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How CBD Works: The Endocannabinoid System Explained

If you’re interested in what CBD can do for you, you may have already come across the term “endocannabinoid system” and wondered if it’s even a real thing. Read on for an explanation of the endocannabinoid system (ECS for short), what current scientific research tells us about the ECS, how consuming CBD affects this system and some of the potential benefits of CBD.

how cbd works the endocannabinoid system explained

What is the endocannabinoid system?

Simply put, the endocannabinoid system is a cell-signaling network within our bodies; it helps regulate and balance many important bodily functions including the immune, endocrine, reproductive, and central and peripheral nervous systems.[1] The prefix “endo” means inner or within, so the endocannabinoid system is the system within our bodies that deals with the cannabinoids our body naturally produces.


The ECS was first identified in the 1990s when researchers L.A. Matsuda et al. investigated the mechanisms responsible for the effect marijuana has on the central nervous system.[2] Although the ECS was only discovered relatively recently, scientists have found that components of the ECS evolved over 600 million years ago.[3] The endocannabinoid system is found in all vertebrates, including humans, dogs, cats, birds and reptiles.


Over the last thirty years, research has expanded our understanding of this neuromodulating system and continues to discover how the ECS works and recognize its potential as a therapeutic target for treatment of a variety of disorders.


The ECS modulates many physiological functions

The endocannabinoid system plays an important role in maintaining homeostasis of the human body.[4] Our bodies are complex systems that must constantly adjust according to the conditions we face in order to maintain a certain balance for optimal functioning. This process is referred to as homeostasis and is exemplified by our body’s reaction to heat by sweating to maintain a healthy body temperature.


The ECS plays a role in regulating a wide variety of bodily systems including:

  • neuroprotection (the protection of your nervous system, including modulating neurotransmitter levels)[5]

  • neurogenesis and neuronal plasticity

  • embryological development

  • regulation of hormones

  • mood

  • sleep/wake cycle[6]

  • motivation

  • learning and memory processing

  • modulation of pain perception

  • motor control

  • immune and inflammatory responses

  • regulation of heart rate, blood pressure and bronchial functions (carrying air to & from the lungs)

  • mitochondrial production and function (mitochondria are known as the powerhouse of the cell, they’re responsible for energy production)

  • appetite

  • lipid synthesis

  • glucose metabolism

  • bone metabolism[7]

  • control of natural cell death (this process is called apoptosis and is especially relevant to responding to cancer, which is out of control cell growth)


What makes up the endocannabinoid system?

The components of the ECS are found throughout the body: in the brain, the gastrointestinal tract, connective tissues, glands, and immune cells. The ECS exists as a network throughout the body composed of three parts: endocannabinoids, endocannabinoid receptors, and enzymes.


Endocannabinoids

Endocannabinoids are naturally occurring lipid-based retrograde neurotransmitters. Endocannabinoids differ from conventional neurotransmitters such as serotonin, by operating in a regulatory manner for conventional neurotransmitters rather than distributing information directly. These molecules are known as endogenous ligands, which act as keys that fit into specific ‘locks’, called receptors, that exist throughout the body. There are two main endocannabinoids that have been identified: anandamide (AEA) and 2-arachidonoylglyerol (2-AG).


Anandamide (AEA)

The endocannabinoid AEA is a short-lived molecule that helps regulate our brain’s reward system, among other processes. It is capable of binding to both known endocannabinoid receptors (CB1 and CB2), however it has a higher affinity for CB1 receptors and is mainly found in the central nervous system. AEA is produced by the body on an as-needed basis, meaning that the body produces them when a need arises rather than having them stored in the body like other biological compounds. It is quickly broken down by the enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA).


Scientists have hypothesized that AEA is responsible for the experience of “runner’s high” – the blissful state runners, and other endurance exercisers, experience during and after a bout of exercise.[8] The molecule’s name even hints at this effect – the prefix comes from the Sanskrit word “ananda” which translates to joy or bliss.


2-arachidonoylglyerol (2-AG)

While anandamide is produced in relatively small quantities, more recently discovered endocannabinoid 2-arachidonoylglycerol is produced in much larger amounts (over 170x [9]) and does most of the work when it comes to maintaining homeostasis. Unlike anandamide, 2-AG has equal affinity with the CB1 and CB2 receptors and scientists believe it may play a large role in the attenuation of neural cell functions, including calming stimulated neurons after excitation.[10]


Endocannabinoid Receptors

As described above, endocannabinoid receptors act as locks, sitting in the cell membrane awaiting activation by an endocannabinoid ligand binding to it. When an endocannabinoid binds with an endocannabinoid receptor, it activates the endocannabinoid system. The regulatory effect will depend on the location and type of the receptor as well as which endocannabinoid binds to it.


