Palmitoylethanolamide

Last updated
Palmitoylethanolamide
Palmitoylethanolamide.png
Names
Preferred IUPAC name
N-(2-Hydroxyethyl)hexadecanamide [1]
Other names
  • Hydroxyethylpalmitamide
  • Palmidrol
  • N-Palmitoylethanolamine
  • Palmitylethanolamide
Identifiers
3D model (JSmol)
AbbreviationsPEA
ChEMBL
ChemSpider
ECHA InfoCard 100.008.062 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 208-867-9
KEGG
MeSH palmidrol
PubChem CID
UNII
  • InChI=1S/C18H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-18(21)19-16-17-20/h20H,2-17H2,1H3,(H,19,21) X mark.svgN
    Key: HXYVTAGFYLMHSO-UHFFFAOYSA-N X mark.svgN
  • CCCCCCCCCCCCCCCC(=O)NCCO
Properties
C18H37NO2
Molar mass 299.499 g·mol−1
AppearanceWhite crystals
Density 910 mg mL−1
Melting point 93 to 98 °C (199 to 208 °F; 366 to 371 K)
log P 5.796
Hazards
Flash point 323.9 °C (615.0 °F; 597.0 K)
Related compounds
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator [2] 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, [3] through which it exerts a variety of biological effects, some related to chronic inflammation and pain. [2]

Contents

A main target of PEA is proposed to be the peroxisome proliferator-activated receptor alpha (PPAR-α). [3] [4] PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119. [5] PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2. [6] However, primary research supports the conclusion that the presence of PEA (or other structurally related N-acylethanolamines) enhances anandamide activity by an "entourage effect". [7] [8] [ non-primary source needed ]

Some primary research reports support the conclusion that PEA levels are altered and that the endocannabinoid system (ECS) is "imbalanced" in acute and chronic inflammation. [9] [ non-primary source needed ] A primary research article, for instance, has reported that the deregulation of cannabinoid receptors and their endogenous ligands accompanies the development and progression of β-amyloid-induced neuroinflammation. [10] [ non-primary source needed ]

In some primary research studies,[ non-primary source needed ] PEA has been shown to have anti-inflammatory, [4] anti-nociceptive, [11] neuroprotective, [12] and anticonvulsant properties. [13]

Early and recent studies

Palmitoylethanolamide was discovered in 1957.[ citation needed ] Indications for its use as an anti-inflammatory and analgesic date from before 1980.[ citation needed ] In that year, researchers described what they called "N-(2-hydroxyethyl)-palmitamide" as a natural anti-inflammatory agent, stating, "We have succeeded in isolating a crystalline anti-inflammatory factor from soybean lecithin and identifying it as (S)-(2-hydroxyethyl)-palmitamide. The compound also was isolated from a phospholipid fraction of egg yolk and from hexane-extracted peanut meal."[ This quote needs a citation ]

In 1975, Czech physicians described the results of a clinical trial[ clarification needed ] looking at joint pain, where the analgesic action of aspirin versus PEA were tested; both drugs were reported to enhance joint movements and decrease pain. [14] In 1970 the drug manufacturer Spofa in Czechoslovakia introduced Impulsin, a tablet dose of PEA, for the treatment and prophylaxis of influenza and other respiratory infections.[ citation needed ] In Spain, the company Almirall introduced Palmidrol in tablet and suspension forms in 1976, for the same indications.[ citation needed ]

In the mid-1990s, the relationship between anandamide and PEA was described; [15] [ non-primary source needed ] the expression of mast cell receptors sensitive to the two molecules was demonstrated by Levi-Montalcini and coworkers.[ according to whom? ][ non-primary source needed ] During this period, more insight into the functions of endogenous fatty acid derivatives emerged, and compounds such as oleamide, palmitoylethanolamide, 2-lineoylglycerol and 2-palmitoylglycerol were explored for their capacity to modulate pain sensitivity and inflammation via what at that time was thought to be the endocannabinoid signalling pathway. [16] [17]

Primary reports also have provided evidence that PEA downregulates hyperactive mast cells in a dose-dependent manner, [18] and that it alleviates pain elicited in mouse models. [11] [ verification needed ] PEA and related compounds such as anandamide also seem to have synergistic effects in models of pain and analgesia. [19]

Animal models

In a variety of animal models, PEA seems to have some promise;[ editorializing ][ citation needed ] researchers have been able to demonstrate relevant clinical efficacy in a variety of disorders, from multiple sclerosis to neuropathic pain. [20] [21]

