Cannabinoid
Phytocannabinoids
Phytocannabinoids
-----------------

[thumb\|right\|The bracts surrounding a cluster of *[Cannabis sativa](/wiki/Cannabis_sativa "Cannabis sativa")* flowers are coated with cannabinoid\-laden [trichomes](/wiki/Trichomes%23Plant_trichomes "Trichomes#Plant trichomes").](/wiki/File:Kolkata-Kut.jpg "Kolkata-Kut.jpg")
[thumb\|right\|*[Cannabis indica](/wiki/Cannabis_indica "Cannabis indica")* plant](/wiki/File:Cannabis_indica.jpg "Cannabis indica.jpg")
The classical cannabinoids are concentrated in a viscous [resin](/wiki/Resin "Resin") produced in structures known as glandular [trichomes](/wiki/Trichome "Trichome"). At least 113 different cannabinoids have been isolated from the *[Cannabis](/wiki/Cannabis "Cannabis")* plant.

All classes derive from cannabigerol\-type (CBG) compounds and differ mainly in the way this precursor is cyclized. The classical cannabinoids are derived from their respective 2\-[carboxylic acids](/wiki/Carboxylic_acid "Carboxylic acid") (2\-COOH) by [decarboxylation](/wiki/Decarboxylation "Decarboxylation") (catalyzed by heat, light, or [alkaline](/wiki/Alkaline "Alkaline") conditions).

### Well known cannabinoids

The best studied cannabinoids include [tetrahydrocannabinol](/wiki/Tetrahydrocannabinol "Tetrahydrocannabinol") (THC), [cannabidiol](/wiki/Cannabidiol "Cannabidiol") (CBD) and [cannabinol](/wiki/Cannabinol "Cannabinol") (CBN).

#### Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. *Delta*\-9\-[tetrahydrocannabinol](/wiki/Tetrahydrocannabinol "Tetrahydrocannabinol") (Δ9\-THC, THC) and [delta\-8\-tetrahydrocannabinol](/wiki/Delta-8-tetrahydrocannabinol "Delta-8-tetrahydrocannabinol") (Δ8\-THC), through intracellular CB1 activation, induce [anandamide](/wiki/Anandamide "Anandamide") and [2\-arachidonoylglycerol](/wiki/2-arachidonoylglycerol "2-arachidonoylglycerol") synthesis produced naturally in the body and brain. These cannabinoids produce the effects associated with [cannabis](/wiki/Cannabis_%28drug%29 "Cannabis (drug)") by binding to the CB1 cannabinoid receptors in the brain.

#### Cannabidiol

Cannabidiol (CBD) is mildly [psychotropic](/wiki/Psychotropic "Psychotropic"). Evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis. Cannabidiol has little affinity for [CB1](/wiki/Cannabinoid_receptor%23CB1 "Cannabinoid receptor#CB1") and [CB2](/wiki/Cannabinoid_receptor%23CB2 "Cannabinoid receptor#CB2") receptors but acts as an indirect antagonist of cannabinoid agonists. It was found to be an antagonist at the putative new cannabinoid receptor, [GPR55](/wiki/GPR55 "GPR55"), a [GPCR](/wiki/GPCR "GPCR") expressed in the [caudate nucleus](/wiki/Caudate_nucleus "Caudate nucleus") and [putamen](/wiki/Putamen "Putamen"). Cannabidiol has also been shown to act as a [5\-HT1A receptor](/wiki/5-HT1A_receptor "5-HT1A receptor") agonist. CBD can interfere with the uptake of [adenosine](/wiki/Adenosine "Adenosine"), which plays an important role in biochemical processes, such as energy transfer. It may play a role in promoting sleep and suppressing arousal.

CBD shares a [precursor](/wiki/wikt:Precursor "Precursor") with THC and is the main cannabinoid in CBD\-dominant *Cannabis* strains. CBD has been shown to play a role in preventing [the short\-term memory loss associated with THC](/wiki/Cannabis_and_memory "Cannabis and memory").

