An N-acylethanolamine (NAE) is a type of fatty acid amide where one of several types of acyl groups is linked to the nitrogen atom of ethanolamine, and highly metabolic formed by intake of essential fatty acids through diet by 20:4, n-6 and 22:6, n-3 fatty acids,[1][2] and when the body is physically and psychologically active,.[3][4] The endocannabinoid signaling system (ECS) is the major pathway by which NAEs exerts its physiological effects in animal cells with similarities in plants, and the metabolism of NAEs is an integral part of the ECS,[5] a very ancient signaling system, being clearly present from the divergence of the protostomian/deuterostomian,[6][7] and even further back in time, to the very beginning of bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmicmembranes. Fatty acid metabolites with affinity for CB receptors are produced by cyanobacteria, which diverged from eukaryotes at least 2000million years ago (MYA), by brown algae which diverged about 1500 MYA, by sponges, which diverged from eumetazoans about 930 MYA, and a lineages that predate the evolution of CB receptors, as CB1 – CB2 duplication event may have occurred prior to the lophotrochozoan-deuterostome divergence 590 MYA. Fatty acid amide hydrolase (FAAH) evolved relatively recently, either after the evolution of fish 400 MYA, or after the appearance of mammals 300 MYA, but after the appearance of vertebrates. Linking FAAH, vanilloid receptors (VR1) and anandamide (NAE 20:4) implies a coupling among the remaining ‘‘older’’ parts of the endocannabinoid system, monoglyceride lipase (MGL), CB receptors, that evolved prior to the metazoan–bilaterian divergence (ie, between extant Hydra and leech), but were secondarily lost in the Ecdysozoa, and 2-Arachidonoylglycerol (2-AG).[8]
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.[9] 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.[10]
N-Palmitoylethanolamine (PEA: C18H37NO2; 16:0) is the amide of palmitic acid (C16H32O2; 16:0) and ethanolamine. It is a ligand at CB2 receptors,[21][22] and PPAR-α.[23] It has anti-inflammatory activity and also attenuates pain sensation in mammals, whose levels are increased following neuroinflammatory or neuropathic conditions in both animals and humans, possibly to exert a local anti-inflammatory and analgesic action.[19][24][25][26] NAE 16:0 has also been identified in plants including corn, and seeds of cotton, okra, tomato, castor bean, soya bean and peanuts,[27] but its physiological functions remain unknown,[28]
N-alpha-Linoleoylethanolamide (ALEA: C20H35NO2; 18:3, ω-3) or Anandamide (18:3, n-3),[29] is a metabolic product of the omega-3 fat α-linoleic acid (ALA: C18H30O2; 18:3, ω-3) and ethanolamine (MEA: C2H7NO).[30]
N-Stearoylethanolamine (SEA: C20H41NO2; 18:0) is the amide of stearic acid (C18H36O2) and ethanolamine (MEA: C2H7NO). It has pro-apoptotic activity. It operates independently of the known cannabinoid and vanilloid receptors targeted by anandamide.[31] It is an inhibitor of the sphingolipid signaling pathway, via specific ceramidase inhibition (ceramidase converts ceramide to sphingosine) and blocks the effects of TNF- and arachidonic acid on intracellular Ca2+ concentration.[34][35][36]
These bioactive lipid amides are generated by the membrane enzyme NAPE-PLD, and natural bile acids regulate this essential process.[46] 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.[47]
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),[48] followed by conversion of these intermediates to NAEs by glycerophosphodiesterase-1 (GDE1). Another pathway uses a phospholipase C (PLC) to produce phopho-N-arachidonoylethanolamine (pAEA) from NAPE, widely found in phospholipids,[49] followed by conversion of pAEA into NAE 20:4 (AEA) by phosphatases such as PTPN22 and SHIP1.[50]
The effects of NAE 20:4 (AEA) and another endocannabinoid2-Arachidonoylglycerol (2-AG: C23H38O4; 20:4, ω-6), with tissue levels of 2-AG usually several tens to several hundreds of times those of AEA,[51] 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).[52]
Raphael Mechoulam that described and named Anandamide in 1992. He said:
Look, I believe there are 8billion people on this planet, and I believe there are 8billion 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.[16] in the YouTube video The Scientist, released in 2015.[58]
Several researchers have found, that NAE, and especially 20:4 anandamide (AEA: C22H37NO2; 20:4, ω-6), is a part of the reproductive system,[64] 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 fertilizedembryo 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) plays a key role, because, for the embryo to become attached to the lining of the uterus, a particular amount (temporary reduction by high Fatty acid amide hydrolase FAAH) of NAE 20:4 (AEA),[65] present at the uterine lining (uterine epithelium), is necessary for the fertilized embryo can attach itself to the uterine wall, i.e. implantation. 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 to pregnancy,[66][67] by synchronizingtrophoblast differentiation and uterine preparation to the receptive state.
