The endocannabinoid system: How does marijuana produce its effects?

Many of us have heard of some of the transmission systems found in the human body. Take, for instance, the sympathetic nervous system, which triggers the fight-or-flight response. However, less has been heard of the more recently discovered endocannabinoid system, or ECS. This is rather surprising considering that it could be fundamental to almost every aspect of our bodily functions. Here we explain it in detail to help you understand how cannabis produces its effects.

The endocannabinoid system comprises a vast network of chemical signals and cell receptors which are densely packed in our body. For example, the ‘cannabinoid’ receptors in the brain outnumber many other types of receptors that are affected by different neurotransmitters.

Neurotransmitters are molecules used by the brain cells, or neurons, to communicate with each other. One neuron sends a message to the next neuron by releasing certain neurotransmitters, such as dopamine or serotonin, in an infinitesimal space that separates a neuron from the next.

Cannabinoid receptors act as ‘traffic officers’ that control the levels and activity of most neurotransmitters. To stimulate these receptors, our body produces molecules called endocannabinoids (endo = ‘inside’). They have a similar structure to that of the molecules of the cannabis plant, which are also known as phytocannabinoids (phyto = ‘plant’). The first endocannabinoid ever discovered was named anandamide after the Sanskrit word ananda, which means ‘bliss’.

Using a close simile, we could say that cannabinoid receptors act as a lock on the door of cell signalling, whereas endocannabinoids are the key that activates their mechanism. Cannabinoid receptors are located on the surface of the cells, where they ‘listen’ to the conditions outside the cell. They transmit information about these changing conditions to the inside of the cell, thus initiating the appropriate cellular response.

Thanks to this intricate system of ‘locks and keys’ spread over our body, the endocannabinoid system acts as an invisible spider that moves around to maintain its balance or homeostasis, i.e. the stability of our internal environment. For instance, if an external force, like the pain produced by a lesion or a fever, alters the body’s homeostasis, the endocannabinoid system is activated to help it return to its ideal functional state.

How was the endocannabinoid system discovered?

We’ve only known about the existence of the endocannabinoid system for about 30 years, but its discovery is possibly one of the most important scientific discoveries to date. It was in 1988 that the neuropharmacologist Allyn Howlett and her team at the University of St. Louis first discovered a THC-sensitive receptor in the brain of lab mice. A few years earlier, in 1964, Raphael Mechoulam and his colleagues at the Hebrew University of Jerusalem managed to isolate tetrahydrocannabinol (THC), only to discover that it was the main psychoactive compound found in cannabis.

But why would the human body produce receptors if they had no natural cannabinoids to communicate with? The discovery of the cannabinoid receptors encouraged researchers to look for phytocannabinoid-like chemicals within the human body that would naturally interact with these newly discovered receptors. What they found was endocannabinoids, which act as ‘chemical messengers’ and help coordinate and regulate everything we feel, think, and do.

How does the endocannabinoid system work?

Hence, the ECS comprises three central components:

Endocannabinoids: The body produces them as it needs them, which makes it difficult to work out what the typical levels are for each. Experts have so far identified two primary endocannabinoids:

• Anandamide (AEA)
• 2-Arachidonoylglycerol (2-AG)

Cannabinoid receptors: These are found in most parts of the body. Endocannabinoids bind to them to indicate that the ECS needs to act. There are two main receptors:

• CB1 receptors – mainly found in the central nervous system.
• CB2 receptors – mainly found in the peripheral nervous system, especially in immune cells.

Endocannabinoids can bind to any of these receptors. The resulting effects will depend on where the receptor is located and on which endocannabinoid the receptor binds to. For example, some endocannabinoids may target the CB1 receptors on a spinal nerve to help alleviate pain, whilst others may bind to a CB2 receptor in the immune cells to signal that the body is experiencing inflammation.

Enzymes: They are responsible for breaking down endocannabinoids once they have performed their function, thus preventing them from accumulating in the body. There are two main enzymes responsible for this:

• Fatty Acid Amide Hydrolase (FAAH), which decomposes anandamide.
• Monoacylglycerol lipase, also known as MAG lipase, which normally decomposes 2-AG.

How does THC interact with the endocannabinoid system?

When a person smokes or inhales cannabis, THC gets into the lungs and is then absorbed into the bloodstream. Within a few minutes, the circulatory system transports the THC molecules to all body tissues, including the brain, where THC can alter the neural chemistry, producing its psychoactive effects.

The THC molecules that cross the blood-brain barrier will find that they perfectly fit into the receptors, in the same way as endocannabinoids. This is because the chemical structure of THC is similar to that of anandamide, which allows the body to recognise THC and alter normal brain communication. This affects areas that have an influence on pleasure, memory, thinking, concentration, movement, coordination, and sensory or time perceptions.

For instance, THC can alter the functioning of the hippocampus and the orbitofrontal cortex, which are areas of the brain that allow a person to form new memories and change their focus of attention. As a result, the use of marijuana causes effects on the thinking process and interferes with a person’s ability to learn and perform complex tasks.

THC can also alter the functioning of the cerebellum and the basal ganglia, which are the areas of the brain that regulate balance, posture, coordination, and reaction time. This is why marijuana users may not be able to drive safely after consumption.

THC also activates the brain’s reward system, which includes regions that control the response to healthy and pleasurable behaviours, such as eating and sex. THC stimulates the neurons in the reward system so they release dopamine at higher levels than those usually observed in response to natural rewarding stimuli. This dopamine ‘wave’ teaches the brain to repeat the rewarding behaviour, which helps explain the addictive properties of cannabis.

How does CBD work in the endocannabinoid system?

The other prominent cannabinoid is cannabidiol (CBD). Unlike THC, CBD is non-psychoactive and doesn’t generally produce any adverse effects. Experts aren’t completely sure how CBD interacts with the endocannabinoid system, but they do know that it doesn’t bind to the CB1 and CB2 receptors like THC.

Many believe that CBD works by preventing endocannabinoids from breaking down, which would translate into them producing several different effects in the body. Others claim that it probably binds to a receptor that has not yet been discovered. While the details are still under discussion, research suggests that CBD can be of great help when dealing with pain, nausea, and other symptoms associated with multiple conditions.

How about endocannabinoid deficiency?

Some experts believe in a theory known as Clinical Endocannabinoid Deficiency (CECD). This theory suggests that low endocannabinoid levels in the body or ECS dysfunction may contribute to the development of certain illnesses.

A 2016 article, which reviews over 10 years of research on this subject, suggests that this theory could explain why some people develop migraine, fibromyalgia, or IBS. None of these pathologies have a clear underlying cause and are often resistant to treatment.

If CECD truly plays a role in these conditions, targeting the endocannabinoid system or the production of endocannabinoids could be the missing key to treatment. However, further research is still needed regarding this.

There’s no doubt the endocannabinoid system plays a vital role in keeping our internal processes stable, but there’s clearly a lot that we still don’t know about it. However, as experts develop a better understanding of its purpose, ECS could be the key to revolutionising the history of medicine like we’ve never seen before.