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Cannabidiol

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Not to be confused with cannabinol or cannabinodiol.
Cannabidiol
Clinical data
Trade namesEpidiolex
AHFS/Drugs.comInternational Drug Names
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Bioavailability13–19% (oral),[2] 11–45% (mean 31%; inhaled)[3]
Elimination half-life9 h[2]
Identifiers
  • 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.215.986 Edit this at Wikidata
Chemical and physical data
FormulaC21H30O2
Molar mass314.4636 g·mol−1
3D model (JSmol)
Melting point66 °C (151 °F)
Boiling point180 °C (356 °F)
(range: 160–180 °C)[4]
  • Oc1c(c(O)cc(c1)CCCCC)[C@@H]2\C=C(/CC[C@H]2\C(=C)C)C
  • InChI=1S/C21H30O2/c1-5-6-7-8-16-12-19(22)21(20(23)13-16)18-11-15(4)9-10-17(18)14(2)3/h9,12-13,17-18,22-23H,2,5-8,10-11H2,1,3-4H3/t17-,18+/m0/s1 checkY
  • Key:ZTGXAWYVTLUPDT-ZWKOTPCHSA-N checkY
 ☒NcheckY (what is this?)  (verify)
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Cannabis
Cannabis
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  • Semi-synthetic cannabinoids
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Related

Cannabidiol (CBD) (INN)[5] is one of at least 113 active cannabinoids identified in cannabis.[6][7] It is a major phytocannabinoid, accounting for up to 40% of the plant's extract.[8] CBD is considered to have a wide scope of potential medical applications – due to clinical reports showing the lack of side effects, particularly a lack of psychoactivity (as is typically associated with ∆9-THC), and non-interference with several psychomotor learning and psychological functions.

Research

The bud of a Cannabis sativa flower coated with trichomes bearing cannabidiol and other cannabinoids

Epilepsy

Dravet syndrome is a rare form of epilepsy that is difficult to treat. It is a catastrophic form of intractable epilepsy that begins in infancy. Initial seizures are most often prolonged events and in the second year of life other seizure types begin to emerge.[9] A number of high profile and anecdotal reports have sparked interest in treatment of Dravet syndrome with cannabidiol.[10]

Some cannabis/hemp extract preparations containing CBD are marketed as dietary supplements and claim efficacy against Dravet Syndrome. One such preparation is marketed under the tradename Charlotte's Web Hemp Extract.[11][12] Blended/suspended in oil, the supplement contains 0.3% THC (see Legal status below, classified as hemp).

GW Pharmaceuticals is seeking FDA approval to market a liquid formulation of pure plant-derived CBD, under the trade name Epidiolex (containing 99% cannabidiol and less than 0.10% Δ9-THC) as a treatment for Dravet syndrome. Epidiolex was granted fast-track status and is in late stage trials following positive early results from the drug.[10][13][14][needs update][15][16]

A 2014 review stated that cannabidiol has been claimed, anecdotally, to be of benefit in helping people with epilepsy. Information in the review stated that there is no established mechanism of action and the lack of high-quality evidence in this area precluded conclusions being drawn.[17]

A 2016 review states that because of the poor quality of available data, "no conclusions can be drawn" about the effectiveness of cannabidiol as an epilepsy treatment.[18]

Psychosis

There is tentative evidence that CBD had an anti-psychotic effect, but research in this area is limited.[19][20]

Safety

CBD safety in humans has been studied in multiple small studies, suggesting that it is well tolerated at doses of up to 1500 mg/day (p.o.) or 30 mg (i.v.).[21]

Pharmacodynamics

Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists.[22][23] While one would assume that this would cause cannabidiol to reduce the effects of THC, it may potentiate THC's effects by increasing CB1 receptor density or through another CB1-related mechanism.[24] It may also extend the duration of the effects of THC via inhibition of the cytochrome P-450-3A and 2C enzymes.[25]

