The Endocannabinoid System

The Endocannabinoid System

The human body is enormously complex, and even after doubling human life expectancy in a mere century, the medical and scientific communities have barely scratched the surface of how our minds and bodies really work. The recent and ongoing discovery of the endocannabinoid system has opened the door to the underlying mechanisms of observable phenomena that even Freud predicted but could not identify.

What makes up the endocannabinoid system?

Like most other signaling systems, endocannabinoid system is composed of three essential parts:

  • several Gi/o protein-coupled receptors;
  • their endogenous arachidonyl ligands;
  • enzymes which synthesize and degrade those ligands. 

The receptors of the endocannabinoid system are the most abundant protein receptors in the human body – more numerous than all other protein receptors – dopamine, serotonin, GABA, glutamate, etc. – combined.

58% of transmembrane receptors in the brain are CB1 cannabinoid receptors.

This ubiquitous and pervasive system plays a key role in many nervous system functions, regulating: 

  • Pleasure;
  • Memory;
  • Cognition;
  • Mood;
  • Neural Plasticity;
  • Concentration;
  • Motor Activity;
  • Awareness of Time;
  • Appetite;
  • Pain Threshold and Perception;
  • Integration of the Senses. 

 

It also plays several roles in the immune system: 

  • cell differentiation and activation;
  • gene transcription;
  • anti- and pro-inflammatory cascades;
  • cellular chemotaxis.

     The endocannabinoid system regulates regulation.

 Ethan Russo, MD
  Board-certified neurologist,
  Psychopharmacology researcher
  Former Senior Medical Advisor to GW Pharmaceuticals

The two most well known endocannabinoids are arachidonylethanolamide (AEA)more commonly known as anandamide – and 2-arachidonoylglycerol (2-AG).

Not long after ∆9-THC was first isolated from the cannabis plant by Rafael Mechoulam, scientists realized that the human body had a unique and as-yet undiscovered receptor upon which THC exerted its psychoactive effects.

As the science of the endocannabinoid system progressed, its true roles have slowly but surely bubbled to the surface, and answered many questions that have baffled the healthcare community since antiquity, from the role of dreams and memory consolidation, to how inflammation really works.

This article outlines some of the more well-understood endocannabinoids, cannabinoid receptors, and the role of the endocannabinoid system as it relates to health and disease.

So, maintaining a healthy endocannabinoid system means maintaining a healthy lifestyle. Benefits of optimizing your endocannabinoid system may include:

The endocannabinoid system is highly impactful and complex but relies largely on a few key endocannabinoids and receptors to function properly.

What are endocannabinoids?

Endogenous cannabinoids, or endocannabinoids, are neurotransmitters naturally produced by the body. They bind to cannabinoid receptors, specifically CB1 and CB2 receptors, located throughout the brain, immune system, and elsewhere. Examples include anandamide, 2-arachidonoylglycerol (2-AG), n-arachidonoyl dopamine (NADA), and virodhamine (OAE).

Endocannabinoids are created and perform in the reverse of more well-known neurotransmitters like serotonin, dopamine, and norepinephrine.

For example, dopamine is produced in advance, stored, and then released from the presynaptic cell in response to stimuli. The dopamine crosses a synapse to reach and activate the postsynaptic cell, which then causes you to feel happy, motivated, and focused. (Dopamine plays a role in several other neurological and motor functions, but is most often associated with your brain’s reward system.)

Endocannabinoids, on the other hand, are key components of cellular membranes the body is able to manufacture on demand, not in advance, and they travel backward: endocannabinoids first leave the postsynaptic cell and end their journey in the presynaptic cell. This process allows the postsynaptic cell to regulate the flow of neurotransmitters coming from the presynaptic cell.

While all endocannabinoids play an important role in regulating pre- and postsynaptic activity, one of the best researched is anandamide, perhaps for its reputation as the “bliss molecule.”

Anandamide: The Bliss Molecule

Anandamide was first discovered and isolated in the early 1990s and is synthesized in the parts of the brain responsible for memory, motivation, and higher thought processes. Because of its positive effects on mood, it is called the “bliss molecule” (ananda translates to “bliss” in Sanskrit).

