Endocannabinoid System: Ultimate Guide

The endocannabinoid system (ECS) is a body system associated with the central and peripheral nervous systems. The endocannabinoid system is stimulated or inhibited by plant cannabinoids and by the body’s own natural cannabinoids. It plays a large role in signaling that creates effects in the body like changes in serotonin levels and reduced inflammation.

Because the endocannabinoid system is found throughout the body and can influence the conditions of the body, it can have a major role in medical conditions and diseases.7 The endocannabinoid system has been observed playing a protective role against many diseases and disorders like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome-related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and Tourette’s syndrome.

Pharmaceuticals vs. CBD

Through understanding the endocannabinoid system, you can better understand the therapeutic effects of cannabinoids. Currently, cannabinoid-based drugs like nabilone, dronabinol, Sativex, and Epidiolex are coming into greater use as the benefits of CBD and medical marijuana become better understood.

Endocannabinoid System: Real or Fake?

The endocannabinoid system is real, and present in most mammals from dogs, cats, and horses, to humans. Two main types of cannabinoid receptors have been identified in the ECS, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2).7. Receptors GPR55 and TRPV1 have also been shown to interact with the S and play a larger role interacting with the cannabis-derived cannabinoid CBD, while the cannabis-derived cannabinoid THC interacts largely with CB1.

Cannabinoid receptors also interact with the body’s own natural endocannabinoids like anandamide and 2-arachidonoyl glycerol.7 Endocannabinoids are not stored in the body, they act on demand, so if there are not enough endocannabinoids in the body it may create a cannabinoid deficiency.

One of the most common features of all endocannabinoids is the ability to suppress pain sensitivity.7 If the body is balanced by supplementing deficient cannabinoids, symptoms like pain sensitivity can be decreased (see CBD oil for pain).

What is the Role of the Endocannabinoid System?

The endocannabinoid system is a key player in several biological mechanisms in the body. Enhancing the activity of the ECS can produce effects like pain reduction, nausea reduction, inflammation reduction, and relief from conditions like epilepsy, glaucoma, and muscle spasms.7

It is thought that when CB1 is activated, the body will respond in ways that discourage obesity and substance abuse, and may also benefit cardiometabolic risk.7 CB2 activation is thought to play a role in analgesia (reduced pain sensation), bone growth, and combat atherosclerosis and hepatic fibrosis.

By manipulating cannabinoid intake or by manipulating endocannabinoid receptor sensitivity to stimulation, doctors and researchers can find new ways to approach diseases and disorders. So far cannabinoid and ECS research have been difficult because animal models have endocannabinoid systems that slightly differ between species.

The Animal Endocannabinoid System

For example, dogs take up cannabinoids more readily through their digestive system than humans do. This can be done via using products specifically made for dogs, such as CBD pet products. These small differences between dogs and humans can complicate research but have given great insight into the workings of the endocannabinoid system.

How Does CBD Help the Endocannabinoid System?

Tetrahydrocannabinol (THC) was the first cannabinoid to be discovered, followed by cannabidiol (CBD).11 THC and CBD both come from the cannabis plant and can be present in different proportions depending on the plant variety. THC largely affects the CB1 receptors of the central nervous system and produces a psychoactive high when taken in large enough doses.

At first, it was believed that the effects of CBD were very limited, but research over the last two decades has revealed that it is a potent anti-inflammatory agent that can counteract the psychoactive and memory impairing effects of THC.11 In addition to relieving inflammation and neuroprotection, CBD oil may have effects that help improve symptoms of anxiety, chronic pain, sleep, arthritis, and many other diseases and disorders.

Endocannabinoid System Diagram

The endocannabinoid system is like a web of locks and keys. When plant cannabinoids or endocannabinoids unlock the cannabinoid receptors, neurotransmitter signals are released and create a cascade of chemical changes that produce a larger effect in the body.

Endocannabinoid System
CB1 receptors are found concentrated in the brain and central nervous system. CB2 receptors are present mostly in organs associated with the immune system.

Functions of the Endocannabinoid System

There are various functions of the endocannabinoid system in the body. Each function might have a unique method of how to use CBD oil (or cannabis in general) that is preferred.

