N-Acylethanolamine

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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]

General chemical structure of N-acylethanolamines

ExamplesEdit

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.[26] 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.[27]

At least two pathways distinct from NAPE-PLD have been proposed as metabolic pathways for NAE 20:4 (AEA) formation. One pathway involves the double-O-deacylation of NAPEs by α,β-hydrolase (ABHD4) to form glycerophospho-N-acylethanolamines (GP-NAEs),[28] followed by conversion of these intermediates to NAEs by glycerophosphodiesterase-1 (GDE1). Another pathway utilizes a phospholipase C (PLC) to produce phopho-N-arachidonoylethanolamine (pAEA) from NAPE, widely found in phospholipids,[29] followed by conversion of pAEA into NAE 20:4 (AEA) by phosphatases such as PTPN22 and SHIP1.[30]

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).[31]

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,[32] as well as immunosuppression.[33] 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.[27]

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.[34] in the YouTube video The Scientist, released in 2015.[35]

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.[36][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,[37][38] and provide evidence of cannabinoid modulation of aggression, emesis, feeding behavior, locomotor activity, reproductive behaviors, vocal learning, sensory perception and stress responses.[39][40]

NAE and the reproductive systemEdit

Several researches have found, that NAE, and especially 20:4 anandamide (AEA: C22H37NO2; 20:4, ω-6), is a part of the reproductive system,[41] 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,[42] and a later possible miscarriage.[43]

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.[44]

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,[45][46][47] and able to switch from agonist to antagonist depending on firing rate,[48] 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.[49]

MoodEdit

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]

LongevityEdit

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),[50] where n-7 fatty acids are precursors for the production of omega-4 fatty acids like palmitolinoleic acid (16:2),[51] 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),[52] 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.[53]

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.[21]

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

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.[54][37]

Metabolic production of NAEsEdit

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,[55] 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.[18]

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,[56][33][57] as well as to oxygenated eicosanoid ethanolamides, prostaglandins, and leukotrienes, all believed to be important signaling compounds.[58]

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,[59] as PGE2 and PGD2 are pro-inflammatory mediators responsible for the induction of inflammation,[56] PGE2-EA and PGD2-EA are contrary both growth inhibitory and can induce apoptosis,[60] 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).[61]

Fatty acid amide hydrolase (FAAH) is the main degrading enzyme of NAE 20:4 (AEA) and NAE 18:1 (OEA), which have opposite effects on food intake and energy balance. AEA, an endogenous ligand of CB1 cannabinoid receptors, enhances food intake and energy storage, whereas OEA binds to peroxisome proliferator-activated receptors-α to reduce food intake and promoting lipolysis, thereby FAAH deficiency promotes energy storage and enhances the motivation for food, through the enhancement of AEA levels rather than promoting the anorexic effects of OEA.[62] Tetrahydrocannabinol (THC: C21H30O2) is found to lower production of NAE 20:4 (AEA) by a biphasic response after THC injection reaching maximal values at 30 min., where AEA increased slightly from 0.58 ± 0.21 ng/ml at baseline to 0.64 ± 0.24 ng/ml, and after reaching maximal concentrations, EC plasma levels decreased markedly to a nadir of 300 min after THC administration to 0.32 ± 0.15 ng/ml for AEA, and returned to near baseline levels until 48 hours after the experiment, in 25 healthy volunteers who received a large intravenous dose of THC (0.10 mg/kg).[47]

A FAAH 385A mutant alleles have been found to have a direct effect on elevated plasma levels of NAE 20:4 (AEA) and related NAEs in humans, and biomarkers that may indicate risk for severe obesity that suggest novel ECS obesity treatment strategies,[63] as leptin increases the FAAH activity and reduces NAE 20:4 (AEA) signaling, particularly within the hypothalamus, to promote a suppression of food intake, a mechanism that is lost in diet-induced obesity and modulated by a human genetic variant (C385A) of the FAAH gene.[64] The cannabinoid type 1 receptors (CB1) and their endogenous ligands, the endocannabinoids, present in peripheral organs, such as liver, white adipose tissue, muscle, and pancreas, where it regulate lipid and glucose homeostasis, and dysregulation of it, has been associated with the development of obesity, characterized by chronic mild inflammation,[65] and its sequelae, such as dyslipidemia and diabetes, are involved in modulating food intake and the motivation to consume palatable food.[66]