Anandamide has been shown to stop cancer cell formation, reduce anxiety and depression, and even increase neurogenesis in patients with Alzheimer’s disease.  Recently, it has even been proven that anandamide helps produce the ‘runner’s high’ you experience after intense exercise.

A 2015 study by German researchers examined the role of different neurochemicals in creating the runner’s high in mice; previously, endorphins were believed to be solely responsible for generating those pronounced post-workout feelings of contentment and happiness. Surprisingly, the researchers found endorphin molecules to be too large to pass the blood-brain barrier, leading them to conclude that the activation of cannabinoid receptors by anandamide is primarily responsible for reducing stress and pain after exercise.

Further studies have found anandamide to play a significant role in babies’ and mothers’ lives from conception to breastfeeding.

In a 2009 study, researchers found that anandamide levels rose significantly during ovulation in women who would become pregnant via intracytoplasmic sperm injection (ICSI) and in-vitro fertilization (IVF) methods. The study concludes, “Our observations suggest that in successful pregnancy, a higher plasma AEA [anandamide] level at ovulation and a significantly lower level during implantation are required.”

A comprehensive review of the roles endocannabinoids play in human reproduction also points to anandamide as being imperative for successful embryo implantation and fetal development. The review states that abnormal function of endocannabinoids or their receptors, especially as they relate to the placenta, could result in pregnancy complications.

Finally, anandamide, along with the 2-AG endocannabinoid, may be pivotal in triggering a suckling response in newborn babies. A 2006 scientific review found correlations between increased levels of these endocannabinoids and baby mice’s ability to latch and suckle. The mice pups naturally had high levels of endocannabinoids within their first day of being born, and as they suckled, their endocannabinoid levels were replenished by the mother’s milk. When the mice pups were given a CB1 receptor antagonist, which prevented the CB1 receptor from being activated by anandamide or 2-AG, the newborn mice were not able to suckle.

As you can see, anandamide is important for regular and healthy bodily function. So how can you make sure you have enough of it? A primary building block in the synthesis of anandamide is arachidonic acid (AA), an omega-6 fatty acid found almost exclusively in animal foods (e.g. different meats and eggs), but can also be found in pasta and grain dishes. As long as you are eating a varied and balanced diet, chances are you are getting enough AA to maintain regular anandamide levels.

Interestingly, anandamide is chemically similar to tetrahydrocannabinol (THC), the cannabinoid from the cannabis plant responsible for the ‘high’ most people associate with consuming marijuana. Because anandamide and THC are similarly structured, they both activate the CB1 receptors with similar potency. However, THC comes with a slew of mind-altering effects, and while it may bring feelings of psychedelic bliss for some, it is no substitute for the bliss molecule.

2-AG: The Real Agonist

Another primary endocannabinoid, 2-arachidonoylglycerol does not receive quite the same amount of attention but has been shown to be present at concentrations 170x greater than anandamide in the brain.

Moreover, while anandamide is a selective partial agonist for the CB1 receptor, 2-AG is a full agonist at both the CB1 and CB2 receptors. In other words, 2-AG is much more effective at activating cannabinoid receptors than anandamide.

2-AG is one of the neurotransmitters that play a significant role in the body’s immune response. 2-AG was found to exhibit an immunosuppressive effect by causing the body to generate lower levels of cytokines, which are small proteins, produced in immune cells that initiate and promote inflammatory responses in the body.

One of the most celebrated attributes of 2-AG is its neuroprotective effects. In both cases of brain injury and neurodegenerative conditions like Parkinson’s Disease, increased amounts of 2-AG were found to protect the brain from further damage.

Like anandamide, 2-AG originates from arachidonic acid but differs in that it is also synthesized using glycerol (also referred to as glycerin). In food, glycerol is often used as a sweetener, filler, and preservation agent. Recently, glycerol has also shown up as a prominent ingredient in e-cigarette vaping liquid.

