N-Acylethanolamine: Difference between revisions

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== The evolutionary harm reduction program ==
== The evolutionary harm reduction program ==
The central [[Thesis statement|thesis]] is, that [[harm reduction]] is not only a [[social concept]], but also a [[biological]] one. More specifically, [[evolution]] does not make [[moral]] distinctions in the selection process, but utilizes a cannabis-based approach to harm reduction in order to promote [[survival of the fittest]]. Evidence provided from peer-reviewed scientific literature supports the hypothesis, that humans, and all [[Animal|animals]],<ref>{{cite journal | vauthors = Silver RJ | title = The Endocannabinoid System of Animals | journal = Animals | volume = 9 | issue = 9 | date = September 2019 | pmid = 31527410 | pmc = 6770351 | doi = 10.3390/ani9090686 }}</ref> since the primordial [[Cannabinoid receptor|CB receptor]] evolved at least 600 million years ago; a date that broadly consistent with the [[Cambrian]] [[Cambrian explosion|explosion]],<ref>{{Cite web| vauthors = McPartland JM |date=2002|title=Sourcing the Code: Searching for the Evolutionary Origins of Cannabinoid Receptors, Vanilloid Receptors, and Anandamide|url=http://cannabis-med.org/data/pdf/2002-01-3.pdf|url-status=live|website=cannabis-med.org}}</ref> make and use internally produced cannabis-like products (endocannabinoids) as part of the evolutionary harm reduction program. More specifically, endocannabinoids [[Homeostasis|homeostatically]] regulate all [[Biological system|body systems]] ([[cardiovascular]], [[Digestive system|digestive]], [[Endocrine system|endocrine]], [[Excretory system|excretory]], [[Immune system|immune]], [[Nervous system|nervous]], [[Human musculoskeletal system|musculo-skeletal]], [[Reproductive system|reproductive]]), and modulating endocannabinoid activity have therapeutic potential in almost all diseases affecting humans.<ref>{{Cite web| vauthors = Mechoulam R |date=2019|title=Research on Cannabinoids Over the Decades and What’s to Come - Raphael Mechoulam|url=https://www.youtube.com/watch?v=4-KQh0VrYyw|url-status=live|website=YouTube}}</ref> Therefore, the health of each individual is dependant on this system are working appropriately.<ref name=":11" /><ref>{{Cite web|vauthors = Anderson DM, Rees DI, Sabia JJ |date=January 2012|title=High on Life? Medical Marijuana Laws and Suicide|url=http://ftp.iza.org/dp6280.pdf|url-status=live|website=Institute for the Study of Labor (IZA)}}</ref>
The central [[Thesis statement|thesis]] is, that [[harm reduction]] is not only a [[social concept]], but also a [[biological]] one. More specifically, [[evolution]] does not make [[moral]] distinctions in the selection process, but utilizes a cannabis-based approach to harm reduction in order to promote [[survival of the fittest]]. Evidence provided from peer-reviewed scientific literature supports the hypothesis, that humans, and all [[Animal|animals]],<ref>{{cite journal | vauthors = Silver RJ | title = The Endocannabinoid System of Animals | journal = Animals | volume = 9 | issue = 9 | date = September 2019 | pmid = 31527410 | pmc = 6770351 | doi = 10.3390/ani9090686 }}</ref> since the primordial [[Cannabinoid receptor|CB receptor]] evolved at least 600 million years ago; a date that broadly consistent with the [[Cambrian]] [[Cambrian explosion|explosion]],<ref>{{Cite web| vauthors = McPartland JM |date=2002|title=Sourcing the Code: Searching for the Evolutionary Origins of Cannabinoid Receptors, Vanilloid Receptors, and Anandamide|url=http://cannabis-med.org/data/pdf/2002-01-3.pdf|url-status=live|website=cannabis-med.org}}</ref> make and use internally produced cannabis-like products (endocannabinoids) as part of the evolutionary harm reduction program. More specifically, endocannabinoids [[Homeostasis|homeostatically]] regulate all [[Biological system|body systems]] ([[cardiovascular]], [[Digestive system|digestive]], [[Endocrine system|endocrine]], [[Excretory system|excretory]], [[Immune system|immune]], [[Nervous system|nervous]], [[Human musculoskeletal system|musculo-skeletal]], [[Reproductive system|reproductive]]), and modulating endocannabinoid activity have therapeutic potential in almost all diseases affecting humans.<ref>{{Cite web| vauthors = Mechoulam R |date=2019|title=Research on Cannabinoids Over the Decades and What’s to Come - Raphael Mechoulam|url=https://www.youtube.com/watch?v=4-KQh0VrYyw|url-status=live|website=YouTube}}</ref><ref>{{Cite journal|last=Bachhuber|first=Marcus A.|last2=Saloner|first2=Brendan|last3=Cunningham|first3=Chinazo O.|last4=Barry|first4=Colleen L.|date=2014-10-01|title=Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1898878?__hstc=9292970.8a6d480b0896ec071bae4c3d40c40ec7.1407456000124.1407456000125.1407456000126.1&__hssc=9292970.1.1407456000127&__hsfp=1314462730|journal=JAMA Internal Medicine|language=en|volume=174|issue=10|pages=1668|doi=10.1001/jamainternmed.2014.4005|issn=2168-6106}}</ref><ref>{{Cite journal|last=Bradford|first=Ashley C.|last2=Bradford|first2=W. David|last3=Abraham|first3=Amanda|last4=Bagwell Adams|first4=Grace|date=2018-05-01|title=Association Between US State Medical Cannabis Laws and Opioid Prescribing in the Medicare Part D Population|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2676999|journal=JAMA Internal Medicine|language=en|volume=178|issue=5|pages=667|doi=10.1001/jamainternmed.2018.0266|issn=2168-6106}}</ref> Therefore, the health of each individual is dependant on this system are working appropriately.<ref name=":11" /><ref>{{Cite web|vauthors = Anderson DM, Rees DI, Sabia JJ |date=January 2012|title=High on Life? Medical Marijuana Laws and Suicide|url=http://ftp.iza.org/dp6280.pdf|url-status=live|website=Institute for the Study of Labor (IZA)}}</ref>


