What is the Endocannabinoid System (ECS)?

What is the endocannabinoid system? Every person – and many mammals – has their own endocannabinoid system (ECS), a complex network of receptors, lipids, and enzymes that plays a large role in governing homeostasis and how we individually experience cannabis. While the ECS was identified only in the late 1980s, it quickly became one of the most important scientific discoveries to date. The ECS is involved in sleep, appetite, immune function, and much, much more.

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Table of Contents
  1. What is the Role of the Endocannabinoid System (ECS)?
  2. The Basics of the Endocannabinoid System (ECS)
    What are endocannabinoids?
    What is Anandamide?
    What is 2-AG, 2-Arachidonoylglycerol?
    What are cannabinoid receptors? (CB1 and CB2 Receptors)
    Cannabinoid Degrading Enzymes
  3. How does the endocannabinoid system work?
    Anandamide’s effects on the body
    2-AG’s effects on the body
    Additional interactions with the ECS
  4. What Are the Differences Between Endocannabinoids and Phytocannabinoids?
  5. How Does Cannabidiol (CBD) Affect the Endocannabinoid System?
  6. How Does THC Affect the Endocannabinoid System?
    CBD or THC? And What is the Entourage Effect?
    What is Clinical Endocannabinoid Deficiency (CED) and What Causes It?
    How Do You Heal the Endocannabinoid System?
    What Foods Contain Cannabinoids?
    How Can I Strengthen My Endocannabinoid System?
    How Does Long-term Use of Cannabis Affect the Endocannabinoid System?
    How Long Does It Take for Cannabinoid Receptors to Return to Normal?
  7. The Endocannabinoid System – More Research is Needed

What is the Role of the Endocannabinoid System (ECS)?

The ECS is intimately involved in homeostasis – keeping the body’s physiological processes stable and in balance. The ECS is involved in regulating many of life’s most essential processes, including:

  • Reward perception
  • Reproduction
  • Inflammatory response
  • Immune system function
  • Appetite
  • Pain-sensation
  • Mood
  • Memory
  • The pleasurable effects of exercise
  • And of course, mediating the pharmacological and experiential effects of cannabis.

In short, the ECS does a lot more than you might think. Let’s explore the basics of the ECS and the role it plays.

The Basics of the Endocannabinoid System (ECS)

As mentioned above, the human endocannabinoid system works throughout the body to help maintain homeostasis and work at peak performance. The ECS’ most essential elements include endocannabinoids, the CB1 receptors and CB2 receptors, and the enzymes that break cannabinoids down.

What are endocannabinoids?

Cannabinoids are chemicals found in cannabis (and many other plants) that interact with the ECS. Tetrahydrocannabinol (THC), the molecule known for its intoxicating effects, and cannabidiol (CBD), known for promoting relaxation, are some of the more well-known cannabinoids, but the cannabis plant contains over 150 different types of these chemicals. Not only that, the human body generates its own version of cannabinoids that interact with other elements of the ECS, called endocannabinoids.

Endocannabinoids are cannabinoids produced by the body, which bind to receptors found in immune cells, throughout the nervous system, up and down the spine, in every brain cell, and even in the skin.

Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) are the two primary endocannabinoids.

What is Anandamide?

Anandamide is the human body’s naturally-occurring THC. Anandamide was discovered in the 1990s and named for the Sanskrit word “ananda,” meaning eternal happiness — it interacts with the body in a similar way to THC, which makes it easy to remember!

Chemical formula for anandamide. Skeletal formula.
Anandamide (C22H37NO2). Source.

What is 2-AG, 2-Arachidonoylglycerol?

2AG is a full agonist of both the CB1 and CB2 receptors. This means that 2AG fits into the CB1 and CB2 receptors fully (called an agonist), and can have both pain-killing and anti-inflammatory effects. 2-AG is present at relatively high levels in the central nervous system (CNS).

