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Endocannabinoid System: everything you want to know

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Endocannabinoid System - Cannabiscientia

 

Thanks to the cannabis plant, scientists have managed to decipher the primordial language that our cells use to communicate.

From the uterus to the coffin, for countless generations, the Endocannabinoid System has guided and protected organisms. But at least until the late 1990s, aside from a few segments in the scientific community, few people knew about the Endocannabinoid System.

Doctors, journalists, public officials... hardly anyone was updated on the latest evidence from scientific research, which managed to discover and explain why cannabis is such a versatile remedy, and why it is, by far, the most popular illicit substance in the world.

 

INDEX

 

1. THE ENDOCANNABINOID SYSTEM: ITS HISTORY AND DISCOVERIES

“Using a plant that has been around for thousands of years, we have discovered a new physiological system of immense importance”

1.1 FROM THE PLANT TO THE HUMAN BODY: HOW AND WHEN THE ENDOCANNABINOID SYSTEM WAS DISCOVERED

Says Raphael Mechoulam, considered the father of the international cannabinoid research community. “We wouldn't have gotten there if we hadn't looked at the plant.” [1]

In the two decades that have followed the identification and synthesis of tetrahydrocannabinol (THC), the psychoactive molecule in cannabis, by scientists Mechoulam, colleague Yoel Gaoni and their research team in 1964 in Israel, scientists have learned a great deal on the pharmacology, biochemistry and clinical effects of cannabis.

However, no one yet really knew how this plant worked, what it actually did (at a molecular level) on the brain to alter consciousness, stimulate appetite, decrease nausea, quell (epileptic) seizures, and relieve pain. No one understood why smoking cannabis could stop muscle spasms in Multiple Sclerosis patients within seconds; no one knew why it improved mood.

In 1973, American researchers at John Hopkins University identified receptor sites in the brain capable of binding opioids (substances such as morphine and heroin). After this discovery, various scientists expected that the discovery of cannabis receptor sites would follow shortly thereafter. [2]

Yet, 15 years passed before a study funded by the US government, carried out at the St. Louis University School of Medicine, determined that the mammalian brain has receptor sites, i.e. specialized proteins, which, incorporated into cell membranes, they respond pharmacologically to the molecules present in the cannabis resin.

 

1.2 HOW AND WHEN THE DISCOVERY OF CANNABINOID RECEPTORS HAPPENED

A molecule similar to THC and synthesized by Pfizer (CP55,940) allowed researchers to begin mapping the precise positions of cannabinoid receptors in the brain, following the signals emanating from a radioactive tag "linked" to this molecule. It will not be surprising to discover that the regions of maximum receptor concentration have been identified:

  • in the hippocampus (memory),
  • cerebral cortex (cognition),
  • cerebellum (motor coordination),
  • basal ganglia (movement),
  • hypothalamus (appetite),
  • amygdala (emotions),
  • periaqueductal gray matter (pain).

These areas represent the sites of cannabis' main effects on the brain.
Cannabinoid receptors, however, are not present in the areas of the brain that control cardiovascular and respiratory functions, and this coincides with the non-lethality of an overdose of THC (unlike, for example, high doses of opioids). [3]

On July 18, 1990, at a conference of the Institute of Medicine of the National Academy of Science (USA), Dr. Lisa Matsuda announced that she and her colleagues at the National Institute of Mental Health (NIMH) had made a fundamental discovery, by locating the precise DNA sequence that encodes the THC-sensitive receptors present in the mouse brain.

Dr. Matsuda also disclosed the news that she had successfully cloned the cannabis sensitive receptor, and named it with the acronym CB1. [4]

Humans also have the same receptor, which consists of a string of 472 amino acids strung like beads in a chain that bobs in and out of the cell membrane seven times.

Cannabinoid receptors function as tools for encoding changes, little scanners perpetually primed to pick up biochemical signals flowing around the cell.

These electrifying innovations opened the doors to the “Decade of the Brain,” as defined at the meeting of the National Academy of Science.

During the 1990s, in fact, there were more advances in neuroscience than in all previous years.

 

1.3 HOW AND WHEN THE DISCOVERY OF ENDOCANNABINOIDS HAPPENED

Just as the studies on opium resulted in the discovery of endorphins, (the natural morphine-like of our brains), equally, research on cannabis would have led to the discovery of natural substances, produced by our bodies, similar to THC: our “ internal cannabis”, so to speak.

