:Anandamide

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 and nuclear magnetic resonance spectroscopy.{{cite journal | vauthors = Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R | title = Isolation and structure of a brain constituent that binds to the cannabinoid receptor | journal = Science | volume = 258 | issue = 5090 | pages = 1946–1949 | date = December 1992 | pmid = 1470919 | doi = 10.1126/science.1470919 | bibcode = 1992Sci...258.1946D }} 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.{{cite journal | vauthors = Scherma M, Masia P, Satta V, Fratta W, Fadda P, Tanda G | title = Brain activity of anandamide: a rewarding bliss? | journal = Acta Pharmacologica Sinica | volume = 40 | issue = 3 | pages = 309–323 | date = March 2019 | pmid = 30050084 | pmc = 6460372 | doi = 10.1038/s41401-018-0075-x }} 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 CB₁ cannabinoid receptors in the central nervous system, and CB₂ cannabinoid receptors in the periphery.{{cite journal | vauthors = Pacher P, Bátkai S, Kunos G | title = The endocannabinoid system as an emerging target of pharmacotherapy | journal = Pharmacological Reviews | volume = 58 | issue = 3 | pages = 389–462 | date = September 2006 | pmid = 16968947 | pmc = 2241751 | doi = 10.1124/pr.58.3.2 }} The latter appear to be involved in functions of the immune system. Cannabinoid receptors were originally discovered as 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 under research for its potential involvement in 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.{{cite journal | vauthors = Piomelli D | title = THC: moderation during implantation | journal = Nature Medicine | volume = 10 | issue = 1 | pages = 19–20 | date = January 2004 | pmid = 14702623 | doi = 10.1038/nm0104-19 | s2cid = 29207064 }} 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.{{cite journal | vauthors = El-Talatini MR, Taylor AH, Konje JC | title = The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle | journal = Fertility and Sterility | volume = 93 | issue = 6 | pages = 1989–1996 | date = April 2010 | pmid = 19200965 | doi = 10.1016/j.fertnstert.2008.12.033 | doi-access = free }} Subsequently, anandamide has been proposed as a biomarker of infertility, but so far lacks any predictive values in order to be used clinically.{{cite journal | vauthors = Rapino C, Battista N, Bari M, Maccarrone M | title = Endocannabinoids as biomarkers of human reproduction | journal = Human Reproduction Update | volume = 20 | issue = 4 | pages = 501–516 | year = 2014 | pmid = 24516083 | doi = 10.1093/humupd/dmu004 | doi-access = free }}

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.{{cite journal | vauthors = Crane NA, Schuster RM, Fusar-Poli P, Gonzalez R | title = Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences | journal = Neuropsychology Review | volume = 23 | issue = 2 | pages = 117–137 | date = June 2013 | pmid = 23129391 | pmc = 3593817 | doi = 10.1007/s11065-012-9222-1 }} The binding relationship of anandamide and the CB1/CB2 may affect neurotransmission of dopamine, serotonin, GABA, and glutamate.{{cite journal | vauthors = Fantegrossi WE, Wilson CD, Berquist MD | title = Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems | journal = Drug Metabolism Reviews | volume = 50 | issue = 1 | pages = 65–73 | date = February 2018 | pmid = 29385930 | pmc = 6419500 | doi = 10.1080/03602532.2018.1428343 }}

Endocannabinoids may disturb homeostasis in several ways: by enhancing hunger sensations, encouraging increased food intake, and shifting energy balance towards energy storage. A resultant decrease in energy expenditure is observed.{{cite journal | vauthors = Schulz P, Hryhorowicz S, Rychter AM, Zawada A, Słomski R, Dobrowolska A, Krela-Kaźmierczak I | title = What Role Does the Endocannabinoid System Play in the Pathogenesis of Obesity? | journal = Nutrients | volume = 13 | issue = 2 | pages = 373 | date = January 2021 | pmid = 33530406 | pmc = 7911032 | doi = 10.3390/nu13020373 | doi-access = free }}