However, low FAAH expression and high NAE 20:4 (AEA) levels at the interimplantation sites, prior to successful implantation, have been reported, and a later possible miscarriage, as AEA levels are inversely correlated with FAAH levels in peripheral blood mononuclear cells (PMNCs) and FAAH levels are found lower in women who consequently miscarry compared with those who progress beyond the first trimester. A consequence also found in women undergoing in vitrofertilization and embryo transfer, as low activity of FAAH in PMNCs and high plasma AEA levels after embryo transfer show failure to achieve a successful pregnancy. As well, high AEA level also inhibits BeWo trophoblast cell proliferation, in a dose-dependent manner, via the CB2 receptor, suggest that FAAH acts as a barrier to the AEA maternal-fetal transfer. So, high plasma AEA levels can be used as a marker of early pregnancy loss in patients with threatened miscarriage, as altered modulation of the ECS contribute to the spontaneous pregnancy loss.[68]
This is in line with a study of 50 women, where NAE 20:4 (AEA) hydrolase activity was lower in the seven women who miscarried than in the 43 who did not (60.43 pmol/min per mg protein [SD 29.34] vs 169.60 pmol/min per mg protein [30.20], and another study showing that all 15 women in the low AEA hydrolase group had miscarriages, compared with one of the 105 women with high concentrations at or above the threshold of hydrolase.[69]
An earlier 2004 research into 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, as either silencing or amplification of NAE 20:4 (AEA) signaling via CB1 receptors causes oviductal retention or blastocyst incompetence for implantation. The report estimates that aberrant cannabinoid signaling impedes coordinated oviductal smooth musclecontraction 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.[70]
Likewise, there is also demonstrated CB1 expression in the first trimester placenta characterized by a spatial-temporal modulation. But, at term, there is found lack of FAAH and high CB1 expression at placental villous tissue of non-laboring compared with laboring.[68]
After birth, CB1 receptors appears to be critical for milk sucking by newborn, as it apparently activate oral-motor musculature, by 2-AG (C23H38O4; 20:4 ω-6) in the breast milk, activation, as elevated levels of 2-AG modulate infant appetite and health,[81] as well as NAE 20:4 (AEA) act as a neuroprotectant, also by providing retrograde signaling in the developing postnatal brain, with observations suggest that children may be less prone to psychoactive side effects of Δ9-tetrahydrocannabinol (THC: C21H30O2) or endocannabinoids than adults, as very low density of CB1, and neonatal cardiac cells express CB2, but not CB1 receptors,[79] suggest a promising future for cannabinoids in pediatric medicine for conditions including non-organic failure-to-thrive and cystic fibrosis.[67][82]
Mood
As the euphoricfeeling 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.[4]
However in posttraumatic stress disorder (PTSD), circulating NAE 20:4 (AEA) are found associated with overall mood states and exercise-induced improvements in women with and without PTSD, as AEA significantly increased following aerobic exercise for both groups, whereas the circulation of the endocannabinoid 2-AG only increased in women without PTSD, thereby AEA was associated with lower depressive mood, confusion, and total mood disturbance within the PTSD group and consistent with the discovery of a greater eCB tone, and particularly AEA, following pharmacological and/or non-pharmacological manipulations that may be beneficial for improving psychological outcomes, as mood and cognition among PTSD and possibly other psychiatric populations.[83]
NAE and endocannabinoids is an integral component of stress recovery, both centrally and peripherally, through regulation of the HPA axis, and reduction in circulating NAE 20:4 (AEA) content in major depression, and exposure to stress, is found to increase inflammatory markers by down-regulating the circulating content of the endogenous anti-inflammatory molecules, through their activation of PPAR-α, palmitoylethanolamine (PEA: C18H37NO2; 16:0) and Oleoylethanolamine (OEA: C20H39NO2; 18:1, ω-9), as NAE catabolism is accelerated by stress and by the same FAAH catabolic pathway.[84]
And possible why cannabinoids are seen highly used in the prison population, and among those who have been imprisoned, and is clearly involved in daily life in prison, where detainees in some prisons estimated the current use of cannabis/hashish to be as high as 80%, and staff estimate 50%, described analgesic, calming, self-help to go through the prison experience, relieve stress, facilitate sleep, prevent violence, and a social peacemaker, where the introduction of a more restrictive regulation induced fear of violence, increased trafficking and a shift to other drug use.[90][91] As seen in the Danish prisons that reflect a ‘treatment guarantee’ embedded in a policy of zero tolerance and intensified disciplinary sanctions, launched by the Danish Government (Regeringen, 2003) and inspired by US drug policy called The Fight against Drugs, with introduction of better fence systems, more sniffer-dogs, and cell and body search of inmates, with an increasingly repressive response to drugs, including zero tolerance and harsher punishment like isolation, that reflects the same chain of destruction as the steps seen to the Holocaust,[92] to make clients drug free and preparing them for a life without crime.[93]