If you do not have enough of these critical endogenous cannabinoids, it can lead to clinical endocannabinoid deficiency.

CB1 & CB2 Cannabinoid Receptors

Not only do humans produce their own cannabinoids, but they also have cannabinoid receptors designed specifically to recognize and respond to them. These receptors are called CB1 and CB2.

CB1 receptors exist in full numbers on your brain’s nerve cells, or neurons, especially those in the hypothalamus, hippocampus, and amygdala, which are primarily responsible for regulating hormones, memory, and emotion, respectively. CB1 receptors are also found in the central nervous system (CNS), intestines, muscles, thyroid gland, and various other organs and glands.

Poorly functioning CB1 receptors can lead to a number of consequences, including:

  • Decreased brain energy and function.
  • Age-related decline in cognitive faculties
  • Irregular hormone production in the thyroid gland, which controls metabolism, digestion, and heart rate.
  • Fatty liver disease.
  • Irregular food intake.

CB2 receptors (first discovered in 1993) occur most commonly in the spleen, tonsils, thymus, and immune cells; only a small number exist in the brain. CB2 receptors are best known for their role in regulating immune function through their ability to trigger and stop immune responses, including inflammation.

Changes in CB2 receptor function plays a role in human disease; whether cardiovascular, gastrointestinal, neurodegenerative, psychiatric, autoimmune, or cancerous, virtually any ailment of the body or mind is linked to abnormal CB2 function.

Together, the body’s endocannabinoids and the CB1 and CB2 receptors that bind with them form the endocannabinoid system.

What is the role of cannabinoid receptors?

Cannabinoid receptors are the most widely expressed G protein-coupled receptors in humans: they’re more numerous than all other GPCRs combined.

This well-established fact of human biology has been overlooked for years, thanks in part to the stigma against the only known agonist of these receptors, marijuana. Nonetheless, CB1 receptors specifically are immensely important in the regulation of neurotransmission patterns, especially inhibitory GABAergic transmission in the cortex, hippocampus, and amygdala.

Depolarization-Induced Suppression of Inhibition

The functional role of cannabinoid receptors in the brain is to facilitate depolarization-induced suppression of inhibition. Also known as agonist-induced disinhibition, this phenomenon occurs when a presynaptic action potentially causes the retrograde release of endocannabinoids from the postsynaptic dendrite which activate inhibitory CB1 receptors found on the inhibitory basket cells serving to tonically inhibit the activity of neuron A.

In other words, when neuron A signals Glutamate to neuron B, neuron B releases endocannabinoids which inhibit the basket cells serving to inhibit neuron A, with the ultimate effect of increasing the likelihood that neuron A will generate another action potential.

Because the endocannabinoid system (ECS) regulates the activity of several other neurotransmitter systems, ECS dysregulation can have far-reaching implications that are equally difficult to elucidate. On the other hand, many common conditions from Acne to Alzheimer’s disease have unknown pathogenesis but affect areas of the body known to express cannabinoid receptors. Taken together, these facts suggest that the endocannabinoid system could be a novel and highly-effective target in the treatment of diverse disorders of the central and peripheral nervous systems.

Clinical Endocannabinoid Deficiency (CECD)

Clinical endocannabinoid deficiency is a condition where an individual has a lower amount of endogenous cannabinoids than considered necessary to live healthily.

Scientists now believe CECD may play a role in the following conditions:

Consider for a moment all the medications physicians prescribe on a daily basis for these conditions—and then think of the side effects that can accompany those drugs. For the most part, traditional medications provide some form of relief but also present new issues in the form of unwanted side effects.

If you are suffering from endocannabinoid deficiency, you may be able to improve your condition by making small changes to your diet and/or vitamin and supplement regimen.

Conditions Related to CECD

Neuroprotective mechanisms promote neurogenesis, and reduce neuro-inflammation and oxidative stress.

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Inhibition of the anti-inflammatory cascade and modulation of PPARγ limits the progression of arthritic disease.

