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Cannabinoids (/kəˈnæbənɔɪdzˌ ˈkænəbənɔɪdz/) are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds.^[1]^[2] The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary intoxicating compound in cannabis.^[3]^[4] Cannabidiol (CBD) is a major constituent of temperate Cannabis plants and a minor constituent in tropical varieties.^[5] At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four (i.e., THCA, CBDA, CBCA and their common precursor CBGA) have been demonstrated to have a biogenetic origin.^[6] It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort,^[7] and earlier in Echinacea.

Phytocannabinoids are multi-ring phenolic compounds structurally related to THC,^[8] but endocannabinoids are fatty acid derivatives. Nonclassical synthetic cannabinoids (cannabimimetics) include aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides as well as eicosanoids related to endocannabinoids.^[3]

Uses

Medical uses include the treatment of nausea due to chemotherapy, spasticity, and possibly neuropathic pain.^[9] Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".^[9]

Cannabinoid receptors

Before the 1980s, cannabinoids were speculated to produce their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate.Cite error: The <ref> tag has too many names (see the help page). These receptors are common in animals. Two known cannabinoid receptors are termed CB₁ and CB₂,^[10] with mounting evidence of more.^[11] The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.^[12]

The Endocannabinoid System (ECS) regulates many functions of the human body. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.^[13]

Cannabinoid receptor type 1

CB₁ receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus^[10] and the striatum. They are also found in the cerebellum and in both male and female reproductive systems. CB₁ receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. CB1 is also found in the human anterior eye and retina.^[14]

Cannabinoid receptor type 2

CB₂ receptors are predominantly found in the immune system, or immune-derived cells^[15]^[16]^[17]^[18] with varying expression patterns. While found only in the peripheral nervous system, a report does indicate that CB₂ is expressed by a subpopulation of microglia in the human cerebellum.^[19] CB₂ receptors appear to be responsible for immunomodulatory^[18] and possibly other therapeutic effects of cannabinoid as seen in vitro and in animal models.^[17]

Phytocannabinoids

The bracts surrounding a cluster of *Cannabis sativa* flowers are coated with cannabinoid-laden trichomes.

The classical cannabinoids are concentrated in a viscous resin produced in structures known as glandular trichomes. At least 113 different cannabinoids have been isolated from the Cannabis plant.^[6] To the right, the main classes of cannabinoids from Cannabis are shown.^{[citation needed]}

All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.^[20] The classical cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).^{[citation needed]}

Well known cannabinoids

The best studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN).

Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol (Δ⁹-THC, THC) and Delta-8-Tetrahydrocannabinol (Δ⁸-THC), through intracellular CB₁ activation, induce anandamide and 2-arachidonoylglycerol synthesis produced naturally in the body and brain^{[citation needed]}^{[dubious – discuss]}. These cannabinoids produce the effects associated with cannabis by binding to the CB₁ cannabinoid receptors in the brain.^[21]

Cannabidiol

Cannabidiol (CBD) is mildly psychotropic. Evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis.^[22] Cannabidiol has little affinity for CB₁ and CB₂ receptors but acts as an indirect antagonist of cannabinoid agonists.^[23] It was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.^[24] Cannabidiol has also been shown to act as a 5-HT_1A receptor agonist.^[25] CBD can interfere with the uptake of adenosine, which plays an important role in biochemical processes, such as energy transfer. It may play a role in promoting sleep and suppressing arousal.^[26]

CBD shares a 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.^[27]

There is tentative evidence that CBD has an anti-psychotic effect, but research in this area is limited.^[28]^[22]

Cannabinol

Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors.^[29]^[30]^[31] Through its mechanism of partial agonism at the CB1R, CBN is thought to interact with other kinds of neurotransmission (e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).

CBN was the first cannabis compound to be isolated from cannabis extract in the late 1800s. Its structure and chemical synthesis were achieved by 1940^[32], followed by some of the first pre-clinical research studies to determine the effects of individual cannabis-derived compounds in vivo.^[33] Although CBN shares the same mechanism of action as other more well-known phytocannabinoids (e.g., delta-9 tetrahydrocannabinol or D9THC), it has a lower affinity 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.^[34]^[33] 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.^[34]

Biosynthesis

Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBGA. Next, CBGA is independently converted to either CBG, THCA, CBDA or CBCA by four separate 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 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 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 attached to the aromatic 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, Echinacea angustifolia, Acmella oleracea, Helichrysum umbraculigerum, and Radula marginata.^[35] The best-known cannabinoids that are not derived from Cannabis are the lipophilic alkamides (alkylamides) from Echinacea species, most notably the cis/trans isomers dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamide.^[35] At least 25 different alkylamides have been identified, and some of them have shown affinities to the CB₂-receptor.^[36]^[37] In some Echinacea species, cannabinoids are found throughout the plant structure, but are most concentrated in the roots and flowers.^[38]^[39] Yangonin found in the Kava plant has significant affinity to the CB1 receptor.^[40] Tea (Camellia sinensis) catechins have an affinity for human cannabinoid receptors.^[41] A widespread dietary terpene, beta-caryophyllene, a component from the essential oil of cannabis and other medicinal plants, has also been identified as a selective agonist of peripheral CB₂-receptors, in vivo.^[42] Black truffles contain anandamide.^[43] Perrottetinene, a moderately psychoactive cannabinoid,^[44] has been isolated from different Radula varieties.

Most of the phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents.

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 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) 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 purposes are usually bred for high THC content or for a specific chemical balance.

Quantitative analysis of a plant's cannabinoid profile is often determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). 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, especially by cytochrome P450 mixed-function oxidases, mainly CYP 2C9.^[45] Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication.^[45]

Some is also stored in fat in addition to being metabolized in the liver. Δ⁹-THC is metabolized to 11-hydroxy-Δ⁹-THC, which is then metabolized to 9-carboxy-THC.^[46] Some cannabis metabolites 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), but an integration of past consumption over an approximately month-long window. This is because they are fat-soluble, lipophilic molecules that accumulate in fatty tissues.^[47]

Research shows the effect of cannabinoids might be modulated by aromatic compounds produced by the cannabis plant, called terpenes. This interaction would lead to the entourage effect.^[48]

Cannabinoid-based pharmaceuticals

Nabiximols (brand name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC.^[49] Also included are minor cannabinoids and terpenoids, ethanol and propylene glycol excipients, and peppermint flavoring.^[50] The drug, made by GW Pharmaceuticals, was first approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis, making it the first cannabis-based medicine. It is marketed by Bayer in Canada.^[51] Sativex has been approved in 25 countries; clinical trials are underway in the United States to gain FDA approval.^[52] In 2007, it was approved for treatment of cancer pain.^[50] 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.^[53]

Dronabinol (brand name Marinol) is a THC drug used to treat poor appetite, nausea, and sleep apnea.^[54] It is approved by the FDA for treating HIV/AIDS induced anorexia and chemotherapy induced nausea and vomiting.^[55]^[56]^[57]

The CBD drug Epidiolex has been approved by the Food and Drug Administration for treatment of two rare and severe forms of epilepsy,^[58] Dravet and Lennox-Gastaut syndromes.^[59]

Separation

Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic.^[60] Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with carbon dioxide is an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or other distillation techniques.^[61] Also, techniques such as SPE or SPME are found useful in the extraction of these compounds.^[62]

History

The first discovery of an individual cannabinoid was made, when British chemist Robert S. Cahn reported the partial structure of Cannabinol (CBN), which he later identified as fully formed in 1940.