== Cosmic birth of NAE elements by star death ==
== Cosmic birth of NAE elements by star death ==
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And due to the chemical ability to build [[Fatty acid|chains]] and [[Skeletal formula|rings]], carbon (C) forms with quite a few other elements, like hydrogen (H), oxygen (O), nitrogen (N), [[phosphorus]] (P) and [[sulfur]] (S) the basis of the myriad of the chemical compounds, [[Protein|proteins]], [[DNA]], [[Carbohydrate|carbohydrates]], [[Lipid|lipids]], etc. of living organisms.
And due to the chemical ability to build [[Fatty acid|chains]] and [[Skeletal formula|rings]], carbon (C) forms with quite a few other elements, like hydrogen (H), oxygen (O), nitrogen (N), [[phosphorus]] (P) and [[sulfur]] (S) the basis of the myriad of the chemical compounds, [[Protein|proteins]], [[DNA]], [[Carbohydrate|carbohydrates]], [[Lipid|lipids]], etc. of living organisms.


[[NASA]]-funded [[Scientist|scientists]] have evidenced, that some building blocks of DNA, a [[nucleic acid]], and the molecule that carry [[Genetic code|genetic]] instructions for life, found in meteorites, were likely created in [[Universe|space]]. The research supports the theory, that a "kit" of finished parts created in space and delivered to Earth by [[Meteorite fall|meteorite]] and [[Impact event|comet]] impact, has aided the [[Abiogenesis|origin of life]].<ref>{{Cite web|last=Callahan|first=Michael P.|date=2011|title=DNA Building Blocks Can Be Made in Space|url=https://www.youtube.com/watch?v=1g7AKVZ3HC4|url-status=live|website=YouTube}}</ref>
[[NASA]]-funded [[Scientist|scientists]] have evidenced, that some building blocks of DNA, a [[nucleic acid]], and the molecule that carry [[Genetic code|genetic]] instructions for life, found in meteorites, were likely created in [[Universe|space]]. The research supports the theory, that a "kit" of finished parts created in space and delivered to Earth by [[Meteorite fall|meteorite]] and [[Impact event|comet]] impact, has aided the [[Abiogenesis|origin of life]].<ref>{{Cite web|last=Callahan|first=Michael P.|date=2011|title=DNA Building Blocks Can Be Made in Space|url=https://www.youtube.com/watch?v=1g7AKVZ3HC4|url-status=live|website=YouTube}}</ref>


