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Why CBD and cannabis have such powerful effects on the body

Reading time: 12 minutes

Eighty years ago, the most active organic substances found in the Cannabis sativa (marijuana) plant, THC and CBD, were discovered. Twenty years later in 1965, the heyday of psychedelics, pot, free love and anti-war protests, Raphael Mechoulam, an Israeli organic chemist, managed to synthesize both molecules in his laboratory, initiating a frenzy of research into THC (delta-9-tetrahydrocannabinol), the most psychoactive element of the plant. 

CBD (cannabidiol), which had no psychoactive effects, was basically ignored until a few small studies revealed its calming impact on anxiety and its anti-seizure effects in people suffering from epilepsy. Then the race to discover just how and why these substances influenced human physiology—and the mind—was on.

People have been using cannabis for thousands of years to treat everything from insomnia to gastrointestinal issues, arthritis to migraine. By the time the twentieth century rolled around, there were hundreds of medical patents filed on cannabis-based “cures” for gout, “female problems” and epilepsy, to name a few. 

“Ancient healing systems like traditional Chinese medicine and Ayurveda in India, they all knew about the endocannabinoid system,” says Dr Kristina Ranna, Chief Medical Officer at Endoverse in the Czech Republic. “They didn’t name it, but they worked with it. In Ayurveda, for example, the food, monitoring fat intake and treatment with special oils really work well with the endocannabinoid system.”

By the late 1980s, a new technique called radiolabeling was developed that enabled researchers to target and track molecules, determining how and where they moved through the body. This technology finally led to the discovery of the cannabinoid receptors CB1 and CB2—molecules on the cell surface that recognize, bind and transmit THC and CBD molecules. 

With the presence of receptors, finally, researchers understood why cannabinoids from a source outside the body had physiological and mental effects, and the search shifted to the human body itself. If there were cannabinoid receptors, there also could be cannabis-like substances the body was creating on its own.

With the discovery of anandamide and 2-arachidonoyl-glycerol (2-AG), two unsaturated fatty acids made in the body that bind to the CB1 and CB2 receptors, producing a number of reactions in the body similar to the healing effects (but not the high) of cannabis, the presence of the endocannabinoid system was revealed. But it took several decades before the sheer magnitude and complexity of the endocannabinoid system (also known as the ECS) were understood.

As described by a group of researchers writing in the Public Library of Science, “Metaphorically the ECB [endocannabinoid] system represents a microcosm of psychoneuroimmunology or mind-body medicine.”1 

“Realizing there are cannabinoid receptors all over the body and endogenous cannabinoids impacting everything, regulating our heart, our nervous system, the homeostatic balance of the body, our skin and all of our tissues—it’s been a real ‘gotcha’ moment for everybody,” says Dr Carrie Newbold, Research Director for eCS Clinics in Australia. 

“In terms of how the ECS functions in a healthy human body, we’ve got a bit of an idea about what it does. Maybe it turns off pain receptors. Maybe it turns on the production of dopamine. We really don’t know the specifics of how it operates yet.”

Dr Ranna agrees that our scientific understanding of the endocannabinoid system is in its infancy. “I think the ECS can be imagined in almost a higher philosophic context and meaning,” says Ranna. “It’s everywhere in our body, and it seems to connect all the functions of our body. It’s revealing that everything is connected with everything else in our body. Maybe it’s the postman for information dissemination throughout the body. We just don’t know yet.”

If the mechanics of the ECS in a healthy system are still a mystery, how the system works in a dysfunctional, unhealthy body is even more of an unknown. In addition, medical researchers now believe that many disease conditions are attributable to a dysfunction or slowing down of the ECS. 

The level of endocannabinoid activity in specific areas of the body, such as the immune system where most CB2 receptors are found, is apparently dependent upon the extent of upregulation (increase) or downregulation (decrease) in the production of cannabinoid receptors. 

The correct amount creates a harmonious balance throughout the ECS referred to as endocannabinoid tone. Studies now show that many conditions such as fibromyalgia, irritable bowel syndrome, migraine and other “treatment-resistant” disorders may well result from  a lack of endocannabinoid tone—a dysfunctional or sluggish endocannabinoid system.2 There is even an official term for the condition: clinical endocannabinoid deficiency syndrome (CEDS).

Symptoms of CEDS can be as simple as not sleeping well, getting frequent headaches and experiencing anxiety. They can be as severe and complex as having fibromyalgia. Lower levels of circulating endocannabinoids have also been found in children with autism spectrum disorder.3 

What makes the ECS slow down? The answers are still up for grabs. 

“They aren’t stored like other neurotransmitters, so if we don’t have the building blocks to make the endocannabinoids, we’re not going to have enough capacity to make the volume of endocannabinoids we need,” says Dr Newbold. 