Two years later, in 1942,^[63] American chemist, Roger Adams, made history when he discovered Cannabidiol (CBD).^[64] Progressing from Adams research, in 1963^[65] Israeli professor Raphael Mechoulam^[66] later identified the stereochemistry of CBD. The following year, in 1964,^[65] Mechoulam and his team identified the stereochemistry of Tetrahydrocannabinol (THC).^{[citation needed]}

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.^{[citation needed]}

Endocannabinoids

Anandamide, an endogenous ligand of CB₁ and CB₂

Endocannabinoids are substances produced from within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for endogenous ligand for the receptors.Cite error: The <ref> tag has too many names (see the help page).^[67]

Types of endocannabinoid ligands

Arachidonoylethanolamine (Anandamide or AEA)

Anandamide was the first such compound identified as arachidonoyl ethanolamine. The name is derived from the Sanskrit word for bliss and -amide. It has a pharmacology similar to THC, 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.^[68] Anandamide is found in nearly all tissues in a wide range of animals.^[69] Anandamide has also been found in plants, including small amounts in chocolate.^[70]

Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamine, have similar pharmacology. All of these compounds are members of a family of signalling lipids called N-acylethanolamines, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamide, which possess anti-inflammatory and anorexigenic effects, respectively. Many N-acylethanolamines have also been identified in plant seeds^[71] and in molluscs.^[72]

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.^[68] 2-AG is present at significantly higher concentrations in the brain than anandamide,^[73] and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo.^[10] In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.^[74]

2-Arachidonyl glyceryl ether (noladin ether)

In 2001, a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain.^[75] 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.^[76] It binds to the CB₁ cannabinoid receptor (K_i = 21.2 nmol/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.^[68]

N-Arachidonoyl dopamine (NADA)

Discovered in 2000, NADA preferentially binds to the CB₁ receptor.^[77] Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.^[78]^[79]

Virodhamine (OAE)

A fifth endocannabinoid, virodhamine, or O-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB₂ and a partial agonist at CB₁, it behaves as a CB₁ antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.^[80]

Lysophosphatidylinositol (LPI)

Lysophosphatidylinositol is the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth endocannabinoid.^[81]

Function

Endocannabinoids serve as intercellular 'lipid messengers',^[82] 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 neurotransmitters such as dopamine, endocannabinoids differ in numerous ways from them. For instance, they are used in retrograde signaling between neurons.^[83] Furthermore, endocannabinoids are 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 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, 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 has been found in bovine and human maternal milk.^[84]

A review by Matties et al. (1994) summed up the phenomenon of gustatory enhancement by certain cannabinoids.^[85] 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.^[86]

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 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 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 is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.^[87] ^{[citation needed]}

"Runner's high"

The runner's high, the feeling of euphoria that sometimes accompanies aerobic exercise, has often been attributed to the release of endorphins, but newer research suggests that it might be due to endocannabinoids instead.^[88]

Synthetic cannabinoids

Historically, laboratory synthesis of cannabinoids was often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam.^[89] Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.^[90]

Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.^[91]

When synthetic cannabinoids are used recreationally, they present significant health dangers to users.^[92] In the period of 2012 through 2014, over 10,000 contacts to poison control centers in the United States were related to use of synthetic cannabinoids.^[92]

Medications containing natural or synthetic cannabinoids or cannabinoid analogs:

Dronabinol (Marinol), is Δ⁹-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic
Nabilone (Cesamet, Canemes), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III
Rimonabant (SR141716), a selective cannabinoid (CB₁) receptor inverse agonist once used as an anti-obesity drug under the proprietary name Acomplia. It was also used for smoking cessation

Other notable synthetic cannabinoids include:

JWH-018, a potent synthetic cannabinoid agonist discovered by John W. Huffman at Clemson University. It was often sold in legal smoke blends collectively known as "spice". Several countries and states have moved to ban it legally.
JWH-073
CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC.
Dimethylheptylpyran
HU-210, about 100 times as potent as THC^[93]
HU-211, a synthetic cannabinoid derived drug that acts on NMDA instead of endocannabinoid system
HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II.
SR144528, a CB₂ receptor antagonist/ inverse agonist^[94]
WIN 55,212-2, a potent cannabinoid receptor agonist
JWH-133, a potent selective CB₂ receptor agonist
Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine
AM-2201, a potent cannabinoid receptor agonist

Recently, the term "neocannabinoid" has been introduced to distinguish these designer drugs from synthetic phytocannabinoids (THC or CBD obtained by chemical synthesis) or synthetic endocannabinoids.^[95]

