Dr. Meletis CBD Book Chapters 1-3

By June 17, 2020CBD, Dr. Meletis

Chapter 1

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


By Chris D. Meletis, N.D.


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.1 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.


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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Chapter 2

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


Cannabidiol (CBD) from hemp oil has taken center stage recently as a way to address many areas of health including supporting a healthy pain response in the joints and other areas of the body, dealing with occasional sleep problems and everyday stress, and supporting a healthy attention span, focus, and concentration, to name just a few of its benefits. (I summarized its health benefits in Table 1 of Chapter 1, and I’ll be talking more about those benefits as this book unfolds.) In June 2018, CBD ended up even more in the spotlight when the US Food and Drug Administration (FDA) approved the first CBD-based drug, Epidiolex®, for treatment of rare, severe epilepsy.


Is CBD the Answer to the Opioid Addiction Crisis?


Overuse of opioid drugs, which are highly addictive and lead to fatal overdoses, has hit epidemic proportions. Every day, 128 people in the United States die from an opioid overdose.1

It’s estimated that 21% to 29% of people using opioids for chronic pain misuse these drugs.2

Not only are opioids potentially dangerous, but taking opioids can actually backfire. Sometimes a patient taking opioids for the treatment of pain could instead make the pain worse since they react even more to certain painful stimuli.3


This crisis has its origins in 1937, when German scientists at the IG Farben company first synthesized the opioid medication methadone to use for surgery-related pain. They claimed it was less addictive than morphine or heroin. However, this claim was clearly false. Methadone is longer-acting than morphine or heroin.4 It’s more addictive than these substances and causes withdrawal symptoms that last longer.4


Pharmaceutical companies began releasing new opioid painkillers including Vicodin® (a combination of Hydrocodone Bitartrate and acetaminophen) in 1984, OxyContin® in 1995, and Percocet® (Oxycodone plus acetaminophen) in 1999.5 This led to an onslaught of opioid over-prescribing. After all, the pharmaceutical industry assured physicians that these medications were not addictive.1


In 2007 came a turnaround point. Purdue Frederick Company Inc., an affiliate of Purdue Pharma, along with three of the company’s executives admitted to misbranding OxyContin®. The company had made false statements about the drug, claiming it was less addictive than other opioids and that people taking it were less likely to abuse it. Purdue Frederick pleaded guilty to criminal charges and paid $634 million in fines.6


Clearly, we need another alternative to support a healthy pain response. And that alternative may very well be CBD, which does not produce a high and isn’t addictive. Later in this book, I’ll discuss CBD’s ability to support comfortable knee and hip joints, as well as promote a healthy pain response in the neck, back, and more. For now, let’s take a look at the way in which CBD can benefit so many areas of health.


How CBD Works


CBD has shown a lot of promise both in doctor’s offices and in studies.  But how does this hemp-derived cannabinoid work?


As a reminder, in Chapter 1, I covered CBD’s effects on CB1 and CB2 receptors and how CBD acts like a key that fits into those receptor locks. These receptors are part of what’s known as the endocannabinoid system, which plays a role in keeping us healthy, both physically and mentally. I also discussed the other receptors that CBD acts upon and explained that two main endocannabinoids produced in the body—anandamide (AEA) and 2-arachidonoylglycerol (2-AG)—activate these same receptors. A lot of what we know about CBD comes from what researchers have observed about the effects of AEA and 2-AG on the body.


