CBD And The Endocannabinoid System | How It works

Gleb Oleinik
Authored: Oct 30, 2018
Updated: Aug 21, 2020
CBD And The Endocannabinoid System: How Does It Work?

A Comprehensive Guide to the Endocannabinoid System

Discovered in the 1990s, the endocannabinoid system (ECS) is one of the major systems of the human body. It has an immense impact on our health by regulating key physiological processes, including:
 

  • Mood
  • Stress
  • Metabolism
  • Brain function
  • Immune function
  • Pain
  • Sleep

 

In doing so, the ECS helps keep your body in a healthy state of balance.

 

Throughout this article, we’re going to discuss how the ECS works, how CBD affects it, how you can keep it in balance, and why it holds so much promise in improving human health.

 

What Does the Endocannabinoid System Do?

The main role of the ECS is maintaining what’s called homeostasis: a state of internal balance. When something upsets this delicate balance, such as stress, injury, or illness, the ECS is activated to help steer things back to normal.

 

A simple way to imagine this is to consider inflammation. Inflammation is our body's natural defense mechanism to help identify and eliminate "harmful" agents, following injury or infection. Ultimately, the inflammatory response eliminates what our body perceives as a harmful agent, removes damaged tissue, and allows the body to begin healing. 

 

But too much inflammation is bad for the body and plays a major role in most chronic diseases.

 

The ECS regulates inflammation and many other processes to keep them functioning at just the right level — not too much and not too little.  This helps maintain your overall health and well-being.

 

Research suggests that the ECS influences a wide variety of critical processes, including:1

 

  • Metabolism, appetite, and digestion
  • Mood, stress, and emotions
  • Memory, learning, neuronal development, and other brain functions
  • Inflammation and other immune system functions
  • Cardiovascular system function
  • Liver function
  • Pain perception
  • Sleep
  • Skin function
  • Thermogenesis and body temperature

 

These findings explain why researchers are excited about the potential therapies targeting the ECS to help with a wide variety of health disorders.

 

How Does the Endocannabinoid System Work?

The endocannabinoid system is composed of three major elements: cannabinoid receptors, endocannabinoids, and special enzymes that create and break down these compounds.

 

This biological system is incredibly old, having evolved over 500 million years ago, which is why it's present in many other animals, including mammals, birds, fish, and reptiles.2

 

Endocannabinoids

Cannabinoids are compounds that bind to and activate cannabinoid receptors. THC and CBD from cannabis are not the only cannabinoids out there; the human body also makes its own endogenous cannabinoids, called endocannabinoids (endo meaning “within”).

 

The two main endocannabinoids are called anandamide and 2-arachidonoylglycerol (2-AG). They’re produced by our bodies as needed and broken down shortly after, which is why they were difficult for scientists to discover.

 

Cannabinoid Receptors

Receptors are protein molecules found in cells that can interact with specific compounds, producing a variety of biological effects. So far, researchers have identified two main cannabinoid receptors which they named CB1 and CB2.

 

However, further research suggests there are other receptors that could eventually be recognized as part of the ECS, such as GPR55.3

 

Anandamide and 2-AG can bind to these cannabinoid receptors, influencing a wide variety of biological responses including anxiety and pain perception.

 

Phytocannabinoids (cannabinoids sourced from plants) such as THC can also interact with cannabinoid receptors.

 

Cannabinoid receptors are found in all major body tissues, including the brain, spinal cord, skin, immune cells, bones, fat, liver, pancreas, muscle, heart, blood vessels, kidneys, and the digestive tract.

 

However, CB1 receptors are especially abundant in the brain and other parts of the central nervous system, whereas CB2 is most common in immune system cells and tissues.4

 

Enzymes

The third major component of the ECS are the enzymes that make and break down endocannabinoids.

 

The two most important of these enzymes are monoacylglycerol lipase (MGL), currently thought to break down the majority of 2-AG, and fatty acid amide hydrolase (FAAH), which breaks down anandamide.5

 

These enzymes help regulate the levels of endocannabinoids in our bodies at a given time and place, which makes sense given the role of the ECS in maintaining a delicate state of balance.