Released to a daily life environment, where the highest scores for quality of life is observed among habitual cannabis users, followed by occasional users, whereas both non-users and dysfunctional users present less favorable score, and non-users reported more depression or anxiety symptoms and a lower quality of life, than occasional and habitual users, found in a Brazilian cross-sectional study involving more than 7400 adults (6620 recreational cannabis users and 785 non-users), even illegal.[94][95] And other findings imply that a causal link between marijuana use and violence is primarily due to its illegality, and thus would not exist in an environment in which marijuana use, at least medicinally (MML), as a first choice in any situation, is legalized, to correct the injustices of cannabis prohibition, as the legalization of cannabis for adult use is found being increasingly embraced in several countries and local entities, coursed by the economic and human suffering of cannabis prohibition, which have fallen most heavily upon disadvantaged minority populations, and for countries, in which cannabis consumption before constituted a traditional habit, also in religion, and practiced for hundreds or thousands of years,[96][97][98] without being subject to any social opprobrium, as no correlation between Marijuana use and criminal behavior are found, correlates with a reduction in homicide and assault rates, after introduction of state MML.[99][100][101] Followed by an almost 5% estimated reduction in the total suicide rate, for the period 1990 through 2007, with an 11% percent reduction for 20- through 29-year-old males, and a 9% reduction in the suicide rate of 30- through 39-year-old males.[102] And the secondary mortality attributing to herbal cannabis is found extremely rare, and usually associated with misadventures with law enforcement, and the prison experience and of solitary confinements.[103][104]
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 related circulating NAEs and familiar 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),[105] where n-7 fatty acids are precursors for the production of omega-4 fatty acids like palmitolinoleic acid (16:2),[106] 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),[107] 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.[108]
It is found that 3T3-L1adipocytesconverteicosapentaenoic acid (EPA: C20H30O2; 20:5, ω-3) to NAE 20:5 (EPEA: C22H35NO2; 20:5, ω-3) or Anandamide (20:5, n-3) and docosahexaenoic acid (DHA: C22H32O2; 22:6, ω-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, may be involved in the immune-modulating activity of fish-oil derived NAEs.[39]
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 on 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.[109][60]
The World Health Organization (WHO) estimate hemp, a culture CO2 negative, - a crop that is capable in the carbon cycle of removing more CO2 from the ambient than it emits, where production of biomass produce between 8 and 12 tons of CO2, but seize between 10 and 15 tons per hectare, with the possibility to sequester up to 22 tons of CO2 from the increased dry matter of the stem, where 80% of atmospheric carbon is sequestered and stored, by a nitrogenfertilization between 0 and 120kg per hectare,[60] with roots that by various physicians and herbalists in the latter part of 17th century, was recommended to treat fever, inflammation, gout, arthritis, and joint pain, as well as skin burns and hard tumors, beside more,[110] as well as to have modest antimicrobial activity against Cryptococcus neoformans by ergost-5-en-3-ol,[111] and potent antimicrobial activity against Escherichia coli by p-coumaroyltyramine,[112][113] as having what is considered to be an optimal 3:1 balance of omega 6 to omega 3 essential fatty acids, and where hempseed oil, of which 80% are polyunsaturated fatty acids, of which 60% are omega-6 linoleic acid (LA: C18H32O2), the precursor of NAE 20:4 (AEA) and other NAEs, and 20% are omega-3 alpha-linolenic acid (ALA: C18H30O2), the precursor of NAE 18:3 (ALEA: C20H35NO2; 18:3, ω-3) or Anandamide (18:3, n-3),[29][30] is the only one that is in perfect balance according to what the human body needs – 3:1, and a pound (454 gram) of hemp seed, of which 43% are protein, can provide all the protein, essential fatty acids, and dietary fiber necessary for human survival for two weeks, or 33 gram a day.[2][114][115][116][117][118]
And their absence has been found responsible for the development of a wide range of diseases such as metabolic disorders,[3]cardiovascular disorders, inflammatory processes, viral infections, certain types of cancer and autoimmune disorders,[119] as well as skin disorders, as cutaneous cannabinoid ("c[ut]annabinoid") signaling is deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration, and its dysregulation is implicated to contribute to several diseases and disorders, e.g., atopic dermatitis, psoriasis, scleroderma, acne, hair growth and pigmentation disorders, keratin diseases, various tumors, and itch, as the endocannabinoids (eCBs; e.g., NAE 20:4; AEA), the eCB-responsive receptors (e.g., CB1, CB2), as well as the complex enzyme and transporter apparatus involved in the metabolism of the ligands, show to be expressed in several tissues, including the skin,[120] where 18 prostanoids, 12 hydroxy-fatty acids, 9 endocannabinoids and N-acyl ethanolamides (NAEs), and 21 non-hydroxylatedceramides and sphingoid bases, of which several demonstrating significantly different expression in the tissues assayed, demonstrate the diversity of lipid mediators involved in maintaining tissue homeostasis in resting skin and hint at their contribution to signaling, cross-support, and functions of different skin compartments.[121]