In 1992, a collaboration between researchers William Devane, Lumir Hanus, Roger Pertwee and Raphael Mechoulam brought to light a new neurotransmitter, therefore called "endogenous cannabinoid" or, for short, "endocannabinoid", a molecule that binds with the same receptors of the brain that are sensitive to THC.
The researchers called this substance “Anandamide”, (abbreviated to AEA), deriving the word from Ananda, the Sanskrit for “happiness”, “bliss”. [5]

In 1995, Mechoulam's group discovered, in parallel with another group of Japanese researchers, a second important endocannabinoid, 2-arachidonylglycerol, abbreviated to "2-AG". This endocannabinoid binds not only to the CB1 receptors present mainly in the brain, but also to a second type, called CB2 receptors. [6] ; [7]

 

1.4 WHEN IS THE ENDOCANNABINOID SYSTEM RECOGNIZED BY THE INTERNATIONAL SCIENTIFIC COMMUNITY?

Endocannabinoids and their receptors emerged as a “hot topic” among scientists sharing their findings in hyper-specialized journals and at annual symposiums hosted by the International Cannabinoid Research Society (ICRS).
Since 1990, annual meetings of specialized scientists studying the Endocannabinoid System began, which were later formalized as a scientific research society since 1992, under the name ICRS.

The society, founded in the United States by around fifty delegates (now there are more than 500 from all over the world), was originally supported by research funds from the American government.

Exchanges within the ICRS began to attract the attention of big pharmaceutical companies, who were paying attention to the latest discoveries in cannabinoid science, while few people outside the scientific community were aware of them.

Advances in the nascent, ever-expanding scientific field would pave the way for new therapy strategies for various pathologies, such as:

  • the cancer,
  • diabetes,
  • neuropathic pain,
  • arthritis,
  • osteoporosis,
  • obesity,
  • Alzheimer's,
  • Multiple Sclerosis,
  • depression and many other diseases. [8]

 

1.5 THE 1990s: A NEW SCIENTIFIC ERA FOR CANNABIS

For all this to happen, the cloning of the cannabinoid receptor in 1990 was crucial. Since that extraordinary discovery, the doors were opened for scientists to test the receptors with various substances, trying them like keys in a lock.
Some keys, called "agonist" molecules in pharmacology, were able to open the lock; others, the "antagonists", to block it.

The researchers also developed genetically modified mice, called "knockout", lacking the cannabinoid receptor. When THC was administered to a “knockout” mouse, this molecule did not generate any effects, as the THC had no lock to bind to, and therefore could not trigger any activity.
This was further evidence that THC worked by activating cannabinoid receptors in the central nervous system. [9]

Finally, after 50 centuries of medicinal use, the scientific basis of therapeutic cannabis was starting to come into focus…

 

2. ENDOCANNABINOID SYSTEM: WHAT IT IS AND WHAT ARE ITS FUNCTIONS

The Endocannabinoid System is a biological system of communication between cells, which regulates important functions of the organism, both in humans and in many animals.


2.1 WHICH COMES FIRST, THE CANNABIS PLANT OR THE ENDOCANNABINOID SYSTEM?

By tracing the molecular pathways of THC, scientists accidentally discovered a unique and hitherto unknown molecular signature that is involved in the regulation of a wide range of biological functions.


Scientists called this new signaling pathway the "Endocannabinoid System" (abbreviated to ECS from English), after the plant that led to its identification. The name might suggest that the plant came first, but in reality, as Dr. John McPartland, physician and phytochemist and Cannabis researcher since the early 1980s, explains:

By comparing the genetics of cannabinoid receptors in different species, we estimate that the Endocannabinoid System evolved in primitive animals over 600 million years ago. This ancient internal sign existed long before cannabis appeared on Earth, when the most complex forms of life were sponges. [10]

Dr. John McPartland

 

2.2 WHY DOES THE ENDOCANNABINOID SYSTEM EXIST?

The Endocannabinoid System is present in fish, reptiles, worms, leeches, amphibians, birds and mammals – in all animals except insects.
Given its long evolutionary history, scientists have deduced that the Endocannabinoid System must serve functions of fundamental importance to animal physiology.