 

How Does THC Affect the Endocannabinoid System?

Tetrahydrocannabinol (THC) is the main psychoactive cannabinoid found in cannabis. THC is similar in structure to anandamide and binds mainly to the CB1 receptor.

 

This produces the mind-altering “high” experienced by cannabis users as well as other effects, such as increased appetite and pain relief. THC can also cause some people to feel increased feelings of anxiety or paranoia.

 

The effects of THC last longer than endocannabinoids because it’s not regulated and broken down by ECS enzymes.

 

How Does CBD Affect the Endocannabinoid System?

Unlike THC, cannabidiol (CBD) is a non-intoxicating cannabinoid, which means it doesn’t get you high. CBD is also unique because it doesn’t directly bind to cannabinoid receptors.

 

Rather, CBD’s main effect is reducing the activity of FAAH, the enzyme that breaks down the endocannabinoid anandamide. This results in higher anandamide levels, which may be beneficial for some individuals. Research on the potential benefits continues to show promise (e.g., antipsychotic effects for schizophrenic patients).

 

Aside from this, research shows that CBD changes the function of the CB1 receptor,6 which may explain how it counteracts THC’s intoxicating effects.

 

CBD also seems to interact with other receptors7 that may eventually be recognized as being part of the ECS.

 

How Was the Endocannabinoid System Discovered?

The ECS was discovered by accident. Researchers wanted to find out how THC produced its effects on the brain and in 1990 they discovered that it binds to a specific receptor, which they called the first cannabinoid receptor (CB1).8

 

This was a groundbreaking development because it meant that the human body must produce its own cannabinoids to interact with this receptor.

 

In the next several years, researchers confirmed the existence of the endocannabinoids anandamide and 2-AG, the second cannabinoid receptor (CB2), and the enzymes that break them down: all of the major components of the ECS.

 

As we can see, the ECS is a relatively recent discovery, which is why we’re still learning more about it.

 

Clinical Endocannabinoid Deficiency

Research suggests that dysfunction of the ECS called clinical endocannabinoid deficiency (CECD) may be responsible for a variety of difficult-to-treat disorders. This theory was first proposed by leading cannabis researcher Dr. Ethan Russo in 2001.

 

Scientific evidence for CECD has been steadily growing.

 

One 2016 paper detailed the findings of more than a decade of studies,9 suggesting that this deficiency may be responsible for migraines, fibromyalgia, irritable bowel syndrome, and many other chronic conditions.

 

These findings suggest that targeting the ECS could be a groundbreaking way to treat disorders that don’t seem to have a clear cause and have largely stumped conventional medicine.

 

The Amazing Potential of the Endocannabinoid System

The fact that the ECS is involved in virtually every important bodily function and that its dysfunction may have major negative effects, suggests that this system has immense therapeutic potential to benefit human health.

 

That’s why researchers are hopeful that therapies aimed at the ECS, such as CBD-rich cannabis preparations or compounds that reduce the breakdown of endocannabinoids, may be used to help with disorders affecting everything from metabolism to sleep.

 

There’s still a lot more to learn about the ECS and scientists are discovering something new every day.

 

So far, there’s evidence10 that influencing ECS function may help with mental disorders, neurodegenerative conditions such as Alzheimer’s disease, cardiovascular conditions, spinal cord injury, multiple sclerosis, arthritis, osteoporosis, hypertension, and glaucoma.

 

The ECS may hold the key for better treatment of obesity, diabetes, and even cancer.

 

Endocannabinoid System Genetics

Everybody’s body is different, so it’s not surprising that the ECS can differ as well. This may explain why people respond to cannabis differently and might even offer a clue to differences in brain function and predisposition to certain disorders.

 

For example, some people have a genetic variation in the gene that produces the FAAH enzyme11 which leads to a decreased activity of the enzyme. As a result, these individuals have naturally higher anandamide levels, which may contribute to lower overall anxiety and other effects.

 

Similarly, there's research showing that certain variations of ECS genes may contribute to drug addiction and other health disorders, including ADHD, PTSD, depression, and obesity.12

 

How to Stimulate the Endocannabinoid System

Emerging research suggests that there are many ways to promote a healthy endocannabinoid system, aside from what is known of the effects of cannabis-based products.