Cortical glutamatergic transmission may be modulated by endocannabinoids during stress and fear habituation.{{cite journal | vauthors = Kamprath K, Plendl W, Marsicano G, Deussing JM, Wurst W, Lutz B, Wotjak CT | title = Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling | journal = Genes, Brain and Behavior | volume = 8 | issue = 2 | pages = 203–211 | date = March 2009 | pmid = 19077175 | doi = 10.1111/j.1601-183X.2008.00463.x | s2cid = 21922344 | doi-access = free }}

Blockade of CB1 receptors was found to improve lipid resistance and lipid profile in obese subjects with type 2 diabetes.{{cite journal | vauthors = Gruden G, Barutta F, Kunos G, Pacher P | title = Role of the endocannabinoid system in diabetes and diabetic complications | journal = British Journal of Pharmacology | volume = 173 | issue = 7 | pages = 1116–1127 | date = April 2016 | pmid = 26076890 | pmc = 4941127 | doi = 10.1111/bph.13226 }} Elevated anandamide levels are found in people with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and liver fibrosis.{{cite journal | vauthors = Kimberly WT, O'Sullivan JF, Nath AK, Keyes M, Shi X, Larson MG, Yang Q, Long MT, Vasan R, Peterson RT, Wang TJ, Corey KE, Gerszten RE | title = Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis | journal = JCI Insight | volume = 2 | issue = 9 | pages = e92989 | date = May 2017 | pmid = 28469090 | pmc = 5414569 | doi = 10.1172/jci.insight.92989 }}

The American Academy of Dermatology has named topical anandamide a promising therapy for cutaneous lupus erythematosus.{{cite journal |doi=10.1016/j.jaad.2023.07.014 |title=43357 Encapsulated anandamide: A promising therapy for cutaneous lupus erythematosus |date=2023 |journal=Journal of the American Academy of Dermatology |volume=89 |issue=3 |pages=AB1 | vauthors = McCormick E, Nussbaum D, Draganski A, Garcia S, Desai S, Friedman J, Friedman A }}{{cite web | url=https://www.managedhealthcareexecutive.com/view/a-new-treatment-in-a-new-package-for-cutaneous-lupus-erythematosus | title=A New Treatment in a New Package for Cutaneous Lupus Erythematosus | date=19 March 2023 }}

In humans, anandamide is biosynthesized from N-arachidonoyl phosphatidylethanolamine (NAPE). In turn, NAPE arises by transfer of arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme.{{cite journal | vauthors = Natarajan V, Reddy PV, Schmid PC, Schmid HH | title = N-Acylation of ethanolamine phospholipids in canine myocardium | journal = Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism | volume = 712 | issue = 2 | pages = 342–355 | date = August 1982 | pmid = 7126608 | doi = 10.1016/0005-2760(82)90352-6 }}{{cite journal | vauthors = Cadas H, di Tomaso E, Piomelli D | title = Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain | journal = The Journal of Neuroscience | volume = 17 | issue = 4 | pages = 1226–1242 | date = February 1997 | pmid = 9006968 | pmc = 6793739 | doi = 10.1523/JNEUROSCI.17-04-01226.1997 | doi-access = free }} Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and N-acetylphosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD), with other key enzymes yet to be identified.{{Cite journal |last=Maccarrone |first=Mauro |date=2017-05-29 |title=Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years |url=http://journal.frontiersin.org/article/10.3389/fnmol.2017.00166/full |journal=Frontiers in Molecular Neuroscience |volume=10 |doi=10.3389/fnmol.2017.00166 |issn=1662-5099 |pmc=5447297 |pmid=28611591 |doi-access=free}}

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 – which are mainly involved in the absorption of lipids in the small intestine – modulate its biogenesis.{{cite journal | vauthors = Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G | title = Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids | journal = Structure | volume = 23 | issue = 3 | pages = 598–604 | date = March 2015 | pmid = 25684574 | pmc = 4351732 | doi = 10.1016/j.str.2014.12.018 }}