In Chapter 1, I also delved briefly into the effects of an enzyme known as FAAH. This enzyme breaks down the endocannabinoid AEA. In doing so, it generally weakens AEA’s beneficial effects. AEA is sometimes called the “bliss molecule” since it plays an important part in maintaining a happy mood and staying optimistic. CBD can increase levels of AEA by blocking FAAH.7 Blocking FAAH may help support pain management and neurodegenerative health, maintain healthy levels of beta-amyloid proteins, and relieve occasional stress and frustration.8-12 When people take opioids, they start to become tolerant to the drugs’ effects, so they have to take higher and higher doses for these medications to remain effective. Based on results of animal research, blocking FAAH may also stop this tolerance to opioids.13  




In this chapter, I am going to introduce another enzyme involved in the endocannabinoid system. It’s called monoacylglycerol lipase—MAGL for short. While FAAH breaks down the endocannabinoid AEA, MAGL breaks down AEA’s endocannabinoid sibling 2-AG.14 In animal studies, blocking MAGL maintains gastric health when taking non-steroidal anti-inflammatory drugs (NSAIDs).14 These type of drugs—such as aspirin and ibuprofen—are extremely damaging to gastric health and can cause ulcers. Patients with ulcerative colitis also have elevated MAGL levels, suggesting that in these people the endocannabinoid 2-AG is being broken down faster.15


Blocking MAGL also can strengthen the intestinal wall, possibly reducing leaky gut.14 This is a condition where weakened intestinal walls leads to the escape of food particles and inflammatory substances into the circulation. This can cause problems throughout the body. Leaky gut is linked to food intolerances, brain health, and much more. In fact, in my patients, I have noticed that resolving leaky gut leads to dramatic improvements in overall health.


CBD reduces MAGL’s ability to break down the endocannabinoid 2-AG.16  CBD’s ability to block MAGL’s actions may be part of the reason it can produce feelings of calm during occasional stress, promote a healthy gastrointestinal tract, and reduce cravings in people with addictions.14,16,17 By blocking the enzymes FAAH and MAGL, CBD may protect the GI tract from the negative effects of NSAIDs since the GI damage caused by these medications is linked to FAAH and MAGL activity.18,19

Beyond CBD’s Healthful Properties


CBD is the most talked about cannabinoid in hemp because it’s found in high levels. But hemp also contains other phytocannabinoids that are beneficial to health. These are found at much lower levels than CBD, but work together with CBD to provide synergistic benefits. And these other phytocannabinoids even have healthful properties on their own. One of these phytocannabinoids is cannabigerol (CBG). CBG is antibacterial and supports a healthy inflammatory response.20,21 What’s more, it can promote well-being and happiness, thanks to its ability to increase the “bliss molecule” anandamide.22


CBG also promotes a healthy pain response, supports healthy cells in the colon and other areas of the body, and is neuroprotective.22-25 In fact, CBG and CBD each have different neuroprotective effects, indicating they can work together to support brain and nervous system health in people with neurodegenerative concerns.25 In addition, Cannabis with high levels of CBD and CBG inhibits the activity of the enzyme aldose reductase in human cell culture studies.26 Blocking aldose reductase is involved in diabetic health.


Cannabinol (CBN) is another phytocannabinoid in hemp. In animal research, CBN teamed up with CBD to support comfortable muscles and temporomandibular health.27


The “Hemptourage Effect”


Two decades ago, Doctors Mechoulam and Ben-Shabat proposed a concept known as the entourage effect.28,29 Originally, it referred to the ability of certain endocannabinoid system components to boost the beneficial effects of the two most important actors in this system: anandamide and 2-arachidonylglycerol.28


Today, the entourage effect is commonly used to refer to an interesting phenomenon: the ability of CBD to work together with its other minor components to produce even greater health benefits. The term “hemptourage effect” is now used to describe the potential synergistic interactions that take place between the CBD in hemp oil and hemp’s other constituents.


Terrific Terpenes


Substances in hemp that work together with CBD are called terpenes, which contain beneficial compounds known as terpenoids, the largest group of plant chemicals. Some of these terpenes are also found in cannabis and are responsible for its aroma. The table below shows some of the ways these terpenes can promote health.


Some Terpenes Found in Hemp and How They Benefit Health22,29
D-Limonene • Also found in citrus fruits, d-limonene is relaxing. In rodent studies, it has increased brain levels of two hormones related to mood and happiness: serotonin and dopamine (DA).

• Inhaling citrus fragrance improved mood in depressed human subjects. Nine of the 12 subjects were able to stop taking antidepressant medications.