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External links

Media related to Cannabinoids at Wikimedia Commons

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@@ Line 1: / Line 1: @@
 {{Short description|Compounds found in cannabis}}
 {{Cannabis sidebar}}
-'''Cannabinoids''' ({{IPAc-en|k|ə|ˈ|n|æ|b|ə|n|ɔɪ|d|z|,|_|ˈ|k|æ|n|ə|b|ə|n|ɔɪ|d|z}}) are several structural classes of compounds found in the [[Cannabis|cannabis plant]] primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds.<ref>{{cite journal | vauthors = Abyadeh M, Gupta V, Paulo JA, Gupta V, Chitranshi N, Godinez A, Saks D, Hasan M, Amirkhani A, McKay M, Salekdeh GH, Haynes PA, Graham SL, Mirzaei M | display-authors = 3 | title = A Proteomic View of Cellular and Molecular Effects of Cannabis | journal = Biomolecules | volume = 11 | issue = 10 | pages = 1411–1428 | date = September 2021 | pmid = 34680044 | pmc = 8533448 | doi = 10.3390/biom11101411 | doi-access = free }}</ref><ref>{{cite web |title= Marijuana, also called: Cannabis, Ganja, Grass, Hash, Pot, Weed |url=https://medlineplus.gov/marijuana.html |website=Medline Plus |date=3 July 2017}}</ref> The most notable cannabinoid is the phytocannabinoid [[tetrahydrocannabinol]] (THC) (delta-9-THC), the primary intoxicating compound in [[Cannabis (drug)|cannabis]].<ref name="lambert">{{cite journal | vauthors = Lambert DM, Fowler CJ | title = The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 16 | pages = 5059–5087 | date = August 2005 | pmid = 16078824 | doi = 10.1021/jm058183t }}</ref><ref>{{cite book|title=Cannabinoids |url=https://archive.org/details/cannabinoidshand00pert |url-access=limited | veditors = Pertwee R |publisher=Springer-Verlag |year=2005 |isbn=978-3-540-22565-2 |page=[https://archive.org/details/cannabinoidshand00pert/page/n11 2]}}</ref> [[Cannabidiol]] (CBD) is a major constituent of temperate Cannabis plants and a minor constituent in tropical varieties.<ref>{{cite web|url=http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1962-01-01_3_page005.html |title=Bulletin on Narcotics – 1962 Issue 3 – 004 |publisher=UNODC (United Nations Office of Drugs and Crime) |date=1962-01-01 |access-date=2014-01-15}}</ref> At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four (i.e., THCA, CBDA, CBCA and their common precursor CBGA) have been demonstrated to have a biogenetic origin.<ref name=":0">{{cite journal | vauthors = Aizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, Navarro P, Etxebarria N, Usobiaga A | display-authors = 6 | title = Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes | journal = Journal of Natural Products | volume = 79 | issue = 2 | pages = 324–331 | date = February 2016 | pmid = 26836472 | doi = 10.1021/acs.jnatprod.5b00949 | url = https://figshare.com/articles/journal_contribution/Evolution_of_the_Cannabinoid_and_Terpene_Content_during_the_Growth_of_Cannabis_sativa_Plants_from_Different_Chemotypes/5028338 }}</ref> It was reported in 2020 that phytocannabinoids can be found in other plants such as [[rhododendron]], [[licorice]] and [[liverwort]],<ref>{{cite journal | vauthors = Gülck T, Møller BL | title = Phytocannabinoids: Origins and Biosynthesis | journal = Trends in Plant Science | volume = 25 | issue = 10 | pages = 985–1004 | date = October 2020 | pmid = 32646718 | doi = 10.1016/j.tplants.2020.05.005 | s2cid = 220465067 }}</ref> and earlier in [[Echinacea]].
+'''Cannabinoids''' ({{IPAc-en|k|ə|ˈ|n|æ|b|ə|n|ɔɪ|d|z|,|_|ˈ|k|æ|n|ə|b|ə|n|ɔɪ|d|z}}) are several structural classes of compounds found in the [[cannabis]] plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds.<ref>{{cite journal | vauthors = Abyadeh M, Gupta V, Paulo JA, Gupta V, Chitranshi N, Godinez A, Saks D, Hasan M, Amirkhani A, McKay M, Salekdeh GH, Haynes PA, Graham SL, Mirzaei M | display-authors = 3 | title = A Proteomic View of Cellular and Molecular Effects of Cannabis | journal = Biomolecules | volume = 11 | issue = 10 | pages = 1411–1428 | date = September 2021 | pmid = 34680044 | pmc = 8533448 | doi = 10.3390/biom11101411 | doi-access = free }}</ref><ref>{{cite web |title= Marijuana, also called: Cannabis, Ganja, Grass, Hash, Pot, Weed |url=https://medlineplus.gov/marijuana.html |website=Medline Plus |date=3 July 2017}}</ref> The most notable cannabinoid is the phytocannabinoid [[tetrahydrocannabinol]] (THC) (delta-9-THC), the primary intoxicating compound in [[Cannabis (drug)|cannabis]].<ref name="lambert">{{cite journal | vauthors = Lambert DM, Fowler CJ | title = The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 16 | pages = 5059–5087 | date = August 2005 | pmid = 16078824 | doi = 10.1021/jm058183t }}</ref><ref>{{cite book|title=Cannabinoids |url=https://archive.org/details/cannabinoidshand00pert |url-access=limited | veditors = Pertwee R |publisher=Springer-Verlag |year=2005 |isbn=978-3-540-22565-2 |page=[https://archive.org/details/cannabinoidshand00pert/page/n11 2]}}</ref> [[Cannabidiol]] (CBD) is a major constituent of temperate Cannabis plants and a minor constituent in tropical varieties.<ref>{{cite web|url=http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1962-01-01_3_page005.html |title=Bulletin on Narcotics – 1962 Issue 3 – 004 |publisher=UNODC (United Nations Office of Drugs and Crime) |date=1962-01-01 |access-date=2014-01-15}}</ref> At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four (i.e., THCA, CBDA, CBCA and their common precursor CBGA) have been demonstrated to have a biogenetic origin.<ref name=":0">{{cite journal | vauthors = Aizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, Navarro P, Etxebarria N, Usobiaga A | display-authors = 6 | title = Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes | journal = Journal of Natural Products | volume = 79 | issue = 2 | pages = 324–331 | date = February 2016 | pmid = 26836472 | doi = 10.1021/acs.jnatprod.5b00949 | url = https://figshare.com/articles/journal_contribution/Evolution_of_the_Cannabinoid_and_Terpene_Content_during_the_Growth_of_Cannabis_sativa_Plants_from_Different_Chemotypes/5028338 }}</ref> It was reported in 2020 that phytocannabinoids can be found in other plants such as [[rhododendron]], [[licorice]] and [[liverwort]],<ref>{{cite journal | vauthors = Gülck T, Møller BL | title = Phytocannabinoids: Origins and Biosynthesis | journal = Trends in Plant Science | volume = 25 | issue = 10 | pages = 985–1004 | date = October 2020 | pmid = 32646718 | doi = 10.1016/j.tplants.2020.05.005 | s2cid = 220465067 }}</ref> and earlier in [[Echinacea]].
 Phytocannabinoids are multi-ring phenolic compounds structurally related to THC,<ref>Pate, DW (1999). Anandamide structure-activity relationships and mechanisms of action on intraocular pressure in the normotensive rabbit model. Kuopio University Publications A. Pharmaceutical Sciences Dissertation 37, {{ISBN|951-781-575-1}}</ref> but endocannabinoids are fatty acid derivatives. Nonclassical synthetic cannabinoids (cannabimimetics) include [[aminoalkylindole]]s, 1,5-diarylpyrazoles, [[quinoline]]s, and arylsulfonamides as well as [[eicosanoid]]s related to endocannabinoids.<ref name=lambert />
-==Uses==
+== Uses ==
-Medical uses include the treatment of [[nausea]] due to [[chemotherapy]], [[spasticity]], and possibly [[neuropathic pain]].<ref name=Al2018/> Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".<ref name=Al2018>{{cite journal | vauthors = Allan GM, Finley CR, Ton J, Perry D, Ramji J, Crawford K, Lindblad AJ, Korownyk C, Kolber MR | display-authors = 6 | title = Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms | journal = Canadian Family Physician | volume = 64 | issue = 2 | pages = e78–e94 | date = February 2018 | pmid = 29449262 | pmc = 5964405 }}</ref>
+Medical uses include the treatment of [[nausea]] due to [[chemotherapy]], [[spasticity]], and possibly [[neuropathic pain]].<ref name=Al2018 /> Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".<ref name=Al2018>{{cite journal | vauthors = Allan GM, Finley CR, Ton J, Perry D, Ramji J, Crawford K, Lindblad AJ, Korownyk C, Kolber MR | display-authors = 6 | title = Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms | journal = Canadian Family Physician | volume = 64 | issue = 2 | pages = e78–e94 | date = February 2018 | pmid = 29449262 | pmc = 5964405 }}</ref>
 == Cannabinoid receptors ==