2-Arachidonoylglycerol, 2-AG. Chemical formula of 2-AG in skeletal format. C23H38O4
2-Arachidonoylglycerol (2-AG), C23H38O4. Source.

What are cannabinoid receptors?

Cannabinoid receptors are found in every cell in the human body, making the ECS work like a mainframe for the central and peripheral nervous systems (CNS and PNS). Cannabinoids and endocannabinoids, therefore, communicate directly or indirectly with a wide range of receptors, including CB1 receptors, CB2 receptors, GPR55 receptors, opioid receptors, dopamine receptors, serotonin receptors, and much more.

CB1 Receptors

CB1 receptors congregate most densely in the central nervous system and are largely responsible for how cannabinoids interact with the brain. Molecules like THC bind to CB1 receptors and can cause psychoactive effects.

How exactly do cannabinoids have this effect on brain cells? Well, cannabinoids that bind to CB1 receptors can decrease the release of two proteins called glutamate or GABA (gamma-aminobutyric acid). Glutamate stimulates or excites the nervous system, GABA calms it down. When glutamate levels are high, GABA levels are often low, and vice-versa. Glutamate = go, GABA = stop.

THC blocks the production of GABA. This means that fewer “stop” signals are transmitted and creates a buildup of the “go” signal, glutamate, which can increase the overall amount of dopamine circulating the body, which causes a psychoactive “high”. Limiting GABA release also suppresses inhibition, a common form of short-term plasticity.

Here’s several other effects the activation of CB1 receptors causes in the body:

  • Impact our sense of time
  • Increases our appetite and desire for food
  • Painkilling or pain-distracting effects
  • Antiemetic (anti-nausea) effects
  • An “up” and excited psychoactive effect (that high doses of THCV can provide) or a more “down” and relaxing effect associated with THC.
Structure of CB1 and CB2 receptors. Blue = CB1, green = CB2.
Blue – CB1 receptor structure. Green – CB2 receptor structure. Author: Esculapio at Wikipedia. CC BY-SA 3.0.

CB2 Receptors

CB2 receptors can be found most densely in the immune system, but are also found on some neurons in the brain, gastrointestinal system, and peripheral nervous system (PNS).

Research implicates CB2 receptors in a variety of functions, including immune suppression, causing apoptosis (cell death), and the induction of cell movement & development.

CB2 receptor agonists (compounds that activate CB2 receptors) may have significant anti-inflammatory properties that can help treat pain and inflammation. Research has found that targeting CB2 receptors can be useful for the treatment of autoimmune disorders and arthritis.

Cannabinoid Degrading Enzymes

The third component of the endocannabinoid system are enzymes that metabolize and break down cannabinoids and endocannabinoids. Two primary enzymes include fatty acid amide hydrolase (FAAH), which breaks down anandamide and THC, and monoacylglycerol lipase (MAGL), responsible for eliminating 2-AG. These prevent dangerous levels of endo- and phytocannabinoids from building up in the body.

The Endocannabinoid System (ECS). How THC moves along the ECS. Synaptic signaling.
The Endocannabinoid System (ECS). Synaptic signaling of THC across the presynapse and postsynapse.

How does the endocannabinoid system work?

The main endocannabinoids produced naturally by the body, anandamide and 2-AG interact with CB1 and CB2 receptors in different ways before being eliminated by their corresponding enzymes.

Anandamide’s effects on the body

Anandamide is degraded by the enzyme fatty acid amide hydrolase (FAAH), which is an enzyme that breaks down THC and anandamide. Anandamide is a weak partial agonist of CB1 receptors and weak agonist of CB2 receptors, meaning that it has some euphoric and anti-inflammatory effects.

THC inhibits FAAH, which leads to elevated anandamide levels that increase dopamine and induce cannabis’ psychoactive and analgesic effects. Anandamide plays a role in the regulation of hunger and the generation of motivation and pleasure.