In the mouse forced swimming test, palmitoylethanolamide was comparable to fluoxetine for depression. [22] An Italian study published in 2011 found that PEA reduced the raised intraocular pressure of glaucoma. [23] In a spinal trauma model, PEA reduced the resulting neurological deficit via the reduction of mast cell infiltration and activation. PEA in this model also reduced the activation of microglia and astrocytes. [24] Its activity as an inhibitor of inflammation counteracts reactive astrogliosis induced by beta-amyloid peptide, in a model relevant for neurodegeneration, probably via the PPAR-α mechanism of action. [25] [ verification needed ] In models of stroke and other CNS trauma, PEA exerted neuroprotective properties. [12] [26] [27] [28] [29]

Animal models of chronic pain and inflammation

Chronic pain and neuropathic pain are indications for which there is high unmet need in the clinic. PEA has been tested in a variety of animal models for chronic and neuropathic pain, because cannabinoids, such as THC, have been proven to be effective in neuropathic pain states. [30] The analgesic and antihyperalgesic effects of PEA in two models of acute and persistent pain seemed to be explained at least partly via the de novo neurosteroid synthesis. [31] [32] In chronic granulomatous pain and inflammation model, PEA could prevent nerve formation and sprouting, mechanical allodynia, and PEA inhibited dorsal root ganglia activation, which is a hallmark for winding up in neuropathic pain. [33] The mechanism of action of PEA as an analgesic and anti-inflammatory molecule is probably based on different aspects.[ editorializing ][ citation needed ] PEA inhibits the release of both preformed and newly synthesised mast cell mediators, such as histamine and TNF-alpha. [34] PEA, as well as its analogue adelmidrol (di-amide derivative of azelaic acid), can both down-regulate mast cells. [35] PEA reduces the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and prevents IkB-alpha degradation and p65 NF-kappaB nuclear translocation, the latter related to PEA as an endogenous PPAR-alpha agonist. In 2012 it became clear that PEA can also reduce reperfusion injury and the negative impact of shock on various outcome parameters, such as renal dysfunction, ischemic injury and inflammation, most probably via the PPAR-alpha pathway.[ editorializing ][ citation needed ] Studies have shown that PEA activates activates PPAR-alpha and TRPV1 receptors that control inflammation and the sensation of pain. [36] Among the reperfusion and inflammation markers measured PEA could reduce the increase in creatinine, γGT, AST, nuclear translocation of NF-κBp65; kidney MPO activity and MDA levels, nitrotyrosine, PAR and adhesion molecules expression, the infiltration and activation of mast cells and apoptosis. [37]

The biological responses to PEA dosing in animal models and in humans are being investigated vis-à-vis its involvement in a repair mechanism relevant to patient conditions of chronic inflammation and chronic pain. [38] [ verification needed ] In a model of visceral pain (inflammation of the urinary bladder) PEA was able to attenuate the viscero-visceral hyper-reflexia induced by inflammation of the urinary bladder, one of the reasons why PEA is currently explored in the painful bladder syndrome. [39] In a different model for bladder pain, the turpentine-induced urinary bladder inflammation in the rat, PEA also attenuated a referred hyperalgesia in a dose-dependent way. [40] Chronic pelvic pain in patients seem to respond favourably to a treatment with PEA. [41] [42]

Activity in non-neuronal cells

PEA, as an N-acylethanolamine, has physico-chemical properties comparable to anandamide,[ clarification needed ] and, while it is not strictly an endocannabinoid, it is often studied in conjunction with anandamide because of their overlapping synthetic and metabolic pathways.[ non-primary source needed ]N-acylethanolamines such as PEA often act as signaling molecules, activating receptors and regulating a variety of physiological functions.[ non-primary source needed ] PEA is known to activate intracellular, nuclear and membrane-associated receptors,[ non-primary source needed ] and to regulate many physiological functions related to the inflammatory cascade and chronic pain states.[ non-primary source needed ] Endocannabinoid lipids like PEA are widely distributed in nature, in a variety of plant, invertebrate, and mammalian tissues.[ non-primary source needed ]

PEA's mechanism of action sometimes is described as Autacoid Local Injury Antagonism (acronym ALIA), [15] and PEA under this nomenclature is an ALIAmide. Levi-Montalcini and coworkers presented evidence in 1993 that lipid amides of the N-acylethanolamine type, such as PEA, are potential prototypes of naturally occurring molecules capable of modulating mast cell activation, and her group used the acronym ALIA in that report.[ non-primary source needed ] [43] An autocoid is a regulating molecule, locally produced. An ALIAmide is an autocoid synthesized on-demand in response to injury, and acts locally to counteract such pathology. Soon after the breakthrough paper of Levi-Montalcini, the mast cell appeared to be an important target for the anti-inflammatory activity of PEA. Since 1993, at least 25 papers have been published on the various effects of PEA on mast cells. These cells are often found in proximity to sensory nerve endings, and their degranulation can enhance the nociceptive signal, the reason why peripheral mast cells are considered to be pro-inflammatory and pro-nociceptive. [44] PEA's activity is currently seen as a new inroad in the treatment of neuropathic pain and related disorders based on overactivation of glia and glia-related cells, such as in diabetes and glaucoma. [45] Microglia plays a key role in the winding up phenomenon and central sensitization. [46] [47]