• D-limonene also supported healthy immunity.

Myrcene • Supports a healthy inflammatory response and a healthy liver after exposure to toxins.

• In rodent studies, acts like an analgesic and relaxes muscles.

• Promotes relaxation and sleep.



• Also found in lavender, linalool is calming.


• Acted as an anti-convulsant in rodents and inhibited seizures.


• Compared with a placebo, inhaling lavender decreased the use of morphine opioids in morbidly obese people who underwent gastric banding surgery.



α-Pinene • α-Pinene is the most common terpenoid in nature. In addition to hemp, it’s found in conifer trees and other plant essential oils, where it acts like a natural insect repellant.

• It supports a healthy inflammatory response.

• A human study found it supported lung health by clearing the airways.

• It supports cognitive function. This could mean it acts synergistically with CBD in counteracting the short-term memory problems caused by THC intoxication after marijuana use.

• In a mouse study, essential oils that included pinene and limonene enhanced absorption of estrogen through the skin.

Nerolidol • Also found at low levels in citrus fruit peels, nerolidol is calming.

• A rodent study found it supports colon health.

• It may also be able to stop fungal growth.

• May weaken protozoan parasites such as malaria and leishmania.

Caryophyllene (Humulene) • Also found in lemon balm (Melissa officinalis) and eucalyptus.

• Serves as a natural insecticide and antifungal in plants.

• May block fungal growth.  An 8% concentration eradicated a fungal infection in 15 days.

• In cell culture research, it stopped blood platelets from sticking together.

• Reduced paw swelling in rodents given an inflammatory substance.

Phytol • Present in hemp extracts through the breakdown of chlorophyll and tocopherol.

• Leads to relaxation thanks to its ability to raise levels of the calming neurotransmitter GABA. It blocks an enzyme responsible for breaking down GABA.

beta-Amyrin • Supports a healthy inflammatory response and the body’s response to unwanted microorganisms and fungus.



Teaming Up with Terpenes


Many terpenes found in hemp may work together with CBD and other phytocannabinoids in hemp. In fact, many terpenes have complimentary actions to CBD. Take a look at the table below to get an idea how these terpenes work together with other components of hemp oil. Since this is such a large topic, I’ll devote a chapter to terpenes later on in the book.


How Terpenes Work Together with Other Hemp Components22
Limonene + Linalool + Pinene + CBD  

• CBD reduces the increased sebum production linked to acne.


• Limonene was more effective at suppressing Propionibacterium acnes, an acne-related pathogen, compared with triclosan. Linalool and limonene are known to reduce markers of P. acnes-related inflammation.


• Pinene suppresses  P. acnes and Staph spp.

• CBD supports cognitive function in people exposed to THC from cannabis, which is known to affect memory.  In cell culture, CBD also reduces formation of beta-amyloid proteins. Low levels of beta-amyloid is linked to a healthy memory during aging.  Limonene, pinene, and linalool likely work with CBD to support cognitive health through their ability to improve mood.

• Pinene also improves mental focus, thus acting synergistically to CBD’s ability to support a sharp memory.

Pinene + CBD + CBG • Pure CBD and CBG blocked methicillin-resistant Staphylococcus aureus

(MRSA) in a structure-activity study. This type of study looks at the link between a substance’s chemical structure and its actual biological activity against a microorganism.


• High-pinene essential oils were also effective against MRSA and other antibiotic-resistant bacteria.

Limonene + linalool + CBD • CBD is calming and reduces everyday stress.  Researchers have proposed that using limonene and linalool with CBD could add to CBD’s relaxing effects since both of these terpenes are also very calming.


Hemp’s Powerful Health Benefits


Now that I’ve discussed the mechanisms involved in the beneficial effects of CBD and other components of hemp, in the chapters that follow I’ll go into detail about the specific ways CBD from hemp oil can make you feel happier and healthier.