  1. Memory
  2. Appetite
  3. Energy Balance
  4. Metabolism
  5. Stress Response
  6. Immune System


The hippocampus is the area of the brain involved in working memory, but not reference memory.11 It is also a site with a very high density of CB1 receptors and large amounts of anandamide. In rodent models, detrimental effects on working memories can be created by CB1 agonists like THC and anandamide.

By contrast, the release of the intrahippocampal substance AM251 can prevent memory consolidation and avoidance.11 This effect is thought to be the result of decreased acetylcholine release which can prevent neurological degradation like that found in Alzheimer’s disease.


When it comes to the role of adverse memories in fear responses, and in conditions like anxiety and PTSD, CB1 agonists acting in the brain’s amygdala are able to help extinguish fearful adverse memories.11 In this capacity, the ability of cannabinoids to aid in memory extinction can be helpful in treating the conditioned behaviors of mental health disorders.

Because different cannabinoids can have different effects, and because different cannabinoid receptors can act differently depending on the area of the brain, there are no single CBD effects on brain memory.11


Cannabinoids can affect appetite and metabolism through the endocannabinoid system. While cannabinoids like THC and anandamide can stimulate appetite through CB1 receptors, the natural cannabinoid 2-AG has a lesser effect on appetite stimulation through the CB2 receptor.15

The stimulation of CB1 receptors by THC or anandamide is strongly associated with appetite stimulation.15 This effect may be desirable for some, such as those suffering nausea or anorexia. Many strains of cannabis are also very effective at suppressing appetite, so the general effect of appetite stimulation from cannabis does not apply to all types of the plant.

Weight Loss and CBD

CBD, which works indirectly on the endocannabinoid system has not been observed to stimulate the appetite. When it comes to consuming CBD for weight loss, CBD and another non-psychoactive cannabinoid, cannabigerol (CBG) may help reduce appetite.3 Another way that CBD for weight loss works is that it helps turn fat into brown fat which is burned off faster.13

Energy Balance

Along with affecting eating behavior, the endocannabinoid system’s modulation of neuron activity can also influence energy balance.8 The CB1 receptors of the central nervous system are associated with the motivation to eat, commonly called the “munchies.” The endocannabinoid system goes much further than this stoner stereotype though.

Much of the regulation of energy balance occurs in organs of the peripheral nervous system.8 The endocannabinoid system is present in the liver and pancreas, and also in fat tissue and muscle. Through these parts of the peripheral nervous system, the endocannabinoid system is involved in regulating the balanced production of lipids and glucose (fats and sugars).

CBD and Obesity

Conditions like obesity and diabetes have been linked to dysregulation of the endocannabinoid system, so many new therapies are looking for solutions to obesity and diabetes that target the endocannabinoid system. There is some evidence that blocking CB1 activation may balance metabolic dysregulation from the endocannabinoid system.8 CBD is a cannabinoid known to block CB1 activation.

Many people think that using CBD for obesity and CBD for diabetes may turn out to be effective novel options for targeting the pathology of those conditions. Since obesity and diabetes can lead to cardiovascular disease, researchers are hopeful.


As discussed, the endocannabinoid system can influence energy balance and food intake, which are two major components of metabolism. The ECS can do this through CB1 and CB2 receptors, and from indirect stimulation. Different cannabinoids, naturally or from plants, have differential effects on metabolism, appetite, and energy balance.

The ECS can specifically modulate appetite by acting on the mesolimbic areas of the brain.1 It also acts on tissues of the peripheral nervous system like fat cells and liver cells, skeletal muscle, insulin production in the pancreas, and on the tissue to the gastrointestinal tracts.

Stress Response

“Anxiety is an innate behavioural state associated with the anticipation of potential future threats that allows an organism to avoid potentially dangerous or harmful situations.” -Beat Lutz, et al. 2015

Stress-response is strongly linked to anxiety. Both use inputs from multiple senses to evaluate potential danger. If danger is sensed, the body sends chemical signals to initiate a response.10 This involves complex cascades of neuron signals and hormonal and behavioral outputs.

How Anxiety Affects The Body

  • Avoidance of stressful stimulus
  • Hypervigilance
  • Increased heart rate
  • Decreased motion

When the effects of stress and anxiety become chronic, they can lead to psychiatric conditions and physical deterioration. These negative effects can disrupt normal functions such as job performance and social engagement. The endocannabinoid system can influence stress response through multiple mechanisms.

