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Cannabinoids 101

Written By Margaret Roche

How the endocannabinoid system (ECS) works: the key to understanding CBD and other cannabinoids

The ultimate guide for practitioners

When considering the use of CBD and other hemp-derived cannabinoids, healthcare providers and wellness practitioners are looking to gain understanding of the various cannabinoids and how they interact with the body’s endocannabinoid system (ECS). For example, practitioners are asking, what is the difference between hemp-derived cannabinoids, such as cannabidiol (CBD), and cannabis (marijuana) derived cannabinoids such as delta-9-tetrahydrocannabinol (THC)?  What is the endocannabinoid system (ECS)? How do the unique components of each cannabinoid interact with the body’s endocannabinoid system? Discovering the answers to these questions will enable professionals to gain confidence in helping clients navigate the use of these natural plant products.

What is Cannabis: Hemp vs Marijuana?

There is some confusion around and misuse of the term cannabis.  Even though marijuana is commonly referred to as cannabis, technically, both hemp and marijuana come from the cannabis plant (Cannabis genus). Hemp and marijuana are both cannabis but different chemical varieties (i.e., chemovars) of either the species Cannabis sativa (C. sativa) or Cannabis indica (C. indica); cannabis can also be a combination of the two as a result of crossbreeding. 2

Cannabis contains more than 500 different chemical compounds that work synergistically effecting the body in certain ways. These biologically active compounds can be classified as phytocannabinoids, terpenoids, and flavonoids.  Hundreds of varieties of cannabis are cultivated with varying amounts of these compounds for different medicinal effects. 1

The primary difference between hemp and marijuana is that marijuana is specifically bred for high levels of the psychoactive compound delta-9-tetrahydrocannabinol (THC) and hemp is bred for high levels of CBD and other cannabinoids.

What is the difference between hemp and marijuana plants?

HempMarijuana
Is it Cannabis?YesYes
THC ConcentrationLowHigh
CBD ConcentrationHighLow
PsychoactiveNoYes

There is no difference between the CBD — or any other cannabinoid — found in hemp vs. CBD found in marijuana. No matter which species of plant the cannabinoid is derived from (e.g., indica or sativa), CBD is the same compound and the physiological effects are the same. 

Understanding the Endocannabinoid System (ECS)

The endocannabinoid System (ECS) is sometimes referred to as the endogenous cannabinoid system. It is a molecular system responsible for regulating and balancing many critical bodily functions. The ECS is an active network of chemical signals and cellular receptors. This network is concentrated in our brains and found abundantly throughout the body. Its job is to maintain a stable environment in the body, regardless of the physiological insult. The ECS connects brain activity to states of physical health and disease.

The major functions of the ECS include:
1. Modulating pleasure (e.g., wellbeing, energy, bliss)
2. Balancing the body in response to external or internal stressors (i.e., maintaining homeostasis).

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Bodily functions regulated through the cannabinoid receptors include:

  • Digestion and appetite
  • Immune system functioning
  • Inflammation
  • Sleep
  • Fertility and reproduction
  • Regulation of temperature 
  • Memory
  • Pain perception
  • Pleasure and reward 

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Although there is still much to be learned about the ECS, scientists have discovered three key elements of the system, including:

  1. Endogenous cannabinoids also called endocannabinoids
  2. Endocannabinoid receptors (found in the nervous system and throughout the body) that bind with endogenous or exogenous cannabinoids
  3. Enzymes (which help make and break down cannabinoids)

There are several key elements involved in how the body maintains homeostasis via of the endocannabinoid system.

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The History of the Endocannabinoid System (ECS)

Although named after cannabinoids found in the cannabis plant, the endocannabinoid system (ECS) has been present in the body long before humans began using cannabis, evolving over 500 million years. In the 1990s, organic chemist Raphael Mechoulam, an Israeli professor of Medicinal Chemistry at the Hebrew University of Jerusalem, discovered the endocannabinoid system more than 20 years after isolating THC as the psychoactive compound in cannabis. In an effort to understand the pathway to how THC causes a person to get high, a system of lock and key chemical receptors was identified where THC was the key that initiated a series of neurotransmissions that changed the message the cell was sending.  From there, naturally occurring receptor “keys” or endogenous cannabinoids, otherwise known as endocannabinoids, have been discovered.