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  2. Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015 Apr;156(4):569-76.
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  8. Crivelaro do Nascimento G, Ferrari DP, Guimaraes FS, et al. Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson’s disease. Neuropharmacology. 2020 Feb;163:107808.
  9. Greco R, Demartini C, Zanaboni AM, et al. FAAHinhibition as a preventive treatment for migraine: A pre-clinical study. Neurobiol Dis. 2020 Feb;134:104624.
  10. Sun J, Zhou YQ, Chen SP, et al. The endocannabinoid system: Novel targets for treating cancer induced bonepain. Biomed Pharmacother. 2019 Dec;120:109504.
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Chapter 3

CBD and Its Role in Calming Stress


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.


Fear, stress, and anxiety are normal responses triggered when the body perceives threats to survival. However, in modern times, we encounter situations such as deadlines at work, unemployment, financial challenges, caring for our elderly relatives, and many other situations that cause our body to get stuck in stress mode. This leads to excessive and ongoing fear, stress, and anxiety. A number of mental disorders are also associated with excessive fear and anxiety, including  generalized anxiety disorder (GAD), panic disorder (PD), post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), and obsessive-compulsive disorder (OCD).

CBD can soothe mild stress and anxiety by virtue of its effects on the central nervous system.1,2

CBD interacts with several receptors that regulate fear and anxiety-related behaviors such as the cannabinoid receptor CB1, the serotonin 5-HT1A receptor, and the transient receptor potential (TRP) vanilloid type 1 (TRPV1) receptor.3 I discussed these receptors in detail in chapter 1. Remember that CBD works through the endocannabinoid system. And the endocannabinoid system plays an important role in reducing stress and anxiety.

Your Body’s Own Stress-Reduction Mechanism

The endocannabinoid system regulates emotional behavior. It determines how you respond to unpleasant events and leads to an appropriate response to stress.4-6 As I talked about in previous chapters, endocannabinoids that are part of the endocannabinoid system activate CB1 receptors. These endocannabinoids act like locks that fit into the receptor “key.” Activation of CB1 receptors regulates anxiety and fear.6 In animal research, CB1 receptor activation led to an improved response to bad memories.7

When you’re under stress, your body is tasked with sending you back into your non-stress state of peaceful balance. In order to accomplish this, it performs what’s called a negative feedback loop. The loop begins when stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This leads to a stress response or stress cascade, as it’s sometimes called. This stress cascade helps the body make the necessary changes required to cope with stress. When the body is knocked out of balance by a stressor it triggers the release of corticotropin-releasing hormone (CRH) from the brain region known as the hypothalamus. This in turn leads to the release of adrenocortiotropin hormone (ACTH) into the circulation. This is a signal for the adrenal cortex to release glucocorticoids into the blood. In an effort to restore your body back into the pre-stress state, the glucocorticoids stop the release of CRH, shutting down the stress response.8

The activation of CB1 receptors also play a critical role in this negative feedback loop that occurs as your body deals with stress. CRH release can lead to anxiety. CRH increases the production of the enzyme fatty acid amide hydrolase (FAAH), which reduces the endocannabinoid anandamide (AEA) within the amygdala of the brain. By activating the CB1 receptor, CRH release is cut off and AEA levels increase, which can have a calming effect.9 On the other hand, chronic, unpredictable stress can throw off the endocannabinoid system in the hippocampus and amygdala of the brain, leading to anxiety.10

CBD works through the endocannabinoid system to soothe stressful feelings.11 Although CBD doesn’t act directly on the CB1 receptor, it can act indirectly.11 It also blocks the actions of FAAH and in doing so increases levels of AEA.11 It may counteract the FAAH-raising effects of CRH.11 CBD can also work through the serotonin receptor.12 Serotonin is a “feel-good” hormone that contributes to feelings of calm and relaxation.

CBD can also modify blood flow in brain areas that are involved in anxiety, such as the amygdala, hippocampus, hypothalamus, and cingulate cortex.13 This is another way in which CBD can produce feelings of calm and relaxation.