CB1 and THC

When it comes to CB1 and consuming THC, small amounts of THC can help relieve stress and anxiety, but large doses can increase anxiety and even induce paranoia.10 CBD can reduce anxiety and depression symptoms by elevating 5-HT and glutamate levels in the prefrontal cortex to balance endocannabinoid deficiencies in limbic brain areas.5, 9 CBD’s ability to increase 5-HT signaling and regulate glutamate and serotonin production is attributed to its effectiveness in relieving symptoms of anxiety from chronic stress.

Immune Function

The endocannabinoid system helps to regulate the immune system by modulating the response of different cell types, affecting the balance of immune system compounds called cytokines, inducing apoptosis (programmed cell death), and downregulating innate and adaptive immune responses.12

By suppressing aspects of the immune system and altering the cells and compounds that respond to immune system stimulation, cannabinoids like CBD can mediate adverse immune responses like inflammation and oxidative cell damage. Because of these effects, CBD and the endocannabinoid system show promise in the ability to combat immune system-related diseases and disorders like liver damage.

Female Reproduction System

There is evidence that high doses of marijuana smoking can affect fertility. The endocannabinoid system is linked to the female reproductive system through the peripheral nervous system’s CB2 ECS receptors.2 When it comes to the ovaries specifically, the full endocannabinoid system is active including, CB1, CB2, and other ECS receptors. The endocannabinoid system affects the oviducts, uterus, and endometrial cells. Endocannabinoids play a definite role in oocyte and follicle maturation, embryo transport through the oviduct and implantation of the blastocyst.

Menstruation and the Endocannabinoid System

Naturally, anandamide concentrations in the body increase during a woman’s menstrual cycle during the time of ovulation, which has lead researchers to look further into the effect of the endocannabinoid system of the female reproductive system.2 Cannabis users have been shown to have reduced fertility. However, cannabinoids may have positive effects on the female reproductive system too.

Many ovarian dysfunctions are linked to obesity, and in turn, metabolic function.2 Cannabinoids could play a positive role in restoring regular ovulation when they are used in a way that improves metabolism and aids weight loss.

CBD for Endometriosis

Researchers are looking further at the relationship between the ECS and the female reproductive system when it comes to complex female reproductive disorders as well. It is thought that there may be a link between the ECS, the obesity-induced production of leptin, and polycystic ovarian syndrome (PCOS).2 Endometrial cancer and benign endometriosis are also likely influenced by cannabinoids, but the overall effects of cannabinoids on the ECS of the female reproductive system need to be studied further to better understand the impacts.

Do Dogs Have an Endocannabinoid System?

More and more pet owners are using CBD for dogs with conditions like osteoarthritis, inflammation, dermatitis, and anxiety. Oddly, much of what veterinarians know about the endocannabinoid system in dogs has been a byproduct of research intended to elucidate its workings in the human body.

Dogs have endocannabinoid systems very similar to human ECS. The major difference between the ECS in canines and humans is how different cannabinoids are absorbed, and the distribution of endocannabinoid receptors. For example, dogs oxidize CBD through a biological pathway called 6 β-hydroxylation, whereas humans produce 7-oic acid group metabolites of cannabidiol.4 CBD is also more bioavailable to dogs through the digestive system. While human absorption of CBD through the digestive system can be under 5%, dogs can absorb up to 19% or the CBD they orally consume.4, 14

Evolution and the Endocannabinoid System

Predator-prey competition can be a major driving force for evolution.6 Cannabis is a great example of how plants can come to contain chemicals like CBD help (potentially) how the consumer’s body functions. The cannabinoids found in cannabis may exist to ward off consumption, but like many other plants, humans have found ways to manipulate those effects for their benefit.

In the case of cannabis, the endocannabinoid system has been the link to its medicinal effects which have been taken advantage of since ancient times. Not only have humans, dogs, and other animals evolved a biological system that has analogous plant compounds, humans have also manipulated the cannabis plant to take advantage of this bond.

Final Thoughts

While deep research continues to unravel this historically new body system, plant breeders and geneticists are working to create new varieties of cannabis that contain cannabinoid balances specifically designed to target certain aspects of the endocannabinoid system. On the whole, the endocannabinoid system is a gateway to new ways to manage our health and combat diseases and disorders from cancer and epilepsy to inflammation, pain, and anxiety.


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