The Endocannabinoid System: How Cannabis Interacts With the Body

By The Canningma’s Matan Weil, provided exclusively to Benzinga Cannabis.

Discovered by scientists in the early 1990s, the endocannabinoid system is responsible for regulating many basic functions throughout the body. The system can be activated by cannabinoids that are naturally created by the body — and those found in the cannabis plant, which, as you might have guessed, is where it got its name.

Among the functions regulated by the endocannabinoid system (ECS) are memory, appetite, temperature, the immune system, sleep, pain, and the female reproductive system. By regulating these functions, the ECS is believed to help maintain balance, or homeostasis, in the body.

The endocannabinoid system: What it is and how it works

In order to understand what the ECS is, it’s helpful to imagine the process of how it works.

Take pain, for example. 

Let’s imagine Emma is jogging with her dog in the park. She trips on a rock and twists her ankle.  Emma immediately feels pain, which is a reaction to the impact of hitting the ground.  

Once the fall is over, however, the immediate pain isn’t as necessary anymore so the central nervous system (CNS) recruits enzymes to slow down and stop the pain signals. These enzymes then create special molecules called endocannabinoids, primarily anandamide and 2-AG, to get the job done.

Commonly referred to as the “bliss molecule,” anandamide plays a key role in the regulation of mood and emotion. Low anandamide levels are linked to depression, anxiety, and schizophrenia. Many of the prescription medications used to treat pain and depression increase levels of anandamide.

2-AG (2-Arachidonoylglycerol)
Research shows that one of the main functions of 2-AG is to reduce inflammation while regulating other essential functions of the immune system. Like anandamide, 2-AG is involved in the regulation of mood, emotion, and pain perception, while also playing a role in memory, reproductive health, and sleep cycle regulation.

These endocannabinoids are messengers of sorts, but ones that only activate certain cells — kind of like a key that only opens a certain type of lock. 

These “locks” are actually receptors that sit on the cells throughout the body. The main ones are CB1 and CB2. (CB stands for cannabinoid receptor.) 

In Emma’s case, the enzymes created endocannabinoids, which activated the right receptors that told cells in her body to start relieving her pain.  This process actually happens in split seconds. 

Once the endocannabinoids have done their job, another group of enzymes shows up to break them down.

How scientists discovered the ECS

What does the endocannabinoid system have to do with cannabis? It has everything to do with the order in which scientists discovered the different molecules. 

Cannabinoid receptors, the locks attached to cells in our bodies, were only discovered because researchers were trying to understand how plant-based cannabinoids (phyto-cannabinoids) like THC interact with the body. So they were named cannabinoid receptors, after the main chemicals that activates them.

Only later, scientists discovered that the body produces very similar molecules that fit the same receptors, or locks. They were named endocannabinoids. (Endo means “internal” and phyto means “plant related.”)

If cannabinoid receptors are the locks, you can think of endocannabinoids, like anandamide, as the original master key. THC, the primary cannabinoid in cannabis, is more like a spare key — it activates some of the same receptors as anandamide. However it works a little differently, partly because THC is a phytocannabinoid and it can take the body hours or even a few days to break it down. 

Cannabinoid receptors: Why cannabis can help so many conditions

While we don’t yet know exactly how cannabis works, we do know that it can interact with the ECS, which is present all over the body. 

We know that the ECS is very active in the brain, and specifically in areas that involve conditions such as Parkinon’s disease, Alzheimer’s disease, chronic pain, stress, epilepsy and autism spectrum disorder (ASD). 

Cannabinoid receptors are also abundant in the immune system, which explains why cannabis can help for people who suffer from conditions such as Crohn’s disease, and ulcerative colitis. These receptors also exist on skin cells, where cannabis can interact with dermatologic conditions such as psoriasis, and they’re present in the lungs, which correlates with pulmonary conditions. 

In short, the main reason why cannabis is effective for so many different conditions is because it interacts with a system that is present in cellular receptors all over the body. 

There are two main types of cannabinoid receptors, aptly named cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2).

CB1 Receptors
CB1 receptors are found throughout the body, with the highest concentrations found in the brain and spinal cord. The CB1 receptors in the hypothalamus regulate metabolism, while CB1 receptors in the amygdala are responsible for regulating emotional response. CB1 receptors are also abundant in nerve endings.

CB2 Receptors
While CB2 receptors are also found throughout the body, they are concentrated most within the peripheral nervous system — the nerves extending from the brain and spinal cord to other areas of the body. That means CB2 receptors regulate organ function and muscle movement. CB2 receptors also play a role in the immune system. When activated, CB2 receptors reduce inflammation.

Functions of the ECS

Scientists believe that one of the roles of the endocannabinoid system is to maintain homeostasis, or balance, in the body. We know today that the ECS affects and regulates a number of body functions, systems, and conditions and diseases:

Memory and learning

Cannabinoid receptors are involved in the processes that regulate cognition, memory, and learning. CB1 receptors are highly concentrated in regions of the brain associated with cognition and memory, and are shown to control both cognitive processes and emotional behavior.