A simulated [[Comet]] impact on the surface of the [[earth]], as it probably would look like 3.8 billion years ago at the [[Late Heavy Bombardment|late heavy bombardment]] show, that [[Amino acid|amino acids]] (i.e. [[Organic compound|organic]] compounds arisen from [[amine]] (-NH2) and [[carboxylic acid]] (-COOH) [[Functional group|functional groups]], producing [[Protein|proteins]]) in [[water]] is able to make [[Peptide bond|peptide bonds]] (i.e. bonds from the carboxyl group of one amino acid to the amino group of the other amino acid), and [[Peptide|peptides]] from the heat of the impact, and this could be a spark to early life on earth.<ref>{{Cite web|title=New Evidence That Comets Deposited Building Blocks of Life on Primordial Earth|url=https://www.newswise.com/articles/new-evidence-that-comets-deposited-building-blocks-of-life-on-primordial-earth|access-date=2021-04-03|website=www.newswise.com|language=en}}</ref>
⚫
Using the samples returned by the [[spacecraft]] [[Stardust (spacecraft)|Stardust]], other scientists discovered the amino acid [[glycine]] (C<sub>2</sub>H<sub>5</sub>NO<sub>2</sub>) fully formed in a [[comet tail]], but this glycine was not like this on Earth; it was built with some subtle differences - traces of [[Carboxylic acid|COOH]]'s important presence and [[Interstellar medium|interstellar]] heritage, as well as strengthened the theory of [[panspermia]], which claims that these "seeds" of life are widespread throughout the [[universe]].<ref>{{Cite web|last=Schultz|first=Colin|date=2011|title=Amino Acids from Interstellar Space|url=https://www.youtube.com/watch?v=uAr6MbzRuEg|url-status=live|website=YouTube}}</ref>

⚫
Using the samples returned by the [[spacecraft]] [[Stardust (spacecraft)|Stardust]], other scientists discovered the amino acid [[glycine]] (C<sub>2</sub>H<sub>5</sub>NO<sub>2</sub>) fully formed in a [[comet tail]], but this glycine was not like this on Earth; it was built with some subtle differences - traces of [[Carboxylic acid|COOH]]'s important presence and [[Interstellar medium|interstellar]] heritage, as well as strengthened the theory of [[panspermia]], which claims that these "seeds" of life are widespread throughout the [[universe]],<ref>{{Cite web|last=Schultz|first=Colin|date=2011|title=Amino Acids from Interstellar Space|url=https://www.youtube.com/watch?v=uAr6MbzRuEg|url-status=live|website=YouTube}}</ref> and among the most widespread and versatile signaling molecules ever discovered.<ref>{{Cite journal|last=Maccarrone|first=Mauro|last2=Bab|first2=Itai|last3=Bíró|first3=Tamás|last4=Cabral|first4=Guy A.|last5=Dey|first5=Sudhansu K.|last6=Di Marzo|first6=Vincenzo|last7=Konje|first7=Justin C.|last8=Kunos|first8=George|last9=Mechoulam|first9=Raphael|last10=Pacher|first10=Pal|last11=Sharkey|first11=Keith A.|date=2015|title=Endocannabinoid signaling at the periphery: 50 years after THC|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420685/|journal=Trends in pharmacological sciences|volume=36|issue=5|pages=277–296|doi=10.1016/j.tips.2015.02.008|issn=0165-6147|pmc=4420685|pmid=25796370}}</ref>


Further other scientists have used the [[radio telescope]] ([[Green Bank Telescope|GBT]]) in [[West Virginia]] to study a giant [[Interstellar cloud|cloud of gas]] about 25,000 [[Light-year|light-years]] from Earth, near the center of our [[Milky Way]]. The chemicals found in the cloud include one [[molecule]] that is thought to be a precursor to a key element in DNA and another that may have a role in the formation of the [[amino acid]], [[alanine]] (Ala: C<sub>3</sub>H<sub>7</sub>NO<sub>2</sub>).
Further other scientists have used the [[radio telescope]] ([[Green Bank Telescope|GBT]]) in [[West Virginia]] to study a giant [[Interstellar cloud|cloud of gas]] about 25,000 [[Light-year|light-years]] from Earth, near the center of our [[Milky Way]]. The chemicals found in the cloud include one [[molecule]] that is thought to be a precursor to a key element in DNA and another that may have a role in the formation of the [[amino acid]], [[alanine]] (Ala: C<sub>3</sub>H<sub>7</sub>NO<sub>2</sub>).