The NAE substitutes, the phytocannabinoids from the flowers and fruits, like the psychoactive compound Δ9-tetrahydrocannabinol (THC: C21H30O2) and the nonpsychotropic compounds cannabidiol (CBD: C21H30O2), and leaves (THCA/CBDA: C22H30O4),[122] from the plant, are also potent PPARγ agonist with neuroprotective activity,[123][124][125] and found to modulate inflammatory responses by regulating the production of cytokines from keratinocytes in several experimental models of skin inflammation, by CB2 and TRPV1 activation, where CBD dose-dependently elevates the levels of NAE 20:4 (AEA) and inhibits poly-(I:C)-induced release of MCP-2, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α, in allergic contact dermatitis (ACD),[126] through the endocannabinoid system (ECS), and where FAAH–deficient mice, which have increased levels of NAE 20:4, displayed reduced allergic responses in the skin,[127] as the activation of CB1 or CB2 increases endocannabinoid levels by inhibiting fatty acid amide hydrolase (FAAH) or adenylyl cyclase, and activation of CB1 is tightly associated with the generation of cellularceramides.[13]
Beside the CB1 receptors being triggers of the generation of ceramides that mediate neuronalcell fate, the skin CB1 receptor aktivation also increases ceramides, with long-chain fatty acids (FAs) (C22–C24), which mainly account for the formation of the epidermal barrier, through activation of ceramide synthase, CerS 2 and CerS 3, thereby resulting in the enhancement of epidermal permeability barrier function in IL-4 inflamed skin.[13]
*Anandamide (AEA: C22H37NO2; 20:4,n-6) is an N-acylethanolamine resulting from the formal condensation of the carboxy group of arachidonic acid (AA: C20H32O2; 20:4-n6) with the amino group of ethanolamine (C2H7NO), bind preferably to CB1 receptors.[130]
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,[1] and endogenously released NAE 20:4 and 2-arachidonylglycerol (2-AG: C23H38O4; 20:4,n-6), the ester metabolic formed from omega-6-arachidonic acid (AA: C20H32O2; 20:4, n-6) and glycerol (C3H8O3), are also found to activate CB2 receptors in addition,[34] where 2-AG is the physiological ligand.[131]
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,[143] as PGE2 and PGD2 are pro-inflammatory mediators responsible for the induction of inflammation,[140] PGE2-EA and PGD2-EA are contrary both growth inhibitory and can induce apoptosis,[144] 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).[145]
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.[146] Tetrahydrocannabinol (THC: C21H30O2) is found to lower production of NAE 20:4 (AEA) and 2-AG, that is synthesized in an on-demand manner when needed for activation,[147] by a biphasic response after THC injection reaching maximal values at 30 min., where AEA increased slightly from 0.58 ± 0.21ng/ml at baseline to 0.64 ± 0.24ng/ml, and 2-AG from 7,60 ± 4,30ng/ml to 9,50 ± 5,90ng/ml, and after reaching maximal concentrations, EC plasma levels decreased markedly to a nadir of 300 min after THC administration to 0.32 ± 0.15ng/ml for AEA, and 5,50 ± 3,01ng/ml for 2-AG, and returned to near baseline levels until 48 hours after the experiment, in 25 healthy volunteers who received a large intravenous dose of THC (0.10mg/kg).[74]
Insulin medication and intraoperative doses of insulin is also found, but not recognized by companies producing and selling medication to general public also as a slimming formula like Wegovy, to get its anorectic effect by the involvement of FAAH activity, which, beside of other NAE's, degrade NAE 20:4 (AEA),[148] suggest that insulin may play a key role in the obesity-linked dysregulation of the adipose ECS at the gene level.[149] And is possible why the European Medicines Agency (EMA) in 2023 are investigating several reports from European countries about suicidal thoughts and thoughts of self-harm in patients, who have been treated with Novo Nordisk's popular medicines for obesity and diabetes.[150] An outcome also seen in the CB1 receptor blocker rimonabant, an anorecticantiobesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects,[122][86] and happening at the same time as EMA, has raised a safety alert for Wegovy, that also applies to the companies diabetes medication Ozempic, based on a study that suggests that the active substance in the two preparations, can increase the risk of thyroid cancer in patients with type 2 diabetes.[151]
FAAH expression, that metabolizes NAE 20:4 (AEA) involved in the regulation of emotional reactivity, into ethanolamine and arachidonic acid, is found significantly increased in depressive-like phenotypes, where knockout or pharmacological inhibition of FAAH effectively reduces depressive-like behavior, with a dose-dependent effect, that elicits anxiolytic and antidepressant-like effects, like the NAE 20:4 (AEA) substitutes ∆9-THC and other cannabinoids that may contribute to the overall mood-elevating properties of cannabis,[95][152][153] and differences in FAAH expression in depressive-like phenotypes were largely localized to animal prefrontal cortex (PFC), hippocampus and striatum, containing high densities of CB1 receptors.[154][155] As well as FAAH levels in amygdala and PFC are elevated in borderline personality disorder, which relates to the hostility and aggression, are consistent with the model, that lower endocannabinoid tone perturb PFC circuitry that regulates emotion and aggression, provide preliminary evidence of elevated PFC FAAH binding in any psychiatric condition.[88]