Researchers have since been learning more about the endocannabinoid system and its role in the human body. The endocannabinoid system was named “one of the most important physiologic systems involved in establishing and maintaining human health,” according to a study published in the journal Cerebrum. 3

How the ECS Works

The ECS is an essential biological network that sends cellular signals via neurotransmitters. The system is comprised of endocannabinoids (neurotransmitters), cannabinoid receptors and enzymes that work together to regulate various bodily functions by inhibiting or facilitating nerve impulse transmission (i.e., neuromodulation).  The ECS is vital to maintaining homeostasis and is not restricted to one organ or body part.

Three key elements of the body’s Endocannabinoid System:

  1. Endogenous cannabinoids also called endocannabinoids
    • Neurotransmitters that send chemical messages
    • Act as keys to “unlock” receptors.
    • Different cannabinoids have unique “keys” that can illicit different responses from the same receptor.
  2. Endocannabinoid receptors
    1. Found in the nervous system and throughout the body
    2. Act as “locks” that the endocannabinoid “key” bind to in order to initiate biochemical actions.
    3. Both endogenous and exogenous cannabinoids bind to the endocannabinoid receptors
  3. Enzymes
    1. Help make and break down cannabinoids

Note: exocannabinoids are those that come from outside sources, such ss plants and lab-made substances. Endocannabinoids are those that naturally occur in the ECS.

What Are Cannabinoids?

Cannabinoids are chemical messengers that work within the ECS by interacting with specific receptors. Cannabinoids act as keys that unlock the receptors, but several “keys,” or forms of cannabinoids, work to unlock each receptor. The result is that each type of cannabinoid can evoke a unique response when interacting, or “unlocking’’ the same receptor.  There are two types of cannabinoids, including endocannabinoids (those naturally made inside the body), and exocannabinoids (those that come from outside sources such as from plants [phytocannabinoids] and lab-made substances).

Endocannabinoids

Endogenous cannabinoids are neurotransmitters.  They are similar to cannabis-like substances but they are naturally manufactured and regulated throughout the human body.  Although the term “cannabinoid” is common in the health and wellness field today, practitioners may be unaware of their significance in the human body which makes and regulates its own cannabinoids, called endogenous cannabinoids or “endocannabinoids.”

The system that regulates endocannabinoids in the body is the endocannabinoid system (ECS).  The ECS is the most widespread receptor system in the human body and regulates many essential bodily functions to maintain homeostasis. There is significant scientific research data to back the validity of the ECS and how endocannabinoids, endocannabinoid receptors, and enzymes work together to maintain homeostasis in the body. 17 To fully understand the therapeutic effect of exogenous cannabinoids in the body, such as those found in cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), and other cannabinoids, it’s imperative to learn how the ECS functions.

Endocannabinoids are comprised of fatty acids, such as omega-3 fatty acids and glycerol.  Endocannabinoids are naturally occurring chemical messengers (i.e., neurotransmitters) that send signals from one nerve cell to another across the synapse between neurons. 

The human body produces endocannabinoids as they are needed. This makes it difficult for scientists to calculate “normal” levels of endocannabinoids. But what is scientifically known is that there are two primary endogenous cannabinoids, including: 

  • 2-AG (2-archidonoyl glycerol)
  • Anandamide (arachidonoyl ethanolamide or AEA)

Although there may be additional endocannabinoids, their function in the human body has not been clearly identified. 

Endocannabinoids and their receptors are found in the brain, organs, tissues, glands, and the cells of the immune system. 5 They function as the bridge connecting the mind and body. 5 Endocannabinoids work on the:

  • Immune system
  • Nervous system
  • Organs (all the body’s organs, including the brain)

Neurons make Anandamide, and 2-AG on demand to maintain homeostasis. Although these specific cannabinoids are found throughout the body, each one interacts with a specific type of receptor to perform a unique function. For example, Anandamide primarily interacts with CB1 receptors in the brain; 2-AG mostly interacts with CB2 receptors in the immune system.5

Anandamide and 2-AG, control the level of neurotransmitters sent to influence the intensity and length of responses. Once the body’s level of homeostasis is reached, these endocannabinoids are quickly broken down by enzymes to stop their responses. 

Exocannabinoids

Cannabinoids found in plants, or made in a lab, are referred to as “exocannabinoids” they are sometimes referred to as “exogenous cannabinoids.” Exocannabinoids mimic the function of endocannabinoids by stimulating the same receptors to maintain homeostasis.

Plant forms of cannabinoids (phytocannabinoids) are substances that stimulate cannabinoid receptors; some of the most common phytocannabinoids include:

  • Cannabidiol (CBD)
  • Delta-9-tetrahydrocannabinol (THC)

Read more about other phyocannabinoids here.