“For example, anandamide (the major endocannabinoid made in the body) is made from omega-3 and omega-6 fatty acids. But since our balance in eating these fatty acids has shifted in the standard diet, we no longer have the proper balance of these fatty acids in our systems. Maybe that’s an issue. Maybe the CB1 and CB2 receptors are downregulated because of pharmaceuticals or pesticides, or maybe the enzymes that break endocannabinoids down are overactive for some reason. 

“If you’re smoking a lot of marijuana, maybe your endocannabinoid system is getting all it needs from external sources and is slowing down endogenous production. It’s one big system, and we just don’t know.”

The endocannabinoid system

The endocannabinoid system or ECS is present within the nervous system of the human body starting at its earliest developmental stages. It is made up of three parts: 

  • Endocannabinoids, neurotransmitters (signaling molecules) created in the human body that are similar in molecular structure and effect as the phytocannabinoids created by the Cannabis sativa plant, better known as marijuana; 
  • Cannabinoid receptors, molecules found on cell surfaces in various organs and parts of the body that recognize and bind with endocannabinoids;
  • Enzymes that either synthesize or break down endocannabinoids.

The ECS is involved in the regulation of metabolic, endocrine, cardiovascular and renal (kidney) functions, and cannabinoid receptors are found in all parts of the human body. An especially high concentration of CB1 receptor is found in the brain—in the midbrain, the hippocampus, cerebral cortex, cerebellum, amygdala and other areas—and the CB2 receptor is found in organs related to the immune system and its regulation of inflammation and infection. 

Studies have now shown that the ECS is involved in maintaining the homeostatic balance (optimal functioning) of the human body. It directly impacts brain function and brain development in both embryonic and early life stages. It helps regulate the immune system, metabolism, the gut, the central nervous system and the endocrine system, impacting everything from hormone production to pain levels, mood, appetite, sexual activity and our ability to sleep well at night.

One unusual biological aspect of the ECS is that it’s what’s called a “retrograde system.” This means it functions backward to the way other neurotransmitters in the body generally work. 

Neurotransmitters are chemical messengers created by presynaptic nerve cells and stored there until a signal stimulates their release, whereupon they cross what’s known as the synaptic cleft (the space between two nerve cells) and arrive on the postsynaptic cells, triggering whatever chemical action they are designed to initiate. 

Endocannabinoids, however, are not stored. They are created “on demand,” and then they’re released from postsynaptic cells, cross the synaptic cleft in reverse and attach to endocannabinoid receptors on the presynaptic cells. This opposing action allows endocannabinoids to regulate the production and release all other types of neurotransmitters in the body, regulating nerve cell communication throughout the central nervous system.

The major players 

There have been at least 144 cannabinoids discovered in marijuana, from THC (delta-nine-tetrahydrocannabinol), the potent psychotropic found in marijuana, to the highly therapeutic CBD (cannabidiol), which doctors regularly prescribe for pain mitigation, seizure disorders like epilepsy, Crohn’s disease and Parkinson’s disease. Less well-known cannabinoids like CBG, CBC, CBN and THCV are also being researched for their possible medical applications. 

So what cannabinoids are created in our bodies? And what receptor sites exist to receive them?

Endocannabinoids

Anandamide (arachidonoyl ethanolamide or AEA) is a neurotransmitter and the first endogenous (made in the body) cannabinoid to be discovered and studied. The name comes from the Sanskrit word ananda, meaning “bliss.” 

Anandamide acts upon CB1 and CB2 receptors, taking what’s called an “agonist” role. Agonists are chemicals that induce a reaction after binding to a specific receptor, as opposed to antagonists, which block a receptor from reacting. Although it has quite a different chemical structure and no psychotropic effects, of all the endocannabinoids, anandamide acts the most like the cannabinoid THC, the most psychoactive component of cannabis. 

Anandamide is synthesized in the brain in areas that affect movement, cognitive function, memory and motivation, pain, pleasure and appetite.

Anandamide’s activation of CB1 receptors in an area of the brain called the thalamus may impact pain perception as well as  the sleep/wake cycle.1 Anandamide has been strongly associated with promoting sleep as well as increasing levels of adenosine, a molecule known to induce sleep.2 

Adenosine is also known to relax the blood vessels and restore a normal heart rhythm in people with arrhythmia. This may explain the antihypertensive effects of anandamide, which may aid in controlling high blood pressure. As well, anandamide is a modulator of inflammation and may prove useful in treating chronic kidney and cardiovascular disease.3 

Anandamide is involved in modulating the reward system in the brain and is thought to be involved in addiction and drug abuse. But some studies have suggested it might also be possible to modulate anandamide in a way that can help treat addiction.4 Additionally, anandamide has potent anti-anxiety effects.5  