-Before the 1980s, cannabinoids were speculated to produce their [[physiological]] and behavioral effects via nonspecific interaction with [[cell membranes]], instead of interacting with specific [[membrane-bound]] [[Receptor (biochemistry)|receptors]]. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate.<ref name=pmid2848184>{{cite journal | vauthors = Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC | title = Determination and characterization of a cannabinoid receptor in rat brain | journal = Molecular Pharmacology | volume = 34 | issue = 5 | pages = 605–613 | date = November 1988 | pmid = 2848184 | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2848184 | ref = 56 }}</ref> These receptors are common in animals. Two known cannabinoid receptors are termed [[CB1 receptor|CB<sub>1</sub>]] and [[CB2 receptor|CB<sub>2</sub>]],<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> with mounting evidence of more.<ref name="pmid15866316">{{cite journal | vauthors = Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G | display-authors = 6 | title = Evidence for novel cannabinoid receptors | journal = Pharmacology & Therapeutics | volume = 106 | issue = 2 | pages = 133–145 | date = May 2005 | pmid = 15866316 | doi = 10.1016/j.pharmthera.2004.11.005 }}</ref> The human brain has more cannabinoid receptors than any other [[G protein-coupled receptor]] (GPCR) type.<ref name="Medical Physiology">{{cite book| veditors = Boron WG, Boulpaep EL |title=Medical Physiology: A Cellular and Molecular Approach |year=2009 |publisher=Saunders |isbn=978-1-4160-3115-4 |page=331}}</ref>
+Before the 1980s, cannabinoids were speculated to produce their [[physiological]] and behavioral effects via nonspecific interaction with [[cell membranes]], instead of interacting with specific [[membrane-bound]] [[Receptor (biochemistry)|receptors]]. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate.<ref name=PMID 2848184>{{cite journal | vauthors = Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC | title = Determination and characterization of a cannabinoid receptor in rat brain | journal = Molecular Pharmacology | volume = 34 | issue = 5 | pages = 605–613 | date = November 1988 | pmid = 2848184 | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2848184 | ref = 56 }}</ref> These receptors are common in animals. Two known cannabinoid receptors are termed [[CB1 receptor|CB<sub>1</sub>]] and [[CB2 receptor|CB<sub>2</sub>]],<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> with mounting evidence of more.<ref name="pmid15866316">{{cite journal | vauthors = Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G | display-authors = 6 | title = Evidence for novel cannabinoid receptors | journal = Pharmacology & Therapeutics | volume = 106 | issue = 2 | pages = 133–145 | date = May 2005 | pmid = 15866316 | doi = 10.1016/j.pharmthera.2004.11.005 }}</ref> The human brain has more cannabinoid receptors than any other [[G protein-coupled receptor]] (GPCR) type.<ref name="Medical Physiology">{{cite book| veditors = Boron WG, Boulpaep EL |title=Medical Physiology: A Cellular and Molecular Approach |year=2009 |publisher=Saunders |isbn=978-1-4160-3115-4 |page=331}}</ref>
 The [[Endocannabinoid system|Endocannabinoid System]] (ECS) regulates many functions of the human body. The ECS plays an important role in multiple aspects of [[Neuron|neural]] functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.<ref>{{cite book | vauthors = Kalant H | chapter = Effects of cannabis and cannabinoids in the human nervous system. | title = The effects of drug abuse on the human nervous system | date = January 2014 | pages = 387–422 | publisher = Academic Press | doi = 10.1016/B978-0-12-418679-8.00013-7 | isbn = 978-0-12-418679-8 }}</ref>
@@ Line 19: / Line 20: @@
 === Cannabinoid receptor type 2 ===
 {{Main|Cannabinoid receptor type 2}}
-CB<sub>2</sub> receptors are predominantly found in the [[immune system]], or immune-derived cells<ref>{{cite journal | vauthors = Marchand J, Bord A, Pénarier G, Lauré F, Carayon P, Casellas P | title = Quantitative method to determine mRNA levels by reverse transcriptase-polymerase chain reaction from leukocyte subsets purified by fluorescence-activated cell sorting: application to peripheral cannabinoid receptors | journal = Cytometry | volume = 35 | issue = 3 | pages = 227–234 | date = March 1999 | pmid = 10082303 | doi = 10.1002/(SICI)1097-0320(19990301)35:3<227::AID-CYTO5>3.0.CO;2-4 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P | display-authors = 6 | title = Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations | journal = European Journal of Biochemistry | volume = 232 | issue = 1 | pages = 54–61 | date = August 1995 | pmid = 7556170 | doi = 10.1111/j.1432-1033.1995.tb20780.x | doi-access = free }}</ref><ref name="pmid21295074">{{cite journal | vauthors = Pacher P, Mechoulam R | title = Is lipid signaling through cannabinoid 2 receptors part of a protective system? | journal = Progress in Lipid Research | volume = 50 | issue = 2 | pages = 193–211 | date = April 2011 | pmid = 21295074 | pmc = 3062638 | doi = 10.1016/j.plipres.2011.01.001 }}</ref><ref name="Saroz acsptsci.9b00049">{{cite journal | vauthors = Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL | title = Cannabinoid Receptor 2 (CB<sub>2</sub>) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes | journal = ACS Pharmacology & Translational Science | volume = 2 | issue = 6 | pages = 414–428 | date = December 2019 | pmid = 32259074 | pmc = 7088898 | doi = 10.1021/acsptsci.9b00049 }}</ref> with varying expression patterns. While found only in the peripheral nervous system, a report does indicate that CB<sub>2</sub> is expressed by a subpopulation of [[microglia]] in the human [[cerebellum]].<ref name="pmid15266552">{{cite journal | vauthors = Núñez E, Benito C, Pazos MR, Barbachano A, Fajardo O, González S, Tolón RM, Romero J | display-authors = 6 | title = Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study | journal = Synapse | volume = 53 | issue = 4 | pages = 208–213 | date = September 2004 | pmid = 15266552 | doi = 10.1002/syn.20050 | s2cid = 40738073 }}</ref> CB<sub>2</sub> receptors appear to be responsible for immunomodulatory<ref name="Saroz acsptsci.9b00049"/> and possibly other therapeutic effects of cannabinoid as seen in vitro and in animal models.<ref name="pmid21295074" />
+CB<sub>2</sub> receptors are predominantly found in the [[immune system]], or immune-derived cells<ref>{{cite journal | vauthors = Marchand J, Bord A, Pénarier G, Lauré F, Carayon P, Casellas P | title = Quantitative method to determine mRNA levels by reverse transcriptase-polymerase chain reaction from leukocyte subsets purified by fluorescence-activated cell sorting: application to peripheral cannabinoid receptors | journal = Cytometry | volume = 35 | issue = 3 | pages = 227–234 | date = March 1999 | pmid = 10082303 | doi = 10.1002/(SICI)1097-0320(19990301)35:3<227::AID-CYTO5>3.0.CO;2-4 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P | display-authors = 6 | title = Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations | journal = European Journal of Biochemistry | volume = 232 | issue = 1 | pages = 54–61 | date = August 1995 | pmid = 7556170 | doi = 10.1111/j.1432-1033.1995.tb20780.x | doi-access = free }}</ref><ref name="pmid21295074">{{cite journal | vauthors = Pacher P, Mechoulam R | title = Is lipid signaling through cannabinoid 2 receptors part of a protective system? | journal = Progress in Lipid Research | volume = 50 | issue = 2 | pages = 193–211 | date = April 2011 | pmid = 21295074 | pmc = 3062638 | doi = 10.1016/j.plipres.2011.01.001 }}</ref><ref name="Saroz acsptsci.9b00049">{{cite journal | vauthors = Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL | title = Cannabinoid Receptor 2 (CB<sub>2</sub>) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes | journal = ACS Pharmacology & Translational Science | volume = 2 | issue = 6 | pages = 414–428 | date = December 2019 | pmid = 32259074 | pmc = 7088898 | doi = 10.1021/acsptsci.9b00049 }}</ref> with varying expression patterns. While found only in the peripheral nervous system, a report does indicate that CB<sub>2</sub> is expressed by a subpopulation of [[microglia]] in the human [[cerebellum]].<ref name="pmid15266552">{{cite journal | vauthors = Núñez E, Benito C, Pazos MR, Barbachano A, Fajardo O, González S, Tolón RM, Romero J | display-authors = 6 | title = Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study | journal = Synapse | volume = 53 | issue = 4 | pages = 208–213 | date = September 2004 | pmid = 15266552 | doi = 10.1002/syn.20050 | s2cid = 40738073 }}</ref> CB<sub>2</sub> receptors appear to be responsible for immunomodulatory<ref name="Saroz acsptsci.9b00049" /> and possibly other therapeutic effects of cannabinoid as seen in vitro and in animal models.<ref name="pmid21295074" />
 == Phytocannabinoids ==
-{{see also|Comparison of phytocannabinoids}}
+{{See also|Comparison of phytocannabinoids}}
 [[File:Kolkata-Kut.jpg|thumb|right|The bracts surrounding a cluster of ''[[Cannabis sativa]]'' flowers are coated with cannabinoid-laden [[Trichomes#Plant trichomes|trichomes]].]]
@@ Line 28: / Line 29: @@
 The classical cannabinoids are concentrated in a viscous [[resin]] produced in structures known as glandular [[trichome]]s. At least 113 different cannabinoids have been isolated from the ''[[Cannabis]]'' plant.<ref name=":0" /> To the right, the main classes of cannabinoids from ''Cannabis'' are shown.{{citation needed|date=May 2018}}
