View source for Anandamide

{{short description|Chemical compound (fatty acid neurotransmitter)}}
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|ImageFile1 = Anandamide_skeletal.svg
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|PIN = (5''Z'',8''Z'',11''Z'',14''Z'')-''N''-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide
|OtherNames = ''N''-arachidonoylethanolamine<!-- amine is actually correct here, despite pubchem (see talk page) --><br />arachidonoylethanolamide
|Section1={{Chembox Identifiers
|CASNo_Ref = {{cascite|correct|CAS}}
|CASNo = 94421-68-8
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|ChemSpiderID = 4445241
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|ChEMBL = 15848
| KEGG = C11695
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|StdInChI = 1S/C22H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-22(25)23-20-21-24/h6-7,9-10,12-13,15-16,24H,2-5,8,11,14,17-21H2,1H3,(H,23,25)/b7-6-,10-9-,13-12-,16-15-
|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
|StdInChIKey = LGEQQWMQCRIYKG-DOFZRALJSA-N
|InChI = 1/C22H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-22(25)23-20-21-24/h6-7,9-10,12-13,15-16,24H,2-5,8,11,14,17-21H2,1H3,(H,23,25)/b7-6-,10-9-,13-12-,16-15-
|InChIKey = LGEQQWMQCRIYKG-DOFZRALJBA
|SMILES1 = CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCO
|SMILES = O=C(NCCO)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
|MeSHName = Anandamide
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|Section2={{Chembox Properties
|Formula = C<sub>22</sub>H<sub>37</sub>NO<sub>2</sub>
|MolarMass = 347.53 g/mol
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'''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|''N''-acylethanolamines]] (NAE). Anandamide takes its name from the [[Sanskrit]] word ''ananda'' ([[wikt:आनन्द|आनन्द]]), meaning "joy, bliss, delight," plus [[amide]]. Anandamide, the first discovered [[endocannabinoid]], engages with the body's [[endocannabinoid system]] by binding to the same [[Cannabinoid receptor|cannabinoid receptors]] that [[Tetrahydrocannabinol|THC]] found in [[Cannabis (drug)|cannabis]] acts on. Anandamide can be found within tissues in a wide range of animals.<ref>{{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 }}</ref><ref>{{cite journal | vauthors = Martin BR, Mechoulam R, Razdan RK | title = Discovery and characterization of endogenous cannabinoids | journal = Life Sciences | volume = 65 | issue = 6–7 | pages = 573–595 | date = July 1999 | pmid = 10462059 | doi = 10.1016/S0024-3205(99)00281-7 }}</ref> It has also been found in plants, such as the [[Theobroma cacao|cacao]] tree.<ref>{{cite journal | vauthors = di Tomaso E, Beltramo M, Piomelli D | title = Brain cannabinoids in chocolate | journal = Nature | volume = 382 | issue = 6593 | pages = 677–678 | date = August 1996 | pmid = 8751435 | doi = 10.1038/382677a0 | bibcode = 1996Natur.382..677D }}</ref>

Anandamide is derived from the non-oxidative metabolism of [[arachidonic acid]], an [[Essential fatty acid|essential]] [[omega-6 fatty acid]]. It is synthesized from ''N''-arachidonoyl phosphatidylethanolamine by multiple pathways.<ref name="Wang_2009">{{cite journal | vauthors = Wang J, Ueda N | title = Biology of endocannabinoid synthesis system | journal = Prostaglandins & Other Lipid Mediators | volume = 89 | issue = 3–4 | pages = 112–119 | date = September 2009 | pmid = 19126434 | doi = 10.1016/j.prostaglandins.2008.12.002 | department = secondary }}</ref> 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 possible therapeutic use.<ref>{{cite book |doi=10.1016/S0074-7742(09)85005-8 |title=The Endocannabinoid System as a Target for Novel Anxiolytic and Antidepressant Drugs |series=International Review of Neurobiology |date=2009 |volume=85 |pages=57–72 |isbn=978-0-12-374893-5 | vauthors = Gaetani S, Dipasquale P, Romano A, Righetti L, Cassano T, Piomelli D, Cuomo V |pmid=19607961 }}</ref><ref name="pmid32292082">{{cite journal | vauthors = Fazio D, Criscuolo E, Piccoli A, Barboni B, Fezza F, Maccarrone M | title = Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold? | journal = Expert Opinion on Drug Discovery | volume = 15 | issue = 7 | pages = 765–778 | date = July 2020 | pmid = 32292082 | doi = 10.1080/17460441.2020.1751118 }}</ref>

== 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]] and [[nuclear magnetic resonance spectroscopy]].<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> Since the 1992 findings, many studies have been completed to examine ANA further, including research on behavioral and molecular effects.