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Appetite regulation

Researchers recognized decades ago that food intake is controlled by a complex process involving neurological, behavioral, and endocrine system function. Studies suggest that modulating cannabinoid receptors is essential for regulating food intake and metabolizing macronutrients and fat. There’s also strong evidence that modulating endocannabinoid signaling could be instrumental in the management of obesity and eating disorders.


The body maintains a core temperature in the face of a different external environmental temperature using the sympathetic nervous system, adjusting heart rate, and vasoconstriction, to help the body adjust and maintain internal balance. In addition, our body sometimes intentionally raises our core temperature to fight infection, with the endocannabinoid system playing a role.

Immune system function

Researchers believe endocannabinoid messengers can have both an inhibitory and stimulatory effect on the immune system by interacting with CB2 receptors. Researchers have hypothesized that modulating endocannabinoids could provide a novel therapeutic approach for the treatment of inflammation and autoimmune diseases, and are also in the preliminary stages of investigating the role of the ECS for the treatment of asthma, multiple sclerosis, osteoarthritis, and some forms of cancer. 

Female reproductive processes

Researchers note a complex interplay between the ECS with the hypothalamus, pituitary gland, and the ovarian axis, with CB1 receptors believed to modulate numerous complex activities. While the cannabinoids in cannabis (as opposed to endocannabinoids) are shown to potentially disrupt female reproduction by decreasing estrogen and progesterone levels, ECS involvement in female reproduction suggests modulation of the endocannabinoid system is essential for reproductive success.

Sleep and sleep cycles

Sleep cycles are regulated by circadian rhythms, which are regulated by exposure to light and darkness. The ECS also plays a role here, with research showing that the activation of CB1 receptors induces sleep in laboratory settings, while the endocannabinoid system also helps stabilize sleep patterns due to its effect on homeostatic recovery. 

Pain perception

The ECS is now understood to be one of the systems in the regulation of pain. Endocannabinoids and their corresponding receptors are found in the pain circuits of the nervous system, from the nerve endings of the peripheral nervous system to the brain. Researchers have discovered that the more anandamide found in the bloodstream, the lower the level of pain perception.

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Autonomic Processes

The autonomic nervous system regulates numerous essential functions within the body. It has two branches: sympathetic and parasympathetic. The sympathetic nervous system is responsible for the “flight or fight” response, while the parasympathetic system is credited with “rest and digest.” Some of the many processes regulated by the autonomic nervous system include heart rate, digestion, thermoregulation, respiration, pupil dilation, and blood pressure. 

How do we know all this? To understand the potential roles of the ECS, researchers observed mice that were genetically modified to lack CB1 receptors. What they noticed was that the mice displayed issues with learning and memory, reward and addiction, pain, neuroinflammation and degeneration, metabolism and food intake, bone mass, and more — leading to the discovery that the receptors regulate these functions. Later on, the same process was repeated with CB2 receptors, and researchers learned of its involvement in several conditions; such as autoimmune inflammatory diseases, chronic pain, alcohol and nicotine addiction, stress responses, and more. 

Researching cannabis and the ECS

Research on the ECS and cannabis is fairly young. The first cannabinoid receptor (CB1) was discovered in 1988 by an American research team from St Louis University, and the first endocannabinoid (anandamide) was discovered in Israel only four years later by Bill Devane, Lumir Hanus and Raphael Mechoulam. 

To top it all off, cannabis was completely prohibited for decades, making it inaccessible as a treatment. That means most of the early evidence of its medical uses was based on anecdotal evidence from people who were technically breaking the law. 

Not all cannabis is the same

There are hundreds of different chemicals in any given cannabis plant. Each of the thousands of cannabis strains, or chemovars, has a unique chemical profile — meaning it has different combinations and ratios of those chemicals.

In contrast, most pharmaceutical medications have a few active compounds. 

Therein lies the challenge researchers face when trying to understand how cannabis interacts with the ECS. Instead of being able to study the effects of one compound on one receptor, in order to fully understand how cannabis works, scientists will have to examine thousands of different combinations of compounds and receptors. 

This is partly why doctors and scientists don’t yet know which, or what kind of cannabis strains best treat specific medical conditions or symptoms. Patients seeking cannabis treatment often have to go through a lot of trial and error before finding a strain that gives them relief. 

New horizons for cannabis and ECS research

Researchers are hard at work trying to find anomalies in the expression of the ECS in patients suffering from different conditions to understand if and how cannabis could help.

One of the leading researchers in the field of cannabis therapeutics, Dr Ethan Russo, has found preliminary evidence of endocannabinoid dysregulation in patients suffering from fibromyalgia, migraines, IBS, ASD, multiple sclerosis, diabetic neuropathy, PTSD, recurrent miscarriages, and bipolar disorder. 

Among the problems still facing medical cannabis researchers is how to match cannabis chemovars — or even individual cannabinoids or combinations of them — to specific illnesses and patients who might benefit from them.

The good news is that the cannabis industry is booming and regulations that once prevented cannabinoid research are being loosened around the world. There is more funding than ever, and universities and companies are carrying out a dizzying number of studies that aim to better understand the ECS and how it interacts with cannabinoids — those produced by our body and those from cannabis.

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