There is tentative evidence that CBD has an anti\-psychotic effect, but research in this area is limited.

#### Cannabinol

Cannabinol (CBN) is a mildly [psychoactive](/wiki/Psychoactive_drug "Psychoactive drug") cannabinoid that acts as a low affinity [partial agonist](/wiki/Partial_agonist "Partial agonist") at both CB1 and CB2 receptors.******** Through its mechanism of partial agonism at the CB1R, CBN is thought to interact with other kinds of [neurotransmission](/wiki/Neurotransmission "Neurotransmission") (e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).

CBN was the first cannabis compound to be isolated from [cannabis](/wiki/Cannabis "Cannabis") extract in the late 1800s. Its structure and chemical synthesis were achieved by 1940****, followed by some of the first pre\-clinical research studies to determine the effects of individual cannabis\-derived compounds [in vivo](/wiki/In_vivo "In vivo"). Although CBN shares the same [mechanism of action](/wiki/Mechanism_of_action "Mechanism of action") as other more well\-known [phytocannabinoids](/wiki/Phytocannabinoids "Phytocannabinoids") (e.g., delta\-9 [tetrahydrocannabinol](/wiki/Tetrahydrocannabinol "Tetrahydrocannabinol") or D9THC), it has a lower [affinity](/wiki/Affinity_%28pharmacology%29 "Affinity (pharmacology)") for CB1 receptors, meaning that much higher doses of CBN are required in order to experience physiologic effects (e.g., mild sedation) associated with CB1R agonism. Although scientific reports are conflicting, the majority of findings suggest that CBN has a slightly higher affinity for CB2 as compared to CB1\. Although CBN has been marketed as a sleep aid in recent years, there is a lack of scientific evidence to support these claims, warranting skepticism on the part of consumers.

### Biosynthesis

Cannabinoid production starts when an [enzyme](/wiki/Enzyme "Enzyme") causes [geranyl pyrophosphate](/wiki/Geranyl_pyrophosphate "Geranyl pyrophosphate") and [olivetolic acid](/wiki/Olivetolic_acid "Olivetolic acid") to combine and form [CBGA](/wiki/CBGA_%28cannabinoid%29 "CBGA (cannabinoid)"). Next, CBGA is independently converted to either [CBG](/wiki/Cannabigerol "Cannabigerol"), [THCA](/wiki/Tetrahydrocannabinolic_acid "Tetrahydrocannabinolic acid"), [CBDA](/wiki/CBDA "CBDA") or [CBCA](/wiki/CBCA_%28cannabinoid%29 "CBCA (cannabinoid)") by four separate [synthase](/wiki/Synthase "Synthase"), FAD\-dependent dehydrogenase enzymes. There is no evidence for enzymatic conversion of CBDA or CBD to THCA or THC. For the propyl homologues (THCVA, CBDVA and CBCVA), there is an analogous pathway that is based on CBGVA from divarinolic acid instead of olivetolic acid.

### Double bond position

In addition, each of the compounds above may be in different forms depending on the position of the double bond in the [alicyclic](/wiki/Alicyclic_compound "Alicyclic compound") carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called Δ9\-THC, while the minor form is called Δ8\-THC. Under the alternate [terpene](/wiki/Terpene "Terpene") numbering system, these same compounds are called Δ1\-THC and Δ6\-THC, respectively.

### Length

Most classical cannabinoids are 21\-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the [side\-chain](/wiki/Side_chain "Side chain") attached to the [aromatic](/wiki/Aromatic_hydrocarbon "Aromatic hydrocarbon") ring. In THC, CBD, and CBN, this side\-chain is a pentyl (5\-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3\-carbon) chain. Cannabinoids with the propyl side chain are named using the suffix *varin* and are designated THCV, CBDV, or CBNV, while those with the heptyl side chain are named using the suffix *phorol* and are designated THCP and CBDP.