-All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.<ref name="FellermeierEisenreich2001">{{cite journal | vauthors = Fellermeier M, Eisenreich W, Bacher A, Zenk MH | title = Biosynthesis of cannabinoids. Incorporation experiments with (13)C-labeled glucoses | journal = European Journal of Biochemistry | volume = 268 | issue = 6 | pages = 1596–1604 | date = March 2001 | pmid = 11248677 | doi = 10.1046/j.1432-1327.2001.02030.x | doi-access = free }}</ref> The classical cannabinoids are derived from their respective 2-[[carboxylic acid]]s (2-COOH) by [[decarboxylation]] (catalyzed by heat, light, or [[alkaline]] conditions).<ref>Patentdocs. Patent application title: [http://www.faqs.org/patents/app/20120046352 Controlled cannabis decarboxylation.] US Patent application number: 20120046352. Retrieved 28 December 2013</ref>
+All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.<ref name="FellermeierEisenreich2001">{{cite journal | vauthors = Fellermeier M, Eisenreich W, Bacher A, Zenk MH | title = Biosynthesis of cannabinoids. Incorporation experiments with (13)C-labeled glucoses | journal = European Journal of Biochemistry | volume = 268 | issue = 6 | pages = 1596–1604 | date = March 2001 | pmid = 11248677 | doi = 10.1046/j.1432-1327.2001.02030.x | doi-access = free }}</ref> The classical cannabinoids are derived from their respective 2-[[carboxylic acid]]s (2-COOH) by [[decarboxylation]] (catalyzed by heat, light, or [[alkaline]] conditions).{{Citation needed}}
 === Well known cannabinoids ===
@@ Line 35: / Line 36: @@
 ==== Tetrahydrocannabinol ====
 {{Main|Tetrahydrocannabinol}}
-Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. ''Delta''-9-[[tetrahydrocannabinol]] (Δ<sup>9</sup>-THC, THC) and [[Delta-8-Tetrahydrocannabinol]] (Δ<sup>8</sup>-THC), through intracellular CB<sub>1</sub> activation, induce [[anandamide]] and [[2-arachidonoylglycerol]] synthesis produced naturally in the body and brain{{citation needed|date=February 2019}}{{dubious|date=July 2019}}. These cannabinoids produce the effects associated with [[Cannabis (drug)|cannabis]] by binding to the CB<sub>1</sub> cannabinoid receptors in the brain.<ref>[https://www.drugabuse.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-effects How does marijuana produce its effects?], drugabuse.gov</ref>
+Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. ''Delta''-9-[[tetrahydrocannabinol]] (Δ<sup>9</sup>-THC, THC) and [[Delta-8-Tetrahydrocannabinol]] (Δ<sup>8</sup>-THC), through intracellular CB<sub>1</sub> activation, induce [[anandamide]] and [[2-arachidonoylglycerol]] synthesis produced naturally in the body and brain{{citation needed|date=February 2019}}{{dubious|date=July 2019}}. These cannabinoids produce the effects associated with [[Cannabis (drug)|cannabis]] by binding to the CB<sub>1</sub> cannabinoid receptors in the brain.<ref>{{Cite web|last=Abuse|first=National Institute on Drug|date=--|title=How does marijuana produce its effects?|url=https://nida.nih.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-effects|access-date=2023-01-05|website=National Institute on Drug Abuse|language=en}}</ref>
 ==== Cannabidiol ====
 {{Main|Cannabidiol}}
-Cannabidiol (CBD) is mildly [[psychotropic]]. Evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis.<ref name=2015CBDantipsychReview/> Cannabidiol has little affinity for [[Cannabinoid receptor#CB1|CB<sub>1</sub>]] and [[Cannabinoid receptor#CB2|CB<sub>2</sub>]] receptors but acts as an indirect antagonist of cannabinoid agonists.<ref name="recentadvances">{{cite journal | vauthors = Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO | title = Cannabidiol--recent advances | journal = Chemistry & Biodiversity | volume = 4 | issue = 8 | pages = 1678–1692 | date = August 2007 | pmid = 17712814 | doi = 10.1002/cbdv.200790147 | s2cid = 3689072 }}</ref> It was found to be an antagonist at the putative new cannabinoid receptor, [[GPR55]], a [[GPCR]] expressed in the [[caudate nucleus]] and [[putamen]].<ref>{{cite journal | vauthors = Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ | display-authors = 6 | title = The orphan receptor GPR55 is a novel cannabinoid receptor | journal = British Journal of Pharmacology | volume = 152 | issue = 7 | pages = 1092–1101 | date = December 2007 | pmid = 17876302 | pmc = 2095107 | doi = 10.1038/sj.bjp.0707460 }}</ref> Cannabidiol has also been shown to act as a [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] agonist.<ref name="pmid16258853">{{cite journal | vauthors = Russo EB, Burnett A, Hall B, Parker KK | title = Agonistic properties of cannabidiol at 5-HT1a receptors | journal = Neurochemical Research | volume = 30 | issue = 8 | pages = 1037–1043 | date = August 2005 | pmid = 16258853 | doi = 10.1007/s11064-005-6978-1 | s2cid = 207222631 }}</ref> CBD can interfere with the uptake of [[adenosine]], which plays an important role in biochemical processes, such as energy transfer. It may play a role in promoting sleep and suppressing arousal.<ref>{{cite journal | vauthors = Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS | title = Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 367 | issue = 1607 | pages = 3364–3378 | date = December 2012 | pmid = 23108553 | pmc = 3481531 | doi = 10.1098/rstb.2011.0389 }}</ref>
+Cannabidiol (CBD) is mildly [[psychotropic]]. Evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis.<ref name=2015CBDantipsychReview /> Cannabidiol has little affinity for [[Cannabinoid receptor#CB1|CB<sub>1</sub>]] and [[Cannabinoid receptor#CB2|CB<sub>2</sub>]] receptors but acts as an indirect antagonist of cannabinoid agonists.<ref name="recentadvances">{{cite journal | vauthors = Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO | title = Cannabidiol--recent advances | journal = Chemistry & Biodiversity | volume = 4 | issue = 8 | pages = 1678–1692 | date = August 2007 | pmid = 17712814 | doi = 10.1002/cbdv.200790147 | s2cid = 3689072 }}</ref> It was found to be an antagonist at the putative new cannabinoid receptor, [[GPR55]], a [[GPCR]] expressed in the [[caudate nucleus]] and [[putamen]].<ref>{{cite journal | vauthors = Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ | display-authors = 6 | title = The orphan receptor GPR55 is a novel cannabinoid receptor | journal = British Journal of Pharmacology | volume = 152 | issue = 7 | pages = 1092–1101 | date = December 2007 | pmid = 17876302 | pmc = 2095107 | doi = 10.1038/sj.bjp.0707460 }}</ref> Cannabidiol has also been shown to act as a [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] agonist.<ref name="pmid16258853">{{cite journal | vauthors = Russo EB, Burnett A, Hall B, Parker KK | title = Agonistic properties of cannabidiol at 5-HT1a receptors | journal = Neurochemical Research | volume = 30 | issue = 8 | pages = 1037–1043 | date = August 2005 | pmid = 16258853 | doi = 10.1007/s11064-005-6978-1 | s2cid = 207222631 }}</ref> CBD can interfere with the uptake of [[adenosine]], which plays an important role in biochemical processes, such as energy transfer. It may play a role in promoting sleep and suppressing arousal.<ref>{{cite journal | vauthors = Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS | title = Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 367 | issue = 1607 | pages = 3364–3378 | date = December 2012 | pmid = 23108553 | pmc = 3481531 | doi = 10.1098/rstb.2011.0389 }}</ref>
 CBD shares a [[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 [[cannabis and memory|the short-term memory loss associated with THC]].<ref name=NatureCBDMemory>{{Cite journal| vauthors = Frood A |title=Key ingredient staves off marijuana memory loss |journal=Natur |doi=10.1038/news.2010.508|year=2010}}</ref>
@@ Line 46: / Line 47: @@
 ==== Cannabinol ====
-{{Main articles|Cannabinol}}
+{{Main|Cannabinol}}
-Cannabinol (CBN) is a mildly [[Psychoactive drug|psychoactive]] [[cannabinoid]] that acts as a low affinity [[partial agonist]] at both CB1 and CB2 receptors.'''<ref name="Rhee_1997">{{cite journal |display-authors=6 |vauthors=Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R |date=September 1997 |title=Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase |journal=Journal of Medicinal Chemistry |volume=40 |issue=20 |pages=3228–3233 |doi=10.1021/jm970126f |pmid=9379442}}</ref>'''<ref name=":02">{{Cite journal |last=Sampson |first=Peter B. |date=2021-01-22 |title=Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the "Big Two" |url=https://pubmed.ncbi.nlm.nih.gov/33356248 |journal=Journal of Natural Products |volume=84 |issue=1 |pages=142–160 |doi=10.1021/acs.jnatprod.0c00965 |issn=1520-6025 |pmid=33356248|s2cid=229694293 }}</ref>'''<ref name="NCI_C84510">{{Cite web |title=Cannabinol (Code C84510) |url=https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C84510 |work=NCI Thesaurus |publisher=National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services}}</ref>''' Through its mechanism of partial agonism at the CB1R, CBN is thought to interact with other kinds of [[neurotransmission]] (e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).