From marine urochordates to small nematodes, all vertebrate and many invertebrate species share the Endocannabinoid System as an essential part of life and adaptation to environmental changes. [11]

The discovery of the Endocannabinoid System brings extraordinary implications for almost every area of ​​medical science, including reproductive biology. Dr. Mauro Maccarrone, professor of biochemistry and one of the leading experts in the field, describes the Endocannabinoid System as the "guardian angel" of reproduction. [12]

In fact, endocannabinoid signaling proves to be decisive throughout the entire reproductive process in mammals: from spermatogenesis to fertilization, passing through transport in the oviduct of the zygote, implantation of the embryo in the uterus, fetal development, and even for the development of the small once born.

The receptors of this system proliferate in the placenta and facilitate the so-called "cross-talk", i.e. the communication that exists between the embryo and the mother. [13] ; [14]

 

2.3 WHAT FUNCTIONS DOES THE ENDOCANNABINOID SYSTEM PERFORM?

In each tissue the Endocannabinoid System carries out different tasks, but the objective is always the same: maintaining homeostasis, or bio-balance, or maintaining a stable internal environment, despite the oscillations of the external environment.

Cannabinoids promote homeostasis at all levels of biological life, from the sub-cellular to the organs and whole organism and, probably, to the interaction between organisms.

Here's an example: autophagy, a process in which a cell sequesters part of its contents to be self-digested and recycled, is mediated by the Endocannabinoid System. This process keeps normal cells alive, allowing them to sustain a balance between the synthesis, breakdown, and subsequent recycling of cellular products; on the other hand, however, it has a deadly effect on malignant tumor cells, causing them to commit programmed cellular suicide. [15] ; [16]

Naturally, tumor cell death promotes body-wide homeostasis and survival.

Professor Vincenzo Di Marzo, one of the most influential pharmacologists in the world, has been conducting research on the Endocannabinoid System since the late 1980s, publishing hundreds of pioneering discoveries; he, together with colleagues Tiziana Bisogno and Luciano DePetrocellis, summarized the functions of the Endocannabinoid System as:
a central regulator capable of modulating and balancing the main activities of organisms such as eating, sleeping, relaxing, protecting and forgetting. [17]

Vincenzo Di Marzo, Tiziana Bisogno and Luciano DePetrocellis

Although these observations have now been integrated by twenty years of scientific research, the description of the Campania researchers in 1998 remains an excellent simplification of the main functions of the ECS.

 

2.4 HOW THE ENDOCANNABINOID SYSTEM PROTECTS THE NERVOUS SYSTEM

Before the discovery of the Endocannabinoid System, it was known that the signaling known in neurobiology as "anterograde" (or from the Greek, antodromic, which we will illustrate in "How does a cannabinoid receptor work?") occurred only during the development phases of the embryonic brain. Discovering and studying the Endocannabinoid System has turned this concept on its head, as it has been highlighted that this signaling modality is also used in the adult brain.

We know that endocannabinoids choreograph “a wide range of processes in embryonic brain development,” according to MacPartland's definition, including the proliferation of stem cells and their differentiation, a process driven by extracellular signals transmitted to cannabinoid receptors. [18]

Since the late 1990s, scientists have learned that cannabinoid signaling can also regulate adult neurogenesis (i.e. the growth of brain cells) and the migration of stem cells. [19]

We also know that following strokes and other neurological traumas, high levels of endocannabinoids are released in the brain, testifying to the neuroprotective properties of the ECS, which are described by Professor Mechoulam as:
A general protection network, which works in conjunction with the immune system and various other physiological systems. [20]

Professor Mechoulam

Mechoulam's Nobel-nominated findings launched a direct challenge to scientific orthodoxy by revealing that the brain has a natural repair kit, an innate protection and regeneration mechanism that can heal brain cells.

It is for this reason that the Endocannabinoid System exists in so many different species and has survived millennia of evolution: a glitch in the system could result in serious problems, including (in women) ectopic pregnancy and miscarriages.
The Israeli neuroscientist Ester Fride demonstrated that so-called "knockout" mice, i.e. with the Endocannabinoid System blocked, resemble children suffering from growth retardation in height and weight. Without cannabinoid receptors, mice lose vitality and die prematurely.