Revision as of 15:42, 3 April 2021

General chemical structure of N-acylethanolamines

An N-acylethanolamine (NAE) is a type of fatty acid amide formed when one of several types of acyl group is linked to the nitrogen atom of ethanolamine. These amides conceptually can be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamines.[1] Another route relies on the transesterification of acyl groups from phosphatidylcholine by an N-acyltransferase (NAT) activity.[citation needed] The suffixes -amine and -amide in these names each refer to the single nitrogen atom of ethanolamine that links the compound together: it is termed "amine" in ethanolamine because it is considered as a free terminal nitrogen in that subunit, while it is termed "amide" when it is considered in association with the adjacent carbonyl group of the acyl subunit. Names for these compounds may be encountered with either "amide" or "amine" varying by author.[2]

Examples

Examples of N-acylethanolamines include:[3]

These bioactive lipid amides are generated by the membrane enzyme NAPE-PLD, and natural bile acids regulate this essential process.[25] An in vivo active NAPE-PLD inhibitor called LEI-401 was found to be CNS-active, and modulated NAE biosynthesis. It had similar effects as a cannabinoid CB1 receptor antagonist, which could be reversed by co-treatment with a FAAH inhibitor.[26]

The effects of NAE 20:4 (AEA) and another endocannabinoid 2-Arachidonoylglycerol (2-AG: C23H38O4; 20:4, ω-6 ) is found to be enhanced by “entourage compounds”, NAEs that inhibit their hydrolysis via substrate competition, and thereby prolong their action. These compounds include N-palmitylethanolamide (PEA, NAE 16:0), N-oleoylethanolamide (SEA, NAE 18:0), and cis-9-octadecenoamide (OEA, oleamide, NAE 18:1).[27]

All are members of the endocannabinoidome (eCBome), a complex lipid signaling system composed of more than 100 of fatty acid-derived mediators and their receptors, its anabolic and catabolic enzymes of more than 50 proteins, which are deeply involved in the control of energy metabolism and its pathological deviations,[28] as well as immunosuppression.[29] NAE's are also involved in modulation of different physiological processes such as pain, stress, anxiety, appetite, cardiovascular function and inflammation. A study suggest the presence of an endogenous NAE tone control emotional behavior.[26]

Raphael Mechoulam that described and named Anandamide in 1992. He said:

Look, I believe there are 8 billion people on this planet, and I believe there are 8 billion different personalities. One way of explaining it is, there are several hundred compounds, endocannabinoid-like compounds. They are like anandamide in their chemical structure, that are present in the brain, and it is quite possible that each one of us, has a different, slightly different level of these compounds. And it is quite possible that differences in the endocannabinoid system, endocannabinoid-like system, can have something to do with the different personalities, and that ratios of 10 of these to 10 of others and so on will cause that.[30] in the YouTube video The Scientist, released in 2015.[31]

Beyond vertebrates NAEs are also found to have signaling roles in more primitive organism, implicated as metabolic signals that coordinate nutrient status and lifespan determination in Caenorhabditis elegans, and detected in organisms as diverse as yeast (Saccharomyces cerevisiae), freshwater fish (Esox lucius and Cyprinus carpio), bivalve mollusc (Mytilus galloprovincialis), protists (Tetrahymena thermophila), slime mold (Dictyostelium discoideum), microbes such as bacteria, fungi, and viruses, are all organisms that appear to regulate their endogenous NAE levels via similar enzymatic machinery as mammalian vertebrates, show a widespread occurrence of NAEs, from single-celled organisms to humans, and a highly conserved role for this group of lipids in cell signaling.[32][9] Studies in amphibians and birds show that endocannabinoid signaling may function as a behavioral switch, allowing redirection from less- to more-essential behaviors in response to emergent environmental changes,[33] and provide evidence of cannabinoid modulation of aggression, emesis, feeding behavior, locomotor activity, reproductive behaviors, vocal learning, sensory perception and stress responses.[34][35]

NAE and the reproductive system

Several researches have found, that NAE, and especially 20:4 anandamide (AEA: C22H37NO2; 20:4, ω-6), is a part of the reproductive system,[36] and play a fundamental role for a healthy and successful pregnancy.

A 2006 report from the Pediatrics Department at Vanderbilt University characterized NAE 20:4 (AEA) as “an emerging concept in female reproduction”, because they found a “cannabinoid sensor” mechanism to influence several crucial steps during early pregnancy.