== Research ==
{{outdated|section|date=July 2024}}

According to in vitro research, anandamide effects are mediated primarily by CB<sub>1</sub> [[cannabinoid receptor]]s in the central nervous system, and CB<sub>2</sub> cannabinoid receptors in the periphery.<ref name="pmid16968947">{{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 }}</ref> The latter appear to be involved in functions of the [[immune system]]. Cannabinoid receptors were originally discovered as sensitive to Δ<sup>9</sup>-[[tetrahydrocannabinol]] (Δ<sup>9</sup>-THC, commonly called THC), which is the primary psychoactive cannabinoid found in [[cannabis (drug)|cannabis]]. The discovery of anandamide came from research into CB<sub>1</sub> and CB<sub>2</sub>, 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 (embryology)|implantation]] of the early stage [[embryo]] in its [[blastocyst]] form into the [[uterus]]. Therefore, cannabinoids such as Δ<sup>9</sup>-THC might influence processes during the earliest stages of human pregnancy.<ref name="pmid14702623">{{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 }}</ref> 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.<ref>{{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 }}</ref> Subsequently, anandamide has been proposed as a [[biomarker]] of [[infertility]], but so far lacks any [[predictive value]]s in order to be used clinically.<ref name="RapinoBattista2014">{{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 }}</ref>

===Behavior===
Both the [[Cannabinoid receptor 1|CB1]] and [[Cannabinoid receptor 2|CB2]] receptors (the binding site of anandamide) are under research for a possible role in positive and negative interpretation of environment and setting.<ref>{{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 }}</ref> The binding relationship of anandamide and the CB1/CB2 may affect neurotransmission of dopamine, serotonin, GABA, and glutamate.<ref>{{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 }}</ref>

[[Endocannabinoid]]s may disturb [[homeostasis]] in several ways: by enhancing  [[appetite|hunger sensations]], encouraging increased [[food intake]], and shifting [[energy balance (biology)|energy balance]] towards [[lipogenesis|energy storage]]. A resultant decrease in energy expenditure is observed.<ref>{{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 | page = 373 | date = January 2021 | pmid = 33530406 | pmc = 7911032 | doi = 10.3390/nu13020373 | doi-access = free }}</ref>

Cortical glutamatergic transmission may be modulated by endocannabinoids during stress and fear [[habituation]].<ref>{{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 }}</ref>

===Obesity and liver disease===
Blockade of CB1 receptors was found to improve lipid resistance and lipid profile in obese subjects with [[type 2 diabetes]].<ref>{{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 }}</ref> Elevated anandamide levels are found in people with [[nonalcoholic fatty liver disease]], [[nonalcoholic steatohepatitis]], and [[liver fibrosis]].<ref>{{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 | article-number = e92989 | date = May 2017 | pmid = 28469090 | pmc = 5414569 | doi = 10.1172/jci.insight.92989 }}</ref>

===Topical effects===

The [[American Academy of Dermatology]] has named topical anandamide a promising therapy for cutaneous [[lupus erythematosus]].<ref>{{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 }}</ref><ref>{{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 }}</ref>

== Biosynthesis ==
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|''N''-acyltransferase]] enzyme.<ref name="pmid7126608">{{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 }}</ref><ref name="pmid9006968">{{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 }}</ref> 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),<ref name="Wang_2009" /> with other key enzymes yet to be identified.<ref>{{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}}</ref>

The crystal structure of NAPE-PLD in complex with [[phosphatidylethanolamine]] and [[deoxycholate]] shows how the [[cannabinoid]] anandamide is generated from membrane [[N-acylphosphatidylethanolamines|''N''-acylphosphatidylethanolamines]] (NAPEs), and reveals that [[bile acids]] – which are mainly involved in the [[Lipid metabolism#Lipid absorption|absorption of lipids]] in the small [[intestine]] – modulate its biogenesis.<ref name="Garau">{{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 }}</ref>

== Metabolism ==

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.<ref name="pmid11353819">{{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 }}</ref> High fat diet feeding in mice increases levels of anandamide in the liver and increases [[lipogenesis]].<ref name="pmid15864349">{{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 }}</ref> 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]].<ref name=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 }}</ref> This metabolite is a potent [[agonist]] at the [[TRPV1]] vanilloid receptor, a weak agonist at both CB<sub>1</sub> and CB<sub>2</sub> 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.<ref name="pmid17227290">{{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 }}</ref><ref name="pmid19053765">{{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 }}</ref>

Black pepper contains the alkaloid [[guineesine]], which is an anandamide reuptake inhibitor. It may therefore increase anandamide's physiological effects.<ref>{{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 }}</ref>

== Transport ==

[[Endocannabinoid transporters]] for anandamide and [[2-arachidonoylglycerol]] include the [[heat shock protein]]s ([[Hsp70]]s) and [[Fatty acid-binding protein|fatty acid binding proteins]] (FABPs).<ref name = "pnasus2009">{{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 }}</ref><ref name = "cb2009">{{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 = }}</ref>

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.<ref>{{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 }}</ref>

== See also ==
* [[Virodhamine]]

== References ==
{{Reflist|30em}}

== External links ==
{{refbegin}}
* {{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 | url-access = subscription }}
{{refend}}

{{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]]