Clinical relevance

Effects of oral dosing of PEA has been explored in humans, and include clinical trials for a variety of pain states, for inflammatory and pain syndromes. [42] [48] [49] [50] [51] Daily doses range from 300 to 1200 mg per day. [52] In a 2017 systematic meta-analysis involving 10 studies including data from 786 patients receiving PEA for pain-related indications and 512 controls, PEA was found to be associated with pain reduction significantly greater than observed in controls (P < 0.001). [53] Positive influences have also been observed in dermal applications, specifically atopic eczema, which may be linked to PPAR alpha activation. [48] [54] [ verification needed ]

In a 2015 analysis of a double blind placebo controlled study of PEA in sciatic pain, the Numbers Needed to Treat was 1.5. Its positive influence in chronic pain, and inflammatory states such as atopic eczema, seems[ editorializing ] to originate mainly from PPAR alpha activation. [48] [54] [ verification needed ] Since 2012 a number of new trials have been published, among which studies in glaucoma. [55] [56] PEA also seems[ editorializing ] to be one of the factors responsible for the decrease in pain sensitivity during and after sport, comparable to the endogenous opiates (endorphines). [57] [ verification needed ]

From a clinical perspective the most important and promising indications for PEA are linked to neuropathic and chronic pain states, such as diabetic neuropathic pain, sciatic pain, CRPS, pelvic pain and entrapment neuropathic pain states. [38] [42] [49] [50] [58] [59] In a blind trial reported in a conference proceeding, patients affected by pain from synovitis or TMJ osteoarthritis (N=25, in total[ clarification needed ]) were randomly assigned to PEA or ibuprofen groups for two weeks; the decrease in pain reported after two weeks was significantly higher for the PEA-treated group, likewise for improved masticatory function. [60] [61] [ better source needed ] In 2012, 20 patients with thalidomide and bortezomib induced neuropathy were reported to have improved nerve functions and less pain after a two-month treatment with PEA. [62] The authors pointed out that although a placebo effect might play a role in the reported pain relief, the changes in neurophysiological measures clearly indicated that PEA exerted a positive action on the myelinated fibre groups. Sixteen men and fourteen women with two major types of neuropathic pain refractory to analgesic treatment—peripheral diabetic neuropathy (4 men, 7 women) or post-herpetic neuralgia (12 men, 7 women) [63] —whose symptoms spanned eight pain categories ("burning", "osteoarticular", "piercing", etc. [64] ) who were under prior treatment with pregabalin were transferred to PEA, after which pregabalin treatment was gradually reintroduced; all were responding well after 45 days, and presented significant decreases in pain scores (without drug-drug interactions).[ verification needed ] [65]

In 2013, a metareview was published on the clinical efficacy and safety of PEA in the treatment of the common cold and influenza, based on reports from six double-blind, placebo, randomized controlled trials,[ verification needed ] addressing PEA's proposed anti-inflammatory and retinoprotectant effects. [66]

In 2019, significant increases in fatty acid amides including PEA, arachidonoylethanolamide, and oleoylethanolamide were noted in a Scottish woman with a previously undocumented variant of congenital insensitivity to pain. This was found to be a result of a combination of a hypomorphic single nucleotide polymorphism of fatty acid amide hydrolase (FAAH), alongside a mutation of the pseudogene, FAAH-OUT. The pseudogene was previously considered to be non-coding DNA, FAAH-OUT was found to be capable of modulating the expression of FAAH, making it a possible future target for novel analgesia/anxiolytic drug development. [67] [68]

In 2020, PEA has been suggested as a drug that may prove beneficial for the treatment of lung inflammation caused by SARS-CoV-2 infection. [69] A pharmaceutical company called FSD Pharma have entered PEA into a Phase 1 clinical trial under the name FSD-201, and has approval from the FDA for progressing to Phase 2a for this indication. [70]

Metabolism

PEA is metabolized by the cellular enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amide hydrolase (NAAA), the latter of which has more specificity toward PEA over other fatty acid amides. [71]

Safety

PEA is generally considered safe, and without adverse drug reactions (ADRs) or drug interactions. A 2016 study assessing safety claims in sixteen clinical trials, six case reports/pilot studies and a meta‐analysis of PEA as an analgesic, concluded that for treatment periods up to 49 days, clinical data argued against serious ADRs at an incidence of 1/200 or greater. [72] A 2016 pooled meta-analysis involving twelve studies found that no serious ADRs were registered and/or reported. [73] No data on interactions with PEA have been reported. Based on its mechanism, PEA may be considered likely to interact with other PPAR-α agonists used to treat high triglycerides; this remains unconfirmed.