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,[156] 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 FAAHgene.[157] 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 glucosehomeostasis, and dysregulation of it, has been associated with the development of obesity, characterized by chronic mild inflammation,[158] and its sequelae, such as dyslipidemia and diabetes, are involved in modulating food intake and the motivation to consume palatable food.[159]
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.[160]
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.[166] And also by using multivariablelogistic regression, and after adjusting for potential confounders, patients with cannabis abuse (daily consumption) is found 55% less likely to have hepatocellular carcinoma (adjusted odds ratio, 0.45, 95% confidence interval, 0.42–0.49) compared with patients without cannabis abuse in the periode 2002 – 2014.[138]
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.[142]
NAE 20:4 (AEA: C22H37NO2) which is similar in structure to N-arachidonoyl glycine (Nagly: C22H35NO3 – a carboxylic acidCOOH) are metabolically interconnected, as oxidation of the hydroxyl group of NAE 20:4 (AEA) leads to NAgly, preferring G-protein coupled receptor (GPR) 118, 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 saturatedstructures, 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.[167] Also the amino acid residue at 296 and the hydroxyl groups of THC, 11-hydroxy-THC (11-OH-THC: C21H30O3) are critical for potentiation of glycine receptors (GlyRs) and for some of the cannabis-induced analgesic and therapeutic effects.[75]
It is also found that long-chain fatty acidconjugates 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.[168][169] 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 their 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?".[170][167][171][172][173]
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.[175]
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.[176][177]
FAAH inhibitors are seen to both increase alcohol consumption (NAE 20:4; AEA) and prevent against oxidative stress caused by bingeethanol consumption, and as NAE 16:0 (PEA) and NAE 18:1 (OEA), through the endocannabinoidome-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 homeostaticmechanism 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 affectivestate, like the anxiety,[178] associated to alcohol withdrawal.[179] Or poorer recall of verbal and nonverbal information, as well as reduced visuospatialskills 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.[180]
The cannabinoid CB1 receptor play a critical role in mediating the adolescent behavior, because enhanced CB1 density and endocannabinoid (eCB) signaling occur transiently during the periode from childhood to adolescence and reverse when adult and mature in normal phenotypes. Reports on enhanced adolescent CB1 signaling, suggest a pivotal role for the CB1 in an adolescent brain as an important molecular mediator of adolescent behavior, as adult CB1 mutant rats exhibit an adolescent-like phenotype with typical high risk seeking, impulsivity, and augmented drug and nondrug reward sensitivity, by an instinctive need or call for activation, and partial inhibition of CB1 activity normalized behavior and led to an adult phenotype, is why it is concluded that the activity state and functionality of the CB1 is critical for mediating adolescent behavior and further turn to an adult phenotype, by normal CB1 downscaling.[181] This is also do to the cannabinoid system and its neurotransmitter NAE 20:4 (AEA), that highly participate in the modulation of human states and appropriate human emotional responses by activation of the CB1 receptor,[178][182] also found in frontal neocortical areas, subserving higher cognitive and executive functions, and in the posterior cingulate, a region pivotal for consciousness and higher cognitive processing.[183][184][185]
Acute administration of ethanol inhibits receptor-mediated release of NAE 20:4 (AEA), whereas chronic ethanol administration increases levels of AEA that participates in the neuroadaptations associated with chronic ethanol exposure, as the inhibition of AEA release by acute ethanol administration, not derive from increased fatty acid ethanolamide degradation by FAAH.[186][187]
However, alcohol (EtOH) is seen to increase levels of NAE 20:4 (AEA), and its precursor N‐arachidonoylphosphatidylethanolamine (N‐ArPE), a glycero-phospho-ethanolamine,[188] 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 winecomponents,[189] and in Humulus lupulus to preserve and flavor beer, widely cultivated for use by the brewing industry, through caryophyllene, a dietary cannabinoid,[190] that is a selective full agonist at CB2 and also act through PPAR nuclear receptors (i.e. PPARα and PPARγ), with countless beneficial and non-psychoactive effects,[191][192][193] that may constitute part of a common brain pathway mediating reinforcement of drugs of abuse including EtOH,[194] by elevated CB1.[195] The 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.[196]
