What is the endocannabinoid system?

What is the endocannabinoid system? This question has been asked by many people who are curious about how cannabis interacts with the human body, and for a good reason. Every person is unique, and with that comes unique ways of responding to medicinal compounds and cannabinoids like THC and CBD. So, let's dive in to learn more about the fantastic endocannabinoid system.

When was the Endocannabinoid System (ECS) Discovered?

This story starts with cannabis (as all the best stories do) and the Israeli researcher Dr. Raphael Mechoulam. In the mid-1960s, Dr. Mechoulam and his colleagues isolated CBD and THC as active compounds in marijuana.

In the decades that followed, scientists studied the biochemistry, pharmacology, and clinical effects of these cannabinoids. Still, none of the research revealed how THC and CBD worked in the human body. The best science could do was a hypothesis that THC exerted its effects by altering cell membranes to change the behavior of cells.

That all changed in 1988 when Dr. Allyn Howlett implemented a novel radiolabeling technique that identified cannabinoid receptors in rat brains. This discovery opened the door to understanding the endocannabinoid system, how it works, and how it is affected by cannabis.

But before you get too excited, it's important to understand that both the science of the endocannabinoid system and the science of cannabis are new and emerging. While we've made real progress and learn more every day, we are a long way off from approaching a comprehensive understanding of the ECS, cannabis, and its effects.

How Does the Endocannabinoid System (ECS) Work?

The endocannabinoid system uses endocannabinoids, cannabinoid receptors, and enzymes that interact in a complex cell signaling network. This network responds to internal and external stimuli to maintain homeostasis (biological harmony) in the body.

What are Endocannabinoids?

Endocannabinoids is short for endogenous cannabinoids. They are lipid-based neurotransmitters that the body produces naturally. For example, nerve cells use neurotransmitters to communicate.

Science has identified two primary endocannabinoids:

• Anandamide (AEA or arachidonoyl ethanolamide)
• 2-Arachidonoyl Glycerol (2-AG)

There's consensus in the scientific community that there are more endocannabinoids in the body, but they remain unknown and undefined.

What are Endocannabinoid Receptors?

Endocannabinoid receptors are found throughout the body on the cellular surface. Endocannabinoids attach and bind to these receptors. This signals the ECS and triggers a response.

Science has identified two primary cannabinoid receptors, and it may be on the threshold of identifying a third:

• The CB1 Receptor: Primarily found in the central nervous system (CNS), there are high levels in the neocortex, hippocampus, cerebellum and brainstem. They are also found on peripheral nerve terminals and extra-neural sites such as the testis, eye, and spleen.
• The CB2 Receptor: Principally located in the immune system both in the brain and periphery, recently, it was found that CB2 may also play a functional role in the CNS.

Is there a CB3 Receptor?

GPR 55 may be a third cannabinoid receptor. Once thought to be an "orphan receptor," it has since been cloned, and we now know that Anandmie and other ligands can bind to it.

Endocannabinoids can attach to CB1 or CB2 receptors. The location of the receptor in the body and where the endocannabinoid attaches will trigger a different response from the ECS and cause different results.

Example: When you are experiencing pain, endocannabinoids may bind to CB1 receptors in the nerves of your CNS to relieve the pain. Alternatively, they could attach to a CB2 receptor in an immune cell to signal the ECS to combat inflammation that may be the source of the pain.

What are Enzymes?

Enzymes are the third piece of the endocannabinoid system. The function of enzymes is to eliminate endocannabinoids once they are used. This ensures that endocannabinoids are used only while they're needed. In addition, this differentiates endocannabinoids from the typical neurotransmitter, which may persist or be stored for later use.

Two primary enzymes serve this vital function.

• FAAH: This enzyme breaks down anandamide.
• MAGL: This enzyme breaks down 2-Arachidonoyl Glycerol.

These three vital components of the ECS are found in just about every major body system, including the brain, nerves, skin, bone, fat tissue, liver, pancreas, skeletal muscle, heart, blood vessels, kidneys, and the gastrointestinal tract.

How Does the Endocannabinoid System Regulate the Body?