These exogenous cannabinoids begin as active acids; after cultivation, they must be heated before chemically mimicking their neutral counterparts and used for consumption.  Although plant forms can mimic the action of endocannabinoids, they differ because they have their own specific enzymes; the human body doesn’t have the right enzymes to immediately break these exocannabinoids down. This leads to longer effects. The result of exogenous cannabinoid ingestion is that although the body may have achieved homeostasis, exocannabinoids may continue to illicit a response for longer than needed.

Endocannabinoid Receptors

Cells throughout the body possess receptors for cannabinoids. When endogenous or exogenous cannabinoids attach to receptors, the ECS is triggered into action.  The sequence of events is as follows:

  1. The presynaptic cell has a flow of neurotransmitters that is greater than desired for the current biological environment.  This imbalance causes a disturbance in the post synaptic cell.
  2. An influx of calcium flows into the postsynaptic cell causing the postsynaptic cell to make an endocannabinoid (key).
  3. The postsynaptic cell sends the endocannabinoid (key) back to the presynaptic cell to attach onto the receptor (lock).
  4. The key in the lock initiates a chemical reaction that modulates the flow of the neurotransmitter thus reinstating homeostasis.

The Inhibitory Feedback Mechanism

The ECS uses an inhibitory feedback mechanism involving retrograde signaling. This means that the signal travels from its target source back to its original source. The signaling instructs neurotransmitters to slow down when they fire too quickly—such as when cooling the body down after a fever has done its job. Other examples where the ECS inhibitory feedback mechanism works:

  • Impede the immune response
  • Lower blood pressure
  • Dilate bronchial passages
  • Normalize overstimulated nerves

See: The Effectiveness of Cannabidiol (CBD) On Inflammation for more information on how the ECS plays an essential role in modulating inflammation using retrograde signaling.

CB1 Receptors

The CB1 cannabinoid receptors are the most plentiful in the human body. 9 They scan the body to receive biochemical cues found in extra-cellular fluid.

CB1 receptors are primarily found in the central nervous system (predominantly in the brain), connective tissue, gonads, glands, and organs, including the pancreas, liver and uterus. When CB1 receptors are activated, they provide anxiety and pain relief, stabilize the mood, and induce pleasure and well-being.

CB2 Receptors

Most of the CB2 receptors are found in the peripheral nervous system, which affects the immune and digestive system. CB2 receptors are also in the GI tract, gut, spleen, liver, heart, kidneys, bones, blood vessels, lymph cells, endocrine glands and reproductive organs. CB2 receptors induce anti-inflammatory effects and may also lend themselves to generating new nerve cells.

Both CB1 and CB2 receptors can be found in many bodily tissues; each receptor is linked with a particular cannabinoid to carry out specific roles in maintaining homeostasis.

Homeostasis

Homeostasis is the body’s way of ensuring that its internal environment is stable. This includes regulating the temperature, hormone levels, heart rate and more, regardless of the outside environment and external stressors. When the body’s homeostasis is out of balance, the ECS helps to get it back on track. For example, when the body’s temperature begins rising, perspiration production, facilitated by the action of the ECS, helps to cool the body down. The process of neuromodulation involves neurons that utilize chemicals to regulate distinct populations of neurons. Neuromodulators in the CNS include serotonin, dopamine, acetylcholine, norepinephrine, histamine, nitric oxide, and several neuropeptides. One example of how the ECS is involved in neuromodulation is how endocannabinoids in the hypothalamus stimulate the appetite. They do this by regulating certain neuropeptides via the endocannabinoid receptors, namely, the CB1 receptors. 4

Enzymes

Once the endocannabinoids connect with their specific receptors and have engendered a state of homeostasis, enzymes are released to break the endocannabinoids down. This occurs to ensure that the body does not get out of balance again. For example, once an overheated body has cooled down from perspiring, the ECS does not continue with its cooling effect. The release of these enzymes ensure that the body does not end up hypothermic.

Federally, hemp derived CBD is legal, however the FDA has not designated CBD, itself, as a dietary supplement or food and beverage additive.  Due to the FDA’s lack of engagement on this topic the states have moved in to fill the regulatory void with varying degrees of regulation.

Learn more about the legalities of CBD here.

According to a 2017 World Health Organization (WHO) report, “In humans, CBD exhibits no effects indicative of any abuse or dependence potential…. To date, there is no evidence of public health-related problems associated with the use of pure CBD.” 12 The WHO report describes CBD as a product that is “generally well tolerated with a good safety profile.” 12

Learn more about CBD safety here.