Similar pathways of hydrolysis or oxidation of NAEs are also found in plant cells.[197][198]
The levels of NAEs increases 10- to 50-fold in tobacco (Nicotiana tabacum) leaves treated with fungalelicitors, 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 pathogenelicitorperception, 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.[34]
In pediatric medicine for conditions including "non-organic failure-to-thrive" and cystic fibrosis.[67] 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 their counterparts, not treated, were shown completely infertile.[201]
To use in expected global heating scenario, in a catastrophic "hothouse Earth," possible well beyond the control of humans,[208][209][210] where "wet bulb temperatures," taken by a thermometer wrapped in a wet cloth, show temperatures of 35C or higher, and considered the limit to human survival and heighten humidity makes it harder for people to cool down via sweating,[211][61] coursed by the pollution of the troposphere, that tight holds 99% of human made solid particle pollution, and keeps CO2 in it for more than 100 years,[212][213][214] for citizens who can't afford an air-condition unit, to cool down and prevent heatstroke with an elevated core body temperature above 40°C with neurologic dysfunctions, that can lead to a syndrome of multiple organ defect,[215] 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.[216][217][218]
*→THCA:COOH: C22H30O4 (heating/storage) → THC: C21H30O2 → THC-OH: C21H30O3 → THC:COOH: C21H28O4 → profound hypothermia, a lowering of body temperature,[219] accompanied by a reduction in oxygen consumption.
In metabolism of THCA from fresh plant material used orally, is conversion to Delta9-THC not observed:[220]
To be protected where head injury is a possibility, as a positive THC screen is associated with significant decreased mortality in adult patients sustaining traumatic brain injury (TBI), as research work, by a 3-year retrospective review of registry data at a Level I center of patients sustaining TBI, find mortality in the THC(+) group (2.4% [2 patients]) significantly decreased compared with the THC(-) group (11.5% [42]) in 446 cases meeting all inclusion criteria.[172] And further have shorter hospital length of stay (LOS) and shorter ventilator days, than THC(-) patients sustaining TBI. For severely injured trauma patients with Injury Severity Score ≥16, a THC(+) screen show significantly lower intensive care unit LOS and mortality (19.3% versus 25.0%) than THC(-) patients, shown by 4849 patients included at two large regional trauma centers between 2014 and 2018.[221]
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.[173][222]
A molecular mechanism through which NAE 20:4 (AEA) plant competitive substitute THC cannabinoid molecules can affect the development of Alzheimer's disease, the leading cause of dementia,[224] or its impact:
THC: C21H30O2 → THC-OH: C21H30O3 → THC:COOH: C21H28O4 → a significantly superior inhibitor of Amyloid beta (Aβ) aggregation and tauphosphorylation, compared to approved drugsprescribed for the treatment of Alzheimer's disease in 2008, through which these molecules directly can affect the development by activation of both CB1 and CB2 receptors, which inhibit the enzyme acetylcholinesterase (AChE), which further prevent AChE-induced amyloid β-peptide (Aβ) aggregation, as they also are able to bind to the anionic site of AChE, a region involved in and critical for amyloid formation, as well as by promoting the brain's intrinsic repair mechanisms, and promote neurogenesis, endocannabinoid signaling has demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress.[225][226][227] However other phytochemicals that are present in Cannabis sativa is found to interact with each other in a synergistic fashion, called the entourage effect, that seems to have greater therapeutic potential when administered together, rather than individually.[228][229][134][230]
A synergistic outcome that also show different cannabinoids can be effective against harmful bacteria including those that are resistant to common antibiotics, like Methicillin-resistant Staphylococcus aureus (MRSA) causing various types of life-threatening infections, such as septic shock, endocarditis and severe pneumonia, coursed by the misuse of antibiotics, which is the leading cause of the emergence of antibiotic-resistant bacteria. They do so by inhibit the formation of biofilms and also eradicate pre-existing ones, was showcased in 1976, where it was discovered that THC and CBD can be used as bacteriostatic agents and are able to kill a panel of human pathogenic strains, and later a panel of cannabinoids are found able to do the same in different bacteria strains.[231][232]