 

Omega-3 Fatty Acids

Your body uses fatty acids from dietary sources to make endocannabinoids.

 

There’s some early evidence that reducing the ratio of omega-6/omega-3 fatty acids by increasing your intake of omega-3 and decreasing omega-6 fatty acids may help optimize the endocannabinoid system for some individuals.13

 

In particular, research suggests that excessive intake of omega-6 fatty acids can desensitize and downregulate (reduce the number of) your cannabinoid receptors.14

 

Improving the omega-6/omega-3 ratio is also widely recognized as one of the best ways to reduce systemic inflammation and the risk of many chronic health disorders15 that are particularly common in Western countries, such as cardiovascular disease and cancer.

 

Herbs

Many plant-based compounds can also interact with the endocannabinoid system:

 

  • A 2010 study reported that compounds called catechins found in tea can bind to cannabinoid receptors16
  • Curcumin, the main active ingredient of the popular anti-inflammatory herb turmeric, has been shown to increase brain levels of endocannabinoids17
  • Several studies have shown that the terpene compound beta-caryophyllene, found in many edible plants, stimulates CB2 receptors18
  • Panaxynol, one of the compounds in Asian ginseng, can bind to cannabinoid receptors19
  • Moderate amounts of caffeine may stimulate the ECS, whereas high, chronic doses may have the opposite effect20

 

Dark Chocolate

Furthermore, research shows that chocolate contains several compounds similar in structure to our body’s endocannabinoids.21

 

These compounds may be able to mimic the effects of cannabinoids by activating cannabinoid receptors or reducing the breakdown of anandamide.

 

Their levels are highest in raw cacao and dark chocolate and may offer an explanation for the strong cravings for chocolate experienced by many people.

 

Getting Exercise

We all know that exercise is great for your health, and here’s another reason why. Studies in rodents suggest that physical activity and long-term exercise in particular lead to a more balanced endocannabinoid system.

 

Similarly, human studies report that medium to high-intensity exercise such as running, hiking, and biking can boost anandamide levels and potentially increase the number of CB1 receptors.22

 

These findings also suggest that anandamide could be the molecule responsible for the “runner’s high,” the feeling of euphoria often experienced after prolonged cardiovascular exercise.

 

Managing Stress

Chronic stress is known to cause a wide range of negative effects on our health. As such, it’s not surprising that some rodent studies have shown that chronic stress can lead to decreased endocannabinoid levels.23

 

Conversely, managing, and relieving stress can help reverse these effects. There are many ways to achieve this, including getting regular exercise, meditating, doing yoga, and socializing. There’s even evidence that acupuncture, a common stress relief practice, can boost endocannabinoid levels.24

 

Avoiding Alcohol Consumption

Studies suggest that alcohol consumption can influence the ECS. In one study, researchers gave rats a high dose of ethanol and found reduced levels of anandamide in the brain and other tissues.25

 

Furthermore, chronic consumption of alcohol has been shown to reduce the density of CB1 receptors.26

 

The Endocannabinoid System: Summing Up

Consisting of cannabinoid receptors, endocannabinoids, and the enzymes that control their metabolism, the ECS has a major impact on our health by helping maintain whole-body homeostasis.

 

We know that it plays a role in regulating everything from pain to sleep and that its dysfunction may be an important link for many difficult-to-treat disorders such as migraines and fibromyalgia.

 

As such, researchers and clinicians are hopeful that therapies targeting the ECS may offer novel solutions to a wide variety of health issues in the future.

 

There are many ways to keep your ECS in balance, such as using CBD and other cannabis-derived preparations, as well as eating specific foods and herbs, and making positive lifestyle changes.

 

References

1.  Aizpurua-Olaizola, Oier, et al. "Targeting the endocannabinoid system: future therapeutic strategies." Drug discovery today 22.1 (2017): 105-110.

2.  McPartland, John M., et al. "Evolutionary origins of the endocannabinoid system." Gene 370 (2006): 64-74.

3.  Brown, A. J. "Novel cannabinoid receptors." British journal of pharmacology 152.5 (2007): 567-575.

4.  Kendall, Debra A., and Guillermo A. Yudowski. "Cannabinoid receptors in the central nervous system: their signaling and roles in disease." Frontiers in cellular neuroscience 10 (2017): 294.