NAE 20:4 related THC treatment have shown to increase culture protein content and reduced methyl-(3)H-thymidine incorporation, and cells treated with THC underwent adipogenesis shown by the expression of PPARγ and had increased lipid accumulation. Basal and IP-stimulated lipolyses were also inhibited by THC, and the effects on methyl-(3)H-thymidine incorporation and lipolysis seem to be mediated through CB1- and CB2-dependent pathways. THC did also decrease NAPE-PLD, the enzyme that catalyzes and converts ordinary lipids into chemical signals like NAE 20:4 (AEA) and NAE 18:1 (OEA), in preadipocytes and increased adiponectin and TGFβ transcription in adipocytes, results that show the ECS interferes with adipocyte biology and may contribute to adipose tissue (AT) remodeling. And this stimulation of adiponectin production and inhibition of lipolysis from THC may be in favor of improved insulin sensitivity under cannabinoid influence.[67]

A full agonist at the CB1 receptor is found able to up-regulate PPARy, and increased (+50%) glucose uptake, the translocation of glucose transporter 4, and intracellular calcium in fat cells, that indicate a role for the local endocannabinoids in the regulation of glucose metabolism in human adipocytes and suggest a role in channelling excess energy fuels to adipose tissue in obese humans.[68] This is consistent with the decreased prevalence of diabetes seen in marijuana users,[69] and significantly reduced body mass index and rates of obesity in Cannabis users,[70][71] as endocannabinoids modulate pancreatic β-cells function, proliferation, and survival, as well as insulin production, secretion, and resistance, where animal and human research suggest that increased activity of the endocannabinoid system, may lead to insulin resistance, glucose intolerance and obesity.[72]

Consistent with the associated reduced prevalence of non-alcoholic fatty liver disease (NAFLD) among cannabis users, that find significantly lower NAFLD prevalence compared to non-users, i.e. 15% lower in non-dependent users and 52% lower in dependent users, and dependent patients had 43% significantly lower prevalence of NAFLD compared to non-dependent patients.[73]

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.[58]

NAE 20:4 (AEA: C22H37NO2) which is similar in structure to N-arachidonoyl glycine (Nagly: C22H35NO3 - a carboxylic acid COOH) are metabolically interconnected, as oxidation of the hydroxyl group of NAE 20:4 (AEA) leads to NAgly, with a molecular structure, that are found of pharmacological interest, as region one confers a high degree of specificity of action, as polyunsaturated residues produce molecules with analgesic and anti-inflammatory action, of which saturated structures, are inactive. Region two is related to metabolic stability as NAgly is degraded by FAAH activity. And last, region 3, the amino acid residue, can have an effect on the analgesic and anti-inflammatory activities depending on steric factors and the chiral nature of the amino acid.[74]

It is found that long-chain fatty acid conjugates from the metabolic hydroxyl oxidation product of the phytocannabinoid, THC (C21H30O2), 11-hydroxy-THC (11-OH-THC: C21H30O3) are proposed to be a form in which THC may be stored within tissues.[75][76] And the last cytochrome P450 oxidation product of THC afford the non-psychoactive and long-living 11-nor-9-carboxy-THC (THC-COOH: C21H28O4) as main metabolite, that in some authors’ opinion, are insufficiently characterized, as an acid metabolite seen as a final product in both cannabis-plants and mammals, with there main unanswered questions, "Could any of the pharmacological effects observed for THC be attributed to THCA (C22H30O4) and/or THC-COOH, and could THC also be a potential pro-drug to another pharmacological entity?".[77][74][78][79][80][81][82]

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).[83]

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.[84]

Another of the main phytocannabinoids, cannabidiol (CBD: C21H30O2) is found to produce a significant increase in serum NAE 20:4 (AEA) levels, by inhibiting the intracellular degradation catalyzed by FAAH, suggest the inhibition of NAE 20:4 (AEA) deactivation may contribute to the antipsychotic effects of CBD, potentially representing a mechanism in the treatment of schizophrenia, with a markedly superior side-effect profile, compare to amisulpride, a potent antipsychotic. CBD were also seen to elevate serum levels of the non-cannabimimetic lipid mediators, NAE 16:0 (PEA) and NAE 18:1 (OEA), but amisulpride did not.[85][80]

FAAH inhibitors are seen to both increase alcohol consumption (NAE 20:4; AEA) and prevent against oxidative stress caused by binge ethanol consumption, and as NAE 16:0 (PEA) and NAE 18:1 (OEA), through the eCBome related peroxisome proliferator-activated receptor-α (PPAR-α) is involved in the actions of NAEs with no endocannabinoid activity, have been reported to exhibit neuroprotective effects, suggest a strengthening of the ECS may reflect a homeostatic mechanism to prevent the neurotoxic effects induced by alcohol with a relevant role of other non-cannabinoid congeners in the alcohol exposure, and the further activation in response to the negative affective state, like the anxiety,[86] associated to alcohol withdrawal.[87] Or poorer recall of verbal and nonverbal information, as well as reduced visuospatial skills related to alcohol hangover and withdrawal symptoms in youth, a relationship not seen in adolescents with similar levels of alcohol involvement if they are heavy users of marijuana.[88]

