Anandamide (ANA), also referred to asN-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter belonging to the fatty acid derivative group known asN-acylethanolamines (NAE). Anandamide takes its name from theSanskrit wordananda (आनन्द), meaning "joy, bliss, delight," plusamide. Anandamide, the first discoveredendocannabinoid, engages with the body'sendocannabinoid system by binding to the samecannabinoid receptors thatTHC found incannabis acts on. Anandamide can be found within tissues in a wide range of animals.[1][2] It has also been found in plants, such as thecacao tree.[3]
Anandamide is derived from the non-oxidative metabolism ofarachidonic acid, anessentialomega-6 fatty acid. It is synthesized fromN-arachidonoyl phosphatidylethanolamine by multiple pathways.[4] It is degraded primarily by thefatty acid amide hydrolase (FAAH) enzyme, which converts anandamide intoethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for possible therapeutic use.[5][6]
Anandamide was discovered byRaphael 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 usingmass spectrometry andnuclear magnetic resonance spectroscopy.[7] 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.[8] Since the 1992 findings, many studies have been completed to examine ANA further, including research on behavioral and molecular effects.
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According to in vitro research, anandamide effects are mediated primarily by CB1cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[9] The latter appear to be involved in functions of theimmune system. Cannabinoid receptors were originally discovered as sensitive to Δ9-tetrahydrocannabinol (Δ9-THC, commonly called THC), which is the primary psychoactive cannabinoid found incannabis. 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 theimplantation of the early stageembryo in itsblastocyst form into theuterus. Therefore, cannabinoids such as Δ9-THC might influence processes during the earliest stages of human pregnancy.[10] Peak plasma anandamide occurs atovulation and positively correlates with peakestradiol andgonadotrophin levels, suggesting that these may be involved in the regulation of anandamide levels.[11] Subsequently, anandamide has been proposed as abiomarker ofinfertility, but so far lacks anypredictive values in order to be used clinically.[12]
Both theCB1 andCB2 receptors (the binding site of anandamide) are under research for a possible role in positive and negative interpretation of environment and setting.[13] The binding relationship of anandamide and the CB1/CB2 may affect neurotransmission of dopamine, serotonin, GABA, and glutamate.[14]
Endogenous anandamide is present at very low levels and has a very shorthalf-life due to the action of the enzymefatty acid amide hydrolase (FAAH), which breaks it down into freearachidonic acid andethanolamine. Studies of piglets show that dietary levels of arachidonic acid and otheressential fatty acids affect the levels of anandamide and other endocannabinoids in the brain.[25] High fat diet feeding in mice increases levels of anandamide in the liver and increaseslipogenesis.[26] Anandamide may be relevant to the development of obesity, at least in rodents.
Paracetamol (known as acetaminophen in the US and Canada) is metabolically combined with arachidonic acid by FAAH to formAM404.[27] This metabolite is a potentagonist at theTRPV1 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 itsanalgesic effects.[28][29]
Black pepper contains the alkaloidguineesine, which is an anandamide reuptake inhibitor. It may therefore increase anandamide's physiological effects.[30]
Anandamide shows a preference for binding tocholesterol andceramide over other membrane lipids. Cholesterol acts as a binding partner for anandamide. Initially, ahydrogen bond 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.[33]
^Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. (December 1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor".Science.258 (5090):1946–1949.Bibcode:1992Sci...258.1946D.doi:10.1126/science.1470919.PMID1470919.
^Martin BR, Mechoulam R, Razdan RK (July 1999). "Discovery and characterization of endogenous cannabinoids".Life Sciences.65 (6–7):573–595.doi:10.1016/S0024-3205(99)00281-7.PMID10462059.
^Gaetani S, Dipasquale P, Romano A, Righetti L, Cassano T, Piomelli D, et al. (2009).The Endocannabinoid System as a Target for Novel Anxiolytic and Antidepressant Drugs. International Review of Neurobiology. Vol. 85. pp. 57–72.doi:10.1016/S0074-7742(09)85005-8.ISBN978-0-12-374893-5.PMID19607961.
^Fazio D, Criscuolo E, Piccoli A, Barboni B, Fezza F, Maccarrone M (July 2020). "Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold?".Expert Opinion on Drug Discovery.15 (7):765–778.doi:10.1080/17460441.2020.1751118.PMID32292082.
^Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. (December 1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor".Science.258 (5090):1946–1949.Bibcode:1992Sci...258.1946D.doi:10.1126/science.1470919.PMID1470919.
^McCormick E, Nussbaum D, Draganski A, Garcia S, Desai S, Friedman J, et al. (2023). "43357 Encapsulated anandamide: A promising therapy for cutaneous lupus erythematosus".Journal of the American Academy of Dermatology.89 (3): AB1.doi:10.1016/j.jaad.2023.07.014.
^Sinning C, Watzer B, Coste O, Nüsing RM, Ott I, Ligresti A, et al. (December 2008). "New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide".Journal of Medicinal Chemistry.51 (24):7800–7805.doi:10.1021/jm800807k.PMID19053765.
^Nicolussi S, Viveros-Paredes JM, Gachet MS, Rau M, Flores-Soto ME, Blunder M, et al. (February 2014). "Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice".Pharmacological Research.80:52–65.doi:10.1016/j.phrs.2013.12.010.PMID24412246.
^Oddi S, Fezza F, Pasquariello N, D'Agostino A, Catanzaro G, De Simone C, et al. (June 2009). "Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins".Chemistry & Biology.16 (6):624–632.doi:10.1016/j.chembiol.2009.05.004.PMID19481477.