2-Arachidonoylglycerol (2-AG), a derivative of arachidonic acid (an essential fatty acid found in cell membranes), binds to both CB1 and CB2 receptors. Mouse studies show that 2-AG may have beneficial effects on cardiovascular health6 and that it has neuroprotective properties, which may be useful in treating traumatic brain injuries.7 In a study using human blood samples, 2-AG activated neutrophils (white blood cells produced in the bone marrow), which modulate inflammation and immune responses,8 and in people with fibromyalgia, increased muscle strength after a 15-week exercise program was associated with higher 2-AG levels.9 

Docosatetraenylethanolamide (DEA) is an endogenous cannabinoid closely related to anandamide. DEA has been found to lower blood pressure.10 

Homo-g-linoenylethanolamide (HLEA) is also closely related to anandamide and believed to act as an agonist at CB1 receptors. 

N-arachidonyldopamine (NADA) is another little-understood endogenous cannabinoid receptor ligand.

Oleamide (cis-9-octadecenoamide) is a long-chain fatty acid similar in function to anandamide that has sleep-inducing effects.11

Palmitoylethanolamide (PEA). While not a cannabinoid itself, PEA enhances the effects of anandamide as well as having anti-inflammatory and pain-reducing effects.12 

Receptor sites

CB1 is a cannabinoid receptor and a member of something called the G protein-coupled receptor family of proteins, which transmit signals that act as molecular switches inside cells. CB1 primarily is found within the brain and central nervous system. Activation of CB1 receptors by endogenous cannabinoids such as anandamide and 2-AG is being actively studied for possible therapeutic effects in neuropsychological disorders and neurodegenerative diseases.13

CB2 is a cannabinoid receptor and also a member of the G protein-coupled receptor family of proteins. It is primarily expressed within the immune system and has been found to control immune cell functions. Current research is investigating how modulating CB2 receptors can be effective in treating autoimmune diseases and inflammatory conditions.14 


 

The healthy endocannabinoid system

Diet

Food is very important for regulating the endocannabinoid system. A balanced diet of organic vegetables, fruits, fish and meats is best. You also need to consume enough healthy saturated and unsaturated fats while eliminating artificial trans fats and highly processed hydrogenated oils from your diet—namely corn oil, soybean oil, safflower, sunflower and canola oil found in processed and fast foods and many microwavable foods such as microwave popcorn. According to Dr Ranna, hemp seed oil and walnut oil are particularly well-balanced and nourishing to the endocannabinoid system.

Studies show that omega-3 fatty acids appear to be regulators of the endocannabinoid system,1 and a balance of omega-3 and omega-6 fatty acids is very important. A ratio of about 1:1 is considered ideal. However, high levels of omega-6 found in fast foods, fried foods and snacks like corn chips and potato chips have pushed the average person’s omega ratio to upward of 1:15.2 This can be balanced by eating more sardines, herring mackerel, salmon and anchovies, all of which are high in omega-3. 

If oily fish isn’t to your taste, omega-3 oils can also be found in eggs from pasture-raised chickens, walnuts, chia seeds, flax seeds, tofu and peanut butter. 

Here are some other foods and spices that have been found to stimulate endocannabinoid production in the body:

Cacao contains anandamide and other “feel good” molecules

Black truffles are another anandamide-rich food

Maca root contains compounds that are cannabimimetic (they mimic cannabinoids)

Holy basil, curcumin, black pepper, cinnamon, cloves, rosemary, oregano and lavender stimulate the ECS, as do the essential oils of these herbs

Echinacea binds with CB2 receptors modulating the immune system

Complementary and alternative medicine (CAM)

Massage, osteopathic treatments and acupuncture have all been shown to increase anandamide levels in the body and increase the number of ECS receptors CB1 and CB2.1 Yoga and meditation have also shown positive effects on anandamide and other endocannabinoids.3

Exercise – Moderate rather than strenuous exercise is recommended to strengthen the ECS.

Sleep – Getting enough consistent sleep is highly beneficial.

What the studies show

What we do know is that endocannabinoids are good for many things that ail us. Studies show that anandamide and 2-AG, the two major endocannabinoids in the body, have a remarkable effect in controlling spasticity in an animal model of multiple sclerosis (MS).4 They appear to play a large role in the mitigation of chronic pain5 as well as pain arising from specific conditions such as endometriosis.6 Not only are they helpful for easing patients through the end stages of cancer, they have been found to reduce tumor growth by modulating cell signaling pathways responsible for cancer cell proliferation and survival.7

Not surprisingly, endocannabinoids affect our state of consciousness, our emotional condition and even our dreams.8 The use of endocannabinoids helps many people decrease their levels of anxiety and fear, allowing them to reduce or eliminate the use of selective serotonin reuptake inhibitors (SSRIs), benzodiazepines and barbiturates, which can have serious side-effects.9 They also help people with sleep disorders.10 

Doctors like Ranna and Newbold frequently counsel patients on how to strengthen their body’s natural endocannabinoid system through diet and lifestyle changes. But they also work with patients using exogenous cannabinoids—the phytocannabinoids CBD and THC from the cannabis plant.