Alcohol (EtOH) is seen to increase levels of NAE 20:4 (AEA), and its precursor N‐arachidonoylphosphatidylethanolamine (N‐ArPE), a glycero-phospho-ethanolamine,[89] significantly, that may be a mechanism for neuronal adaptation and serve as a compensatory mechanism to counteract a continuous presence of EtOH, that together with previous results indicate the involvement of the endocannabinoid system in mediating some of the pharmacological actions alleged of EtOH, also seen in red wine components,[90] and in Humulus lupulus to preserve and flavor beer, widely cultivated for use by the brewing industry, through caryophyllene that is a selective full agonist at CB2,[91][92] and may constitute part of a common brain pathway mediating reinforcement of drugs of abuse including EtOH,[93] by elevated CB1.[94] As, CB1 receptor binding is 20-30% lower in patients with alcohol dependence than in control subjects in all brain regions and is negatively correlated with years of alcohol abuse, and the CB1 receptor binding remain similarly reduced after 2-4 weeks of abstinence, suggests an involvement of CB1 receptors in alcohol dependence in humans.[95]

Similar pathways of hydrolysis or oxidation of NAEs are also found in plant cells.[96][97]

NAE system in plantsEdit

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.[18]

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.[18]

Medical valuesEdit

N-acylethanolamines (NAEs), with its cell-protective and stress-combating action-response of organisms, also produced in neurons, together with N-acyl-phosphatidylethanolamine (NAPE), in response to the high intracellular Ca2+ concentrations that occur in injured neurons,[98] 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.[43] 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.[99]

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.[100]

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.[101][102] In addition, CB1 activation also suppresses release of serotonin, dopamine, acetylcholine and noradrenaline, which are mediating the characteristic cognitive and antidepressant effects.[103]

To use in expected global heating scenario, in a catastrophic “hothouse Earth,” possible well beyond the control of humans,[104][38] for citizens who cant afford an air-condition unit, to cool down and prevent heatstroke with an elevated core body temperature above 40℃ with neurologic dysfunctions, that can lead to a syndrome of multiple organ defect,[105] and cell stress, as it is found, that the CB1 receptor activation, here by a phytocannabinoid Δ9-THC administration, induces profound hypothermia, that is rapid in onset, persistent for 3–4 hours, dose-dependent and is accompanied by a reduction in oxygen (O) consumption, which indicate reduced heat production, as opposed to increased heat loss.[106]

* THCA:COOH: C22H30O4 (heating/storage) → THC: C21H30O2 → THC-OH: C21H30O3 → THC:COOH: C21H28O4 → profound hypothermia accompanied by a reduction in oxygen consumption

In metabolism of THCA from fresh plant material used orally, is conversion to Delta9-THC not observed:[107]

THCA:COOH: C22H30O4THC-OH: C21H30O3THC:COOH: C21H28O4

As the fatty acid amide hydrolase (FAAH) have showed significant decreased in bhang users as compared to controls, and indicating that the decrease in FAAH protein level is closely related to the duration of bhang use, and further revealed that the bhang–induced immunotoxicity, could be attributed to decrease in FAAH protein, bhang could also be a healthy drink/preparation to suppress an overactive immune response.[82][108]

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,[93]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.[31][109][110][111][81][112]

The evolutionary harm reduction programEdit

The central thesis is, that harm reduction is not only a social concept,[113] but also a biological one. More specifically, evolution does not make moral distinctions in the selection process, but utilizes a cannabis-based approach, seen from the oldest pollen consistent with Cannabis dated to 19.6 ago (Ma), in northwestern China, and converge on the northeastern Tibetan Plateau, in the general vicinity of Qinghai Lake, which is deduced as the Cannabis centre of origin, and co-localizes with the first steppe community that evolved in Asia,[114][115] 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,[116] since the primordial CB receptor evolved at least 600 million years ago; a date that broadly consistent with the Cambrian explosion,[117] 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.[79][118][119][120][121] Therefore, the health of each individual is dependant on this system are working appropriately,[41][122] and imagine what could be achieved if signaling through these receptors could be controlled: happy, slim, and healthy people who remember that they're pain-free, by forgetting,[123][124] and ignore it.[125]

Cosmic birth of NAE elements by star deathEdit

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.[126]

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.[127]

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 through Earth's atmosphere, and this could be a spark to early life on earth.[128]

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,[129] and among the most widespread and versatile signaling molecules ever discovered.[130]

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.[131][132]

See alsoEdit

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