### Cannabinoids in other plants

Phytocannabinoids are known to occur in several plant species besides cannabis. These include *[Echinacea purpurea](/wiki/Echinacea_purpurea "Echinacea purpurea")*, *[Echinacea angustifolia](/wiki/Echinacea_angustifolia "Echinacea angustifolia")*, *[Acmella oleracea](/wiki/Acmella_oleracea "Acmella oleracea")*, [*Helichrysum umbraculigerum*](/wiki/Helichrysum "Helichrysum"), and *[Radula marginata](/wiki/Radula_marginata "Radula marginata")*. The best\-known cannabinoids that are not derived from Cannabis are the lipophilic alkamides (alkylamides) from *[Echinacea](/wiki/Echinacea "Echinacea")* species, most notably the cis/trans [isomers](/wiki/Isomers "Isomers") dodeca\-2E,4E,8Z,10E/Z\-tetraenoic\-acid\-isobutylamide. At least 25 different [alkylamides](/wiki/Alkylamide "Alkylamide") have been identified, and some of them have shown affinities to the CB2\-receptor. In some *Echinacea* species, cannabinoids are found throughout the plant structure, but are most concentrated in the roots and flowers. [Yangonin](/wiki/Yangonin "Yangonin") found in the [kava](/wiki/Kava "Kava") plant has significant affinity to the CB1 receptor. Tea ([Camellia sinensis](/wiki/Camellia_sinensis "Camellia sinensis")) [catechins](/wiki/Catechins "Catechins") have an affinity for human cannabinoid receptors. A widespread dietary terpene, [beta\-caryophyllene](/wiki/Beta-caryophyllene "Beta-caryophyllene"), a component from the [essential oil of cannabis](/wiki/Cannabis_flower_essential_oil "Cannabis flower essential oil") and other medicinal plants, has also been identified as a selective agonist of peripheral CB2\-receptors, *[in vivo](/wiki/In_vivo "In vivo")*. [Black truffles](/wiki/Black_truffles "Black truffles") contain anandamide. [Perrottetinene](/wiki/Perrottetinene "Perrottetinene"), a moderately psychoactive cannabinoid, has been isolated from different *[Radula](/wiki/Radula_%28plant%29 "Radula (plant)")* varieties. [Machaeriol A](/wiki/Machaeriol_A "Machaeriol A") and related compounds are found in plants from the *[Machaerium](/wiki/Machaerium_%28plant%29 "Machaerium (plant)")* family.Muhammad I, Li XC, Jacob MR, Tekwani BL, Dunbar DC, Ferreira D. Antimicrobial and antiparasitic (\+)\-trans\-hexahydrodibenzopyrans and analogues from Machaerium multiflorum. *J Nat Prod*. 2003 Jun;66(6\):804\-9\.  

Most of the phytocannabinoids are nearly insoluble in water but are soluble in [lipids](/wiki/Lipid "Lipid"), [alcohols](/wiki/Alcohol_%28chemistry%29 "Alcohol (chemistry)"), and other non\-polar [organic solvents](/wiki/Organic_solvent "Organic solvent").

### Cannabis plant profile

Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant's cannabinoid profile. [Selective breeding](/wiki/Selective_breeding "Selective breeding") has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (commonly called [hemp](/wiki/Hemp "Hemp")) are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for [recreational](/wiki/Recreational_drug_use "Recreational drug use") purposes are usually bred for high THC content or for a specific chemical balance.

[Quantitative analysis](/wiki/Quantitative_analysis_%28chemistry%29 "Quantitative analysis (chemistry)") of a plant's cannabinoid profile is often determined by [gas chromatography](/wiki/Gas_chromatography "Gas chromatography") (GC), or more reliably by gas chromatography combined with [mass spectrometry](/wiki/Mass_spectrometry "Mass spectrometry") (GC/MS). [Liquid chromatography](/wiki/Liquid_chromatography "Liquid chromatography") (LC) techniques are also possible and, unlike GC methods, can differentiate between the acid and neutral forms of the cannabinoids. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.