A Promising Future

In a 2005 paper in the British Journal of Pharmacology, Raphael Mechoulam, the preeminent cannabinoid researcher who discovered the ECS stated, “I sincerely believe that the plant cannabinoids are a neglected pharmacological treasure trove.”28 Since then, researchers have been further identifying the role that cannabinoids play in supporting health and wellness via the ECS. Over the next several years, as the legalities evolve and more research is done, it will be even more important for healthcare professionals and wellness practitioners to be knowledgeable about cannabinoids and the endocannabinoid system.

Resources

  1. Goldstein B. Cannabis Is Medicine. New York, New York: Little, Brown Spark; 2020. 
  2. Eichhorn BS, Wu BS, Rufyikiri AS, et al. An Update on Plant Photobiology and Implications for Cannabis Production. Frontiers in Plant Science. 2019; 29 March.
  3. Alger BE. Getting high on the endocannabinoid system. Cerebrum. 2013;2013:14. Published November 1, 2013.
  4. Matias I, Vergoni AV, Petrosino S, et al. Regulation of hypothalamic endocannabinoid levels by neuropeptides and hormones involved in food intake and metabolism: Insulin and melanocortins. Neuropharmacology. 2008;54(1):206-212.
  5. Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. IJMS. 2018;19(3):833. 
  6. R.L. Holderbrand. Hemp & Cannabidiol: What is a Medicine? Mo Med. 2018 Jul-Aug; 115(4): 306-309.
  7. Baron EP. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: what a long strange trip it’s been... Headache: The Journal of Head and Face Pain. 2015;55(6):885-916.
  8. Congressional Research Service. Defining Hemp: A Fact Sheet. Published March 22, 2019. 
  9. Lu H-C, Mackie K. An introduction to the endogenous cannabinoid system. Biological Psychiatry. 2016;79(7):516-525.
  10. Britannica ProCon.org. States with Legal Cannabidiol (CBD). Updated July 12, 2019.  
  11. Sachs J, McGlade E, Yurgelun-Todd D. Safety and toxicology of cannabinoids. Neurotherapeutics. 2015;12(4):735-746
  12. World Health Organization (WHO). Cannabidiol (CBD) Pre-Review Report. (2017).  
  13. Grinspoon, P. Harvard Health Publishing. Cannabidiol (CBD)-what we know and what we don’t. Updated September 24, 2021.
  14. Mayo Clinic. Healthy Lifestyle Consumer Health. What are the benefits of CBD–and is it safe to use?  Updated December 18, 2021.
  15. Di Marzo V, Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics. 2015;12(4):692-698. doi:10.1007/s13311-015-0374-6 
  16. Konieczny E, Wilson L. Chapter 3: The Endocannabinoid System. In: Healing with CBD: How Cannabidiol Can Transform Your Health without the High. Berkeley, CA: Ulysses Press; 2018:45-62.
  17. 17. Lu H-C, Mackie K. Review of the endocannabinoid system. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2021;6(6):607-615. 
  18. Rech GR, Narouze SN. The endocannabinoid system. Cannabinoids and Pain. Published July,  2021:39-45. 
  19. Sulak D. Introduction to the Endocannabinoid System. NORML. Published June 29, 2020.
  20. Penn State College of Medicine. NTI Meds to be Closely Monitored when Co-Administering with Cannabinoids.
  21. Harvard Health Publishing. Harvard Medical School. CBD and other medications: Proceed with caution.  
  22. Iffland K, Grotenhermen F. An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis and Cannabinoid Research. 2017;2(1):139-154.
  23. World Health Organization (WHO). Cannabidiol (CBD): World Health Organization Expert Committee on Drug Dependence Thirty-Ninth Meeting. 2017. https://www.who.int/medicines/access/controlled-substances/CannabidiolCriticalReview.pdf
  24. Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid system. Int. J Mol. Sci. 2018, 19, 833. doi: 10.3390/ijms19030833 https://doi.org/10.3390/ijms19030833 
  25. Laprairie R, et al. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. British J of Pharmacology, 2015. 172(20): p 4790-4805.  doi:10.1111/bph.13250 https://doi.org/10.1111/bph.13250 
  26. EPIDIOLEX® (cannabidiol) (cannabidiol) prescribing information. https://www.epidolex.com 
  27. Mechoulam R. Plant cannabinoids: a neglected pharmacological treasure trove. Br J Pharmacol. 2005;146(7):913-915. doi:10.1038/sj.bjp.0706415 https://doi.org/10.1038/sj.bjp.0706415
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