CB1 Receptors

CB1 receptors are mainly found in the brain and central nervous system. They are responsible for regulating:

  • appetite

  • immune response

  • movement and coordination

  • pain perception

  • memory

  • emotions and cognition[11]

  • reward system


CB2 Receptors

CB2 receptors are mostly found in the peripheral nervous system, particularly in immune cells. These receptors are responsible for regulating:

  • immune response

  • inflammatory response

  • gastrointestinal functioning

  • bone metabolism

  • pain perception

  • fertility/sperm motility


Other receptors

Some researchers have proposed the existence of other endocannabinoid receptors; however, the existence of these receptors has not yet been scientifically documented.[12]


Enzymes

Enzymes are responsible for deactivating the endocannabinoid system by breaking down endocannabinoids after they’ve carried out their function. Using the lock and key analogy: they remove the key from the lock.


How does CBD interact with the endocannabinoid system?

The cannabinoids found in cannabis are known as phytocannabinoids – meaning that the cannabinoids are naturally synthesized by plants. They may also be referred to as exogenous cannabinoids or exocannabinoids, which means they are not produced from within the body. The two most well-known and researched phytocannabinoids are THC and CBD, and they interact with the endocannabinoid system in different ways.

THC interacts directly with the CB1 receptors and, to a lesser extent, the CB2 receptors. THC is responsible for the psychoactive effects of cannabis, whereas CBD is non-psychoactive and appears to bind to a variety of receptors both directly and indirectly affecting the endocannabinoid system. Interestingly, CBD binds to the CB1 receptor in such a way that it reduces the effects of THC.[13]

Research has shown that one mechanism through which CBD influences the ECS is by decreasing levels of the enzyme FAAH, resulting in higher concentrations of the endocannabinoid AEA.[14] This reduction in FAAH levels decreases neuroinflammation and is associated with a reduction in symptoms of inflammatory pain, depression and anxiety.[15], [16]


Although the underlying mechanisms of action of CBD are still being studied, ample research suggests that CBD may provide symptomatic relief from many conditions, including:

  • multiple sclerosis (MS)

  • epilepsy and seizures[17]

  • arthritis

  • chronic inflammation

  • chronic and acute pain

  • autoimmune disorders

  • depression

  • anxiety

  • nausea

  • schizophrenia[18]

  • irritable bowel syndrome

  • fibromyalgia

  • migraines

  • sleep disorders


Dysfunction of the endocannabinoid system has been implicated in a number of diseases and may be a target for therapeutic intervention.


What is the clinical endocannabinoid deficiency theory?

The clinical endocannabinoid deficiency (CED) theory was proposed by the neurologist Ethan B. Russo in the early 2000s. Russo posited that some chronic disorders like fibromyalgia, irritable bowel syndrome and migraines may be due to a deficiency in the endocannabinoid system. Over the past 20 years researchers have found diminished ECS function in a variety of chronic conditions including those mentioned above as well as in PTSD, multiple sclerosis, ALS, Alzheimer’s disease, Huntington’s disease and Parkinson’s disease.[19] Researchers continue to investigate the link between decreased ECS functioning, these diseases, and what role targeting the ECS may have on their treatment.


Takeaway

The ECS is a complex physiological system that helps our bodies maintain a healthy balanced state. It exists throughout our bodies and is active whether or not you have ever used cannabis. Research suggests that a variety of disorders may be associated with the endocannabinoid system and cannabis may be beneficial in treating the symptoms of the disorders or the disorders themselves. CBD, in particular, has been found to have positive effects for inflammatory and stress-related disorders without the cognitive impairments associated with THC.


If you’re considering trying CBD to treat or manage a chronic condition, it may be helpful to consult a doctor to discuss whether it’s right for you.

REFERENCES

[1] J. Wu, “Cannabis, cannabinoid receptors, and endocannabinoid system: yesterday, today, and tomorrow,” Acta Pharmacologica Sinica 2019 40:3, vol. 40, no. 3, pp. 297–299, Jan. 2019, https://www.nature.com/articles/s41401-019-0210-3.

[2] L. A. Matsuda, S. J. Lolait, M. J. Brownstein, A. C. Young, and T. I. Bonner, “Structure of a cannabinoid receptor and functional expression of the cloned cDNA,” Nature 1990 346:6284, vol. 346, no. 6284, pp. 561–564, 1990, https://www.nature.com/articles/346561a0.

