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, fr ...

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. Neuro ...

. Anandamide was the first

endocannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

to be discovered: it participates in the body's

endocannabinoid system The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed t ...

by binding to

cannabinoid receptors Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recepto ...

, the same receptors that the psychoactive compound

THC 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' ...

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''. Alternatively ...

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 branch of the Indo-European languages. It arose in South Asia after its predecessor languages had diffused there from the northwest in the late ...

word '' ananda'', which means "joy,

bliss BLISS is a system programming language developed at Carnegie Mellon University (CMU) by W. A. Wulf, D. B. Russell, and A. N. Habermann around 1970. It was perhaps the best known system language until C debuted a few years later. Since then, C b ...

, 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 is ...

. 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 ''arachi ...

, an essential

omega-6 fatty acid Omega-6 fatty acids (also referred to as ω-6 fatty acids or ''n''-6 fatty acids) are a family of polyunsaturated fatty acids that have in common a final carbon-carbon double bond in the ''n''-6 position, that is, the sixth bond, counting from ...

. It is synthesized from ''N''-arachidonoyl phosphatidylethanolamine by multiple pathways. It is degraded primarily by the

fatty acid amide hydrolase Fatty acid amide hydrolase or FAAH (, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993. In humans, it is encoded by the gene ''FAAH''.; Fun ...

(FAAH) enzyme, which converts anandamide into

ethanolamine Ethanolamine (2-aminoethanol, monoethanolamine, ETA, or MEA) is an organic chemical compound with the formula or . The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorless, viscous liquid wit ...

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 Raphael Mechoulam ( he, רפאל משולם, bg, Рафаел Мешулам; born 5 November 1930) is an Israeli organic chemist and professor of Medicinal Chemistry at the Hebrew University of Jerusalem in Israel. Mechoulam is best known for h ...

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 receptor Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recepto ...

s 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 the t ...

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 uter ...

. Therefore, cannabinoids such as Δ⁹-THC might influence processes during the earliest stages of human pregnancy. Peak plasma anandamide occurs at

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...

and positively correlates with peak

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...

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 In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

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 state ...

, 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 a ...

s in order to be used clinically. The acute beneficial effects of exercise (termed as ''

runner's high The neurobiological effects of physical exercise are numerous and involve a wide range of interrelated effects on brain structure, brain function, and cognition. A large body of research in humans has demonstrated that consistent aerobic exerci ...

'') seem to be mediated by anandamide in mice. Anandamide is the precursor of a class of physiologically active substances, the

prostamide Prostamides are a class of physiology, physiologically active, lipid-like substances chemically related to prostaglandins. They occur naturally in humans and other animals. The first prostamide, called prostamide E2, was discovered in 1997. Bioche ...

s. 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 In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the Anatomical terms of location#Directional terms, rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hin ...

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 hypotha ...

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 ar ...

to the free amine of

cephalin Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate- ethanolamine to diglycerides, releasing cytidine monophosphate. ''S''-Adenosyl methionine can ...

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 glyce ...

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 Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. ''S''-Adenosyl methionine can s ...

and

deoxycholate Deoxycholic acid is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and chenodeoxycholic acid. Bacteria me ...

shows how the

cannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

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. Primary b ...

– 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 ...

– 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 ato ...

due to the action of the enzyme

(FAAH), which breaks it down into free

and

. Studies of piglets show that dietary levels of arachidonic acid and other

essential fatty acids Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health but cannot synthesize them. Only two fatty acids are known to be essential for humans: alpha-linolenic ac ...

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 syn ...

. 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 inferior ...

(called acetaminophen in the US and Canada) is metabolically combined with arachidonic acid by FAAH to form

AM404 AM404, also known as ''N''-arachidonoylaminophenol, 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 ...

. 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 ago ...

at the

TRPV1 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 th ...

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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the 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 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 (anandamide, AEA, ...

for anandamide and

2-arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present ...

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 importa ...

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 mem ...

and

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetylsphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up ...

more than other

membrane lipid Membrane lipids are a group of compounds (structurally similar to fats and oils) which form the double-layered surface of all cells (lipid bilayer). The three major classes of membrane lipids are phospholipids, glycolipids, and cholesterol. Lipid ...

s, 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 ...

, the endocannabinoid is attracted towards the

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the

apolar In chemistry, polarity is a separation of electric charge leading to a molecule or its chemical groups having an electric dipole moment, with a negatively charged end and a positively charged end. Polar molecules must contain one or more po ...

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 Guineesine (or guineensine) is an alkaloid isolated from long pepper (''Piper longum'') and black pepper (''Piper nigrum''). Research Guineensine inhibits the cellular reuptake of anandamide and 2-arachidonoylglycerol in a mouse model ( EC50 = ...

, which is an anandamide

reuptake inhibitor Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmit ...

. It may therefore increase anandamide's physiological effects. Low dose intake of anandamide has an

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxi ...

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 incl ...

(programmed cell death) ''in vitro'' as opposed to

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

. 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