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 2000 million 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 glycero
phosphodiesterase-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 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.[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 120 kg 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 ± 0.21 ng/ml at baseline to 0.64 ± 0.24 ng/ml, and 2-AG from 7,60 ± 4,30 ng/ml to 9,50 ± 5,90 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 5,50 ± 3,01 ng/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 (0.10 mg/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]
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