The Vanderbilt research team termed this “endocannabinoid signaling in preimplantation embryo development and activation”, because, one of the first things the fertilized embryo must do, is to attach itself to the lining of the uterus, and without becoming attached to the uterine wall, which forms the umbilical cord, there will be no pregnancy. NAE 20:4 (AEA) play a key role, because, for the embryo to become attached to the lining of the uterus, a particular amount (temporary reduction) of NAE 20:4 (AEA), present at the uterine lining, is necessary for the fertilized embryo can attach itself to the uterine wall. NAE 20:4 (AEA) uses the CB1 receptors, that are at high levels on the blastocyst (fertilized egg), to this attachment. So the amount of NAE 20:4 (AEA) directs the outcome of the attachment to the uterine wall via CB1, and thereby, the outcome of pregnancy,[37] and a later possible miscarriage. [38]

An earlier 2004 research in to the course of ectopic pregnancy, a result of embryo retention in the fallopian tube, found that decoupled cannabinoid receptor CB1, can cause retention of embryos in the mouse oviduct, and lead to pregnancy failure. The report estimates that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation, which are crucial to normal oviductal embryo transport. This was also seen in wild-type mice treated with methanandamide (AM-356; C23H39NO2, 20:4, n6), and thereby concluded, that a colocalization of CB1 in the oviduct muscularis implicate a basal endocannabinoid tone of NAE 20:4 (AEA) is needed for oviductal motility and for normal journey of embryos into the uterus.[39]

Another 2004 study published in the American Journal of Obstetrics and Gynecology find NAE 20:4 (AEA) and the phytocannabinoid Δ9-tetrahydrocannabinol (THC: C21H30O2), that can mimic NAE 20:4 (AEA) activation at CB1 and CB2 receptors,[40][41][42] and able to switch from agonist to antagonist depending on firing rate,[43] to exert a direct relaxant effect on human pregnant myometrium in vitro, with equal potency for both compounds, which was mediated through the CB1 receptor. This means that the middle layer of the uterine wall is modulated by NAE 20:4 (AEA) as well.[44]

Mood

As the euphoric feeling described after running, called the "runners high" is, at least in part, due to increased circulating endocannabinoids (eCBs), and these lipid signaling molecules are involved in reward, appetite, mood, memory and neuroprotection, an analysis of endocannabinoid concentrations and moods after singing, dancing, exercise and reading in healthy volunteers, showed that singing increased plasma levels of anandamide (AEA) by 42%, palmitoylethanolamine (PEA) by 53% and oleoylethanolamine (OEA) by 34%, and improved positive mood and emotions. Dancing did not affect eCB levels, but decreased negative mood and emotions. Cycling increased OEA levels by 26%, and reading increased OEA levels by 28%. All the ethanolamines were positively correlated with heart rate. As so, the plasma OEA levels were positively correlated with positive mood and emotions, and AEA levels were seen positively correlated with satiation.[16]

Longevity

A study of 42 eighty years old (octogenarians) humans living in the east-central mountain area of Sardinia, a High-Longevity Zone (HLZ) in Italy, have found, that the endocannabinoidome (eCBome) related circulating NAEs and familar fatty acids are associated with a longer human life or longevity, as increased conjugated linoleic acid (CLA: C18H32O2; 18:2, n-6) and heptadecanoic acid (C17H34O2; 17:0), elevated palmitoleic acid (POA; C16H30O2; 16:1, n-7), a conjugate acid of a palmitoleate (C16H29O2; 16:1, n-7),[45] where n-7 fatty acids are precursors for the production of omega-4 fatty acids like palmitolinoleic acid (16:2),[46] and a significantly increased level of NAE 22:6 (DHEA: C24H37NO2; 22:6, n-3), the metabolite of DHA (C22H32O2; 22:6, n-3), and the two endocannabinoids NAE 20:4 (AEA: C22H37NO2; 20:4, ω-6) and 2-arachidonoyl-glycerol (2-AG: C23H38O4; 20:4, n-6), as well of increased NAE 18:1 (OEA: C20H39NO2; 18:1, ω-9), the amide of palmitic acid (C16H32O2; 16:0) and ethanolamine (MEA: C2H7NO), and increase of 2-linoleoyl-glycerol (2-LG; C21H38O4; 18:2, n-6),[47] derived from linoleic acid (LA: C18H32O2; 18:2, n-6), can indicate a metabolic pattern potentially protective from adverse chronic conditions, and show a suitable physiological metabolic pattern, that may counteract the adverse stimuli leading to age-related disorders such as neurodegenerative and metabolic diseases.[48]

It is found, that 3T3-L1 adipocytes convert eicosapentaenoic acid (EPA: C20H30O2; 20:5, n-3) to NAE 20:5 (EPEA: C22H35NO2; 20:5, ω-3) or Anandamide (20:5, n-3) and docosahexaenoic acid (DHA: (C22H32O2; 22:6, n-3) to NAE 22:6 (DHEA: C24H37NO2; 22:6, ω-3), or Anandamide (22:6, n-3). This conversion to EPEA and DHEA decrease IL-6 and MCP-1 levels, and the combined incubations with PPAR-gamma and CB2 antagonists, suggest a role of these receptors in mediating the reduction of IL-6 by DHEA. These results are in line with the hypothesis, that in addition to other pathways, this formation of NAEs may contribute to the biological activity of n-3 PUFAs, and different targets, including the endocannabinoid system (eCBome), may be involved in the immune-modulating activity of fish-oil derived NAEs.[20]