2-AG’s effects on the body

2-AG is a full agonist of both the CB1 and CB2 receptors and is involved in several essential physiological functions. These include cell division, energy metabolism, and inflammation. 2AG production has been associated with pain relief, anti-inflammation, suppression of vomiting, stimulation of appetite, and the inhibition of tumor growth. Various phytocannabinoids (plant-derived cannabinoids) mimic 2AG to varying degrees.

Additional interactions with the ECS

Both anandamide and 2AG target GPR18/GPR55 and TRP receptors as well, which is why both cannabinoids have analgesic, anti-inflammatory and antiemetic (nausea-reducing) properties.

GPR stands for G Protein-Coupled Receptor, which is a large group of receptors responsible for sensory perception of light, smell and taste, mood regulation, the immune system, and hydration. With this interaction, cannabinoids can be used to dampen an overactive immune system and potentially be useful for treating autoimmune disorders or other instances where inflammation is out of control.

TRP stands for Transient Receptor Potential (TRP). TRP channels regulate a variety of sensations such as pain, temperature, different kinds of tastes, pressure, and vision. Some TRP channels are thought to behave like microscopic internal thermometers in animals that can sense hot or cold.

What Are the Differences Between Endocannabinoids and Phytocannabinoids?

Endocannabinoids are produced naturally by the body. Phytocannabinoids are cannabinoids produced by plants, with the cannabis plant being the most abundant producer of phytocannabinoids that we’ve found/

Endocannabinoids have a range of effects on the ECS, from full antagonism (turn off the cannabinoid receptors) to full agonism (turn on the cannabinoid receptors).

Phytocannabinoids, meanwhile, are more often than not partial antagonists or agonists. Phytocannabinoids also tend to have a weak affinity for CB receptors, meaning that they do not bind to them very tightly. Phytocannabinoids can mimic endocannabinoids, but not fully.

How Does Cannabidiol (CBD) Affect the Endocannabinoid System?

You can read more about how CBD works here. In short, CBD is an indirect antagonist of the body’s cannabinoid receptors CB1 and CB2, a partial agonist of 5-HT1A (a serotonin receptor that regulates mood), an agonist of TRPV1 (a vanilloid receptor that manages pain perception) agonist, and an allosteric modulator of the μ- and σ-opioid receptors, which means it changes how these receptors respond to other compounds.

CBD may be particularly useful as an anti-inflammatory, mood stabilizer, and antispasmodic. This can make CBD helpful for managing chronic pain, anxiety and depression, multiple sclerosis, and epilepsy. If you are looking for a good-quality CBD product from a cannabis dispensary to address such conditions, then get a medical marijuana card from us here at Leafwell!

Cannabidiol (CBD) chemical formula. C21 H30 O2.
CBD’s molecular structure. C21H30O2. Author: Harbin. From Wikipedia Commons. Public Domain picture.

How Does THC Affect the Endocannabinoid System?

You can read more about how THC works here. THC is a partial agonist of both CB1 and CB2 receptors. THC can increase dopamine production in the short term, whereas regular, long-term use THC can blunt dopamine receptors. Low doses of THC can also increase serotonin levels.

THC is an effective painkiller, and could also be useful as an anti-inflammatory, treatment of spasticity, antiemetic (nausea/vomiting prevention), appetite stimulant, and treatment for an overactive bladder.

Tetrahydrocannabinol; THC; Marinol.
Tetrahydrocannabinol (THC), C21H30O2. Author: Yikrazuul. From Wikipedia Commons.

CBD or THC? And What is the Entourage Effect?

It’s not necessarily one or the other: while CBD can help buffer the psychoactivity of THC in equal doses, cannabinoids work in tandem with one another to affect the body. This interactivity is called the “entourage effect” – the combination of cannabinoids, terpenes (smell), and flavonoids (taste) that give each medical marijuana type variety its unique therapeutic effects.

Many have a belief that CBD is the sole medicinal component of cannabis, but this is simply not true. Sure, CBD has its uses, but combining it with THC (even small, non-psychoactive levels) can reportedly make CBD more effective.