Cannabidiol has been found to be an antagonist at the putative cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[26] Cannabidiol has also been shown to act as a 5-HT1A receptor partial agonist,[27] an action which may be involved in its antidepressant,[28][29] anxiolytic,[29][30] and neuroprotective[31][32] effects. Cannabidiol is an allosteric modulator of μ and δ-opioid receptors.[33] Cannabidiol's pharmacological effects have also been attributed to PPAR-γ receptor agonism and intracellular calcium release.[8]

Research suggests that CBD may exert some of its pharmacological action through its inhibition of FAAH, which may in turn increase the levels of endocannabinoids, such as anandamide, produced by the body.[8] It has also been speculated that some of the metabolites of CBD have pharmacological effects that contribute to the biological activity of CBD.[34]

Pharmacokinetic interactions

There is some preclinical evidence to suggest that cannabidiol may reduce THC clearance, modestly increasing THC's plasma concentrations resulting in a greater amount of THC available to receptors, increasing the effect of THC in a dose-dependent manner.[35][36] Despite this, the available evidence in humans suggests no significant effect of CBD on THC plasma levels.[37]

Pharmaceutical preparations

Nabiximols (USAN, trade name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC. The drug was approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis.[38][39] Epidiolex, a drug with cannabidiol as its active pharmaceutical ingredient, received orphan drug status in the United States for treatment of Dravet syndrome in July 2015.[40]

Epidiolex is an oil formulation of CBD extracted from the cannabis plant undergoing clinical trials for refractory epilepsy syndromes.[41]

Chemistry

Cannabidiol is insoluble in water but soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid.[42] In strongly basic media and the presence of air, it is oxidized to a quinone.[43] Under acidic conditions it cyclizes to THC.[44] The synthesis of cannabidiol has been accomplished by several research groups.[45][46][47]

Biosynthesis

Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the last step, where CBDA synthase performs catalysis instead of THCA synthase.[48]

Cannabidiol and THC biosynthesis[49]

Isomerism

Cannabidiol numbering
Cannabidiol numbering
7 double bond isomers and their 30 stereoisomers
Formal numbering Terpenoid numbering Number of stereoisomers Natural occurrence Convention on Psychotropic Substances Schedule Structure
Short name Chiral centers Full name Short name Chiral centers
Δ5-cannabidiol 1 and 3 2-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol Δ4-cannabidiol 1 and 3 4 No unscheduled
Δ4-cannabidiol 1, 3 and 6 2-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol Δ5-cannabidiol 1, 3 and 4 8 No unscheduled
Δ3-cannabidiol 1 and 6 2-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol Δ6-cannabidiol 3 and 4 4 ? unscheduled
Δ3,7-cannabidiol 1 and 6 2-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol Δ1,7-cannabidiol 3 and 4 4 No unscheduled
Δ2-cannabidiol 1 and 6 2-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol Δ1-cannabidiol 3 and 4 4 Yes unscheduled
Δ1-cannabidiol 3 and 6 2-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol Δ2-cannabidiol 1 and 4 4 No unscheduled
Δ6-cannabidiol 3 2-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol Δ3-cannabidiol 1 2 No unscheduled

Based on: Nagaraja, Kodihalli Nanjappa, Synthesis of delta-3-cannabidiol and the derived rigid analogs, Arizona University 1987.

See also: Tetrahydrocannabinol#Isomerism, Abnormal cannabidiol.

