What biological function and therapeutic relevance does the endocannabinoid system have in our body?

What biological function and therapeutic relevance does the endocannabinoid system have in our body?

Over the past three decades, we have gathered a great deal of knowledge about cannabinoids and the endocannabinoid system, and in particular about their possible therapeutic applications.

However, it is obvious that there are still many questions to be resolved in this area. This article is a personal reflection (and therefore subjective and rebuttable) of a question that I think should be understood to rationalize and thereby optimize the therapeutic effects of cannabinoids:

What is this? biological function and therapeutic relevance of the endocannabinoid system in our body?

The CB1 and CB2 cannabinoid receptors are not only present in our species (Homo sapiens), but at least also in all vertebrates and some of the invertebrates analyzed so far. In fact, it is believed that these receptors originated in the evolution of animals (though not plants) a very long time ago, most likely almost 600 million years ago. A first question that can be asked is: Are cannabinoid receptors necessary for an organism to live? The most plausible answer is "no", since various animals without cannabinoid receptors have been obtained in the laboratory using genetic engineering techniques and these animals are viable. Examples are a mammal (the mouse, Mus musculus), an amphibian (the frog Xenopus laevis), a fish (the zebrafish, Danio rerio) and a worm (the nematode Caenorhabditis elegans).

Are cannabinoid receptors necessary , so that an organism can "live well"? In this case the answer seems to be "yes". Although not essential to life, cannabinoid receptors are necessary to maintain the proper functioning and physiological balance of an organism (what we know as "homeostasis"). In fact, the neurons and other cells of our organism hardly produce endocannabinoids under basal operating conditions and begin to produce them "on demand" when they are significantly overactivated. Therefore, the endocannabinoid system is normally regarded as a "silent" system, the function of which is triggered in situations in which the homeostasis of the organism is altered, and the effect of which is therefore aimed at restoring the lost body balance. Without the endocannabinoid system, we could "survive" but not "live well". In Vincenzo di Marzo's words, the endocannabinoid system appears to have evolved to help us relax, nourish, rest, forget (unnecessary or traumatic) and generally protect us from numerous pathological changes.

However, we need to know many precise details about how the endocannabinoid system works in our body. For example, we do not even know in the mouse brain, let alone in the human brain, at which locations (for example at which neuronal synapses) and by what exact mechanisms the endocannabinoids anandamide and / or 2-arachidonylglycerol are produced. We still don't have accurate analytical methods to measure the tiny amounts of endocannabinoids produced at certain synapses (this is only possible in large parts of brain necropsies), let alone in real time and in the human brain. And when we talk about the fact that endocannabinoid levels in humans rise or fall in this or that physiological or pathological situation, we cannot forget that these experimental determinations were carried out in blood plasma or at most and on very few occasions. in the cerebrospinal fluid, but never at the precise cellular sites where these endocannabinoids originated.

It is also important to note that the endocannabinoid system is very pervasive and is expressed in all cell types at every moment of our life, from embryo to aging. The levels of its elements (cannabinoid receptors, endocannabinoids, enzyme systems that metabolize endocannabinoids) change in many diseases, especially some that are (a) difficult to diagnose and treat, (b) involve comorbidity (i.e., more than one of them occurs at the same time on the same patient) and (c) are characterized by sensitization of the central nervous system (ie some normal physiological reactions are amplified so that the patient begins to perceive them as painful or generally harmful to health). Examples of these situations include fibromyalgia, migraines, post-traumatic stress disorder, severe depression, inflammatory bowel diseases and various neuropathies.

There is evidence that cannabinoids at least in some patients alleviate the symptoms associated with these diseases and possibly the " Normalization "of a biological hypoactivity of the endocannabinoid system inherent in them. In my view, however, we still sometimes work in the area of ??association rather than cause and effect, and extrapolating some preclinical evidence to large populations of patients (read "if it works," mice, it becomes in patients " ) or anecdotal clinics work (read, "if it seems to work for one patient, it will work for everyone").

In any case, this concept of "clinical endocannabinoid deficiency", shaped by Ethan Russo (generally abbreviated as CECD), represents an extraordinarily interesting challenge for future scientific-clinical research on cannabinoids. In my opinion, a "big revolution" in the world of medical cannabis is to accurately identify a disease whose primary aetiology was to alter an element of the endocannabinoid system and thereby progress it (and not just alleviate its symptoms). It could be mitigated by specific (endo) cannabinoid treatment (which we could collectively call "cannabipathy").

Another unresolved pathophysiological problem is the so-called "two-phase effects" of cannabinoids, which Raphael Mechoulam and other researchers described a few decades ago. For example, "low" THC doses (and "low" quotes because they vary between individuals) can reduce anxiety, inhibit vomiting, increase intake, and reduce seizures, while "high" THC doses (again) in quotes) can increase anxiety, induce vomiting, reduce absorption and cause seizures. CBD appears to be significantly less likely to produce these two-phase effects in patients than THC, although there is evidence that it can exert them in certain situations in mice (e.g., controlling inflammation in rheumatoid arthritis models).

What could be the two-phase effects of THC? A hypothesis based on groundbreaking studies conducted by Beat Lutz and Giovanni Marsicano’s laboratories on genetically engineered mice suggests that THC in "low" doses would preferentially activate the CB1 receptor, which is excitatory in neurons Type (which produce a neurotransmitter called glutamate), whereas at "high" doses it would preferentially activate the CB1 receptor found in inhibitor-type neurons (which produce a neurotransmitter called a-aminobutyric acid, commonly abbreviated as GABA) the English gamma-aminobutyric acid- produce). Obviously, both processes would produce opposite effects.

Other hypotheses suggest models of differential modulation of the CB1 receptor function that depend not only on the cannabinoid dose but also on the time of exposure to the cannabinoid or the species of the cannabinoid molecule under investigation. The future is likely to provide precise answers to this complex process, which should enable us to better understand and thus perfect the therapeutic effects of cannabinoids.

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