### Pharmacology

Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the [liver](/wiki/Liver "Liver"), especially by [cytochrome P450](/wiki/Cytochrome_P450 "Cytochrome P450") mixed\-function oxidases, mainly [CYP 2C9](/wiki/CYP_2C9 "CYP 2C9"). Thus supplementing with CYP 2C9 [inhibitors](/wiki/Enzyme_inhibitor "Enzyme inhibitor") leads to extended intoxication.

Some is also stored in [fat](/wiki/Adipose "Adipose") in addition to being metabolized in the liver. Δ9\-THC is metabolized to [11\-hydroxy\-Δ9\-THC](/wiki/11-Hydroxy-THC "11-Hydroxy-THC"), which is then metabolized to [9\-carboxy\-THC](/wiki/11-nor-9-Carboxy-THC "11-nor-9-Carboxy-THC"). Some cannabis [metabolites](/wiki/Metabolite "Metabolite") can be detected in the body several weeks after administration. These metabolites are the chemicals recognized by common antibody\-based "drug tests"; in the case of THC or others, these loads do not represent intoxication (compare to ethanol breath tests that measure instantaneous [blood alcohol levels](/wiki/Blood_alcohol_level "Blood alcohol level")), but an integration of past consumption over an approximately month\-long window. This is because they are fat\-soluble, [lipophilic](/wiki/Lipophilic "Lipophilic") molecules that accumulate in fatty tissues.

Research shows the effect of cannabinoids might be modulated by aromatic compounds produced by the cannabis plant, called [terpenes](/wiki/Terpenes "Terpenes"). This interaction would lead to the [entourage effect](/wiki/Entourage_effect "Entourage effect").

#### Modulation of mitochondrial activity

Recent evidence has shown that cannabinoids play a role in the modulation of various mitochondrial processes, including intracellular calcium regulation, activation of apoptosis, impairment of electron transport chain activity, disruption of mitochondrial respiration and ATP production, and regulation of mitochondrial dynamics. These processes contribute to various aspects of cellular biology and can be modified in response to external stimuli. The interaction between cannabinoids and mitochondria is complex, and various molecular mechanisms have been proposed, including direct effects on mitochondrial membranes and receptor\-mediated effects. However, an integrated hypothesis of cannabinoids' actions on these processes has yet to be formulated due to conflicting data and the complexity of the pathways involved.

#### Cannabinoid\-based pharmaceuticals

[Nabiximols](/wiki/Nabiximols "Nabiximols") (brand name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC. Also included are minor cannabinoids and [terpenoids](/wiki/Terpenoids "Terpenoids"), [ethanol](/wiki/Ethanol "Ethanol") and [propylene glycol](/wiki/Propylene_glycol "Propylene glycol") [excipients](/wiki/Excipients "Excipients"), and peppermint flavoring. The drug, made by [GW Pharmaceuticals](/wiki/GW_Pharmaceuticals "GW Pharmaceuticals"), was first approved by Canadian authorities in 2005 to alleviate pain associated with [multiple sclerosis](/wiki/Multiple_sclerosis "Multiple sclerosis"), making it the first cannabis\-based medicine. It is marketed by Bayer in Canada. Sativex has been approved in 25 countries; clinical trials are underway in the United States to gain FDA approval. In 2007, it was approved for treatment of cancer pain. In Phase III trials, the most common adverse effects were dizziness, drowsiness and disorientation; 12% of subjects stopped taking the drug because of the side effects.

[Dronabinol](/wiki/Dronabinol "Dronabinol") (brand names Marinol and Syndros) is a delta\-9\-THC containing drug for treating [HIV/AIDS](/wiki/HIV/AIDS "HIV/AIDS")\-induced [anorexia](/wiki/Anorexia_%28symptom%29 "Anorexia (symptom)") and [chemotherapy\-induced nausea and vomiting](/wiki/Chemotherapy-induced_nausea_and_vomiting "Chemotherapy-induced nausea and vomiting").

