Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

. 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 ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternative ...

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 Sanskrit (; attributively , ; nominally , , ) is a classical language belonging to the Indo-Aryan languages, Indo-Aryan branch of the Indo-European languages. It arose in South Asia after its predecessor languages had Trans-cultural diffusion ...

word '' ananda'', which means "joy, bliss, delight", plus

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

. Anandamide is derived from the non-oxidative metabolism of

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''ara ...

, an essential omega-6 fatty acid. It is synthesized from ''N''-arachidonoyl phosphatidylethanolamine by multiple pathways. 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.

Physiological functions

Anandamide was first described (and named) in 1992 by Raphael Mechoulam and his lab members W. A. Devane and Lumír Hanuš. Anandamide's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB₁ cannabinoid receptors in the central nervous system, and CB₂ cannabinoid receptors in the periphery. The latter are mainly involved in functions of the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

. Cannabinoid receptors were originally discovered as being sensitive to Δ⁹-

tetrahydrocannabinol Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...

(Δ⁹-THC, commonly called THC), which is the primary psychoactive cannabinoid found in

. 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 implantation of the early stage

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

in its

blastocyst The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the ''embryoblast'' which subsequently forms the embryo, and an outer layer of trophoblast cells called th ...

form into the

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

. Therefore, cannabinoids such as Δ⁹-THC might influence processes during the earliest stages of human pregnancy. Peak plasma anandamide occurs at ovulation and positively correlates with peak estradiol and

gonadotrophin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chorionic ...

levels, suggesting that these may be involved in the regulation of anandamide levels. Subsequently, anandamide has been proposed as a biomarker of

infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...

, but so far lacks any

predictive value Predictive value of tests is the probability of a target condition given by the result of a test, often in regard to medical tests. *In cases where binary classification can be applied to the test results, such yes versus no, test target (such as ...

s in order to be used clinically. The acute beneficial effects of exercise (termed as '' runner's high'') seem to be mediated by anandamide in mice. Anandamide is the precursor of a class of physiologically active substances, the prostamides. Anandamide was found in 2007 to inhibit the proliferation of certain human breast cancer cell lines ''in vitro''. Anandamide is found in chocolate together with two substances that might mimic the effects of anandamide, ''N''-oleoylethanolamine and ''N''-linoleoylethanolamine. 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.

Effects on behavior

The role of the endocannabinoid system on behavior and mood is still being researched. 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. In animal models, anandamide plays a role in the interpretation of stimulus; specifically, optimism and pessimism in the presence of an ambiguous cue. Anandamide has been shown to impair working memory in rats, while THC (the compound in cannabis that binds to the CB1 and CB2 receptors) also shows a deficit in working memory. Studies are under way to explore what role anandamide plays in human behavior, such as eating, sleep patterns, and pain relief. This binding relationship of anandamide and the CB1/CB2 seems to play a role in neurotransmission of dopamine, serotonin, GABA, and glutamate. 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.. Anandamide injected directly into the forebrain reward-related brain structure

nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hyp ...

enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well. Increasing anandamide seems to increase the intrinsic value of food, not necessarily by stimulation of appetite or hunger. Although more scientific information is needed, by comparing the effect of THC/anandamide, it can be inferred that anandamide plays a role in hunger, sleep, pain modulation, working memory, identification of novelty, and interpretation of environment.

Synthesis and degradation

In humans, anandamide is biosynthesized from ''N''-arachidonoyl phosphatidylethanolamine (NAPE). In turn NAPE arises by transfer of

from

lecithin Lecithin (, from the Greek ''lekithos'' "yolk") is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances (and so a ...

to the free amine of cephalin through an ''N''-acyltransferase enzyme. Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as

phospholipase A2 The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glyc ...

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...

and N-acetylphosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD). The crystal structure of NAPE-PLD in complex with phosphatidylethanolamine and deoxycholate shows how the cannabinoid anandamide is generated from membrane ''N''-acylphosphatidylethanolamines (NAPEs), and reveals that

bile acids Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primar ...

– which are mainly involved in the absorption of lipids in the small

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...

– modulate its biogenesis. Endogenous anandamide is present at very low levels and has a very short

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it down into free

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. High fat diet feeding in mice increases levels of anandamide in the liver and increases

lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride s ...

. This suggests that anandamide may play a role in the development of obesity, at least in rodents.

Paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferio ...

(called acetaminophen in the US and Canada) is metabolically combined with arachidonic acid by FAAH to form AM404. This metabolite of paracetamol is a potent

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

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 An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

effects of paracetamol. Endocannabinoid transporters for anandamide and 2-arachidonoylglycerol include the

heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including expo ...

s (

Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...

s) and fatty acid binding proteins (FABPs). It is found that anandamide prefer

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...

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 In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...

, 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.

Research and production

Black pepper contains the alkaloid guineesine, which is an anandamide reuptake inhibitor. It may therefore increase anandamide's physiological effects. Low dose intake of anandamide has an anxiolytic effect, but high dose intake injected directly into the cerebral fluid of the brain of mice shows evident cell

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

(programmed cell death) ''in vitro'' as opposed to necrosis. Although this is contradicted by another study also done in both ''in vitro'' and ''in vivo'' showing neuron growth in the same situation. A Scottish woman with a rare genetic mutation in her FAAH gene with resultant 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.

References

External links