CBD and the Stress of Public Speaking

To test whether CBD can relax people who are under stress, scientists undertook several studies of CBD’s effect on people giving public speeches. In one of those studies, researchers caused anxiety in a group of 57 healthy male subjects by having them perform a simulated public speaking test.14 In this double-blind study, the participants were given different doses of CBD (150 mg, 300 mg, 600 mg) or a placebo. CBD (300 mg) significantly reduced anxiety during the speech.

In an earlier study, researchers compared the effects of the anti-anxiety drugs ipsapirone (5 mg) or diazepam (10 mg) with CBD (300 mg) or placebo in 40 healthy volunteers during a simulated public speaking test.15 Compared to the placebo, CBD or ipsapirone were each effective at reducing the anxiety caused by public speaking.

CBD produced the same effects in people with generalized social anxiety disorder (SAD).16 Because a pronounced fear of public speaking is one hallmark of this disorder, researchers had 24 patients with SAD and 12 healthy controls perform a public speaking test.16 In this double-blind, randomized study, 12 of the SAD subjects took 600 mg of CBD 1½ hours before public speaking, while 12 SAD patients received a placebo. The healthy controls didn’t receive any treatment.

The study authors used three methods of determining anxiety levels in the participants. The scientists looked at ratings on the Visual Analogue Mood Scale (VAMS), which allows study subjects to rate their level of anxiety, cognitive impairment, and sedation,  and the Negative Self-Statement Scale (SSPS-N), which is based upon theories that social anxiety is the result of thinking poorly of yourself and believing others also think poorly of you. The researchers also measured blood pressure, heart rate, skin conductance, and physical reactions to stress at six different points during the public speaking test. Compared with the placebo group, SAD patients taking the CBD experienced significantly less anxiety, cognitive impairment, and emotional discomfort during their speech. The CBD-group also was more relaxed when they were anticipating giving the speech. The SAD patients taking the placebo experienced increases on the Negative Self-Statement Scale. Patients in the CBD group experienced almost no increase in negative self-statements. The responses of the SAD patients given CBD were similar to healthy controls, meaning the CBD led to a more normal stress response in regards to public speaking.


CBD and Blood Pressure Spikes Caused by Stress

Long-term stress is associated with the development of cardiovascular disease.17 Social isolation, depression, not having enough money, stressful family life, and problems at work are linked to both an increased risk of cardiovascular disease and worsening of already existing cardiovascular conditions.18  Evidence from animal studies and some recent interesting human studies suggest that CBD may regulate the body’s cardiovascular response to stress. Restraining rats is a way that researchers cause stress in the animals. In one study, CBD injections reduced the cardiovascular response to restraint stress and the typical stressed out behavior of the animals when restrained.19

Blood pressure rises when a person is under stress. Two human studies have found that CBD may support healthy blood pressure when we’re feeling anxious about a situation or under physical stress. In one of the randomized, placebo-controlled, double-blind studies, researchers gave 26 healthy males 600 mg of oral CBD or a placebo for a week.20 The men participated in isometric exercise and their blood pressure was measured both during rest and during exercise. In response to stress, participants in the CBD group had lower systolic blood pressure both after the initial dose and after repeated seven days of  use. After a week on CBD, the men’s carotid artery widened and the arteries became more flexible. According to the researchers, “CBD reduces BP at rest after a single dose but the effect is lost after seven days of treatment (tolerance); however, BP reduction during stress persists.”

In the other randomized, placebo-controlled, crossover study, nine healthy male subjects were given 600 mg of CBD or a placebo.18 A crossover study is where scientists place the subjects on one protocol (in this case CBD supplementation) for a specific time and then switch the subjects to the placebo for another period of time. The researchers caused stress in the subjects by exposing them to cold and exercise and giving them a test designed to produce mental stress. Diastolic and systolic blood pressure were significantly lower immediately following the stress test in men who had taken CBD. After exposure to cold, men taking the CBD experienced a significant drop in systolic blood pressure and mean arterial pressure. The researchers also found that diastolic blood pressure was significantly less in the men given CBD during cold stress. During exercise stress, CBD lowered systolic blood pressure and mean arterial pressure.