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5-HT1a receptor agonism and induction of endocannabinoid receptors has shown efficacy in several mental health models.

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Balance within the endocannabinoid system helps maintains a multitude of variables relating to homeostasis and our circadian rhythm.

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Chemotherapy harms good cells as well as bad cells. Endocannabinoid regulation protects healthy cells and promotes apoptosis of diseased cells.

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Most acne treatments aim to kill surface bacteria. Regulation of sebocyte activity prevents comedogenesis caused by excessive sebum production.

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PPARγ receptor modulation reduces proinflammatory markers and lymphocyte activation, while inhibition of COX enzymes limits prostaglandin production.

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Endocannabinoid activity reduces seizure frequency and excess excitability by stabilizing glutamatergic and GABAergic signaling.

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The ECS regulates pain sensitivity in the periphery and receptivity centrally; induction of the ECS promotes an increased threshold for pain.

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Alleviate CECD by Maximizing Anandamide and 2-ag Levels

Anandamide has a very short half-life (approximately 5 minutes) and is broken down by fatty acid amide hydrolase (FAAH). CBD oil is an inhibitor of FAAH, meaning it keeps FAAH from breaking anandamide down, thereby increasing overall anandamide levels in the body and brain. CBD oil’s effect on FAAH and ultimately anandamide has even been linked to cannabidiol’s (CBD) ability to treat epilepsy in children.

Other FAAH inhibitors include:

  • N-acylethanolamines (NAE) derived from cacao
    • While cacao has several other known FAAH inhibitors, the stimulant theobromine(also in cacao) is thought to encourage the direct production of anandamide
  • Palmitoylethanolamide, which can be found in:
    • Supplements
    • Soy products
    • Eggs
    • Peanut oil
  • Maca, which is a Peruvian plant you can find in a variety of forms (e.g. powder, supplement, chocolate) at most health food stores
  • Kaempferol, which can be found in a variety of fruits and vegetables including:
    • Apples
    • Tomatoes
    • Potatoes
    • Grapes
    • Onions
    • Broccoli
    • Spinach

Monoacylglycerol Lipase (MAGL) metabolizes around 85% of all 2-AG; to date, there is only one MAGL inhibitor that has been proven to increase 2-AG levels. However, because 2-AG is the primary cannabinoid with activity at the CB2 receptor, attempting to increase the number of receptors, maximizing the effect of available 2-AG, is also a promising treatment strategy.

The probiotic Lactobacillus acidophilus has been shown to increase CB2 receptors in the intestines. Luckily, upping your probiotic consumption is fairly easy—and pretty delicious! A few easily accessible options for increasing your probiotic and Lactobacillus acidophilus intake include:

  • Yogurt
  • Pickles
  • Gouda, mozzarella, and cheddar cheese
  • Buttermilk
  • Kefir
  • Kombucha
  • Miso soup

In addition to reducing the degradation or reuptake of endocannabinoids, it is also possible to support your body’s natural production of these key neurotransmitters. Exercise is one way to boost production, but consuming foods rich in omega-6 fatty acids and proteins containing essential amino acids is also necessary to ensure sufficient endocannabinoid levels in the various systems of the body.

Foods for Endocannabinoid Synthesis

As for general dietary guidelines to ensure you are consuming enough building blocks for endocannabinoids, experts recommend plenty of:

  • Chicken
  • Grass-Fed Beef
  • Fish
  • Pork
  • Hemp
  • Pasture Raised Eggs
  • Shellfish
  • Flaxseed

Alleviate CECD by Introducing Phytocannabinoids

Phytocannabinoids are a group of chemicals found in plants that mimic your body’s own endocannabinoids in structure and function. If you are experiencing CECD, you may be able to supplement the cannabinoids your body is not producing by consuming the following plants and herbs:

  • CBD Oil
  • Kava
  • Black Pepper
  • Rosemary
  • Liverwort
  • Echinacea
  • Cacao (chocolate)
  • Truffles (not the chocolate variety, but still delicious)
This article is meant for informational purposes only and should not be considered medical advice.