Anandamide is derived from the non-oxidative metabolism of
arachidonic acid, an
essentialomega-6 fatty acid. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways.[5] It is degraded primarily by the
fatty acid amide hydrolase (FAAH) enzyme, which converts anandamide into
ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.[6][7]
Anandamide's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB1cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[12] The latter are mainly involved in functions of the
immune system. Cannabinoid receptors were originally discovered as being sensitive to Δ9-
tetrahydrocannabinol (Δ9-THC, commonly called THC), which is the primary psychoactive cannabinoid found in
cannabis. The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors.
Anandamide is also important for the
implantation of the early stage
embryo in its
blastocyst form into the
uterus. Therefore, cannabinoids such as Δ9-THC might influence processes during the earliest stages of human pregnancy.[13] Peak plasma anandamide occurs at
ovulation and positively correlates with peak
estradiol and
gonadotrophin levels, suggesting that these may be involved in the regulation of anandamide levels.[14] Subsequently, anandamide has been proposed as a
biomarker of
infertility, but so far lacks any
predictive values in order to be used clinically.[15]
The acute beneficial effects of exercise (termed as runner's high) seem to be mediated by anandamide in mice.[16] Anandamide is the precursor of a class of physiologically active substances, the
prostamides.[17] Anandamide was found in 2007 to inhibit the proliferation of certain human breast cancer cell lines in vitro.[18]
Anandamide is found in chocolate together with two substances that might mimic the effects of anandamide,
N-oleoylethanolamine and N-linoleoylethanolamine.[19]
Additionally, anandamide and other endocannabinoids are found in the model organism Drosophila melanogaster (fruit fly), although no CB receptors have been found in any insects.[20][21]
Effects on behavior
Both the
CB1 and
CB2 receptors (the bonding site of anandamide) seem to play a role in the identification of positive and negative interpretation of environment and setting.[22] In animal models, anandamide mediates the interpretation of stimulus; specifically, optimism and pessimism in the presence of an ambiguous cue.[23] Anandamide has been shown to impair working memory in rats,[24] while THC (the compound in cannabis that binds to the CB1 and CB2 receptors) also shows a deficit in working memory.[25]
This binding relationship of anandamide and the CB1/CB2 may affect neurotransmission of dopamine, serotonin, GABA, and glutamate.[26] There is currently encouraging, albeit embryonic, evidence for medicinal cannabis in the treatment of a range of psychiatric disorders. Supportive findings are emerging for some key isolates, however, clinicians need to be mindful of a range of prescriptive and occupational safety considerations, especially if initiating higher dose THC formulas.[27]
Anandamide injected directly into the
forebrain reward-related brain structure
nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.[28] Increasing anandamide seems to increase the intrinsic value of food, not necessarily by stimulation of appetite or hunger.[29]
Anandamide may affect hunger, sleep, pain modulation, working memory, identification of novelty, and interpretation of environment.[citation needed]
Endogenous anandamide is present at very low levels and has a very short
half-life due to the action of the enzyme
fatty acid amide hydrolase (FAAH), which breaks it down into free
arachidonic acid and
ethanolamine. Studies of piglets show that dietary levels of arachidonic acid and other
essential fatty acids affect the levels of anandamide and other endocannabinoids in the brain.[33] High fat diet feeding in mice increases levels of anandamide in the liver and increases
lipogenesis.[34] Anandamide may be relevant to the development of obesity, at least in rodents.
Paracetamol (called acetaminophen in the US and Canada) is metabolically combined with arachidonic acid by FAAH to form
AM404.[35] This metabolite of paracetamol is a potent
agonist at the
TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. As a result, anandamide levels in the body and brain are elevated. In this fashion, paracetamol acts as a
pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for the
analgesic effects of paracetamol.[36][37]
It is found that anandamide prefers
cholesterol and
ceramide more than other
membrane lipids, and cholesterol can behave as a binding partner for it, and following an initial interaction mediated by the establishment of a
hydrogen bond, the endocannabinoid is attracted towards the
membrane interior, where it forms a
molecular complex with cholesterol after a functional conformation adaptation to the
apolar membrane milieu, and from there, the complex is further directed to the cannabinoid receptor (CB1) and out.[40]
Research and production
Black pepper contains the alkaloid
guineesine, which is an anandamide
reuptake inhibitor. It may therefore increase anandamide's physiological effects.[41]
Low-dose anandamide has an
anxiolytic effect, while in one study, high doses injected directly into the cerebral fluid of the brain of mice shows evident cell
apoptosis (programmed cell death) in vitro as opposed to
necrosis.[42] That being said, another study conducted under similar conditions demonstrated neuronal growth both in vitro and in vivo.[43]
Another study with rats found that reductions in AEA signaling through FAAH overexpression within the
basolateral complex of amygdala (BLA) appeared to reliably reduce measurements of anxiety and overall levels of
corticosterone, a primary
glucocorticoid in animals like birds, rodents, reptiles and amphibians responsible for
energy regulation,
immune and
stress responses. This is similar to the main glucocorticoid
cortisol in humans. Reduction of AEA in the BLA has been shown to suppress
fear behavior and promote
fear extinction. This suggests possible involvement of AEA intervention in the future for the treatment of
psychological disorders. However, further work in this area of study is needed, as reduced anandamide signaling is believed at this moment to involve CB1 receptors as well as GABAergic and glutamatergic interactions.[45]
Cortical glutamatergic transmission may be modulated by endocannabinoids during stress and fear
habituation.[46] Glutamatergic interaction in the BLA believed to be responsible for changes in anxiety, appears to normalize stress-induced anxiety-like behavior. A study indicated that infusion of the GluK1 receptor agonist ATPA into the BLA enhanced GABAergic neurotransmission, which is currently believed to have a large role in the reduction of anxiety symptoms.[47]
Additionally, the ECs, along with AEA, have been highlighted for their potential involvement in obesity development and harmful effects on lipid and glucose metabolism, which may contribute to insulin resistance and deficiency, both of which are major risk factors for developing
type 2 diabetes mellitus. Blockade of CB1 receptors was found significantly to improve lipid resistance and lipid profile in obese subjects, but also has potential to increase fat accumulation through increased food intake, favored lipogenesis and reduced energy expenditure. This may affect downstream systems like the pancreas, liver, adipose tissue, and skeletal muscle, with inflammation and apoptosis in the case of the pancreas. CB1R inhibition with peripherally restricted antagonists and inverse agonists may aid in the treatment of diabetic neuropathy and neuropathy. CB2R agonists may show promise for the treatment of inflammation, which contributes to renal injury.[48]
A Scottish woman with a rare mutation in her FAAH gene that resulted in elevated anandamide levels was reported to be immune to anxiety, unable to experience fear, and insensitive to pain. The frequent burns and cuts she suffered due to her
hypoalgesia healed more rapidly than was expected.[50][51][52]
Topical Anandamide was found to reduce peripheral neuropathic pain by interaction with peripheral cannabinoid receptors.[53]
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