The Endocannabinoid System (ECS)

What is meant by the endocannabinoid system and how does it work?

In fact, the number of potential components of this system, whose origin was identified from studies on the mechanism of action of the psychotropic ingredient of some cannabis strains, Δ9-tetrahydrocannabinol (THC), has rapidly increased. One can therefore confidently state that science continuously recognizes both the components and the physiological significance and allows understanding to grow. What is certain, however, is that the ECS plays an important role in many essential bodily functions.

The definition of the term endocannabinoid (eCB) will surely change in the near future, as research on it is still relatively young. Around the turn of the century, the ECS was defined as the ensemble of the two G-protein-coupled receptors (GPCRs) CB1 (Cannabinoid Receptor Type-1) and CB2. The CB1 receptor is the most commonly formed receptor in the central nervous system, which further increases its significance. Their two best-studied endogenous ligands – that is, the substances that can bind to them – which are also referred to as eCBs, are N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG). The enzymes that were then assumed to be solely responsible for eCB biosynthesis are called N-acyl-phosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and diacylglycerol lipases (DAGL) α and β, as well as for degradation, the hydrolytic inactivation, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

However, this definition raises some semantic problems, because of the > 80 cannabinoids naturally occurring in cannabis, only THC (as an agonist) and the less common propyl-analog, Δ9-tetrahydrocannabivarin (THCV) (as an antagonist) were able to bind with high affinity to CB1R and CB2R. Therefore, these two receptors should not be defined as "cannabinoid" receptors, but rather as THC/THCV receptors. The definition "cannabinoid receptor" should also include those proteins to which cannabinoids frequently bind, such as the thermosensitive transient receptor potential (TRP) cation channels. As a consequence, "endocannabinoids" should not only refer to the endogenous ligands of CB1R and CB2R, but rather to all ligands of these "cannabinoid receptors".

This results in AEA and 2-AG (which occurs about 1000 times more frequently in the brain than AEA) not being the only eCBs, which in turn implies that other enzymes responsible for the biosynthesis and inactivation of other mediators, which are ultimately included in the list of eCBs, are also assigned to the ECS. This conclusion clearly shows how difficult it can be to delineate a system within an organism, especially when it was discovered very late; but whose relevance is of utmost importance, as we can see from the physiological influences.

What does the ECS do?

According to all current knowledge, the ECS serves to maintain homeostasis. This is meant to keep the body and its functions in balance. A regulated state (whether body temperature, constant supply of oxygen and nutrients, immune defense, tissue development, reproduction, etc.) is a prerequisite for the development, survival, and regeneration of the cells that make up our organism and its function. Each of the target parameters is embedded in complex regulatory circuits that regulate our bodily functions as a whole. The ECS serves to maintain these regulatory circuits by dampening excessive reactions and/or modulating them when regulation is lacking.

The retrograde control in the area of neuronal communication is probably the best researched control function of the eCB so far. In the case of excessive innervation of receptors in the postsynaptic cell, the release of transmitter substances into the synaptic cleft is inhibited by retrograde signal transduction (postsynapse to presynapse). Simply put, the ECS dampens excessive neuronal communication with this mechanism. This naturally has physiological significance, especially at the level of memory performance, pain perception, and emotions.

The physiological relevance is greater than previously assumed. To name a few areas of influence:

The complex function of the ECS

Just as it regulates neuronal communication, the ECS regulates immune functions, especially in areas where the immune system (as previously defined) is less pronounced, such as the brain. The ECS affects the energy balance of neurons and can thus exert neuroprotective effects. The ECS has a direct influence on inflammatory reactions, a part of our immune response, to defend against infections and as part of healing after injuries. AEA is also reported to inhibit functional activities of the immune system, particularly the production of pro-inflammatory cytokines (IL-2, TNF-α, and IF-γ).

The ECS controls the development of our body structure and regulates, via complex molecular gradients, for example, the networking of the embryo's neurons or the differentiation of cell types (e.g., osteoblasts/osteoclasts or myotubes/myofibrils). The ECS influences the endometrium, which is crucial for reproduction, as well as the regulation of spermatogenesis.