  “The variety of patient stories is really quite wonderful,” says Newbold. “I recently had one MS patient who came in quite over the moon about how good she was feeling after starting on CBD. Usually, CBD therapy takes a while to really build up efficacy, but after only trialing for two or three weeks, she started to walk and was able to dress herself.

 “My favorite story at the moment is about my dog, a Great Dane. She had an ear injury where another dog bit her, and it never healed. Because it’s the tip of the ear, there was nothing I could do about it, and every time she would shake her head the wound would open up again. You can imagine what that looked like living in a house with white walls. So, I put this whole-plant CBD topical cream on twice over a two-day period, and the wound was just gone. No more blood on the walls!”

One of Ranna’s patients, Angelo, 50, from Melbourne, Australia, has had Crohn’s disease from the age of five. “I have suffered my whole life and been in and out of hospitals undergoing different surgeries,” he says. “Unfortunately nothing worked. I was also on methotrexate [a chemotherapy drug] and Humira injections [an immunosuppressant] and used steroids off and on. I now have arthritis and osteoporosis through all of my body. But since using the CBD hemp oil and lozenges, it’s helped me with my joints and Crohn’s. I now no longer feel full of anxiety. I am no longer in such severe pain, and my sleep has been amazing!”

How to self-regulate 

“It’s about doing what your mother always told you to do,” says Dr Ranna. “Eat well, get plenty of rest, and make sure you get outside in nature and exercise. Go for a walk or swim. Water is really healing. It helps us to connect with our soul and body. Just being next to the sea or a lake or river really helps. 

“Most of all, be kind to yourself. Name what stresses you and try to work with it in kindness. For example, if your job is stressful, don’t just quit immediately and then stress about money. Find ways to work with your situation that make your life easier.”

Dr Carrie Newbold, Research Director for eCS Clinic in Australia, says that along with proper diet, restful sleep and exercise, osteopathic treatments really help. And when it comes to exercise, be sure not to overdo it. 

“Mid-range exercise helps in anandamide release. Walk around the block and make sure you get a bit puffy, a little bit out of breath. But don’t get into full exertion. It’s the middle range exercises that give the ECS the biggest boost.”

 

RESOURCES

Dr Kristina Ranna, www.endoverse.com

Dr Carrie Newbold, www.ecsclinic.com

 

References

1 

PLoS One, 2014; 9: e89566

2 

Cannabis Cannabinoid Res, 2016; 1: 154–65

3 

Mol Autism, 2019; 10: 2 

4 

FASEB J, 2000; 15: 300–2

5 

Rambam Maimonides Med J, 2013; 4(4): e0022

6 

Cannabis Cannabinoid Res, 2017; 2: 72–80

7 

Handb Exp Pharmacol, 2015; 231: 449–72

8 

CNS Neurol Disord Drug Targets, 2017; 16: 370–9

9 

CNS Spectr, 2007; 12: 211–20

10

Curr Neuropharmacol, 2020; 18: 97–108

 

The major players 

References

1 

Neuroscience, 2014; 265: 72–82

2 

Sleep, 2003; 26: 943–7

3 

Front Biosci (Schol Ed), 2016; 8: 264–77; J Cardiovasc Pharmacol, 2009; 53: 267–76

4 

Acta Pharmacol Sin, 2019; 40: 309–323

5 

Curr Psychiatry Rep, 2019; 21(6): 38

6 

Hypertension, 2000; 35: 679–84

7 

Nature, 2001; 413(6855): 527–31

8 

J Immunol, 2011; 186: 3188–96

9 

Med Sci Sports Exerc, 2020; 52(7): 1617–28

10

Neurogastroenterol Motil, 2011; 23(6): 567–e209

11 

Science, 1995; 268(5216): 1506–9

12

Vet J, 2007; 173: 21–30; Br J Pharmacol, 2008; 155: 837–46

13

Int J Mol Sci, 2018; 19(3): 833

14

Cell Mol Life Sci, 2016; 73: 4449–70

 

The healthy endocannabinoid system

References

1 

PLoS One, 2014; 9: e89566

2 

Biomed Pharmacother, 2006; 60(9): 502–7

3 

Evid Based Complement Alternat Med, 2020; 2020: 8438272

 
 

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