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What Is The Endocannabinoid System and Why Should You Care About It?

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Chapter 1 from 2018 Edition:

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

To keep your mind healthy, your joints strong, your mood calm, and your digestive system comfortable, your body was given an amazing tool. That tool is called the endocannabinoid system. Researchers discovered its existence only as recently as 1988, when they were investigating how cannabinoids found in the marijuana plant (Cannabis sativa) affect the body.

The interesting thing about this system is that you don’t need marijuana to activate it. It’s a perfectly natural pathway that has served humankind and other mammals for millennia. Your body makes its own cannabinoids that work through this same system. These cannabinoids that your body makes are called endocannabinoids. There are also hemp-based cannabinoids (phytocannabinoids)—such as cannabidiol (CBD)—that work through the endocannabinoid system. These phytocannabinoids can even increase levels of your natural cannabinoids. CBD, unlike marijuana, works on the endocannabinoid system without making you high because it does not contain enough tetrahydrocannabinol (THC). That’s the component of marijuana responsible for its psychoactive effects.

Even though your body makes endocannabinoids, many aspects of modern life can lead to an endocannabinoid deficiency (more on this later). That’s when hemp-based CBD oil can be especially effective.


Your Body’s Locks and Keys

Cells throughout your body have receptors. These receptors act like locks. They need certain substances that act like keys to open or close the receptor locks. Depending on the cell’s location in the body and receptor involved, this can open or close different doors to health or disease depending upon whether the substance acting like a receptor key is beneficial or harmful and whether it locks or unlocks the receptor. Substances that bind to receptors to act like keys include drugs, hormones, and neurotransmitters (chemicals released from nerve cells).

In 1988, scientists Allyn Howlett and William Devane at the St. Louis University School of Medicine discovered that brains in mammals have receptors that react to cannabis-derived compounds.1 These receptors are known as cannabinoid receptors. They’re the most abundant form of neurotransmitter receptor in the brain. These cannabinoid receptors respond to endocannabinoids. Plant-derived cannabinoids such as CBD from hemp and THC from marijuana also interact with these receptors.

CB1 and CB2 were the first two cannabinoid receptors discovered.1 CB1 receptors are primarily located in the brain.By contrast, CB2 receptors are located in the gastrointestinal (GI) tract, liver, spleen, endocrine glands, and the reproductive system.1 The immune system and the peripheral nervous system also contain CB2 receptors.1 The peripheral nervous system is the part of the nervous system located outside the brain and spinal cord.


The Endocannabinoid System’s Role in Your Health

There is a lot more for us to learn about the endocannabinoid system’s role in health. However, thousands of studies have now explored the many ways in which this system benefits us. The table below shows in which health concerns the endocannabinoid system plays a role.


  Table 1: The Many Ways the Endocannabinoid System Regulates Health
Gut Health • The endocannabinoid system is involved in regulating visceral pain and irritable bowel syndrome.2,3

• Endocannabinoids also help ensure we don’t get constipated or develop diarrhea.3

• The endocannabinoid system helps regulate intestinal permeability, meaning it can support the health of people with leaky gut.4

• The phytocannabinoid CBD may have a role to play in supporting the health of people with ulcerative colitis.5


Brain Function and Mental Health • Endocannabinoids play a role in the gut-brain axis, the communication that occurs between the gut and the brain.6

• The endocannabinoid system is involved in regulating anxiety, posttraumatic stress disorder, depression, bipolar disorder, and schizophrenia.7


Pain • CB2 receptors stimulate opioid receptors to cause pain relief in a non-addictive manner.8

• CB2 receptors may be involved in blocking the effect of painful stimuli in inflammatory processes of the nervous system.9

• The endocannabinoid system may be the reason why stress can lead to abdominal pain.3

• The pain-relieving effects of acetaminophen may be because one of its metabolites indirectly activates CB1 receptors.10

• The endocannabinoid system also is involved in the regulation of endometriosis-associated pain.11