The importance of a low ratio of omega-6 to omega-3 essential fatty acids

Studies have found, that humans evolved on a diet with a ratio of omega-6 (n-6) to omega-3 (n-3) essential fatty acids (EFA) of about 1:1, whereas in today’s Western diets the ratio is 15/1–16.7/1, or even more. The excessive amounts of n-6 polyunsaturated fatty acids (PUFA) and a very high n-6/n-3 ratio, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas a low n-6/n-3 ratio exert suppressive effects. However, it is found impotent, that this low ratio, should change a bit, depending of disease, as the ratio of 2.5/1 reduce rectal cell proliferation in patients with colorectal cancer, and 2–3/1 suppress inflammation in patients with rheumatoid arthritis, 4/1 is optimum for prevention of cardiovascular disease, showing a 70% decrease in total mortality, and 5/1 have a beneficial effect on patients with asthma, whereas 10/1 have adverse consequences, indicate, that the optimal ‘low ratio’, may vary with the specific disease.[49][33]

Metabolic production of NAEs

Diets in mammals, containing 20:4,n−6 and 22:6,n−3, are found to increase several biologically active NAEs in brain homogenates as metabolic products, like 20:4,n−6 NAE (4-fold), 20:5,n−3 NAE (5-fold), and 22:5,n−3 and 22:6,n−3 NAE (9- to 10-fold). The increase in all of the metabolic NAEs is regarded biologically important, because NAEs having fatty acids with at least 20 carbons and three double bonds bind to CB1 receptors,[50] and endogenously released NAE 20:4 and 2-arachidonylglycerol (2-AG: C23H38O4; 20:4,n-6) are also found to activate CB2 receptors in addition.[17]

The hydrolysis of NAE to free fatty acid (FFA) and ethanolamine (MEA) in animals, is catalyzed by fatty acid amide hydrolase (FAAH) or by a N-acylethanolamine-hydrolyzing acid amidase (NAAA), and the polyunsaturated NAEs such as NAE 18:2, NAE 18:3, or NAE 20:4 can also be oxygenated via lipoxygenase (LOX) or cyclooxygenase (COX), to produce ethanolamide oxylipins, like prostaglandin ethanolamides (prostamide) by COX-2, with various potential bioactivities that may have enhanced affinity with cannabinoid receptors in comparison to their respective non-oxygenated NAEs,[51][29][52] as well as to oxygenated eicosanoid ethanolamides, prostaglandins, and leukotrienes, all believed to be important signaling compounds.[53]

The major COX-2 derived prostanoid product from NAE 20:4 (AEA) are prostaglandin E2 (PGE2) ethanolamide (PGE2-EA; prostamide E2) and PGD2 ethanolamide (PGD2-EA; prostamide D2), might have many important functions,[54] as PGE2 and PGD2 are pro-inflammatory mediators responsible for the induction of inflammation,[51] PGE2-EA and PGD2-EA are contrary both growth inhibitory and can induce apoptosis,[55] as well as that NAE 20:4 (AEA) and/or its prostamide metabolites in the renal medulla, may represent medullipin and function as a regulator of body fluid and the mean arterial pressure (MAP).[56]

In addition to metabolism by FAAH, COX-2 and LOXs, NAE 20:4 (AEA) can also undergo oxidation by several of human cytochrome P450 (CYPs) enzymes, resulting in various oxidized lipid species, some of which have biological relevance as CYP-derived epoxides, that can act as a potent agonist of CB2 receptors.[53]

NSAIDs that inhibit COX2, may find its medical influence from the cannabinoid system, either by inhibiting the break down of NAE 20:4 (AEA) by FAAH (i.e. ibuprofen, indomethacin, flurbiprofen, ibu–am5), or by inhibiting a possible intracellular transporter of endocannabinoids (i.e. acetaminophen).[57]

The phytocannabinoid THC is found to have twenty times the anti-inflammatory potency of aspirin and twice that of hydrocortisone, but in contrast to NSAIDs, it demonstrates no COX inhibition at physiological concentrations.[58]