Let's get back to biological harmony, AKA homeostasis. Our bodies experience constant internal and external stimuli and need to adjust to maintain homeostasis. So, when something brings us out of natural balance, the ECS may temporarily engage to get our operating system back to homeostasis.

Dr. Vincenzo Di Marzo, Research Director at the Institute of Biomolecular Chemistry, described ECS function in this way: "With the 'pro-homeostatic action of the ECS, we mean that this system of chemical signals gets temporarily activated following deviations from cellular homeostasis. When such deviations are non-physiological, the temporarily activated ECS attempts, in a space and time selective manner, to restore the previous physiological situation (homeostasis)."

While the research continues to investigate the many complex ways that the ECS interacts with the human body, the scientific consensus is that the ECS may be a potential therapeutic target in the following physiological conditions:

• Pain sensation
• Thermoregulation
• Memory
• Mood
• Appetite
• Stress
• Sleep
• Metabolism
• Immune response
• Reproduction
• energy balance
• blood pressure
• embryonic development

Beyond that, it may be a target for the treatment of pathological conditions such as:

• Parkinson's disease
• Huntington's disease
• Alzheimer's disease
• multiple sclerosis

ECS and Cannabis

Let's dive a little deeper by answering a few direct questions.

So, how does cannabis affect the endocannabinoid system?

The body's naturally-occurring endocannabinoids, AEA and 2-AG, are very similar to the cannabis-derived cannabinoids CBD and THC. These cannabinoids can mimic endocannabinoids and bind with or otherwise affect CB1 and CB2 receptors. This is how cannabis can cause euphoria, treat pain, or diminish anxiety.

How does THC affect the endocannabinoid system?

According to the National Institute of Health, THC affects the endocannabinoid system because it mimics the chemical structure of anandamide. Both anandamide THC and interact with CB1 receptors. And while both may affect things such as the perception of pain and sense of reward, THC's impact is more pronounced, and the cannabinoid is primarily responsible for marijuana's euphoric high.

THC also interacts with CB2 receptors, but anandamide does not. While most CB1 receptors are located in the CNS, most CB2 receptors are part of the immune system. This may explain why THC has both psychoactive and therapeutic effects.

There is mounting evidence that THC may treat the following symptoms and conditions:

• PTSD
• Nausea
• Insomnia
• Migraines
• Glaucoma
• Poor appetite
• Inflammation and Pain
• Gastrointestinal conditions
• Autoimmune disorders
• Neurodegenerative conditions

How does CBD affect the endocannabinoid system?

While some describe CBD as non-psychoactive, that's not correct. CBD is a mood-altering substance. When people use the term "non-psychoactive," they mean "not intoxicating." CBD does not get you high.

While CBD does not bind with CB1 And CB2 receptors, it does have an effect on other receptors:

1. CBD interacts with serotonin receptor 5-HT1A: This may explain its anti-anxiety effect.
2. CBD interacts with vanilloid receptor TRPV1: This may influence the body's perception of pain.
3. CBD blocks the FAAH enzyme: This prevents the breakdown of anandamide, boosting levels of this feel-good endocannabinoid.

CBD also has a wide range of therapeutic uses. While more research is needed, humans presently use CBD to treat the following symptoms and conditions:

• Insomnia
• Inflammation
• PTSD and anxiety
• Crohn's disease
• Multiple sclerosis
• Opioid withdrawal
• Epilepsy and seizure disorders

Interestingly, there is additional evidence that CBD and THC may work better together in a theory called "The Entourage Effect."

What is The Entourage Effect?

The chemists Raphael Mechoulam and Shimon Ben-ShabaIn coined the term entourage effect in 1999 to describe their theory that the cannabinoids and terpenes in cannabis work synergistically. It was a controversial theory because it clashed with the established belief that marijuana's effects were attributable to THC. The theory remains controversial today due to the lack of cannabis science.

Is there evidence that supports the entourage effect theory?