Joint Health • In rat studies of animals with osteoarthritis, transdermal or oral CBD improved joint health, reduced joint inflammation and swelling, and improved the ability of the animals to bear their own weight. CBD administered in advance of inducing osteoarthritis in animals blocked the development of joint pain and nerve damage.12,13

• Researchers have found cannabinoid receptors on human articular cartilage from patients with symptomatic osteoarthritis.14

Stress • CBD’s role in promoting a calm mood is related to its effects on the serotonin receptor and the ability to control blood flow in regions of the brain involved in anxiety.15

• A number of clinical studies have shown CBD has a calming effect on people who have to give a public speech.16-19

Sleep • Low-dose CBD can be stimulating and lead to wakefulness. However, higher doses of CBD can encourage restful sleep.20

• CBD may reduce stress and improve the quality and quantity of sleep.21

• CBD may be beneficial in REM sleep behavior disorder (a condition where people kick, move, or act out dreams in their sleep) and to feel less sleepy during the day.22

Women’s Health • The endocannabinoid system plays an important role in fertility.23

• The endocannabinoid system is present within ovaries.24

• CBD may reduce discomfort in women with endometriosis.25

• Menopausal health and breast health may also be regulated by the endocannabinoid system.26,27

Men’s Health • CBD may play a role in prostate health.28,29


Urinary Tract Health • Cannabinoid receptors are present in the lower urinary tract and areas involved in urinary tract control.30

• Phytocannabinoids may support the health of the bladder, urethra, and prostate.30

Epilepsy • CBD, administered together with anti-seizure medication, can support the health of people with seizures.31-34
Immunity • The endocannabinoid system can be involved in both enhancing and suppressing immunity.35

• The endocannabinoid system is involved in the body’s response to respiratory syncytial virus (RSV), the primary cause of severe bronchiolitis and pneumonia in children.36-38

• CBD can support a healthy immune response in the liver.39

• All five major cannabinoids—cannabidiol, cannabichromene, cannabigerol, THC, and cannabinol—help control a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of bacteria.40


Inflammation • Cannabinoids play a role in the recruitment of immune cells to the location of intestinal inflammation.41

• Cannabidiol also has been shown to block the production of pro-inflammatory proteins known as cytokines.42

• CBD has reduced markers of inflammation in a number of cell culture and animal studies.43-46

• Cannabinoids ability to support a healthy inflammatory response are not associated with the adverse effects produced by NSAIDs.47




• Researchers have observed low levels of certain endocannabinoids in children with autism spectrum disorder (ASD).48

• Problems with endocannabinoid function are thought to play a role in the social challenges that occur in kids with ASD.49

• In adults with ADHD, CBD may help reduce hyperactivity, impulsivity, and ability to control behavior. However, more studies are needed in this group of people.50


Getting To Know The Endocannabinoids

There are two main endocannabinoids produced in the body: anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These activate CB1, CB2, and other receptors in the endocannabinoid system, serving as the “keys” that fit into the receptor “locks” (more on this later). Each of these endocannabinoids play an important role in health. AEA is involved in the perception of pain, emotional health, and energy metabolism (the body’s generation of energy from nutrients).51 It is nicknamed “the bliss molecule” since it’s involved in mood.

Like AEA, 2-AG is found throughout the body including the brain, cardiovascular system, and intestines.52,1 2-AG may even be involved in orgasms during sex, indicating that AEA isn’t the only bliss molecule.53

Another key player in the endocannabinoid system are enzymes that break down the endocannabinoids. For example, the enzyme fatty acid amide hydrolase—FAAH for short—breaks down AEA.54  Some substances like CBD can increase levels of AEA by blocking FAAH actions.55 Blocking FAAH may help support pain management and neurodegenerative health and relieve occasional anxiety.54