The [CBD](/wiki/Cannabidiol "Cannabidiol") drug Epidiolex has been approved by the [Food and Drug Administration](/wiki/Food_and_Drug_Administration "Food and Drug Administration") for treatment of two rare and severe forms of [epilepsy](/wiki/Epilepsy "Epilepsy"), [Dravet](/wiki/Dravet_syndrome "Dravet syndrome") and [Lennox\-Gastaut](/wiki/Lennox-Gastaut_syndrome "Lennox-Gastaut syndrome") syndromes.

[Nabilone](/wiki/Nabilone "Nabilone") (Cesamet) is an FDA approved synthetic analog of THC, prescribed for the treatment of nausea and vomiting induced by chemotherapy treatment in people who have failed to respond adequately to conventional antiemetic treatments.

### Separation

Cannabinoids can be separated from the plant by [extraction](/wiki/Solvent_extraction "Solvent extraction") with organic [solvents](/wiki/Solvent "Solvent"). [Hydrocarbons](/wiki/Hydrocarbon "Hydrocarbon") and [alcohols](/wiki/Alcohol_%28chemistry%29 "Alcohol (chemistry)") are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with [carbon dioxide](/wiki/Carbon_dioxide "Carbon dioxide") is an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or other [distillation](/wiki/Distillation "Distillation") techniques. Also, techniques such as SPE or SPME are found useful in the extraction of these compounds.

### History

The first discovery of an individual cannabinoid was made, when British chemist [Robert S. Cahn](/wiki/Robert_W._Cahn "Robert W. Cahn") reported the partial structure of Cannabinol (CBN), which he later identified as fully formed in 1940\.

Two years later, in 1942, American chemist, [Roger Adams](/wiki/Roger_Adams "Roger Adams"), made history when he discovered Cannabidiol (CBD). Progressing from Adams research, in 1963 Israeli professor Raphael Mechoulam later identified the [stereochemistry](/wiki/Stereochemistry "Stereochemistry") of CBD. The following year, in 1964, Mechoulam and his team identified the stereochemistry of Tetrahydrocannabinol (THC).

Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the Cannabis plant from the precursor CBG.

#### Emergence of derived psychoactive cannabis products

The [Agriculture Improvement Act of 2018](/wiki/Agriculture_Improvement_Act_of_2018 "Agriculture Improvement Act of 2018") has been interpreted as allowing any hemp\-derived product not exceeding 0\.3% **Δ9\-THC** to be sold legally in the US. Because the law limited only Δ9\-THC levels, many other cannabinoids are generally considered legal to sell and are widely available in stores and online, including [Δ8\-THC](/wiki/Delta-8-Tetrahydrocannabinol "Delta-8-Tetrahydrocannabinol"), [Δ10\-THC](/wiki/Delta-10-Tetrahydrocannabinol "Delta-10-Tetrahydrocannabinol"), [HHC](/wiki/Hexahydrocannabinol "Hexahydrocannabinol"), and [THCP](/wiki/THCP "THCP"), but have not had the same in\-depth research that the Δ9 isomer has on the human body; carrying potential risks in the short\- or long\-term. Other concerns include difficulties for [drug testing](/wiki/Drug_testing "Drug testing") due to novel [metabolites](/wiki/Metabolite "Metabolite"), or high potency/[binding affinity](/wiki/Binding_affinity "Binding affinity") of isomers for [cannabinoid receptors](/wiki/Cannabinoid_receptor "Cannabinoid receptor") showing potential for [abuse](/wiki/Substance_abuse "Substance abuse") (i.e., THCP, which has 33× the binding affinity of Δ9\-THC) From 2021 to 2023, the Δ8\-THC market generated US$2 billion in revenue. Many substances are scheduled at the state level under various synonyms owing to the different dibenzopyran and monoterpenoid naming conventions. Delta\-1, Delta\-6, and Delta 3,4\-Tetrahydrocannabinol are alternative names for Delta\-9, Delta\-8, and Delta\-6a10a Tetrahydrocannabinol, respectively.