Researchers believe CBD’s ability to lower blood pressure during stress may be an added benefit of its calming properties.18 By relaxing the mind, it may relax the body and the cardiovascular system, too.



More Restful Sleep


Stress can lead to insomnia and a lack of restorative sleep. CBD’s calming effect can help promote better sleep even during stressful times. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness.21 In patients with post-traumatic stress disorder (PTSD), CBD combined with routine psychiatric care has improved the quality of sleep and reduced nightmares.22


In a case study, researchers investigated the effects of CBD on a ten-year-old girl with PTSD due to sexual abuse and who had little parental supervision when the girl was under the age of five.23 The girl had tried pharmaceutical medications, but they only provided partial relief and any benefits were only temporary and accompanied by major side effects. On the other hand, CBD oil led to a prolonged decline in anxiety and steadily improved quality and quantity of sleep. The study authors concluded, “This case study provides clinical data that support the use of cannabidiol oil as a safe treatment for reducing anxiety and improving sleep in a young girl with posttraumatic stress disorder.”


Researchers conducted a larger human study of 72 patients whose primary concern was either anxiety or poor sleep.24 The subjects were given CBD along with their usual treatment at a large psychiatric outpatient clinic. CBD supplementation was associated with a significant decline in anxiety in 57 of the patients (79.2%) during the first month of use and the participants continued to feel this increased calmness throughout the study. Sleep improved in 48 of the patients (66.7%) in the first month of CBD supplementation, but these results fluctuated over time, indicating mild improvement. CBD was well tolerated although three of the participants experienced fatigue. The doses used in this study (25 mg/day to 175 mg/day) were much lower compared with other clinical studies that used 300 mg/day to 600 mg/day, which may explain why even though CBD caused a noteworthy decline in anxiety it only resulted in a modest improvement in sleep.


Evidence from rodent studies mirror CBD’s beneficial effects in humans. One group of researchers triggered PTSD-like anxiety in rats by having them navigate a maze.25 CBD blocked the suppression in rapid eye movement (REM) sleep caused by anxiety. Getting enough rapid eye movement sleep, the stage in which most of our dreams occur, is essential to feeling refreshed and energized. It’s also important for learning, memory, and happiness.


Hemp Oil: Teaming Up with Terpenes


Supplementing with hemp oil can provide advantages over CBD alone. As I mentioned in previous chapters, hemp oil contains beneficial compounds known as terpenes, which have their own stress-reducing effects. For example, the terpene d-limonene soothes anxious thoughts by increasing levels of serotonin and dopamine,26 both hormones linked to mood and happiness. Another terpene found in hemp, d-linalool, also promotes relaxation, likely by influencing glutamate and GABA neurotransmitter pathways involved in stress management.27  In mice, d-linalool prevented conflict among the animals.28 Many essential oils known for their stress-relieving properties, such as lavender, contain d-linalool. It’s thought to be the main active component in lavender responsible for the anti-anxiety effects of lavender oil.


A third relaxing terpene in hemp is myrcene. Myrcene calms the mind and promotes sleep.27  Nerolidol and phytol are terpenes that, like their other hemp-derived cousins, promote relaxation.27 Phytol is also found in green tea, and its presence there could explain why green tea is so relaxing even though it contains caffeine.27 Phytol raises levels of the calming neurotransmitter GABA and blocks an enzyme responsible for breaking down GABA.27 In mice, nerolidol increases the animals’ interest in exploring brightly lit open areas, an indication of reduced anxiety.29


Side Benefits of Reducing Stress


By reducing stress, CBD can indirectly enhance a couple other areas of health. First, by promoting feelings of calm under pressure, it can support healthy immunity. Psychological stress is known to reduce immune function.30-33 I will discuss CBD’s potential role in immune support later in this book. Second, by lowering stress, CBD may also support a healthy inflammatory response. Stress is well known to increase inflammation.34 I’ll talk about this aspect of CBD more in future chapters.




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