It may be helpful to think of cannabinoids, flavonoids, and terpenes like a big family: they can get along or fight, but they all live together in the same house and are related to one another. Some of them may have clashing personalities, but they have their unique attributes that balance out each others’ weaknesses.

The terpenes found in CBD and cannabis oil, and what they do.
The terpenes found in cannabis and full-spectrum CBD (cannabidiol) oil.

What is Clinical Endocannabinoid Deficiency (CED) and What Causes It?

CED is a theory posited by Dr. Ethan Russo, who states that, “in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes.”

Essentially, many (but not necessarily all) medical conditions coincide with shortages or a dysregulation of the production, metabolism, and amount of endocannabinoids, or a change in the state or condition of cannabinoid receptors. This disruption or deficit can come from an injury, infection, an event that triggers long-term inflammatory responses, or genetic dysfunction. Research has connected many medical conditions with a CED, including fibromyalgia, migraine, and irritable bowel disorders (IBDs). Chronic pain, insomnia, anxiety, and depression may also all be interlinked symptoms that have CED at its root.

Autoimmune disorders can cause widespread inflammation in the body and cannabinoids may help reduce this inflammation. Dravet and Lennox-Gastaut syndromes (two types of epilepsy) could arise due to the lack of genetic coding for a specific cannabinoid that helps regulate calcium and sodium ions.

In theory, one could have an overabundance of cannabinoids as well. In fact, a patient named Jo Cameron reportedly lacked the genetic code to produce the enzyme FAAH. This resulted in an overabundance of anandamide in her system, meaning she hardly felt any pain or anxiety!

How Do You Heal the Endocannabinoid System?

Phytocannabinoids can act as mimics of the human body’s own endogenous cannabinoids. Shortages from CED can cause health problems, so replacing them is a way of helping address these problems. CBD, THC, CBN, CBG, CBC, THCV and so many others can help replenish these shortages.

Essential fatty acids and nutrients found in foods like chocolate (which contains anandamide), herbs, spices, and tea can naturally stimulate the ECS, as can exercise. Getting more than six hours of sleep can also help regulate the ECS. Playing board and card games may also stimulate the ECS via reward mechanisms – anandamide is released during exercise, as well as the satisfactory completion of a complex task. Reducing stress and alcohol consumption may be another way to help keep the ECS in balance, as these cause inflammation.

What Foods Contain Cannabinoids?

Other than cannabis and hemp, the following foods contain cannabinoids:

  • Clove
  • Black Pepper
  • Cinnamon
  • Oregano
  • Echinacea
  • Broccoli
  • Kale
  • Sprouts
  • Carrots
  • Ginseng
  • Sunflowers
  • Black truffles
  • Kava
  • Chocolate/cacao
  • Rue
  • Liverwort
  • Helichrysum
Black peppercorns. Black pepper contains the terpene beta-caryophyllene, which is also in cannabis and is a CB2 receptor agonist.
Black pepper contains beta-caryophyllene, which is also found in cannabis and is a CB2 receptor agonist Beta-caryophyllene is useful for the treatment of pain and anxiety. Author: Hubertl. From Wikipedia Commons. CC-BY-SA 4.0.

How Can I Strengthen My Endocannabinoid System?

Eat the above foods, get plenty of exercise, sleep regularly, and supplement with cannabinoid-rich medicines as needed. The endocannabinoid system and the immune system are linked, so supporting your immune system will help keep your ECS in balance.

How Does Long-term Use of Cannabis Affect the Endocannabinoid System?

Cannabis is a complex plant, containing at least 150 cannabinoids and other compounds, all with different effects. Some have psychoactive effects, but many do not. When multiple cannabinoids are at play, they can work separately, in opposition, or in tandem with each other. Long-term use of every combination of cannabinoids has yet to be fully studied.

However, long-term use of medical marijuana or cannabinoid-based remedies may have a variety of effects. Long-term use may build up cannabinoids in the body over time and cause different effects than those expected.