Society and culture

Natural sources

Selective breeding by growers in the USA dramatically lowered the CBD content of cannabis; their customers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.[50] To meet the demands of medical cannabis patients, growers are currently developing more CBD-dominant strains.[51]

Cannabidiol is not scheduled by the Convention on Psychotropic Substances. CBD does not cause the "high" associated with the ∆9-THC in marijuana. As the legal landscape and understanding about the differences in medical cannabinoids unfolds, it will be increasingly important to distinguish “medical marijuana” (with noted varying degrees of psychotropic effects and deficits in executive function) – from “medical CBD” (in which the high CBD and low THC content may mitigate psychosis).[52][53][54]

Various breeds/strains of "medical marijuana" are found to have a significant variety in the ratios of CBD-to-THC and are known to contain other non-psychotropic cannabinoids.[55][56] However it is only the amount of ∆9-THC that chemically gives a legal determination as to whether the plant material(s) used for the purposes of extracting CBD are considered hemp, or considered marijuana.

Any psychoactive marijuana, regardless of its CBD content, is derived from the flower (or bud) of the genus cannabis. Non-psychoactive hemp (also commonly-termed industrial hemp), regardless of its CBD content, is any part of the genus cannabis plant, whether growing or not, containing a ∆-9 tetrahydrocannabinol concentration of no more than three-tenths of one percent (0.3%) on a dry weight basis. Certain standards are required for the legal growth and production of hemp. The Colorado Industrial Hemp Program registers growers of industrial hemp and samples crops to verify that the THC concentration does not exceed 0.3% on dry weight basis.[57]

With Charlotte's Web bringing about increased demand for CBD-dominant cannabis, cultivating hemp has captured the attention of U.S. farmers looking to replace dwindling tobacco-growing revenues with renewed hemp "cash crops." In Kentucky, farmers are spurred on by the Industrial Hemp Research Program, established by James Comer, commissioner of agriculture. With backing from Senator Rand Paul, Comer’s legislation[58] created regulations for farmers to legally grow hemp.[59]

Joel Stanley, CEO of Stanley Brothers Social Enterprises, said they plan to invest at least $500,000 to grow therapeutic hemp in Kentucky for their Charlotte's Web cannabidiol oil, saying, "We want to make Charlotte's Web a Kentucky Proud product."[60] In addition, Paul and Comer were able to get a provision added to the federal Farm Bill that legalized hemp production in states like Kentucky to grow the crop. The Agricultural Act of 2014 was signed by President Obama.[61]

During recent years, there has been considerable legislative activity throughout the United States with respect to legalizing the agricultural production of industrial hemp. To date, approximately 11 states have legalized industrial hemp production, including: California, Colorado, Indiana, Maine, Montana, North Dakota, Oregon, South Carolina, North Carolina, Vermont, West Virginia, and Tennessee. Many other states have passed legislation authorizing the cultivation of industrial hemp for pilot projects or studies, including: Connecticut, Delaware, Hawaii, Illinois, Kentucky, Nebraska, and Utah. Additionally, the National Association of State Departments of Agriculture and the National Conference of State Legislatures have both adopted resolutions supporting revisions to the federal rules and regulations authorizing commercial production of industrial hemp.[62][63]

The United States Drug Enforcement Administration, the DEA, recently eased some of the regulatory requirements for those who are conducting FDA-approved clinical trials on cannabidiol (CBD).[64]

Several industrial hemp varieties can be legally cultivated in western Europe. A variety such as "Fedora 17" has a cannabinoid profile consistently around 1% cannabidiol (CBD) with THC less than 0.1%.[65]

Australia

Prescription Medicine (Schedule 4) for therapeutic use containing 2 per cent (2.0%) or less of other cannabinoids commonly found in cannabis (such as ∆9-THC).[66]

Canada

Cannabidiol is a Schedule II drug in Canada. As such, it is only available with a prescription.[67]

UK

Cannabidiol, in an oral-mucosal spray formulation combined with delta-9-tetrahydrocannabinol, is a prescription product available for relief of severe spasticity due to multiple sclerosis (where other anti-spasmodics have not been effective).[68] Cannabidiol produced, sold or imported for sale or recreational use would usually be illegal under the Psychoactive Substances Act 2016.

EU

Cannabidiol is listed in EU Cosmetics Ingredient Database.[69]

References

Template:Research help

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