A 2023 paper seeking the regulation of cannabinoid [terminology](/wiki/Terminology "Terminology") coined the term "derived psychoactive cannabis products" to accurately and usefully distinguish said products whilst excluding unrelated substances.

 Endocannabinoids
--------------------------------------------------------------

[thumb\|[Anandamide](/wiki/Anandamide "Anandamide"), an endogenous [ligand](/wiki/Ligand "Ligand") of CB1 and CB2](/wiki/File:Anandamid.svg "Anandamid.svg")
Endocannabinoids are substances produced from within the body that activate [cannabinoid receptors](/wiki/Cannabinoid_receptor "Cannabinoid receptor"). After the discovery of the first cannabinoid receptor in 1988, scientists began searching for endogenous [ligands](/wiki/Ligand_%28biochemistry%29 "Ligand (biochemistry)") for the receptors.

### Types of endocannabinoid ligands

#### Arachidonoylethanolamine (Anandamide or AEA)

[Anandamide](/wiki/Anandamide "Anandamide") was the first such compound identified as [arachidonoyl](/wiki/Arachidonic_acid "Arachidonic acid") ethanolamine. The name is derived from *ananda*, the [Sanskrit](/wiki/Sanskrit "Sanskrit") word for bliss. It has a pharmacology similar to [THC](/wiki/Tetrahydrocannabinol "Tetrahydrocannabinol"), although its structure is quite different. Anandamide binds to the central (CB1) and, to a lesser extent, peripheral (CB2) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor. 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.

Two analogs of anandamide, [7,10,13,16\-docosatetraenoylethanolamide](/wiki/Docosatetraenoylethanolamide "Docosatetraenoylethanolamide") and *homo*\-γ\-linolenoylethanolamine, have similar [pharmacology](/wiki/Pharmacology "Pharmacology"). All of these compounds are members of a family of signalling lipids called [*N*\-acylethanolamines](/wiki/N-acylethanolamine "N-acylethanolamine"), which also includes the noncannabimimetic [palmitoylethanolamide](/wiki/Palmitoylethanolamide "Palmitoylethanolamide") and [oleoylethanolamide](/wiki/Oleoylethanolamide "Oleoylethanolamide"), which possess [anti\-inflammatory](/wiki/Anti-inflammatory "Anti-inflammatory") and [anorexigenic](/wiki/Anorexigenic "Anorexigenic") effects, respectively. Many *N*\-acylethanolamines have also been identified in plant seeds and in molluscs.

#### 2\-Arachidonoylglycerol (2\-AG)

Another endocannabinoid, 2\-arachidonoylglycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both. 2\-AG is present at significantly higher concentrations in the brain than anandamide, and there is some controversy over whether 2\-AG rather than anandamide is chiefly responsible for endocannabinoid signalling *[in vivo](/wiki/In_vivo "In vivo")*. In particular, one *[in vitro](/wiki/In_vitro "In vitro")* study suggests that 2\-AG is capable of stimulating higher [G\-protein](/wiki/G-protein "G-protein") activation than anandamide, although the physiological implications of this finding are not yet known.

#### 2\-Arachidonyl glyceryl ether (noladin ether)

In 2001, a third, [ether](/wiki/Ether "Ether")\-type endocannabinoid, 2\-arachidonyl glyceryl ether (noladin ether), was isolated from [porcine](/wiki/Porcine "Porcine") brain. Prior to this discovery, it had been synthesized as a stable analog of 2\-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species. It binds to the CB1 cannabinoid receptor (*K*i \= 21\.2 [nmol](/wiki/Nanomole "Nanomole")/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and only weakly to the CB2 receptor.