See also

Related Research Articles

<span class="mw-page-title-main">Anandamide</span> Chemical compound (fatty acid neurotransmitter)

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.

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

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.

<span class="mw-page-title-main">Cannabinoid receptor</span> Group of receptors to cannabinoid compounds

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: endocannabinoids; phytocannabinoids ; and synthetic cannabinoids. All endocannabinoids and phytocannabinoids are lipophilic.

<span class="mw-page-title-main">URB597</span> Chemical compound

URB597 (KDS-4103) is a relatively selective and irreversible inhibitor of the enzyme fatty acid amide hydrolase (FAAH). FAAH is the primary degradatory enzyme for the endocannabinoid anandamide and, as such, inhibition of FAAH leads to an accumulation of anandamide in the CNS and periphery where it activates cannabinoid receptors. URB597 has been found to elevate anandamide levels and have activity against neuropathic pain in a mouse model.

<span class="mw-page-title-main">Endocannabinoid system</span> Biological system of neurotransmitters

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.

<span class="mw-page-title-main">Fatty-acid amide hydrolase 1</span>

Fatty-acid amide hydrolase 1 or FAAH-1(EC 3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) 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. FAAH also regulate the contents of NAE's in Dictyostelium discoideum, as they modulate their NAE levels in vivo through the use of a semispecific FAAH inhibitor.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

<span class="mw-page-title-main">Ajulemic acid</span> Chemical compound

Ajulemic acid (1',1'-Dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid) (DMH-D8-THC-11-OIC) (AB-III-56, HU-239, IP-751, CPL 7075, CT-3, JBT-101, Anabasum, Resunab, Lenabasum) is a synthetic cannabinoid that shows anti-fibrotic and anti-inflammatory effects in pre-clinical studies without causing a subjective "high". Although its design was inspired by a metabolite of delta-9-THC known as delta-9-THC-11-oic acid, ajulemic acid is an analog of the delta-8-THC metabolite delta-8-THC-11-oic acid. It is being developed for the treatment of inflammatory and fibrotic conditions such as systemic sclerosis, dermatomyositis and cystic fibrosis. It does not share the anti-emetic effects of some other cannabinoids, but may be useful for treating chronic inflammatory conditions where inflammation fails to resolve. Side effects include dry mouth, tiredness, and dizziness. The mechanism of action is through activation of the CB2 receptor leading to production of specialized proresolving eicosanoids such as lipoxin A4 and Prostaglandin J2. Studies in animals at doses up to 40 mg/kg show minimal psychoactivity of ajulemic acid, compared to that produced by tetrahydrocannabinol. A composition of ajulemic acid named Lenabasum (formerly Anabasum, Resunab) is being developed by Corbus Pharmaceuticals (formerly JB Therapeutics) for the treatment of orphan chronic life-threatening inflammatory diseases.

<span class="mw-page-title-main">AM404</span> Active metabolite of paracetamol

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.

<span class="mw-page-title-main">GPR55</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.

<span class="mw-page-title-main">Cannabinoid receptor 2</span> Mammalian protein found in Homo sapiens

The cannabinoid receptor 2(CB2), is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids. The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).

<i>N</i>-Arachidonoyl dopamine Chemical compound

N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 receptor) in 2000 and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002. NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.

<i>N</i>-Acylethanolamine Class of chemical compounds

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, and when the body is physically and psychologically active,. 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, a very ancient signaling system, being clearly present from the divergence of the protostomian/deuterostomian, 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. 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 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, but were secondarily lost in the Ecdysozoa, and 2-Arachidonoylglycerol (2-AG).

Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit the reabsorption of endocannabinoid neurotransmitters by the releasing neuron.

<i>N</i>-Arachidonylglycine Chemical compound

N-Arachidonylglycine (NAGly) is a carboxylic metabolite of the endocannabinoid anandamide (AEA). Since it was first synthesized in 1996, NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids. Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor. NaGly is an endogenous inhibitor of fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels. NaGly is found throughout the body and research on its explicit functions is ongoing.

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.

<span class="mw-page-title-main">Cannabis in pregnancy</span> Effects of cannabis consumption during pregnancy

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-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.

PF-3845 is a selective inhibitor of fatty acid amide hydrolase. It results in increased levels of anandamide and results in cannabinoid receptor-based effects. It has anti-inflammatory action in mice colitis models. Antidiarrheal and antinociceptive effects were also seen in mouse models of pain.

An endocannabinoid enhancer (eCBE) is a type of cannabinoidergic drug that enhances the activity of the endocannabinoid system by increasing extracellular concentrations of endocannabinoids. Examples of different types of eCBEs include fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, and endocannabinoid transporter (eCBT) inhibitors. An example of an actual eCBE is AM404, the active metabolite of the analgesic paracetamol and a dual FAAH inhibitor and eCBRI.

References

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