N-Acylethanolamine

[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 cytoplasmic membranes.

[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.

[11] Inhibition of FAAH has been shown to increase the levels of NAEs in vivo and to produce desirable phenotypes, that produce analgesic, anxiolytic, neuroprotective, and anti-inflammatory effects,[12] like in high-level performance athletes (i.e., elite athletes) that present an extraordinary interindividual variability of physical, but also mental traits, that greatly influence their sports accomplishments and their career longevity, by an FAAH genetic polymorphism that produce the SNP rs324420 (C385A allele), associated with a higher sensitivity of FAAH to proteolytic degradation and a shorter half-life, as compared to the C variant, as the A variant displays normal catalytic properties, but an enhanced sensitivity to degradation, leading to increased NAE and anandamide (AEA) signaling.

[13] Examples of N-acylethanolamines include:[14] These bioactive lipid amides are generated by the membrane enzyme NAPE-PLD, and natural bile acids regulate this essential process.

[63][64] Several researchers have found, that NAE, and especially 20:4 anandamide (AEA: C22H37NO2; 20:4, ω-6), is a part of the reproductive system,[65] 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.

[69] 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,[82] 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,[80] suggest a promising future for cannabinoids in pediatric medicine for conditions including non-organic failure-to-thrive and cystic fibrosis.

[85] And in other stress-associated psychiatric disorders, like posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD), characterized by intense and rapidly changing mood states as well as chronic feelings of emptiness, impulsivity, fear of abandonment, unstable relationships, and unstable self-image, showing significantly and cronically reduced content of the NAE 20:4 (AEA) that attenuate depressive and anxious symptoms, by elevated fatty acid amide hydrolase (FAAH) in the amygdala-prefrontal cortex (PFC), that subserves emotion regulation and used to measures of hostility and aggression, provide preliminary evidence of elevated FAAH binding in PFC in any psychiatric condition,[86] may be of great therapeutic interest to psychiatry.

[103] 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.

[110][61] 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 nitrogen fertilization between 0 and 120 kg per hectare,[61] with roots that by various physicians and herbalists in the latter part of the 17th century, was recommended to treat fever, inflammation, gout, arthritis, and joint pain, as well as skin burns and hard tumors, beside more,[111] as well as to have modest antimicrobial activity against Cryptococcus neoformans by ergost-5-en-3-ol,[112] and potent antimicrobial activity against Escherichia coli by p-coumaroyltyramine,[113][114] 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.

[122] 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),[123] from the plant, are also potent PPARγ agonist with neuroprotective activity,[124][125][126] 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),[127] 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,[128] 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 cellular ceramides.

On common diseases including cancers, this conversion show beneficial synergistic effect, when administered with the NAE-fatty acid familiar cannabinoids,[41] like delta(9)-tetrahydrocannabinol (THC: C21H30O2), – a metabolite of delta9-tetrahydrocannabinolic acid (THCA: C22H30O4), a diterpenoid, with a carboxyl group (–COOH) at one end, like 11-Nor-9-carboxy-THC (THC-COOH: C21H28O4), the secondary metabolite of THC, which is formed in the body after cannabis is consumed, that has a role as an anti-inflammatory and a neuroprotective agent,[135] – and a non-narcotic analgesic, a hallucinogen, a cannabinoid receptor agonist and an epitope.

[152] An outcome also seen in the CB1 receptor blocker rimonabant, an anorectic antiobesity drug that was first approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects,[123][87] 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.

[153] 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,[96][154][155] 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.

[159] The cannabinoid type 1 receptors (CB1) and their endogenous ligands, the endocannabinoids, present in peripheral organs, such as liver, white adipose tissue, muscle, and pancreas, where it regulate lipid and glucose homeostasis, and dysregulation of it, has been associated with the development of obesity, characterized by chronic mild inflammation,[160] and its sequelae, such as dyslipidemia and diabetes, are involved in modulating food intake and the motivation to consume palatable food.

[163] This is consistent with the decreased prevalence of diabetes seen in marijuana users,[164] and significantly reduced body mass index (BMI) and rates of obesity in Cannabis users,[165][166] as endocannabinoids modulate pancreatic β-cells function, proliferation, and survival, as well as insulin production, secretion, and resistance, where animal and human research suggest that increased activity of the endocannabinoid system, may lead to insulin resistance, glucose intolerance and obesity.

[169] 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.

[176] 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.

[177] 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.

[199][200] N-acylethanolamines (NAEs), constitute a class of lipid compounds naturally present in both animal and plant membranes, as constituents of the membrane-bound phospholipid, N-Acylphosphatidylethanolamine (NAPE).

NAPE is composed of a third fatty acid moiety linked to the amino head group of the commonly occurring membrane phospholipid, phosphatidylethanolamine.

[34] A study in 2000 find, that higher plants use defense signaling, to combat cellular stressful situations (homeostasis), like in osmotic stress, where high levels of NAEs after a periode of dehydration, are metabolized fast during the first few hours of imbibition, and in response to pathogen elicitors, that lead to signal transduction and membrane protection, in the same way as several mammalian cell types, coupled to endocannabinoid signaling, do, by releasing saturated and unsaturated long-chain NAEs, and saturated medium-chain NAEs, that can act as lipid mediators to modulate ion flux and activate defense gene expression.

[34] N-acylethanolamines (NAEs), with its cell-protective and stress-combating action-response of organisms, also produced in neurons, together with N-acyl-phosphatidylethanolamine (NAPE), in response to the high intracellular Ca2+ concentrations that occur in injured neurons,[202] have shown promise as therapeutic potential in treating bacterial, fungal, and viral infections, as NAEs also exhibit anti-inflammatory, antibacterial, and antiviral properties, which have considerable application potential.

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

[209] To use in expected global heating scenario, in a catastrophic "hothouse Earth," possible well beyond the control of humans,[210][211][212] 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,[213][62] 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,[214][215][216] 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,[217] 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.

[175][224] Fatty acid amide hydrolase (FAAH) inhibition has been found neuroprotective with therapeutic potential against neuropathological states including traumatic brain injury, Alzheimer's, Huntington's, and Parkinson's diseases, and stroke.

[225] 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,[226] or its impact: THC: C21H30O2 → THC-OH: C21H30O3 → THC:COOH: C21H28O4 → a significantly superior inhibitor of Amyloid beta (Aβ) aggregation and tau phosphorylation, compared to approved drugs prescribed 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.

[227][228][229] 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.

[230][231][136][232] 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.

[233][234] Different medication and intervention regimes, and lifestyle modifications, like diet, weight control, exercise, mindfulness as yoga and meditation, and the use of psychoactive substances, like alcohol,[196] tobacco, coffee,[235][236] and cannabis, beside general anaesthesia regimens (i.e. propofol, etomidate, sevoflurane, isoflurane, sufentanil),[237][238] and Insulin medication and intraoperative doses of insulin,[150][151] etc, do also modulate it, either by being a FAAH inhibitor, that blocks the breakdown of NAE 20:4 (AEA), and/or enhance or lowering its production, and/or by activate or inactivate the receptors connected, as arachidonic acid (C20H32O2; 20:4, ω-6), the precursor of NAE 20:4 (AEA) and other eCBs, is present in every cell membrane of the body, and their on demand synthesis is regulated by electrical activity and calcium (Ca2+) shifts.