Similar pathways of hydrolysis or oxidation of NAEs are also found in plant cells.[59][60]

NAE system in plants

N-acylethanolamines (NAEs), constitute a class of lipid compounds naturally present in both animal and plant membranes, as constituents of the membrane-bound phospholipid, N-acylphosphatidylethanolamine (NAPE). NAPE is composed of a third fatty acid moiety linked to the amino head group of the commonly occurring membrane phospholipid, phosphatidylethanolamine.[17]

It is found, that the levels of NAEs increases 10- to 50-fold in tobacco (Nicotiana tabacum) leaves treated with fungal elicitors, as a protection against it, by producing the N-myristoylethanolamine (Myristamide-MEA: C16H33NO2; NAE 14:0), that specific binds to a protein in tobacco membranes with biochemical properties appropriate for the physiological responses, and it do not show identical binding properties to NAE-binding proteins in intact tobacco microsomes, compared to non-intact microsomes. In addition to this, antagonists of mammalian CB receptors was seen to block both of the biological activities previously attributed to NAE 14:0, this endogenous NAE that is accumulated in tobacco cell suspensions and leaves after pathogen elicitor perception, is why it is proposed, that plants possess an NAE-signaling pathway with functional similarities to the “endocannabinoid” pathway of animal systems, and this pathway, in part, participates in xylanase elicitor perception in the tobacco plant, as well as in the Arabidopsis and Medicago truncatula plant tissues.[17]

Medical values

N-acylethanolamines (NAEs), with its cell-protective and stress-combating action-response of organisms, have showed promise as therapeutic potential in treating bacterial, fungal, and viral infections, as NAEs also exhibit anti-inflammatory, antibacterial, and antiviral properties, which have considerable application potential.[9]

In pediatric medicine for conditions including “non-organic failure-to-thrive” and cystic fibrosis.[38] A dysfunction of the endocannabinoid system is researched for a possible determining factor for causing infertility in cystic fibrosis (CF), as the illness is associated with an imbalance of fatty acids, show that mild stimulation of the endocannabinoid system (CB1 and CB2) in infancy and adolescence, appears to normalize many reproductive processes and prevent infertility in CF males. The mild stimulated, were fully fertile, producing offspring comparable by the number of litters and the number of pups as the wild-type mice, and there counterparts, not treated, were shown completely infertile.[61]

As NAE related Cannabis has an ancient tradition of usage as a medicine in obstetrics and gynecology, its extracts, may represent an efficacious and safe alternative for treatment of a wide range of conditions in women including dysmenorrhea, dysuria, hyperemesis gravidarum, and menopausal symptoms.[62]

For the prevention or repairing of a devastating feeling of loneliness at stay-at-home order, COVID-19 lockdowns, solitary confinement etc., as it is found, that social contact increases, whereas isolation decreases, the production of the endogenous marijuanna-like neurotransmitter, NAE 20:4 (AEA), in nucleus accumbens (NAc), which regulate motivated behavior, and this NAE 20:4 (AEA) production, via oxytocin, the neuropeptide reinforcing parental and social bonding, and its consequent activation of CB1 cannabinoid receptors, are necessary and sufficient to express the rewarding properties of social interactions, i.e. social contact reward.[63][64] In addition, CB1 activation also suppresses release of serotonin, dopamine, acetylcholine and noradrenaline, which are mediating the characteristic cognitive and antidepressant effects.[65]

Evidence indicates that several classes of pharmaceuticals upregulate the endocannabinoidome, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate this system: massage and chiropractic, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification, like diet, weight control, exercise, and the use of psychoactive substances, like alcohol, tobacco, coffee, and cannabis, do also modulate it, either by being a FAAH inhibitor, that blocks the breakdown of NAE 20:4 (AEA), and/or enhance or lowering its production, and/or by activate or inactivate the receptors connected.[27][66][67][68][69]

The evolutionary harm reduction program

The central thesis is, that harm reduction is not only a social concept, but also a biological one. More specifically, evolution does not make moral distinctions in the selection process, but utilizes a cannabis-based approach to harm reduction in order to promote survival of the fittest. Evidence provided from peer-reviewed scientific literature supports the hypothesis, that humans, and all animals,[70] since the primordial CB receptor evolved at least 600 million years ago; a date that broadly consistent with the Cambrian explosion,[71] make and use internally produced cannabis-like products (endocannabinoids) as part of the evolutionary harm reduction program. More specifically, endocannabinoids homeostatically regulate all body systems (cardiovascular, digestive, endocrine, excretory, immune, nervous, musculo-skeletal, reproductive), and modulating endocannabinoid activity have therapeutic potential in almost all diseases affecting humans.[72][73][74] Therefore, the health of each individual is dependant on this system are working appropriately.[36][75]

Cosmic birth of NAE elements by star death

NAE 20:4 (AEA: C22H37NO2; 20:4, ω-6) is the amide of arachidonic acid (C20H32O2; 20:4, ω-6) and ethanolamine (MEA: C2H7NO).

