Biological harmony: Endocannabinoid system.

Discovered in the 90s the endocannabinoid system (ES) has allowed us to better understand how the body works. This system is a cellular communication and signaling network carried out through receptors found in the membranes of the body's cells. It is a system involved in the modulation and regulation of the organism, which plays a role in the balance of different neurological, immunological, and cardiovascular processes; as well as in energy and endocrine metabolism.

Interestingly, this communication system is closely related to molecules present in the cannabis plant. In the mid-1960s, research began on this plant and chemical structures of several of its components were identified. At the time there were a series of discoveries made by Dr. Raphael Mechoulam together with his colleague Gaoni, who in their research managed to identify the psychoactive component of cannabis, which is known as Δ9-tetrahydrocannabinol (Δ9-THC).

Twenty years later, Dr. Mechoulam with his collaborators discovered these cannabinoids were coupled to receptors distributed in the human body, thus concluding that these receptors are directed by one or more endogenous components. Mechoulam made second major breakthrough, the discovery of ligands for these receptors, thus establishing the presence of the endocannabinoid system.

The receptors established on the surface of the cells of this system received according to their affinity, a molecule whose interaction allows a signal to be emitted and transmits that information to the interior of the cell; initiating an adequate cellular response according to the related molecule that has been captured by the receptor.

There are several types of receptors on these cell surfaces and the ones that have been studied the most in the ES are CB1, which are very abundant in the central and peripheral nervous system, and CB2 receptors that are found in greater quantity on the surface of cells of the immune system, the gastrointestinal tract and many of the main organs of the body. In this system the CB1 and CB2 receptors belong to the extensive family of G protein-coupled receptors (G-protein coupled receptors, GPCR).

CB1 cannabinoid receptors are the most abundant and widely distributed GPCRs in the brain. One of the functions of CB receptors in the immune system is to modulate the release of cytokines responsible for inflammation and regulation.

These receptors interact naturally with messengers or ligands of the organism itself that are known to help coordinate and regulate what we feel, think and do. These natural ligands are called anandamide and 2-arachidonylglycerol (2-AG). Their interaction works like a padlock and a key.

On the one hand, the endogenous ligand anandamide of the CB1 receptor is a neurotransmitter secreted by neurons and other cells (its presence is common in the thalamus, hippocampus, basal ganglia and cerebellum, as well as in the spleen and heart) whose effects are short-lived in the human body and is linked, like the rest of cannabinoids, to sedation, reduction of vomiting and provocation of appetite, improvement of respiratory function and relaxation; as well as concentration, perception of time and even memory.

On the other hand, 2-AG is another well-studied endocannabinoid and is the main ligand of the CB2 receptor. Found in the body in a much higher concentration than anandamide, 2-AG has an important role in the regulation of appetite, functions of the immune system and pain management.

These interactions between ligands and their receptors, distributed throughout a large part of the body, are known to help adjust most of the vital physiological functions in the body.

The main function of this system is to maintain body homeostasis, that is; biological harmony in response to changes in the environment; that affects all bodily systems or their related functions, such as sleep, appetite, pain, inflammation, metabolism, memory, mood and even reproduction, ensuring that all systems work in coordination with each other.

Maintaining this harmony or homeostasis includes, as mentioned, the immune system; through the activation of CB1 and CB2 receptors found in a wide variety of cells. This system interacts with its endogenous ligands such as anandamide and 2-AG and they are analogous to the phytocannabinoids found in the Cannabis sativa plant. In this way phytocannabinoids are related to the regulation of homeostasis in the organism, as well as; interaction with systems like the immune system and is completely as beneficial for the body as an endogenous cannabinoid is.

In the nervous system, ES through molecules such as anandamide or 2-AG acts as a negative feedback system that regulates the release of other neurotransmitters, mainly γ-aminobutyric acid (GABA), dopamine and, glutamate. The ES releases its endogenous cannabinoids to restore balance and repair alterations, sometimes when it cannot do it alone; phytocannabinoids can be used to restore and improve signaling pathways.

More than 400 known phytocannabinoids have been reported and more than 100 have been studied. Among them you can find tetrahydrocannabinol (THC) that has psychoactive effects and also antiemetic, analgesic, anti-inflammatory, relaxing and bronchodilator properties; cannabichromene (CBC), which is anti-inflammatory and analgesic, cannabidiol (CBD), which has become popular for not being psychoactive and having various properties known as anti-inflammatory, analgesic, neuroprotective, anxiolytic, among others; cannabigerol or CBG which is a precursor to other cannabinoids and has anxiolytic, neuroprotective, analgesic, antibacterial, and more properties. Several of these phytocannabinoids have been studied at the preclinical level and their antitumor action has been demonstrated, which can be very useful in the treatment of pathologies as serious as cancer. CB2 receptor agonists do not cause psychoactive effects, which has made it increasingly a research target in the therapeutic applications of cannabinoids, such as using them as an analgesic, anti-inflammatory, antineoplastic, among others.

Among these properties, a great variety are related to cells of the immune system. There is multiple evidence of the therapeutic use of cannabinoids; for example, cannabidiol (CBD) has a wide range of therapeutic uses, among which there is evidence in the processes of maintaining homeostatic balance through its anxiolytic, anti-inflammatory and analgesic properties, as well as other cannabinoids. On the other hand, THC is that compound with a great taboo for its psychoactive properties that for some are pleasant and for others not so much. It also exerts its action by binding to the receptors of cells of the immune system and can participate in the regulation of balance and homeostasis in the body and protect for example against damage caused by autoimmune attacks slowing down the production of hyperactive T cells and preventing disturbance of the immune system.

The lymphocytes T Helper (Th) are involved in the activation and direction of other cells of the immune system, and are particularly important in the adaptive immune response in the interaction and activation of the system. There is a bias on the part of cannabinoids in the interaction with this type of cells and this involves both types of CB1 and CB2 receptors. For example in the presence of THC the gamma interferon (IFN-γ) and proinflammatory interleukins such as IL12 decrease (the Th1 cells activate macrophages and other antigen presenting cells, if this mechanism is not regulated it can become counterproductive) while other anti-inflammatory cytokines such as IL4 can increase. It is here where the immunosuppression of certain reactions can benefit the body by regulating and avoiding the imbalance in the system.

There is multiple evidence of how cannabis compounds such as THC participate actively and directly in the harmonization, health and balance of our body through the interaction of phytocannabinoids with natural receptors, working similar to endogenous cannabinoids.

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