We know that the levels of endocannabinoids in breast milk have a critical importance for the initiation of feeding in newborns and the interaction between the endocannabinoids present in milk and the receptors present on the tongue allows for balanced appetite and food assimilation, ensuring the infant survival. [21]

Endocannabinoids are the substances that our bodies naturally create to stimulate the receptors of the Endocannabinoid System and life itself would not be possible for those of us who do not have cannabinoid receptors. [22]

 

3. THE CB1 AND CB2 CANNABINOID RECEPTORS

Cannabinoid receptors are present throughout the body, embedded in cell membranes; they are believed to be among the most numerous receptor systems.

When cannabinoid receptors are stimulated, they initiate a variety of physiological processes.

The two classic cannabinoid receptors are: CB1 and CB2.
Many tissues contain both CB1 and CB2 receptors, each linked to a different action.

Other receptor classes besides CB1 and CB2 are also now studied as inherent to the Endocannabinoid System, such as the class of channel receptors that determine transient variations in potential (TRPs), the "orphan" receptors (GPR55, GPR18, GPR3, GPR6) , nuclear receptors PPARs and many others. [23]

 

3.1 WHERE CANNABINOID RECEPTORS ARE DISTRIBUTED

Initially identified in 1988 through the work of Allyn Howlett and William Devane, cannabinoid receptors were found to be much more abundant in the brain than virtually any other type of receptor. [24]

Cannabinoid receptors are widely and variedly distributed in the brain and other parts of the body, and therefore cannabinoids have a broad therapeutic profile.

The CB1 receptor is expressed in the central (brain) and peripheral (nerves) nervous systems and other peripheral organs. CB1 receptors are present in lower densities in:

  • Heart,
  • lungs,
  • testicles,
  • bone marrow,
  • thyme,
  • uterus and ovaries,
  • immune cells.

CB2 receptors are primarily expressed in high density on cells of the immune system, including macrophages, mast cells, and spleen. In the central nervous system they are mainly found in the spinal cord. [25]

 

3.2 WHAT FUNCTIONS DO CANNABINOID RECEPTORS PERFORM?

By using rodents genetically modified so that their cannabinoid receptors are not expressed (a standard procedure in scientific research to understand the functions of the receptors themselves), researchers were able to demonstrate that cannabinoid-based compounds can alter the progression of pathologies and attenuate their experimentally induced symptoms.

So-called “animal models” of osteoporosis, for example, were created in normal mice and “knockout” mice (lacking cannabinoid receptors).
When a synthetic cannabinoid was administered to both groups of mice with osteoporosis, bone damage was mitigated in normal mice but not in those without cannabinoid receptors – highlighting that cannabinoid receptors are instrumental in regulating bone density. [26]

In fact, a group of German researchers later found that the activation of CB2 receptors restrains the formation of cells that resorb bone (known as osteoclasts), down-regulating, that is, decreasing the precursors of osteoclasts and tipping the balance in favor of of osteoblasts, i.e. the cells that facilitate bone formation. [27]

Other experiments established that cannabinoid receptor-induced signaling modulates:

  • pain,
  • inflammation,
  • the appetite,
  • glucose metabolism,
  • gastrointestinal motility,
  • sleep cycles,
  • the “rhythms” of immune cells, hormones, and other mood-altering neurotransmitters, such as serotonin, dopamine, and glutamate.

 

3.3 HOW DOES A CANNABINOID RECEPTOR WORK?

Retrograde signaling functions as an inhibitory feedback system that tells cells to “cool down” when they are firing too much.

When stimulated by THC or its endocannabinoid "cousins", cannabinoid receptors trigger, at a cellular level, a cascade of biochemical changes that puts the brakes on excessive physiological activity.

Normally, neurotransmitters are released from pre-synaptic neurons and act on post-synaptic neurons.

Endocannabinoids are the only neurotransmitters that take part in "retrograde" signaling, a form of "reverse" intracellular communication, in which the stimulation starts from the post-synaptic neuron and is expressed on the pre-synaptic neuron. This decreases neuronal activity and this can result in:

  • reduction of the immune response,
  • reduction of inflammation,
  • muscle relaxation,
  • decrease in blood pressure,
  • dilation of the bronchi,
  • normalization of overstimulated nerves (as in neuropathic pain or epilepsy). [28]

 

4. THE ENDOCANNABINOIDS: ANANDAMIDE AND 2-ARACHIDONOILGLYCEROL

4.1 WHAT IS AN ENDOCANNABINOID?

Endocannabinoids, molecules that our body produces, activate their receptors, which are present throughout the body: in the brain, organs, connective tissues, glands and immune cells.