For example, the relatively rare cannabinoid hyperemesis syndrome (CHS) is thought to be caused by long-term, high-dosage use of THC, where too much THC builds up and causes nausea and vomiting rather than inhibiting it. Why this happens is not precisely known, but it could be due to the overactivation of serotonin and/or the TRP channels, which desensitizes these receptors. This makes regulating homeostasis more challenging.

High consumption of THC can also lessen the amount of REM sleep, which is why consumers sometimes report a lack of dreaming. Although medical marijuana (in particular, THC) can help people achieve restful sleep, less REM activity may have a negative effect on mood and memory formation in the long term. There is plenty of debate surrounding the need for REM sleep and it being needed for a refreshing sleep. THC can, however, increase the amount of time in deep non-REM sleep, which is where cell and tissue repair occurs.

Long-term use of THC may also affect the stress response system (the hypothalamic pituitary adrenal, or HPA, axis), where serotonin, dopamine, cortisol, and norepinephrine receptors are dulled. The blunting effect of cannabis on these receptors can be useful for the treatment of anxiety, PTSD and ADHD/ADD – conditions where the flight-or-fight response has gone awry.

Essentially, cannabis is like any other medication, where long-term use can ultimately start to have harmful effects. The harmful effects of psychoactive cannabinoids may be reduced by utilizing other cannabinoids and terpenes, like CBD and pinene, and proper dosing.

Hot showers can help overcome the negative effects of THC.
Source. Author: Sasha Kargalstev. ALT Text: Hot showers are one way people get over the nausea associated with cannabinoid hyperemesis syndrome (CHS).

How Long Does It Take for Cannabinoid Receptors to Return to Normal?

One of the advantages of using naturally-derived cannabinoids as medicine is that the body breaks them down relatively quickly. It’s difficult to approach dangerous levels of build up and a deadly overdose has yet to be recorded. There are few, if any, substances that humans can ingest with the same safety profile as cannabis.

Those who rarely or occasionally use cannabis will not likely experience much, if any, long-term change to their ECS. Their ECS will likely “reset” within a day or two. Longer-term users may require longer resetting time – anywhere from one week to one month. For most people, stopping cannabis use is not hugely difficult, although some may have a more difficult time. This ability to easily wean off and quit cannabis and cannabinoids is one reason why cannabis could be an “exit drug.”

Toxicity of drugs (LD50) compared to their legal status and dependence potential.
Graph displaying the acute toxicity of drugs (lethal dose) and their dependence potential. Marijuana/cannabis has moderate/low dependence potential, and is not very lethal. This can make cannabis an alternative to powerful, opioid-based painkillers. Data source: Gable, R. S. (2006). Acute toxicity of drugs versus regulatory status. In J. M. Fish (Ed.),Drugs and Society: U.S. Public Policy, pp.149-162, Lanham, MD: Rowman & Littlefield Publishers. Also published at Professor Gable’s faculty page. (archive.org mirror )

The Endocannabinoid System – More Research is Needed

There is still so much to learn about the endocannabinoid system. Cannabis’ illegality across most of the world is largely responsible for the gaps in our knowledge. The ECS is not even a part of the medical curriculum yet!

This means that there is a huge dearth of information, even among health professionals. With a lack of curriculum, it is up to physicians to study this hugely important and complex system on their own time. Leafwell seeks to change this, empowering consumers and physicians alike with the latest, most accurate research and a clear picture of the potential of medical marijuana and the ECS.

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Written by
Dipak Hemraj
Dipak Hemraj

Dipak Hemraj is a published author, grower, product maker, and Leafwell’s resident cannabis expert. From botany & horticulture to culture & economics, he wishes to help educate the public on why cannabis is medicine (or a “pharmacy in a plant”) and how it can be used to treat a plethora of health problems. Dipak wants to unlock the power of the plant, and see if there are specific cannabinoid-terpene-flavonoid profiles suitable for different conditions.

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