Endocannabinoid Deficiency

Certain factors can cause what’s known as endocannabinoid deficiency. This happens when the body doesn’t make enough endocannabinoids to maintain optimal health or there are a reduced number of cannabinoid receptors. For example, early life stress leads to changes in AEA and 2-AG tissue levels within the amygdala and hippocampus regions of the brain.56 Stress in early childhood can also reduce the number of CB1 receptors in all brain regions later in life.56 These changes can lead to an inability to cope with stress as time goes on.56

Endocannabinoid deficiency can also result due to genetic reasons or because of disease or injury.1 Researchers have proposed that endocannabinoid deficiency may be the cause of migraines, fibromyalagia, and irritable bowel syndrome.1 It may also play a role in autism spectrum disorder.1


A Balancing Act

The goal is not always to increase endocannabinoid levels. Instead, sometimes lowering endocannabinoid levels is what is needed for optimal health. We must always strive for a balanced endocannabinoid system. For example, lower AEA was associated with the improvement in migraines that occur when patients with these headaches participate in aerobic exercise.57 In addition, weight loss and improved mood after aerobic exercise training are linked to lower plasma AEA in healthy people.58 In addition, high 2-AG levels are linked to excessive hunger in sleep-deprived people.59 


Beyond Cannabinoid Receptors

Earlier, we discussed the cannabinoid receptors CB1 and CB2. However, endocannabinoids, CBD, and other hemp-derived cannabinoids interact with other receptors, too. Here are some of these other receptors:

  • G-protein coupled receptors (GP- CRs: GPR18, GPR55 and GPR119)– GPR18 is expressed primarily in immune cells while GPR55 is expressed in several brain areas as well as in some neurons with larger diameters.60 GPR55 may also be expressed in the immune system as well as in immune-regulating cells located in the brain and spinal cord known as microglia.60 GPR55 can also be activated in the bone.60
  • Type 1 vanilloid receptors (TRPV1)– These receptors may be involved in some of the beneficial effects of cannabinoids. For example, scientists have found TRPV1 receptors in neurons that play a role in pain management.61
  • Serotonin receptor (5-HT1A) – Scientists have shown that endocannabinoids and plant-derived cannabinoids can affect the serotonin receptor subtype 5-HT1A. Serotonin is known as the “feel-good” neurotransmitter. Optimal levels of this neurotransmitter lead to a sense of well-being and happiness. The mood-boosting effects of CBD are due in part to activation of the 5-HT1A receptor.62
  • Other cannabinoid receptors– Cannabinoids may interact with other receptors. These other receptors may be involved in some of the pain-relieving effects linked to cannabinoids.63,64


The Pain-Killing Endocannabinoid Lookalike

There is a substance known as palmitoylethanolamide (PEA). It’s not an endocannabinoid but it works on the endocannabinoid system by helping the body make better use of the endocannabinoid AEA.65 PEA is best known for its role in pain management. PEA is a natural painkiller.65 Your body makes it when it’s in pain. PEA is also found in some foods including egg yolks, peanuts, and soybeans. However, it’s not found in cannabis.

There’s now a lot of evidence to indicate PEA reduces neuroinflammation, a process that’s linked to pain.65 It does this in part by blocking mast cells and regulating glial cells in the central nervous system.65 If you have hay fever then you’re all too familiar with what overactivated mast cells can do. They release inflammatory substances such as histamine. Glial cells play a role in the health of your neurons.

Researchers reviewed the results of 12 clinical trials to find out whether PEA could reduce pain.65 The researchers concluded that PEA supplementation was better at progressively decreasing pain intensity compared with control. According to these scientists, “These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.”


The Remarkable Cannabinoid System

Cannabinoids—both the endocannabinoids made in your body and hemp-based cannabinoids like CBD—play a role in virtually every area of health. Well-being and happiness, pain management, a healthy digestive system, a good night’s rest, a strong immune system, reproductive health, and healthy joints are all dependent upon this system. Taking steps to keep your endocannabinoid system healthy is therefore critical to optimal health.

Read Chapter 2: CBD’s Mechanisms in the Body: How This Amazing Cannabinoid Keeps You Healthy

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.



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