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.{{cite journal | vauthors = Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V | title = Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 11 | pages = 6402–6406 | date = May 2001 | pmid = 11353819 | pmc = 33480 | doi = 10.1073/pnas.101119098 | doi-access = free | bibcode = 2001PNAS...98.6402B }} High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.{{cite journal | vauthors = Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G | title = Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity | journal = The Journal of Clinical Investigation | volume = 115 | issue = 5 | pages = 1298–1305 | date = May 2005 | pmid = 15864349 | pmc = 1087161 | doi = 10.1172/JCI23057 }} 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 form AM404.{{cite journal | vauthors = Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM | title = Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system | journal = The Journal of Biological Chemistry | volume = 280 | issue = 36 | pages = 31405–31412 | date = September 2005 | pmid = 15987694 | doi = 10.1074/jbc.M501489200 | doi-access = free }} This metabolite is a potent agonist at the TRPV1 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 effects.{{cite journal | vauthors = Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S | title = Paracetamol: new vistas of an old drug | journal = CNS Drug Reviews | volume = 12 | issue = 3–4 | pages = 250–275 | date = September 2006 | pmid = 17227290 | pmc = 6506194 | doi = 10.1111/j.1527-3458.2006.00250.x }}{{cite journal | vauthors = Sinning C, Watzer B, Coste O, Nüsing RM, Ott I, Ligresti A, Di Marzo V, Imming P | title = New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 24 | pages = 7800–7805 | date = December 2008 | pmid = 19053765 | doi = 10.1021/jm800807k }}

Black pepper contains the alkaloid guineesine, which is an anandamide reuptake inhibitor. It may therefore increase anandamide's physiological effects.{{cite journal | vauthors = Nicolussi S, Viveros-Paredes JM, Gachet MS, Rau M, Flores-Soto ME, Blunder M, Gertsch J | title = Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice | journal = Pharmacological Research | volume = 80 | pages = 52–65 | date = February 2014 | pmid = 24412246 | doi = 10.1016/j.phrs.2013.12.010 }}

Endocannabinoid transporters for anandamide and 2-arachidonoylglycerol include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs).{{cite journal | vauthors = Kaczocha M, Glaser ST, Deutsch DG | title = Identification of intracellular carriers for the endocannabinoid anandamide | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 15 | pages = 6375–6380 | date = April 2009 | pmid = 19307565 | pmc = 2669397 | doi = 10.1073/pnas.0901515106 | doi-access = free | bibcode = 2009PNAS..106.6375K }}{{cite journal | vauthors = Oddi S, Fezza F, Pasquariello N, D'Agostino A, Catanzaro G, De Simone C, Rapino C, Finazzi-Agrò A, Maccarrone M | title = Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins | journal = Chemistry & Biology | volume = 16 | issue = 6 | pages = 624–632 | date = June 2009 | pmid = 19481477 | doi = 10.1016/j.chembiol.2009.05.004 | doi-access = }}

Anandamide shows a preference for binding to cholesterol and ceramide over other membrane lipids. Cholesterol acts as a binding partner for anandamide. Initially, a hydrogen 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.{{cite journal | vauthors = Di Scala C, Fantini J, Yahi N, Barrantes FJ, Chahinian H | title = Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter | journal = Biomolecules | volume = 8 | issue = 2 | page = 31 | date = May 2018 | pmid = 29789479 | pmc = 6022874 | doi = 10.3390/biom8020031 | doi-access = free }}

• Virodhamine

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• {{cite news |last1=Daniloff |first1=Caleb |title=The Runner's High |url=https://www.runnersworld.com/runners-stories/a19042332/runners-high/ |work=Runner's World |date=1 February 2017 }}
• {{cite journal | vauthors = Sparling PB, Giuffrida A, Piomelli D, Rosskopf L, Dietrich A | title = Exercise activates the endocannabinoid system | journal = NeuroReport | volume = 14 | issue = 17 | pages = 2209–2211 | date = December 2003 | pmid = 14625449 | doi = 10.1097/00001756-200312020-00015 | s2cid = 1971671 | url = https://escholarship.org/uc/item/426788xv }}

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{{Cannabinoids}}

{{Chocolate}}

{{Neurotransmitters}}

{{Cannabinoid receptor modulators}}

{{Glycine receptor modulators}}

{{Transient receptor potential channel modulators}}

Category:Endocannabinoids

Category:Neurotransmitters

Category:Fatty acid amides

Category:Biomolecules

Category:Hydroxyethyl compounds

Category:CB1 receptor agonists

Category:CB2 receptor agonists

Category:Glycine receptor agonists

Category:Glycine receptor antagonists

Category:Euphoriants

Category:Arachidonyl compounds

Category:Ethanolamines