The central thesis is, that harm reduction is not only a social concept,[243] but also a biological one. More specifically, evolution does not make moral distinctions in the selection process, but uses a cannabis-based approach, seen from the oldest pollen, where Cannabis and Humulusdiverged between 18.23 mya and 27.8 mya ago, and 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,[244] or Yunnan, in the southwest of China, also identified as "the birthplace of tea ... the first area where humans figured out that eating tea leaves or brewing a cup could be pleasant", and helpful, by its cannabimimetic bioactivity of catechin derivatives occurring in tea leaves, as the region of origin,[245][246] to harm reduction to promote survival of the fittest. Evidence provided from peer-reviewed scientific literature supports the hypothesis, that humans, and all animals,[247] since the primordial CB receptor evolved at least 600 million years ago; a date that broadly consistent with the Cambrianexplosion,[248] 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),[237] as a versatile tool available to organisms to fine-tune homeostasis,[249] and modulating endocannabinoid activity have therapeutic potential in almost all diseases affecting humans.[122][250][251][252][253] Therefore, the health of each individual is dependent on this system are working appropriately,[64][102] 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,[254][206] by forgetting,[255][256] and ignore it,[257] achieved though cannabis, the evolutionary byproduct of a plant that evolved as a systemic homeostasis to affect the ECS and to become its natural key, stemming back to aquatic species 400 million years before the arrival of plants and trees.[229][122]
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 atomparticle in every living thing on Earth, was probably produced in and carried from the elements of a dying star.[258]
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.[259]
Using the samples returned by the spacecraftStardust, 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,[261] and among the most widespread and versatile signaling molecules ever discovered.[262]
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 the 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.[263][264]
* → An atom consists of a nucleus, the atom nucleus, and a shell. The atom's positively chargedparticles, protons, lie in the nucleus and consist of the smallest building blocks we know of in the universe, called quarks, which are held together by gluons, are everywhere. Along with the protons are neutrons, which are neutral. Outside the nucleus is the mantle, where the atom's negatively charged particles, electrons, interact (in the form of standing waves), and is the absolute smallest part of an element, that can exist independently, but is most often bound to other atoms that can either belong to the same element or other elements, thereby forming a molecule.[265]
With a spike on a graph, an entourage effect and retrograde signaling, by the motto "Science for Peace", and, also in the spirit of Niels Bohr, the Danish physicist with the first relatively correct model of how an atom looks like, – an international group of about 6000 researchers connected at CERN, by a particle accelerator located 100 meters underground, called LHC Large Hadron Collider 1, which consists of a 27km long tube in a circle, that can accelerate protons to near the speed of light and smash them together, demonstrated on 4 July 2012 the existence of the Higgs particle, a manifestation of the existence of the Higgs field – an invisible field in the entire Universe (symmetry breaking), believed to have emerge at about 1 picosecond (10−12 s) after the Big Bang, and required for atoms and other structures to form, as well as for nuclear reactions in stars, such as the Sun and Betelgeuse. As so, the Higgs field is responsible for this symmetry breaking, and which all particles pass through, and which provide them their mass and thereby, weight, and without this field, all particles and elements in the NAE-structure, would be moving around at the speed of light, because they didn't have a mass, and they and living nature, wouldn't be able to exist.
Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.
Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.
Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands:
Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS).
Tetrahydrocannabivarin is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of pentyl (5-carbon), making it non-psychoactive in lower doses. It has been shown to exhibit neuroprotective activity, appetite suppression, glycemic control and reduced side effects compared to THC, making it a potential treatment for management of obesity and diabetes. THCV was studied by Roger Adams as early as 1942.
Fatty acid desaturases are a family of enzymes that convert saturated fatty acids into unsaturated fatty acids and polyunsaturated fatty acids. For the common fatty acids of the C18 variety, desaturases convert stearic acid into oleic acid. Other desaturases convert oleic acid into linolenic acid, which is the precursor to alpha-linolenic acid, gamma-linolenic acid, and eicosatrienoic acid.
The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.
Fatty-acid amide hydrolase 1 (FAAH) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene FAAH.
2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994–1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).
AM404, also known as N-arachidonoylphenolamine, is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action and anticonvulsant effects. Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.
Oleamide is an organic compound with the formula CH3(CH2)7CH=CH(CH2)7CONH2. It is the amide derived from the fatty acid oleic acid. It is a colorless waxy solid and occurs in nature. Sometimes labeled as a fatty acid primary amide (FAPA), it is biosynthesized from N-oleoylglycine.
