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Credit: Trends in Endocrinology & Nutrition

The quest for a healthy Endo-Cannabinoid System

Emphasis on immunoregulation: The ECS is a disease modifier

The Endo-Cannabinoid System (ECS) is a disperse system, extending throughout the body; it is in constant interplay with all other organ systems promoting homeostasis in almost every aspect. Despite that, the ECS is still neglected and not included in the curricula of medical schools. For this reason a few introductory notes are in order. The ECS is the regulator of cognition, mood, nociception, energy metabolism, oxidation, inflammatory processes and a disease modifier as well.

The ECS consists of receptors, ligands to these receptors and enzymes that synthesize and degrade these ligands. The number of known endocannabinoid receptors is still growing to more that 55; the two most outstanding receptors are CB1R, mainly distributed throughout the nervous system and responsible for the psychoactivity of cannabis, and CB2R, mainly distributed on immune cells, even those “disguised” as specialized cells within other organs. Other receptors include TRPVx, GPR55, PPaRs etc; all these receptors form dimers between them as well as heterodimers with other types of receptors, like opioid, dopamine, serotonin, adenosine, catecholamine receptors and many others, thereby promoting a universal regulatory interplay throughout the body. The ligands to these receptors are the endocannabinoids (ECs): lipids of the eicosanoid family, derivatives of arachidonic acid (AA); the latter abounds in cell membranes; five of these are well characterized to date, but two are well studied: Anandamide (AEA) and 2-Arachidonoyl-Glycerole (2AG). ECs in the nervous system act in negative feedback loops, more or less like neurotransmitters, but, unlike them, they are synthesized and degraded on demand, and not stored in micro-vesicles. Several formerly unrelated morbid conditions are now recognized as ECS deficiencies, including, among many, migraine, autism, fibromyalgia, irritable bowel syndrome etc.

The endocannabinoid system is involved in immunoregulation through the CB2 receptor and through receptor independent biochemical pathways. The mechanisms of immunoregulation by ECs include modulation of immune response in different cell types, effect on cytokine network and induction of immunoapoptosis; in brief, ECs down-regulate the innate and adaptive immune response in most, but not all, instances. Manipulation of endocannabinoids in vivo may constitute a novel treatment modality against inflammatory disorders.

It is obvious that the health of the ECS is of great importance in many ways, including the facing of a viral infection like COVID19. A healthy ECS depends on many factors, most importantly from proper nutrition.

Dietary ω3 fatty acids seem to act as homeostatic regulators of the ECS, acting in opposite directions if consumed by obese or non-obese individuals. Little change in EC levels are seen in individuals with normal weight, not fed a high ω6 diet.

Dietary ω6 fatty acids are also essential, but should be in a balance to ω3s; suggested balance is ω3:ω6=1:1 to 1:3 for proper ECS signaling and prevention of peroxidation in general. Arachidonic acid is an essential component of the ω6 fatty acids.

Probiotics and prebiotics play a significant part in ECS health, but, for a peculiar reason, they are generally not mentioned: They up-regulate CB2Rs residing on immune cells of the gut; they also modulate CB1Rs, depending on conditions, for instance, they down-regulate CB1Rs in obese individuals and help them gain less or no fat.

Some flavonoids, like kaempferol, genistein, epigallocatechine gallate, and curcumin enhance the ECS; same happens with some anthocyanidins, like cyanidin and delphinidin, although with a different mechanism.

Phthalates, pesticides, additives to pesticides like piperonyl butoxide act as ECS disruptors, meaning that consuming organic food may be a sound protective measure, along with intake of detoxifiers, in case of health problems consistent with ECS deficiency not otherwise explained.

Chronic stress impairs the ECS by decreasing levels of AEA and 2AG, and possibly through changes in CB1R expression too. Stress management may reverse the effects of chronic stress on ECS signaling. Anecdotal reports and common experience suggest that techniques such as meditation, yoga, deep breathing exercises and practicing of sex as well, exhibit mild cannabimimetic effects, thereby balancing the system.

Exercise is also an ECS regulator: Long-term exercise leads to sustained elevations of ECs, and predictable CB1R down-regulation.

Chronic alcohol consumption and binge drinking likely desensitize or down-regulate CB1R and impair EC signaling. Alcohol is not compatible with a healthy ECS.

Nicotine is an ECS deregulator: It induces EC production in some areas of the brain, while decreasing them in others. It should be avoided too.

Caffeine, acutely administered, potentiates CB1R-mediated effects through antagonizing adenosine at the A1 receptor (AA1R). At the undisturbed state, AA1Rs tonically inhibit CB1R activity; Caffeine antagonism on AA1Rs sets CB1Rs free of inhibition, thereby enhancing ECS function, for example by letting 2AG activate CB1Rs. During chronic administration of caffeine, the effects are blurred by individual differences in adaptation. In general, CB1Rs are down-regulated.

Chocolate: Cocoa contains small amounts of at least three N-acyl-ethanolamines with cannabimimetic activity, expressed either directly by activating cannabinoid receptors, or indirectly, by increasing AEA levels.

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