The ECS regulates appetite and the resulting intake of food and nutrients. The ECS of the gastrointestinal tract (GI) and the liver. AEA, 2-AG, and OEA (N-oleoylethanolamides) are synthesized in the intestine and liver, where they act locally and in the brain. eCB regulate gut motility at the level of the enteric nervous plexuses, reduce intestinal inflammation through their effect on the immune system, and influence the function of the gut barrier at the epithelial level. eCB and OEA regulate food intake through their effect on enteroendocrine cells in the intestinal wall, the vagus nerve, and in the brain. In the liver, CB1 and CB2 have opposing effects, with CB1 promoting steatosis, fibrogenesis, apoptosis, and proliferation, and CB2 inhibiting these effects.

The Hidden System: Why the Endocannabinoid System Significantly Influences Our Health

The unknown system in the body

We all know the major systems of our body – the cardiovascular system, the respiratory system, the skeletal and muscular system, the endocrine system, and of course the nervous system, which was long considered the control center of all physiological processes. But few know that there is another, overarching system that connects, regulates, and stabilizes all these areas: the endocannabinoid system – abbreviated ECS.

Although it was scientifically discovered in the 1990s, it is still missing from most medical textbooks today. And this despite its importance for our health being hard to overestimate.

Why did the ECS remain undiscovered for so long?

The ECS was discovered during research on the cannabis plant – more precisely through radioactively labeled THC. This discovery was not without controversy. Cannabis was stigmatized for decades, which also hindered scientific investigation. However, the plant has almost nothing to do with the ECS from an evolutionary biological perspective: the system is over 600 million years old, cannabis in its current form at most 50,000.

The role of phytocannabinoids like CBD and THC

Phytocannabinoids, foremost CBD and THC, can specifically modulate the ECS. They act not only directly on the known receptors but also influence enzymes and signaling pathways. More and more studies demonstrate the therapeutic benefits for chronic pain, inflammation, neurological diseases, psychological stress, and hormonal imbalances.

What weakens the ECS – and how can it be strengthened?

Like every biological system, the ECS is also susceptible to stress, especially from:

• Unhealthy diet
• Environmental toxins
• Chronic medication intake
• Emotional stress
• Epigenetic influences

To strengthen the ECS, the following are recommended:

The ECS – key to the health of the future

The endocannabinoid system is not a niche topic – it is a central factor for holistic health and a promising approach for prevention, therapy, and lifestyle optimization. It is time for this system to have its place in medical education and public health awareness.

The brain is not the boss – it is the endocannabinoid system.

Summary

From technical student to cannabinoid pioneer

My name is Philip Schmiedhofer, I am 35 years old and have had an unusual journey – from aspiring aircraft technician through medical technology studies to neuroscience research and finally to cannabinoid medicine. What drives me? The desire to better understand the human body and its self-healing powers – and to apply this knowledge practically.

After a meniscus injury, I first came across the supportive effect of CBD myself. The positive experience sparked my interest in cannabinoids – and so I began to deeply study the research on the endocannabinoid system. Today I lead the SBR Development Holding, which includes among others cannhelp, a pioneering company in the field of CBD products, as well as cannmedic, a distributor specializing in medical cannabinoid products, belong.

What is the endocannabinoid system?

The ECS is a complex network of receptors (CB1, CB2, GPR55, GPR18, GPR119), endogenous ligands such as anandamide and 2-AG, as well as enzymes that synthesize or break them down as needed. It is responsible for the homeostasis, that is, the balance of vital functions in the body – such as pain regulation, sleep, immune defense, digestion, hormone balance, and emotional balance.

A key role is played by the retrograde signal transmission: Endocannabinoids are produced in nerve cells in response to stimuli, travel back to the upstream cell, and inhibit the release of neurotransmitters there – a precise mechanism for fine-tuning neuronal activity.

In summary, the physiological significance of the ECS is underestimated. The ECS is influenced by diet, sleep, stress, exercise, and social interaction, as well as the intake of external cannabinoids (e.g., phytocannabinoids). This partly explains the historical cultivation of the hemp plant and its use as a medicine, recreational substance, and addictive substance. Learn more about phytocannabinoids in our related blog post.