NAE 20:5 (EPEA: C22H35NO2; 20:5, ω-3) or Anandamide (20:5, n-3). It is the amide of eicosapentaenoic acid (EPA: C20H30O2; 20:5, ω-3)

NAE 22:6 (DHEA: C24H37NO2; 22:6, ω-3), or Anandamide (22:6, n-3) "synaptamide", is the amide of docosahexaenoic acid (DHA: C22H32O2; 22:6, ω-3) and ethanolamine (MEA: C2H7NO)

In the heart of a heavy star, like Betelgeuse, and in its core, is where all the ingredients of life (and elements of NAEs) are found made. Deep in its core, the star will fight a futile battle against its own gravity, as it tries to stop itself collapsing under its own weight, is where new elements are made in a sequence of separate stages.

Stage one, is while there is still a supply of hydrogen (H) to burn. As the star burn in hydrogen to helium (He) in the core, are vast amounts of energy released and that energy escapes and thereby creating an outward pressure, which balances the force of gravity, and holds the star off and keeps it stable. But the hydrogen (H) in the core will eventually run out, and the fusion reactions will stop and no energy will be released, and the outward pressure will disappear, and the core will start to collapse and very rapidly leaving a shell of hydrogen (H) and helium (He) behind.

Beneath this shell, as the core collapses, the temperature rises again until at a hundred million degrees, the stage two stars and helium nuclear begin to fuse together. Helium fusion does two things. First, it releases more energy so the collapse is halted, and secondly it produce two more elements in that process. Carbon (C) and oxygen (O), two elements vital for life (and molecules in the NAE structure), with further collapses until it eventually form iron (Fe). And when that happens, the star collapses around itself. And, through a nebula, meteorites and comet impact, this is where all the carbon, hydrogen, oxygen etc. in the NAE molecular structure come from, and every atom in every living thing on the planet earth, was probably produced in and carried from the elements of a dying star.[76]

And due to the chemical ability to build chains and rings, carbon (C) forms with quite a few other elements, like hydrogen (H), oxygen (O), nitrogen (N), phosphorus (P) and sulfur (S) the basis of the myriad of the chemical compounds, proteins, DNA, carbohydrates, lipids, etc. of living organisms.

NASA-funded scientists have evidenced, that some building blocks of DNA, a nucleic acid, and the molecule that carry genetic instructions for life, found in meteorites, were likely created in space. The research supports the theory, that a "kit" of finished parts created in space and delivered to Earth by meteorite and comet impact, has aided the origin of life.[77]

A simulated Comet impact on the surface of the earth, as it probably would look like 3.8 billion years ago at the late heavy bombardment show, that amino acids (i.e. organic compounds arisen from amine (-NH2) and carboxylic acid (-COOH) functional groups, producing proteins) in water is able to make peptide bonds (i.e. bonds from the carboxyl group of one amino acid to the amino group of the other amino acid), and peptides from the heat of the impact, and this could be a spark to early life on earth.[78]

Using the samples returned by the spacecraft Stardust, other scientists discovered the amino acid glycine (C2H5NO2) fully formed in a comet tail, but this glycine was not like this on Earth; it was built with some subtle differences - traces of COOH's important presence and interstellar heritage, as well as strengthened the theory of panspermia, which claims that these "seeds" of life are widespread throughout the universe,[79] and among the most widespread and versatile signaling molecules ever discovered.[80]

Further other scientists have used the radio telescope (GBT) in West Virginia to study a giant cloud of gas about 25,000 light-years from Earth, near the center of our Milky Way. The chemicals found in the cloud include one molecule that is thought to be a precursor to a key element in DNA and another that may have a role in the formation of the amino acid, alanine (Ala: C3H7NO2).

Cyanomethanimine (C2H2N2), is a step in the process that is believed to produce adenine (C5H5N5), one of the four nucleobases that make up the "step" of the ladder-like structure of DNA. The second molecule, called ethanamine (C5H5N), is thought to play a role in the formation of alanine (Ala - C3H7NO2), one of the twenty amino acids in the genetic code.[81][82]

See also

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