A 2011 Review of Studies in The British Journal of Pharmacology found that taking cannabinoids and terpenes together may provide additional therapeutic benefits for the treatment of:

• Pain
• Anxiety
• Inflammation
• Epilepsy
• Cancer
• Fungal Infection

Further, the terpene caryophyllene actually mimics endocannabinoids and binds with the CB2 receptor. This suggests it may have therapeutic effects. There is also significant evidence to suggest that CBD may modulate the effects of THC. Finally, a study regarding the neuroprotective capability of CBD found that CBD may be more effective when taken with THC.

Do Synthetic Cannabinoids Affect the ECS?

The short answer is yes. The discovery of the ECS and the emerging science of how it works have resulted in the creation of drugs by pharmaceutical companies that use synthetic cannabinoids.

1. Marinol and Syndros: Both are made with dronabinol, a synthetic form of THC. These drugs are FDA approved for nausea and vomiting caused by chemotherapy, loss of appetite, and wasting syndrome caused by HIV/AIDS.
2. Nabilone (Cesamet): A synthetic form of THC FDA-approved to treat nausea associated with cancer chemotherapy.
3. Epidiolex: Synthetic cannabidiol approved by the FDA to treat pediatric seizure disorders.

While we're thrilled that these drugs may help people, they raise a serious question:

Why would pharmaceutical companies go to the trouble and expense of manufacturing synthetic cannabinoids and getting FDA approval when perfectly good natural cannabinoids are readily available in the cannabis plant?

Because cannabis has been on Schedule I in the Controlled Substances Act since it was passed in 1973. This made research on the plant nearly impossible. It's also tough to patent a plant, so the pharmaceutical industry can't make money on marijuana. Perhaps that's why they lobby so hard against legalization.

Can Your Endocannabinoid System Be Deficient?

Yes. Clinical endocannabinoid deficiency (CECD) was first presented by Dr. EB Russo. His theory articulates that everyone has an endocannabinoid "tone," which reflects levels of AEA and 2-AG, the acting endocannabinoids, their synthesis, their degradation, and the density of the cannabinoid receptors in the brain.

What happens when your endocannabinoid system is deficient?

In simple terms, CECD may be caused by a deficiency in the endocannabinoid system. This theory is gaining traction as researchers find that activating or deactivating the ECS can treat some medical conditions for which there are inadequate solutions. Some examples include fibromyalgia, irritable bowel syndrome, and depression.

Can Cannabis Provide Relief to CECD?

Possibly. While we have some evidence that some conditions may be associated with endocannabinoid deficiencies, the research doesn't explain how to fully treat these conditions. In theory, cannabis may reduce the symptoms of some of these medical conditions by suppressing the release of FAAH, the enzyme that breaks down anandamide.

In addition, other acidic cannabinoid precursors like cannabigerolic acid (CGBA), tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabidivarinic acid (CBDVA), and tetrahydrocannabivarinic acid (THCVA) may increase endocannabinoid levels by the same mechanism, but more research is needed.

Are There Other Ways to Enhance the ECS?

There sure are. Exercise is one, and getting enough sleep is another. But, of course, maintaining gut health is also a good idea, and a proper diet is essential to that. In fact, did you know that certain spices and foods may enhance ECS activity?

1. Black Pepper and Oregano: These both contain the terpene caryophyllene (also found in cannabis). Caryophyllene is known for its anti-inflammatory and pain-relieving effects because it binds with CB2 receptors like a cannabinoid.
2. Truffles: Research also suggests that they have high concentrations of AEA that may activate the CB1 and CB2 receptors.
3. Dark Chocolate: Cacao beans have N-oleoyl ethanolamine and N-linoleoyl ethanolamine. Both inhibit FAAH to prolong the effects of anandamide.

These are just a few examples of how diet and specific food may enhance ECS function. As a general rule, prebiotic foods that induce the growth of beneficial microorganisms such as bacteria and fungi may also benefit the ECS.

Learn More with Panacea

The human endocannabinoid system and the entourage effect are complex, and science is just beginning to understand them. But what we do know is promising. It's clear that some cannabinoids interact with the endocannabinoid system in ways that improve health and wellness.

Panacea invites you to join us on your journey to a healthier you with cannabis. Visit us anytime, and let our knowledgeable staff guide you to the perfect cannabis product for your needs. Or order online when you want!