5.  NAAA, MGL FAAH1 FAAH. "Endocannabinoid-metabolising enzymesbph_506_110 220.. 221." (2009).

6.  Chung, Hery, Angélica Fierro, and C. David Pessoa-Mahana. "Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study." PloS one 14.7 (2019): e0220025.

7.  Ryberg, E., et al. "The orphan receptor GPR55 is a novel cannabinoid receptor." British journal of pharmacology 152.7 (2007): 1092-1101.

8.  Alger, Bradley E. "Getting high on the endocannabinoid system." Cerebrum: the Dana forum on brain science. Vol. 2013. Dana Foundation, 2013.

9.  Russo, Ethan B. "Clinical endocannabinoid deficiency reconsidered: current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes." Cannabis and cannabinoid research 1.1 (2016): 154-165.

10.  Pacher, Pál, Sándor Bátkai, and George Kunos. "The endocannabinoid system as an emerging target of pharmacotherapy." Pharmacological reviews 58.3 (2006): 389-462.

11.  Dincheva, Iva, et al. "FAAH genetic variation enhances fronto-amygdala function in mouse and human." Nature communications 6.1 (2015): 1-9.

12.  Onaivi, E. S., et al. "Cannabinoid receptor gene variations in drug addiction and neuropsychiatric disorders." Journal of Drug and Alcohol Research 2.1 (2013): 1-11.

13.  Bosch-Bouju, Clémentine, and Sophie Layé. "Dietary Omega-6/Omega-3 and endocannabinoids: Implications for brain health and diseases." Cannabinoids in Health and Disease (2016): 111-142.

14.  McPartland, John M., Geoffrey W. Guy, and Vincenzo Di Marzo. "Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system." PloS one 9.3 (2014): e89566.

15.  Simopoulos, Artemis P. "The importance of the ratio of omega-6/omega-3 essential fatty acids." Biomedicine & pharmacotherapy 56.8 (2002): 365-379.

16.  Korte, G., et al. "Tea catechins’ affinity for human cannabinoid receptors." Phytomedicine 17.1 (2010): 19-22.

17.  Hassanzadeh, Parichehr, and Anna Hassanzadeh. "The CB 1 receptor-mediated endocannabinoid signaling and NGF: the novel targets of curcumin." Neurochemical Research 37.5 (2012): 1112-1120.

18.  Gertsch, Jürg, et al. "Beta-caryophyllene is a dietary cannabinoid." Proceedings of the National Academy of Sciences 105.26 (2008): 9099-9104.

19.  Sharma, Charu, et al. "Small molecules from nature targeting G-protein coupled cannabinoid receptors: potential leads for drug discovery and development." Evidence-Based Complementary and Alternative Medicine 2015 (2015).

20.  Rossi, Silvia, et al. "Caffeine drinking potentiates cannabinoid transmission in the striatum: interaction with stress effects." Neuropharmacology 56.3 (2009): 590-597.

21.  di Tomaso, Emmanuelle, Massimiliano Beltramo, and Daniele Piomelli. "Brain cannabinoids in chocolate." Nature 382.6593 (1996): 677-678.

22.  Sparling, P. B., et al. "Exercise activates the endocannabinoid system." Neuroreport 14.17 (2003): 2209-2211.

23.  Hill, Matthew N., et al. "Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment." Journal of neurochemistry 106.6 (2008): 2322-2336.

24.  Chen, Lin, et al. "Endogenous anandamide and cannabinoid receptor-2 contribute to electroacupuncture analgesia in rats." The Journal of Pain 10.7 (2009): 732-739.

25.  Ferrer, Belen, et al. "Regulation of brain anandamide by acute administration of ethanol." Biochemical Journal 404.1 (2007): 97-104.

26.  Basavarajappa, Balapal S., Thomas B. Cooper, and Basalingappa L. Hungund. "Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain synaptic plasma membrane." Brain research 793.1-2 (1998): 212-218.

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