+Cannabinol (CBN) is a mildly [[Psychoactive drug|psychoactive]] cannabinoid that acts as a low affinity [[partial agonist]] at both CB1 and CB2 receptors.'''<ref name="Rhee_1997">{{cite journal |display-authors=6 |vauthors=Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R |date=September 1997 |title=Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase |journal=Journal of Medicinal Chemistry |volume=40 |issue=20 |pages=3228–3233 |doi=10.1021/jm970126f |pmid=9379442}}</ref>'''<ref name=":02">{{Cite journal |last=Sampson |first=Peter B. |date=2021-01-22 |title=Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the "Big Two" |url=https://pubmed.ncbi.nlm.nih.gov/33356248 |journal=Journal of Natural Products |volume=84 |issue=1 |pages=142–160 |doi=10.1021/acs.jnatprod.0c00965 |issn=1520-6025 |pmid=33356248|s2cid=229694293 }}</ref>'''<ref name="NCI_C84510">{{Cite web |title=Cannabinol (Code C84510) |url=https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C84510 |work=NCI Thesaurus |publisher=National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services}}</ref>''' Through its mechanism of partial agonism at the CB1R, CBN is thought to interact with other kinds of [[neurotransmission]] (e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).
-CBN was the first cannabis compound to be isolated from [[cannabis]] extract in the late 1800s. Its structure and chemical synthesis were achieved by 1940'''<ref name=":3">{{cite journal |vauthors=Pertwee RG |date=January 2006 |title=Cannabinoid pharmacology: the first 66 years |journal=British Journal of Pharmacology |volume=147 |issue=Suppl 1 |pages=S163–S171 |doi=10.1038/sj.bjp.0706406 |pmc=1760722 |pmid=16402100 |quote=Cannabinol (CBN; Figure 1), much of which is thought to be formed from THC during the storage of harvested cannabis, was the first of the plant cannabinoids (phytocannabinoids) to be isolated, from a red oil extract of cannabis, at the end of the 19th century. Its structure was elucidated in the early 1930s by R.S. Cahn, and its chemical synthesis first achieved in 1940 in the laboratories of R. Adams in the U.S.A. and Lord Todd in the U.K.}}</ref>''', followed by some of the first pre-clinical research studies to determine the effects of individual cannabis-derived compounds [[in vivo]].<ref name=":4">{{Cite journal |last=Pertwee |first=Roger G |date=2006 |title=Cannabinoid pharmacology: the first 66 years: Cannabinoid pharmacology |journal=British Journal of Pharmacology |language=en |volume=147 |issue=S1 |pages=S163–S171 |doi=10.1038/sj.bjp.0706406 |pmc=1760722 |pmid=16402100}}</ref> Although CBN shares the same [[mechanism of action]] as other more well-known [[phytocannabinoids]] (e.g., delta-9 [[tetrahydrocannabinol]] or D9THC), it has a lower [[Affinity (pharmacology)|affinity]] 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.<ref name=":5">{{Cite journal |last=Corroon |first=Jamie |date=2021-08-31 |title=Cannabinol and Sleep: Separating Fact from Fiction |journal=Cannabis and Cannabinoid Research |language=en |pages=can.2021.0006 |doi=10.1089/can.2021.0006 |issn=2578-5125 |pmc=8612407 |pmid=34468204}}</ref><ref name=":4" /> 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.<ref name=":5" />
+CBN was the first cannabis compound to be isolated from [[cannabis]] extract in the late 1800s. Its structure and chemical synthesis were achieved by 1940'''<ref name=":3">{{cite journal |vauthors=Pertwee RG |date=January 2006 |title=Cannabinoid pharmacology: the first 66 years |journal=British Journal of Pharmacology |volume=147 |issue=Suppl 1 |pages=S163–S171 |doi=10.1038/sj.bjp.0706406 |pmc=1760722 |pmid=16402100 |quote=Cannabinol (CBN; Figure 1), much of which is thought to be formed from THC during the storage of harvested cannabis, was the first of the plant cannabinoids (phytocannabinoids) to be isolated, from a red oil extract of cannabis, at the end of the 19th century. Its structure was elucidated in the early 1930s by R.S. Cahn, and its chemical synthesis first achieved in 1940 in the laboratories of R. Adams in the U.S.A. and Lord Todd in the U.K.}}</ref>''', followed by some of the first pre-clinical research studies to determine the effects of individual cannabis-derived compounds [[in vivo]].<ref name=":4">{{Cite journal |last=Pertwee |first=Roger G |date=2006 |title=Cannabinoid pharmacology: the first 66 years: Cannabinoid pharmacology |journal=British Journal of Pharmacology |language=en |volume=147 |issue=S1 |pages=S163–S171 |doi=10.1038/sj.bjp.0706406 |pmc=1760722 |pmid=16402100}}</ref> Although CBN shares the same [[mechanism of action]] as other more well-known [[phytocannabinoids]] (e.g., delta-9 [[tetrahydrocannabinol]] or D9THC), it has a lower [[Affinity (pharmacology)|affinity]] 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.<ref name=":5">{{Cite journal |last=Corroon |first=Jamie |date=2021-08-31 |title=Cannabinol and Sleep: Separating Fact from Fiction |journal=Cannabis and Cannabinoid Research |volume=6 |issue=5 |language=en |pages=366–371 |doi=10.1089/can.2021.0006 |issn=2578-5125 |pmc=8612407 |pmid=34468204}}</ref><ref name=":4" /> 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.<ref name=":5" />
 === Biosynthesis ===
@@ Line 64: / Line 65: @@
 Phytocannabinoids are known to occur in several plant species besides cannabis. These include ''[[Echinacea purpurea]]'', ''[[Echinacea angustifolia]]'', ''[[Acmella oleracea]]'', [[Helichrysum|''Helichrysum umbraculigerum'']], and ''[[Radula marginata]]''.<ref name="Woelkart-2008">{{cite journal | vauthors = Woelkart K, Salo-Ahen OM, Bauer R | title = CB receptor ligands from plants | journal = Current Topics in Medicinal Chemistry | volume = 8 | issue = 3 | pages = 173–186 | year = 2008 | pmid = 18289087 | doi = 10.2174/156802608783498023 }}</ref> The best-known cannabinoids that are not derived from Cannabis are the lipophilic alkamides (alkylamides) from ''[[Echinacea]]'' species, most notably the cis/trans [[isomers]] dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamide.<ref name="Woelkart-2008" /> At least 25 different [[alkylamide]]s have been identified, and some of them have shown affinities to the CB<sub>2</sub>-receptor.<ref name="Bauer-1989">{{cite journal | vauthors = Bauer R, Remiger P | title = TLC and HPLC Analysis of Alkamides in Echinacea Drugs1,2 | journal = Planta Medica | volume = 55 | issue = 4 | pages = 367–371 | date = August 1989 | pmid = 17262436 | doi = 10.1055/s-2006-962030 }}</ref><ref>{{cite journal | vauthors = Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, Altmann KH, Gertsch J | display-authors = 6 | title = Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects | journal = The Journal of Biological Chemistry | volume = 281 | issue = 20 | pages = 14192–14206 | date = May 2006 | pmid = 16547349 | doi = 10.1074/jbc.M601074200 | doi-access = free }}</ref>  In some ''Echinacea'' species, cannabinoids are found throughout the plant structure, but are most concentrated in the roots and flowers.<ref name="Perry-1997">{{cite journal | vauthors = Perry NB, van Klink JW, Burgess EJ, Parmenter GA | title = Alkamide levels in Echinacea purpurea: a rapid analytical method revealing differences among roots, rhizomes, stems, leaves and flowers | journal = Planta Medica | volume = 63 | issue = 1 | pages = 58–62 | date = February 1997 | pmid = 17252329 | doi = 10.1055/s-2006-957605 }}</ref><ref>{{cite journal | vauthors = He X, Lin L, Bernart MW, Lian L |year=1998 |title=Analysis of alkamides in roots and achenes of Echinacea purpurea by liquid chromatography–electrospray mass spectrometry |journal=Journal of Chromatography A |volume=815 |issue=2 |pages=205–11 |doi=10.1016/S0021-9673(98)00447-6}}</ref> [[Yangonin]] found in the [[Kava]] plant has significant affinity to the CB1 receptor.<ref>{{cite journal | vauthors = Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V | title = Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand | journal = Pharmacological Research | volume = 66 | issue = 2 | pages = 163–169 | date = August 2012 | pmid = 22525682 | doi = 10.1016/j.phrs.2012.04.003 }}</ref> Tea ([[Camellia sinensis]]) [[catechins]] have an affinity for human cannabinoid receptors.<ref name="urlmissclasses.com">{{cite journal | vauthors = Korte G, Dreiseitel A, Schreier P, Oehme A, Locher S, Geiger S, Heilmann J, Sand PG | display-authors = 6 | title = Tea catechins' affinity for human cannabinoid receptors | journal = Phytomedicine | volume = 17 | issue = 1 | pages = 19–22 | date = January 2010 | pmid = 19897346 | doi = 10.1016/j.phymed.2009.10.001 }}</ref> A widespread dietary terpene, [[beta-caryophyllene]], a component from the [[Cannabis flower essential oil|essential oil of cannabis]] and other medicinal plants, has also been identified as a selective agonist of peripheral CB<sub>2</sub>-receptors, ''[[in vivo]]''.<ref>{{cite journal | vauthors = Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A | display-authors = 6 | title = Beta-caryophyllene is a dietary cannabinoid | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 26 | pages = 9099–9104 | date = July 2008 | pmid = 18574142 | pmc = 2449371 | doi = 10.1073/pnas.0803601105 | doi-access = free | bibcode = 2008PNAS..105.9099G }}</ref> [[Black truffles]] contain anandamide.<ref>{{cite journal | vauthors = Pacioni G, Rapino C, Zarivi O, Falconi A, Leonardi M, Battista N, Colafarina S, Sergi M, Bonfigli A, Miranda M, Barsacchi D, Maccarrone M | display-authors = 6 | title = Truffles contain endocannabinoid metabolic enzymes and anandamide | journal = Phytochemistry | volume = 110 | pages = 104–110 | date = February 2015 | pmid = 25433633 | doi = 10.1016/j.phytochem.2014.11.012 }}</ref> [[Perrottetinene]], a moderately psychoactive cannabinoid,<ref>{{cite journal | vauthors = Chicca A, Schafroth MA, Reynoso-Moreno I, Erni R, Petrucci V, Carreira EM, Gertsch J | title = Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high | journal = Science Advances | volume = 4 | issue = 10 | pages = eaat2166 | date = October 2018 | pmid = 30397641 | pmc = 6200358 | doi = 10.1126/sciadv.aat2166 | bibcode = 2018SciA....4.2166C }}</ref> has been isolated from different ''[[Radula (plant)|Radula]]'' varieties.