[3] J. M. McPartland, “Phylogenomic and chemotaxonomic analysis of the endocannabinoid system,” Brain Research Reviews, vol. 45, no. 1, pp. 18–29, Apr. 2004, https://www.sciencedirect.com/science/article/pii/S0165017304000037.

[4] “The Endocannabinoid System, Our Universal Regulator — Journal of Young Investigators.” https://www.jyi.org/2018-june/2018/6/1/the-endocannabinoid-system-our-universal-regulator (accessed Mar. 20, 2022).

[5] J. C. Ashton, M. J. Dowie, and M. Glass, “The Endocannabinoid System and Human Brain Functions: Insight From Memory, Motor, and Mood Pathologies,” The Endocannabinoid System: Genetics, Biochemistry, Brain Disorders, and Therapy, pp. 115–186, Jan. 2017, https://www.sciencedirect.com/science/article/pii/B9780128096666000058.

[6] E. Murillo-Rodríguez et al., “The Endocannabinoid System May Modulate Sleep Disorders in Aging,” Current Neuropharmacology, vol. 18, no. 2, p. 97, Aug. 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324886/.

[7] A. I. Idris and S. H. Ralston, “Role of cannabinoids in the regulation of bone remodeling,” Frontiers in Endocrinology, vol. 3, no. NOV, p. 136, 2012, https://www.frontiersin.org/articles/10.3389/fendo.2012.00136/full.

[8] A. Dietrich and W. F. McDaniel, “Endocannabinoids and exercise,” British Journal of Sports Medicine, vol. 38, no. 5, pp. 536–541, Oct. 2004, https://bjsm.bmj.com/content/38/5/536.

[9] N. Stella, P. Schweitzer, and D. Piomelli, “A second endogenous cannabinoid that modulates long-term potentiation,” Nature, vol. 388, pp. 773–777, Aug. 1997, https://escholarship.org/content/qt88z4q16s/qt88z4q16s.pdf.

[10] T. Sugiura and K. Waku, “Cannabinoid receptors and their endogenous ligands,” Journal of biochemistry, vol. 132, no. 1, pp. 7–12, 2002, https://doi.org/10.1093/oxfordjournals.jbchem.a003200.

[11] P. Campolongo and V. Trezza, “The endocannabinoid system: A key modulator of emotions and cognition,” Frontiers in Behavioral Neuroscience, vol. 0, no. OCTOBER 2012, pp. 1–6, Oct. 2012, https://www.frontiersin.org/articles/10.3389/fnbeh.2012.00073/full.

[12] E. Fride et al., “Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a ‘CB3’ receptor,” European journal of pharmacology, vol. 461, no. 1, pp. 27–34, Feb. 2003, https://pubmed.ncbi.nlm.nih.gov/12568912/.

[13] R. B. Laprairie, A. M. Bagher, M. E. M. Kelly, and E. M. Denovan-Wright, “Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor,” British Journal of Pharmacology, vol. 172, no. 20, pp. 4790–4805, Oct. 2015, https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.13250.

[14] M. v. Fogaça, A. C. Campos, L. D. Coelho, R. S. Duman, and F. S. Guimarães, “The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling,” Neuropharmacology, vol. 135, pp. 22–33, Jun. 2018, https://www.sciencedirect.com/science/article/pii/S0028390818301023.

[15] G. Donvito et al., “The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain,” Neuropsychopharmacology 2018 43:1, vol. 43, no. 1, pp. 52–79, Aug. 2017, https://www.sciencedirect.com/science/article/pii/S088915912032482X.

[16] J. Giacobbe, A. Marrocu, M. G. di Benedetto, C. M. Pariante, and A. Borsini, “A systematic, integrative review of the effects of the endocannabinoid system on inflammation and neurogenesis in animal models of affective disorders,” Brain, Behavior, and Immunity, vol. 93, pp. 353–367, Mar. 2021, https://www.nature.com/articles/npp2017204.

[17] E. Perucca, “Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?,” Journal of Epilepsy Research, vol. 7, no. 2, p. 61, Dec. 2017, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767492/.

[18] A. Seillier, “The endocannabinoid system as a therapeutic target for schizophrenia: Failures and potentials,” Neuroscience Letters, vol. 759, p. 136064, Aug. 2021, https://www.sciencedirect.com/science/article/pii/S0304394021004420.

[19] E. B. Russo, “Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes,” Cannabis and Cannabinoid Research, vol. 1, no. 1, p. 154, Jan. 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576607/.

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