The two best-studied endocannabinoid molecules are called Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG).
These molecules are synthesized when necessary from arachidonic acid derivatives in the cell membrane, have a local effect and a short bioavailability. In fact, they are rapidly degraded by enzymes specific for endocannabinoids (called fatty acid amide hydrolase, FAAH, and monoacylglycerol lipase, MAGL). [29]

Chemically, endocannabinoids are eicosanoids (fatty acids with 20 carbon atoms), and for this reason during the 2014 ICRS Symposium in Baveno, on Lake Maggiore, it was proposed to change the nomenclature of “endocannabinoids” to “eicosanoids” in order to prevent the stigma that still surrounds the cannabis plant. However, this change never occurred.

 

4.2 WHAT FUNCTIONS DO ENDOCANNABINOIDS PERFORM


Formed "to order" (on request) in the areas in need, starting from fatty acids, AEA and 2-AG impact the body in "predominantly local and specific" ways, says Mechoulam. “Their actions are ubiquitous. They are involved in most of the physiological systems examined." [1]

Endocannabinoids are key players in life's capacity for multidimensional biochemical balance, known as homeostasis

Robert Melamede

Microbiologist and international medical cannabis activist Robert Melamede describes the Endocannabinoid System as the "master mediator" continually multitasking, adjusting and readjusting the complex network of molecular thermostats that controls our physiological rhythm. [30]

Endocannabinoids are also neuromodulators, that is, they allow communication and coordination between different types of neuronal and non-neuronal cells.
For example, when we get hurt, cannabinoids can be found in the area where the wound is, whose function is:

  • reduce the release of activators and sensitizers from injured tissue
  • stabilize nerve cells to prevent them from firing at excessively high frequencies
  • calm nearby immune cells to prevent the release of pro-inflammatory substances

These are three different mechanisms of action, on three different types of cells for one purpose: to minimize the pain and damage caused by the wound. [31]

 

4.3 WHAT IS CLINICAL ENDOCANNABINOID DEFICIENCY?

Endocannabinoid deficiency can result either from a reduction in the number of cannabinoid receptors or from decreased concentrations of Anandamide and/or 2-AG.
Individuals have different innate levels and sensitivities of endocannabinoids. [32]

The human immune system, one of the wonders of physiology, fires up like a furnace when fever is needed to defeat a virus or bacterial invasion. When the job is done, the endocannabinoid signals “turn down the heat,” cool the fever, and restore homeostasis.

Cannabinoids (endogenous, plant-derived or synthetic) are anti-inflammatory substances and literally “cool” the body. But if the endocannabinoid signaling circuitry is out of whack, if the pilot lights the fires too high, if the immune system overreacts to chronic stress or mistakes his own body for a foreign body, then the stage is set for the development of a disease autoimmune or inflammatory disease.

Whether they are the consequence of a poor quality diet, lack of physical exercise, environmental toxins or genetic factors, endocannabinoid deficiencies are associated with a reduced ability or total inability to adapt to chronic stress.
Prolonged exposure to stress depletes the tone of endocannabinoid signaling and this, in turn, generates unfavorable effects for a plethora of physiological processes. [33]

Neurologist and medical cannabis researcher Ethan Russo first hypothesized that "clinical endocannabinoid deficiency" is the basis:

  • of migraine,
  • of fibromyalgia,
  • chronic inflammation of the intestine (MICD),
  • of a group of other conditions, which respond favorably to cannabinoid-based therapies. [32] ; [34]


Deficiencies in the enzymes that are part of the Endocannabinoid System can also have serious effects on pregnancies: we know in fact that a deficiency in FAAH (the enzyme that degrades Anandamide), with a consequent increase in Anandamide, can cause spontaneous abortions. [35]

Infantile colic has also been attributed to a lack of endocannabinoids. [36]

 

5. CONCLUSIONS

The Endocannabinoid System is a complex set of circuits that coordinates many other systems in our body.

In this article we have summarized the stages that led to its identification and the main knowledge on its role as a regulator of many physiological processes.

We have also seen how a variation in the level of cannabinoid receptors, endocannabinoids or the enzymes responsible for their biosynthesis and degradation, can lead to the development of various pathological conditions that can be treated by restoring the normal cannabinoid tone.

 

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