Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the

Sanskrit Sanskrit (; stem form ; nominal singular , ,) is a classical language belonging to the Indo-Aryan languages, Indo-Aryan branch of the Indo-European languages. It arose in northwest South Asia after its predecessor languages had Trans-cultural ...

word ''ananda'' ( आनन्द), meaning "joy, bliss, delight," plus

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

. Anandamide, the first discovered

endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

, engages with the body's

endocannabinoid system The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the central nervous system ( ...

by binding to the same cannabinoid receptors that THC found in

cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...

acts on. Anandamide can be found within tissues in a wide range of animals. It has also been found in plants, such as the cacao tree. 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 a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

, 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 (PUFA) that share a final carbon-carbon double bond in the ''n''−6 position, that is, the sixth bond, counti ...

. 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 Ethanolamine (2-aminoethanol, monoethanolamine, ETA, or MEA) is a naturally occurring organic chemical compound with the formula or . The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorl ...

and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for possible therapeutic use.

Discovery

Anandamide was discovered by Raphael Mechoulam and fellow coworkers in 1992. This was the first marijuana-like substance produced by the human body to be observed. By examining a pig brain and canine gut, they were able to isolate ANA using

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...

and

nuclear magnetic resonance spectroscopy Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a Spectroscopy, spectroscopic technique based on re-orientation of Atomic nucleus, atomic nuclei with non-zero nuclear sp ...

. ANA works within the system of the brain associated with the feeling of reward, and as such, has been the topic of many research studies. Since the 1992 findings, many studies have been completed to examine ANA further, including research on behavioral and molecular effects.

Research

According to in vitro research, anandamide effects are mediated primarily by CB₁

cannabinoid receptor 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 cann ...

s in the central nervous system, and CB₂ cannabinoid receptors in the periphery. The latter appear to be involved in functions of the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

. Cannabinoid receptors were originally discovered as sensitive to Δ⁹-

tetrahydrocannabinol Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It 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) de ...

(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 under research for its potential involvement in the implantation of the early stage

embryo An embryo ( ) is the initial stage of development for 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 sp ...

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 ...

form into the

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

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

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

and positively correlates with peak

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

and gonadotrophin 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 In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

, 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.

Behavior

Both the CB1 and CB2 receptors (the binding site of anandamide) are under research for a possible role in positive and negative interpretation of environment and setting. The binding relationship of anandamide and the CB1/CB2 may affect neurotransmission of dopamine, serotonin, GABA, and glutamate.

Endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

s may disturb

homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...

in several ways: by enhancing hunger sensations, encouraging increased food intake, and shifting energy balance towards

energy storage Energy storage is the capture of energy produced at one time for use at a later time to reduce imbalances between energy demand and energy production. A device that stores energy is generally called an Accumulator (energy), accumulator or Batte ...

. A resultant decrease in energy expenditure is observed. Cortical glutamatergic transmission may be modulated by endocannabinoids during stress and fear

habituation Habituation is a form of non-associative learning in which an organism’s non-reinforced response to an inconsequential stimulus decreases after repeated or prolonged presentations of that stimulus. For example, organisms may habituate to re ...

Obesity and liver disease

Blockade of CB1 receptors was found to improve lipid resistance and lipid profile in obese subjects with

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

. Elevated anandamide levels are found in people with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and

liver fibrosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

Topical effects

The

American Academy of Dermatology The American Academy of Dermatology (AAD) is a non-profit professional organization of dermatologists in the United States and Canada, based in Rosemont, Illinois, near Chicago. It was founded in 1938 and has more than ''21,000'' members. The Acad ...

has named topical anandamide a promising therapy for cutaneous

lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, ...

Biosynthesis

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

from

lecithin Lecithin ( ; from the Ancient Greek "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 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) catalyses the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid "tail" and the glycero ...

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 i ...

and N-acetylphosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD), with other key enzymes yet to be identified. 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, ''S''-Ade ...

and deoxycholate shows how the

cannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

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 in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...

– 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 tract is the largest of the body's systems, after the cardiovascular system. T ...

– modulate its biogenesis.

Metabolism

Endogenous anandamide is present at very low levels and has a very short

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

due to the action of the enzyme fatty acid amide hydrolase (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 are required by humans and other animals for normal physiological function that cannot be synthesized in the body.⁠ As they are not synthesized in the body, the essential fatty acids al ...

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 Adipose tissue, fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in adipose, fat. Lipogenesis encompasses both fatty aci ...

. Anandamide may be relevant to the development of obesity, at least in rodents.

Paracetamol Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...

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

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

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 ...

vanilloid receptor, a weak agonist at both CB₁ and CB₂ receptors, and an inhibitor of anandamide reuptake. Consequently, anandamide levels in the body and brain are elevated. Thus, paracetamol acts as a pro-drug for a cannabimimetic metabolite, which may be partially or fully responsible for its

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects. Black pepper contains the alkaloid guineesine, which is an anandamide reuptake inhibitor. It may therefore increase anandamide's physiological effects.

Transport

Endocannabinoid transporters for anandamide and 2-arachidonoylglycerol include the

heat shock protein Heat shock proteins (HSPs) 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 ex ...

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 and play crucial roles in the development of can ...

s) and fatty acid binding proteins (FABPs). Anandamide shows a preference for binding to

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

and

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of Eukaryote, eukaryotic cells, since they are co ...

over other membrane lipids. Cholesterol acts as a binding partner for anandamide. Initially, a

hydrogen bond In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

facilitates their interaction. Following this, anandamide is drawn towards the membrane interior, where it forms a molecular complex with cholesterol. This process involves a conformational adaptation of anandamide to the apolar membrane environment. Subsequently, the anandamide-cholesterol complex is directed to the cannabinoid receptor (CB1) and then exits.

References

External links

* * {{Transient receptor potential channel modulators Endocannabinoids Neurotransmitters Fatty acid amides Biomolecules Hydroxyethyl compounds CB1 receptor agonists CB2 receptor agonists Glycine receptor agonists Glycine receptor antagonists Euphoriants Arachidonyl compounds Ethanolamines