Methoxy arachidonyl fluorophosphonate, commonly referred as MAFP, is an irreversible active site-directed enzyme inhibitor that inhibits nearly all serine hydrolases and serine proteases. It inhibits phospholipase A2 and fatty acid amide hydrolase with special potency, displaying IC50 values in the low-nanomolar range. In addition, it binds to the CB1 receptor in rat brain membrane preparations (IC50 = 20 nM), but does not appear to agonize or antagonize the receptor, though some related derivatives do show cannabinoid-like properties.
Virodhamine (O-arachidonoyl ethanolamine; O-AEA) is an endocannabinoid and a nonclassic eicosanoid, derived from arachidonic acid. O-Arachidonoyl ethanolamine is arachidonic acid and ethanolamine joined by an ester linkage, the opposite of the amide linkage found in anandamide. Based on this opposite orientation, the molecule was named virodhamine from the Sanskrit word virodha, which means opposition. It acts as an antagonist of the CB1 receptor and agonist of the CB2 receptor. Concentrations of virodhamine in the human hippocampus are similar to those of anandamide, but they are 2- to 9-fold higher in peripheral tissues that express CB2. Virodhamine lowers body temperature in mice, demonstrating cannabinoid activity in vivo.
N-Arachidonyl glycine receptor, also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene. Along with the other previously "orphan" receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors. It has been found to be involved in the regulation of intraocular pressure.
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator PEA has been studied in in vitro and in vivo systems using exogenously added or dosed compound; there is evidence that it binds to a nuclear receptor, through which it exerts a variety of biological effects, some related to chronic inflammation and pain.
IDFP is an organophosphorus compound related to the nerve agent sarin.
The endocannabinoid transporters (eCBTs) are transport proteins for the endocannabinoids. Most neurotransmitters are water-soluble and require transmembrane proteins to transport them across the cell membrane. The endocannabinoids on the other hand, are non-charged lipids that readily cross lipid membranes. However, since the endocannabinoids are water immiscible, protein transporters have been described that act as carriers to solubilize and transport the endocannabinoids through the aqueous cytoplasm. These include the heat shock proteins (Hsp70s) and fatty acid-binding proteins for anandamide (FABPs). FABPs such as FABP1, FABP3, FABP5, and FABP7 have been shown to bind endocannabinoids. FABP inhibitors attenuate the breakdown of anandamide by the enzyme fatty acid amide hydrolase (FAAH) in cell culture. One of these inhibitors (SB-FI-26), isolated from a virtual library of a million compounds, belongs to a class of compounds that act as an anti-nociceptive agent with mild anti-inflammatory activity in mice. These truxillic acids and their derivatives have been known to have anti-inflammatory and anti-nociceptive effects in mice and are active components of a Chinese herbal medicine used to treat rheumatism and pain in human. The blockade of anandamide transport may, at least in part, be the mechanism through which these compounds exert their anti-nociceptive effects.
Cannabis consumption in pregnancy may or may not be associated with restrictions in growth of the fetus, miscarriage, and cognitive deficits. The American College of Obstetricians and Gynecologists recommended that cannabis use be stopped before and during pregnancy. There has not been any official link between birth defects and marijuana use. Cannabis is the most commonly used illicit substance among pregnant women.
N-acyl amides are a general class of endogenous fatty acid compounds characterized by a fatty acyl group linked to a primary amine metabolite by an amide bond. Broadly speaking, N-acyl amides fall into several categories: amino acid conjugates, neurotransmitter conjugates, ethanolamine conjugates, and taurine conjugates. N-acyl amides have pleiotropic signaling functions in physiology, including in cardiovascular function, metabolic homeostasis, memory, cognition, pain, motor control and others. Initial attention focused on N-acyl amides present in mammalian organisms, however recently lipid signaling systems consisting of N-acyl amides have also been found to be present in invertebrates, such as Drosophila melanogaster. N-acyl amides play important roles in many biochemical pathways involved in a variety of physiological and pathological processes, as well as the metabolic enzymes, transporters, and receptors that regulate their signaling.
N-acylethanolamine acid amide hydrolase (NAAA) EC 3.5.1.- is a member of the choloylglycine hydrolase family, a subset of the N-terminal nucleophile hydrolase superfamily. NAAA has a molecular weight of 31 kDa. The activation and inhibition of its catalytic site is of medical interest as a potential treatment for obesity and chronic pain. While it was discovered within the last decade, its structural similarity to the more familiar acid ceramidase (AC) and functional similarity to fatty acid amide hydrolase (FAAH) allow it to be studied extensively.
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↑ PubChem. "Anandamide". pubchem.ncbi.nlm.nih.gov. Retrieved 29 June 2023.
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