, CBD actually increases the presence of anandamide (AEA), the endocannabinoid that mimics the various therapeutic effects of THC. It’s named after ‘Ananda’, a Sanskrit word for ‘bliss.’ CDB does this by inhibiting the enzyme, fatty acid amide hydrolase (FAAH), which is responsible for breaking down anandamide. [5]

Furthermore, CBD interacts with transient potential vanilloid receptor type 1 (TPVR-1), a potential third receptor within the endocannabinoid system. These receptors are involved in the regulation of acute inflammation and pain. One study in mice found that an injection of CBD can reduce acute pain by acting on these receptors [6]

CBD is also believed to interact with 5-HT1A serotonin receptors (increasing mood and reducing stress) and opioid receptors (reducing pain). In one animal-model study, CBD attenuated the effects of acute anxiety, including lowering blood pressure and heart rate. [7]


What is Clinical Endocannabinoid System Deficiency?

Clinical endocannabinoid system deficiency (CED) was first mentioned in 2001 by Dr. Ethan Russo, a neurologist, and scientist internationally renowned for his groundbreaking research within the field of medicinal cannabis. 

He proposed that a dysfunctional ECS or lack of endocannabinoids may be at the root of many neurological disorders that plague society today. His theory is based on the understanding that most neurological disorders characterized by hypersensitivity to pain are associated with neurotransmitter deficiencies. For example, a deficiency of acetylcholine in Alzheimer’s disease, serotonin and norepinephrine in depression, and dopamine in Parkinson's disease. It is hypothesized that supplementing the body with naturally occurring phytocannabinoids from plants could correct these deficiencies, relieved symptoms, and restore balance within the body.  


What Evidence Exists to Support CED?

Despite a great deal of literature, CED has not been recognized by the medical world as an official condition. However, Dr. Ethan Russo presents a great deal of evidence to support CED in a recent literature review published within the Journal of Cannabis and Cannabinoid research.  [9]

Russo believes there is a strong case for CED as an underlying condition for migraines, fibromyalgia and irritable bowel syndrome (IBS). Indeed, numerous studies over the last several decades have shown that cannabinoids can provide relief for various chronic disease. For example, the activation of CB2 receptors has been shown to modulate immune cells, decreasing pain and inflammation. [11]


​​​​The Endocannabinoid System: Future Thoughts

There is a great deal we are yet to learn about the endocannabinoid system and its relationship with cannabis and chronic diseases. Although, recent evidence suggests that improving our understanding of the endocannabinoid system could play an important role in the prevention, management, and even treatment of certain chronic conditions. 


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