-Most of the phytocannabinoids are nearly insoluble in water but are soluble in [[lipid]]s, [[Alcohol (chemistry)|alcohol]]s, and other non-polar [[organic solvent]]s.
+Most of the phytocannabinoids are nearly insoluble in water but are soluble in [[lipid]]s, [[Alcohol (chemistry)|alcohols]], and other non-polar [[organic solvent]]s.
 === Cannabis plant profile ===
@@ Line 78: / Line 79: @@
 Research shows the effect of cannabinoids might be modulated by aromatic compounds produced by the cannabis plant, called [[terpenes]]. This interaction would lead to the [[entourage effect]].<ref name="PMCentourage2011">{{cite journal | vauthors = Russo EB | title = Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects | journal = British Journal of Pharmacology | volume = 163 | issue = 7 | pages = 1344–1364 | date = August 2011 | pmid = 21749363 | pmc = 3165946 | doi = 10.1111/j.1476-5381.2011.01238.x }}</ref>
-====Cannabinoid-based pharmaceuticals====
+==== Cannabinoid-based pharmaceuticals ====
-[[Nabiximols]] (brand name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC.<ref>{{cite journal | vauthors = Keating GM | title = Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex<sup>®</sup>): A Review in Multiple Sclerosis-Related Spasticity | journal = Drugs | volume = 77 | issue = 5 | pages = 563–574 | date = April 2017 | pmid = 28293911 | doi = 10.1007/s40265-017-0720-6 | s2cid = 2884550 }}</ref> Also included are minor cannabinoids and [[terpenoids]], [[ethanol]] and [[propylene glycol]] [[excipients]], and peppermint flavoring.<ref name="ReferenceA">{{cite journal | vauthors = Russo EB | title = Cannabinoids in the management of difficult to treat pain | journal = Therapeutics and Clinical Risk Management | volume = 4 | issue = 1 | pages = 245–259 | date = February 2008 | pmid = 18728714 | pmc = 2503660 | doi = 10.2147/TCRM.S1928 }}</ref> The drug, made by [[GW Pharmaceuticals]], was first approved by Canadian authorities in 2005 to alleviate pain associated with [[multiple sclerosis]], making it the first cannabis-based medicine. It is marketed by Bayer in Canada.<ref>{{cite news | vauthors = Cooper R |title=GW Pharmaceuticals launches world's first prescription cannabis drug in Britain |url= https://www.telegraph.co.uk/finance/newsbysector/pharmaceuticalsandchemicals/7842794/GW-Pharmaceuticals-launches-worlds-first-prescription-cannabis-drug-in-Britain.html |access-date=29 November 2018 |date=21 June 2010}}</ref> Sativex has been approved in 25 countries; clinical trials are underway in the United States to gain FDA approval.<ref name="USATodaySativex">{{cite web |title=3 prescription drugs that come from marijuana |url=https://www.usatoday.com/story/money/personalfinance/2014/03/17/three-drugs-that-come-from-marijuana/6531291/ |website=USA Today |access-date=30 November 2018}}</ref> In 2007, it was approved for treatment of cancer pain.<ref name="ReferenceA"/> 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.<ref name="Schubert">{{cite book | vauthors = Schubert-Zsilavecz M, Wurglics M | title = Neue Arzneimittel | date = 2011–2012 | language = de }}</ref>
+[[Nabiximols]] (brand name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC.<ref>{{cite journal | vauthors = Keating GM | title = Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex<sup>®</sup>): A Review in Multiple Sclerosis-Related Spasticity | journal = Drugs | volume = 77 | issue = 5 | pages = 563–574 | date = April 2017 | pmid = 28293911 | doi = 10.1007/s40265-017-0720-6 | s2cid = 2884550 }}</ref> Also included are minor cannabinoids and [[terpenoids]], [[ethanol]] and [[propylene glycol]] [[excipients]], and peppermint flavoring.<ref name="ReferenceA">{{cite journal | vauthors = Russo EB | title = Cannabinoids in the management of difficult to treat pain | journal = Therapeutics and Clinical Risk Management | volume = 4 | issue = 1 | pages = 245–259 | date = February 2008 | pmid = 18728714 | pmc = 2503660 | doi = 10.2147/TCRM.S1928 }}</ref> The drug, made by [[GW Pharmaceuticals]], was first approved by Canadian authorities in 2005 to alleviate pain associated with [[multiple sclerosis]], making it the first cannabis-based medicine. It is marketed by Bayer in Canada.<ref>{{cite news | vauthors = Cooper R |title=GW Pharmaceuticals launches world's first prescription cannabis drug in Britain |url= https://www.telegraph.co.uk/finance/newsbysector/pharmaceuticalsandchemicals/7842794/GW-Pharmaceuticals-launches-worlds-first-prescription-cannabis-drug-in-Britain.html |access-date=29 November 2018 |date=21 June 2010}}</ref> Sativex has been approved in 25 countries; clinical trials are underway in the United States to gain FDA approval.<ref name="USATodaySativex">{{cite web |title=3 prescription drugs that come from marijuana |url=https://www.usatoday.com/story/money/personalfinance/2014/03/17/three-drugs-that-come-from-marijuana/6531291/ |website=USA Today |access-date=30 November 2018}}</ref> In 2007, it was approved for treatment of cancer pain.<ref name="ReferenceA" /> 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.<ref name="Schubert">{{cite book | vauthors = Schubert-Zsilavecz M, Wurglics M | title = Neue Arzneimittel | date = 2011–2012 | language = de }}</ref>
 [[Dronabinol]] (brand name Marinol) is a THC drug used to treat poor appetite, nausea, and [[sleep apnea]].<ref>{{Cite web|url=https://www.healthcentral.com/article/dronabinol-sleep-apnea-treatment|title=Can Dronabinol Help Treat Sleep Apnea? | work = HealthCentral |access-date=2018-11-04}}</ref> It is approved by the [[Food and Drug Administration|FDA]] for treating [[HIV/AIDS]] induced [[anorexia (symptom)|anorexia]] and [[Chemotherapy-induced nausea and vomiting|chemotherapy induced nausea and vomiting]].<ref name="fda">{{cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf|title=Marinol (Dronabinol)|date=September 2004|publisher=US Food and Drug Administration|access-date=14 January 2018}}</ref><ref>{{cite web|url=http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page2|title=Cannabis and Cannabinoids|date=24 October 2011|publisher=National Cancer Institute|access-date=12 January 2014}}</ref><ref>{{cite journal | vauthors = Badowski ME | title = A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics | journal = Cancer Chemotherapy and Pharmacology | volume = 80 | issue = 3 | pages = 441–449 | date = September 2017 | pmid = 28780725 | pmc = 5573753 | doi = 10.1007/s00280-017-3387-5 }}</ref>
@@ Line 86: / Line 87: @@
 === Separation ===
-Cannabinoids can be separated from the plant by [[solvent extraction|extraction]] with organic [[solvent]]s. [[Hydrocarbon]]s and [[Alcohol (chemistry)|alcohol]]s are often used as solvents. However, these solvents are flammable and many are toxic.<ref>{{cite journal| vauthors = Romano LL, Hazekamp A |title=Cannabis Oil: chemical evaluation of an upcoming cannabis-based medicine |journal=Cannabinoids |date=2013 |volume=7 |issue=1 |pages=1–11|url=http://www.cannabis-med.org/data/pdf/en_2013_01_1.pdf}}</ref> Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with [[carbon dioxide]] is an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or other [[distillation]] techniques.<ref>{{cite journal| vauthors = Rovetto LJ, Aieta NV |title=Supercritical carbon dioxide extraction of cannabinoids from Cannabis sativa L.|journal=The Journal of Supercritical Fluids|date=November 2017|volume=129|pages=16–27|doi=10.1016/j.supflu.2017.03.014}}</ref> Also, techniques such as SPE or SPME are found useful in the extraction of these compounds.<ref>{{cite journal| vauthors = Jain R, Singh R |title=Microextraction techniques for analysis of cannabinoids|journal=TrAC Trends in Analytical Chemistry|volume=80|pages=156–166|doi=10.1016/j.trac.2016.03.012|year=2016}}</ref>