#### *N*\-Arachidonoyl dopamine (NADA)

Discovered in 2000, NADA preferentially binds to the CB1 receptor. Like anandamide, NADA is also an agonist for the [vanilloid receptor subtype 1](/wiki/TRPV1 "TRPV1") (TRPV1\), a member of the [vanilloid](/wiki/Vanilloid "Vanilloid") receptor family.

#### Virodhamine (OAE)

A fifth endocannabinoid, virodhamine, or *O*\-arachidonoyl\-ethanolamine (OAE), was discovered in June 2002\. Although it is a full [agonist](/wiki/Agonist "Agonist") at CB2 and a partial agonist at CB1, it behaves as a CB1 antagonist *[in vivo](/wiki/In_vivo "In vivo")*. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than [anandamide](/wiki/Anandamide "Anandamide") in the [brain](/wiki/Brain "Brain"), but 2\- to 9\-fold higher concentrations peripherally.

#### Lysophosphatidylinositol (LPI)

[Lysophosphatidylinositol](/wiki/Lysophosphatidylinositol "Lysophosphatidylinositol") is the endogenous ligand to novel endocannabinoid receptor [GPR55](/wiki/GPR55 "GPR55"), making it a strong contender as the sixth endocannabinoid.

### Function

Endocannabinoids serve as [intercellular](/wiki/Cellular_communication_%28biology%29%23Intercellular_communication "Cellular communication (biology)#Intercellular communication") '[lipid messengers](/wiki/Lipid_signaling "Lipid signaling")', signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well\-known [monoamine](/wiki/Monoamine "Monoamine") [neurotransmitters](/wiki/Neurotransmitter "Neurotransmitter") such as [dopamine](/wiki/Dopamine "Dopamine"), endocannabinoids differ in numerous ways from them. For instance, they are used in [retrograde signaling](/wiki/Retrograde_signaling "Retrograde signaling") between neurons. Furthermore, endocannabinoids are [lipophilic](/wiki/Lipophilic "Lipophilic") molecules that are not very soluble in water. They are not stored in vesicles and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on\-demand' rather than made and stored for later use.

As [hydrophobic](/wiki/Hydrophobic "Hydrophobic") molecules, endocannabinoids cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do [hormones](/wiki/Hormone "Hormone"), which can affect cells throughout the body.

The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.

The endocannabinoid [2\-AG](/wiki/2-AG "2-AG") has been found in [bovine](/wiki/Bovine "Bovine") and human maternal milk.

A review by Matties et al. (1994\) summed up the phenomenon of gustatory enhancement by certain cannabinoids. The sweet receptor (Tlc1\) is stimulated by indirectly increasing its expression and suppressing the activity of leptin, the Tlc1 antagonist. It is proposed that the competition of leptin and cannabinoids for Tlc1 is implicated in energy homeostasis.

#### Retrograde signal

Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other hand, are described as [retrograde transmitters](/wiki/Retrograde_signaling "Retrograde signaling") because they most commonly travel ‘backward’ against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid\-mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid\-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter [GABA](/wiki/GABA "GABA") is reduced, the net effect is an increase in the excitability of the endocannabinoid\-releasing cell. On the converse, when release of the excitatory neurotransmitter [glutamate](/wiki/Glutamate_%28neurotransmitter%29 "Glutamate (neurotransmitter)") is reduced, the net effect is a decrease in the excitability of the endocannabinoid\-releasing cell. 

#### "Runner's high"

The [runner's high](/wiki/Neurobiological_effects_of_physical_exercise "Neurobiological effects of physical exercise"), the feeling of euphoria that sometimes accompanies aerobic exercise, has often been attributed to the release of [endorphins](/wiki/Endorphins "Endorphins"), but newer research suggests that it might be due to endocannabinoids instead.


What effect does a reduction in glutamate release have on the excitability of an endocannabinoid-releasing cell?