+Cannabinoids can be separated from the plant by [[solvent extraction|extraction]] with organic [[solvent]]s. [[Hydrocarbon]]s and [[Alcohol (chemistry)|alcohols]] are often used as solvents. However, these solvents are flammable and many are toxic.<ref>{{cite journal| vauthors = Romano LL, Hazekamp A |title=Cannabis Oil: chemical evaluation of an upcoming cannabis-based medicine |journal=Cannabinoids |date=2013 |volume=7 |issue=1 |pages=1–11|url=http://www.cannabis-med.org/data/pdf/en_2013_01_1.pdf}}</ref> Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with [[carbon dioxide]] is an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or other [[distillation]] techniques.<ref>{{cite journal| vauthors = Rovetto LJ, Aieta NV |title=Supercritical carbon dioxide extraction of cannabinoids from Cannabis sativa L.|journal=The Journal of Supercritical Fluids|date=November 2017|volume=129|pages=16–27|doi=10.1016/j.supflu.2017.03.014}}</ref> Also, techniques such as SPE or SPME are found useful in the extraction of these compounds.<ref>{{cite journal| vauthors = Jain R, Singh R |title=Microextraction techniques for analysis of cannabinoids|journal=TrAC Trends in Analytical Chemistry|volume=80|pages=156–166|doi=10.1016/j.trac.2016.03.012|year=2016}}</ref>
 === History ===
 The first discovery of an individual cannabinoid was made, when British chemist [[Robert W. Cahn|Robert S. Cahn]] reported the partial structure of Cannabinol (CBN), which he later identified as fully formed in 1940.
-Two years later, in 1942,<ref>{{Cite web|url=https://issuu.com/freedomleaf/docs/freedomleafissue34issuu|title=U.S. Chemist Roger Adams Isolated CBD 75 Years Ago| vauthors = Weinberg B |date=Fall 2018|website=Freedom Leaf|publisher=Freedom Leaf|via=Issuu.com|access-date=2019-03-16|edition=34}}</ref> American chemist, [[Roger Adams]], made history when he discovered Cannabidiol (CBD).<ref>{{Cite web|url=https://cbdorigin.com/history-of-cbd/|title=The History Of CBD - A Brief Overview| vauthors = Cadena A |date=2019-03-08|website=CBD Origin|publisher=CBDOrigin.com|access-date=2019-03-16}}</ref> Progressing from Adams research, in 1963<ref name=":2">{{cite journal | vauthors = Pertwee RG | title = Cannabinoid pharmacology: the first 66 years | journal = British Journal of Pharmacology | volume = 147 | issue = Suppl 1 | pages = S163–S171 | date = January 2006 | pmid = 16402100 | pmc = 1760722 | doi = 10.1038/sj.bjp.0706406 }}</ref> Israeli professor Raphael Mechoulam<ref>{{Cite web|url=https://cannabinoids.huji.ac.il/people/raphael-mechoulam|title=Raphael Mechoulam Ph.D.| vauthors = Mechoulam R |website=cannabinoids.huji.ac.il|publisher=The Hebrew University of Jerusalem|type=Biography|access-date=2019-03-16}}</ref> later identified the [[stereochemistry]] of CBD. The following year, in 1964,<ref name=":2" /> Mechoulam and his team identified the stereochemistry of Tetrahydrocannabinol (THC).{{citation needed|date=December 2013}}
+Two years later, in 1942,<ref>{{Cite web|url=https://issuu.com/freedomleaf/docs/freedomleafissue34issuu|title=U.S. Chemist Roger Adams Isolated CBD 75 Years Ago| vauthors = Weinberg B |date=Fall 2018|website=Freedom Leaf|publisher=Freedom Leaf|via=Issuu.com|access-date=2019-03-16|edition=34}}</ref> American chemist, [[Roger Adams]], made history when he discovered Cannabidiol (CBD).<ref>{{Cite web|url=https://cbdorigin.com/history-of-cbd/|title=The History Of CBD – A Brief Overview| vauthors = Cadena A |date=2019-03-08|website=CBD Origin|publisher=CBDOrigin.com|access-date=2019-03-16}}</ref> Progressing from Adams research, in 1963<ref name=":2">{{cite journal | vauthors = Pertwee RG | title = Cannabinoid pharmacology: the first 66 years | journal = British Journal of Pharmacology | volume = 147 | issue = Suppl 1 | pages = S163–S171 | date = January 2006 | pmid = 16402100 | pmc = 1760722 | doi = 10.1038/sj.bjp.0706406 }}</ref> Israeli professor Raphael Mechoulam<ref>{{Cite web|url=https://cannabinoids.huji.ac.il/people/raphael-mechoulam|title=Raphael Mechoulam Ph.D.| vauthors = Mechoulam R |website=cannabinoids.huji.ac.il|publisher=The Hebrew University of Jerusalem|type=Biography|access-date=2019-03-16}}</ref> later identified the [[stereochemistry]] of CBD. The following year, in 1964,<ref name=":2" /> Mechoulam and his team identified the stereochemistry of Tetrahydrocannabinol (THC).{{citation needed|date=December 2013}}
 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.{{citation needed|date=December 2013}}
@@ Line 101: / Line 102: @@
 {{Further|topic=the functions and regulation of the endocannabinoids|Endocannabinoid system}}
 [[File:Anandamid.svg|thumb|[[Anandamide]], an endogenous [[ligand]] of CB<sub>1</sub> and CB<sub>2</sub>]]</div>
-Endocannabinoids are substances produced from within the body that activate [[cannabinoid receptor]]s. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for endogenous [[ligand (biochemistry)|ligand]] for the receptors.<ref name=pmid2848184/><ref>{{cite journal | vauthors = Katona I, Freund TF | title = Multiple functions of endocannabinoid signaling in the brain | journal = Annual Review of Neuroscience | volume = 35 | pages = 529–558 | year = 2012 | pmid = 22524785 | pmc = 4273654 | doi = 10.1146/annurev-neuro-062111-150420 }}</ref>
+Endocannabinoids are substances produced from within the body that activate [[cannabinoid receptor]]s. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for endogenous [[ligand (biochemistry)|ligand]] for the receptors.<ref name=PMID 2848184 /><ref>{{cite journal | vauthors = Katona I, Freund TF | title = Multiple functions of endocannabinoid signaling in the brain | journal = Annual Review of Neuroscience | volume = 35 | pages = 529–558 | year = 2012 | pmid = 22524785 | pmc = 4273654 | doi = 10.1146/annurev-neuro-062111-150420 }}</ref>
 === Types of endocannabinoid ligands ===
@@ Line 128: / Line 129: @@
 ==== Lysophosphatidylinositol (LPI) ====
-[[Lysophosphatidylinositol]] is the endogenous ligand to novel endocannabinoid receptor [[GPR55]], making it a strong contender as the sixth endocannabinoid.<ref>{{cite journal | vauthors = Piñeiro R, Falasca M | title = Lysophosphatidylinositol signalling: new wine from an old bottle | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1821 | issue = 4 | pages = 694–705 | date = April 2012 | pmid = 22285325 | doi = 10.1016/j.bbalip.2012.01.009 | url = https://zenodo.org/record/895487 }}</ref>
+[[Lysophosphatidylinositol]] is the endogenous ligand to novel endocannabinoid receptor [[GPR55]], making it a strong contender as the sixth endocannabinoid.<ref>{{cite journal | vauthors = Piñeiro R, Falasca M | title = Lysophosphatidylinositol signalling: new wine from an old bottle | journal = Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids | volume = 1821 | issue = 4 | pages = 694–705 | date = April 2012 | pmid = 22285325 | doi = 10.1016/j.bbalip.2012.01.009 | url = https://zenodo.org/record/895487 }}</ref>
 === Function ===
@@ Line 155: / Line 156: @@
 Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.<ref>{{cite journal | vauthors = Lauritsen KJ, Rosenberg H | title = Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana | journal = The American Journal of Drug and Alcohol Abuse | volume = 42 | issue = 4 | pages = 377–384 | date = July 2016 | pmid = 26910181 | doi = 10.3109/00952990.2015.1135158 | s2cid = 4389339 }}</ref>
-When synthetic cannabinoids are used recreationally, they present significant health dangers to users.<ref name=DCES>{{cite web | url = http://www.grassley.senate.gov/sites/default/files/news/upload/3-factor%20analysis%20AB-CHMINACA%20AB-PINACA%20THJ2201%2012172014.pdf | title = N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide(AB-CHMINACA), N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA)and[1-(5-fluoropentyl)-1H-indazol-3-yl](naphthalen-1-yl)methanone(THJ-2201) | publisher = Drug and Chemical Evaluation Section, Office of Diversion Control, [[Drug Enforcement Administration]] | date = December 2014 | journal = | access-date = 2015-01-09 | archive-date = 2018-09-27 | archive-url = https://web.archive.org/web/20180927020404/https://www.grassley.senate.gov/sites/default/files/news/upload/3-factor%20analysis%20AB-CHMINACA%20AB-PINACA%20THJ2201%2012172014.pdf | url-status = dead }}</ref>  In the period of 2012 through 2014, over 10,000 contacts to [[poison control center]]s in the United States were related to use of synthetic cannabinoids.<ref name=DCES/>
+When synthetic cannabinoids are used recreationally, they present significant health dangers to users.<ref name=DCES>{{cite web | url = http://www.grassley.senate.gov/sites/default/files/news/upload/3-factor%20analysis%20AB-CHMINACA%20AB-PINACA%20THJ2201%2012172014.pdf | title = N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide(AB-CHMINACA), N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA)and[1-(5-fluoropentyl)-1H-indazol-3-yl](naphthalen-1-yl)methanone(THJ-2201) | publisher = Drug and Chemical Evaluation Section, Office of Diversion Control, [[Drug Enforcement Administration]] | date = December 2014 | journal = | access-date = 2015-01-09 | archive-date = 2018-09-27 | archive-url = https://web.archive.org/web/20180927020404/https://www.grassley.senate.gov/sites/default/files/news/upload/3-factor%20analysis%20AB-CHMINACA%20AB-PINACA%20THJ2201%2012172014.pdf | url-status = dead }}</ref>  In the period of 2012 through 2014, over 10,000 contacts to [[poison control center]]s in the United States were related to use of synthetic cannabinoids.<ref name=DCES />
 Medications containing natural or synthetic cannabinoids or cannabinoid analogs: