Cannabidiol

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Cannabidiol
Cannabidiol.svg
CBD-3D-balls.png
Clinical data
Trade namesSativex (with THC), Epidiolex
SynonymsCBD
AHFS/Drugs.comInternational Drug Names
Routes of
administration
Inhalation (smoking, vaping), buccal (aerosol spray), oral (solution)[1][2][3]
Drug classCannabinoid
ATC code
  • None
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only) or Dietary Supplement
  • US: Schedule I (except Epidiolex, Schedule V)
Pharmacokinetic data
BioavailabilityOral: 13–19%[4]
Inhaled: 31% (11–45%)[5]
Elimination half-life9 hours[4]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ECHA InfoCard100.215.986 Edit this at Wikidata
Chemical and physical data
FormulaC21H30O2
Molar mass314.464 g/mol
3D model (JSmol)
Melting point66 °C (151 °F)
  (verify)

Cannabidiol (CBD) is a phytocannabinoid discovered in 1940 and initially thought not to be psychoactive.[1][6][7][8][9] It is one of at least 113 cannabinoids identified in hemp plants, accounting for up to 40% of the plant's extract.[8]

Cannabidiol can be taken into the body in multiple different ways, including by inhalation of cannabis smoke or vapor, as an aerosol spray into the cheek, and by mouth. It may be supplied as an oil containing only CBD as the active ingredient (no added THC or terpenes), a full-plant CBD-dominant hemp extract oil, capsules, dried cannabis, or as a prescription liquid solution.[1][3]

Side effects of CBD include somnolence, decreased appetite, diarrhea, fatigue, malaise, weakness, sleeping problems, and others.[3] It does not have intoxicating effects like those caused by THC, and may have an opposing effect on disordered thinking and anxiety produced by THC.[7][10][11] CBD has been found to interact with a variety of different biological targets, including cannabinoid receptors and other neurotransmitter receptors.[7][12] The mechanism of action of CBD in terms of its psychoactive and therapeutic effects is not fully clear.[7]

In the United States, the CBD drug Epidiolex has been approved by the Food and Drug Administration for treatment of two epilepsy disorders.[13] The U.S. Drug Enforcement Administration has assigned Epidiolex a Schedule V classification while non-Epidiolex CBD remains a Schedule I drug prohibited for any use.[14] CBD is not scheduled under any United Nations drug control treaties, and in 2018 the World Health Organization recommended that it remain unscheduled.[15]

Medical uses[edit]

Epilepsy[edit]

Medical reviews published in 2017 and 2018 incorporating numerous clinical trials concluded that cannabidiol is an effective treatment for certain types of childhood epilepsy.[16][17]

An orally administered cannabidiol solution (brand name Epidiolex) was approved by the US Food and Drug Administration in June 2018 as a treatment for two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome.[13]

Other uses[edit]

Preliminary research on other possible therapeutic uses for cannabidiol include several neurological disorders, but the findings have not been confirmed by sufficient high-quality clinical research to establish such uses in clinical practice.[7][18][19][20][21][22]

Side effects[edit]

Preliminary research indicates that cannabidiol may reduce adverse effects of THC, particularly those causing intoxication and sedation, but only at high doses.[23] Safety studies of cannabidiol showed it is well-tolerated, but may cause tiredness, diarrhea, or changes in appetite as common adverse effects.[24] Epidiolex documentation lists sleepiness, insomnia and poor quality sleep, decreased appetite, diarrhea, and fatigue.[3]

Potential interactions[edit]

Laboratory evidence indicated that cannabidiol may reduce THC clearance, increasing plasma concentrations which may raise THC availability to receptors and enhance its effect in a dose-dependent manner.[25][26] In vitro, cannabidiol inhibited receptors affecting the activity of voltage-dependent sodium and potassium channels, which may affect neural activity.[27] A small clinical trial reported that CBD partially inhibited the CYP2C-catalyzed hydroxylation of THC to 11-OH-THC.[28]

Pharmacology[edit]

Pharmacodynamics[edit]

Cannabidiol has very low affinity for the cannabinoid CB1 and CB2 receptors but is said to act as an indirect antagonist of these receptors.[29][30] At the same time, it may potentiate the effects of THC by increasing CB1 receptor density or through another CB1 receptor-related mechanism.[31]

Cannabidiol has been found to act as an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain.[32] It has also been found to act as an inverse agonist of GPR3, GPR6, and GPR12.[12] Although currently classified as orphan receptors, these receptors are most closely related phylogenetically to the cannabinoid receptors.[12] In addition to orphan receptors, CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist,[33] and this action may be involved in its antidepressant,[34][35] anxiolytic,[35][36] and neuroprotective effects.[37][38] It is an allosteric modulator of the μ- and δ-opioid receptors as well.[39] The pharmacological effects of CBD have additionally been attributed to PPARγ agonism and intracellular calcium release.[8]

Research suggests that CBD may exert some of its pharmacological action through its inhibition of fatty acid amide hydrolase (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.[40]

Cannabidiol is metabolized in the liver as well as the gut by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms.[3]

Pharmacokinetics[edit]

The oral bioavailability of CBD is 13 to 19%, while its bioavailability via inhalation is 11 to 45% (mean 31%).[4][5] The elimination half-life of CBD is 18–32 hours.[22]

Pharmaceutical preparations[edit]

Nabiximols (brand name Sativex) is a patented medicine containing CBD and THC in equal proportions. The drug was approved by Health Canada in 2005 for prescription to treat central neuropathic pain in multiple sclerosis, and in 2007 for cancer related pain.[41][42]

Chemistry[edit]

Cannabidiol is insoluble in water but soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid.[43] In strongly basic media and the presence of air, it is oxidized to a quinone.[44] Under acidic conditions it cyclizes to THC,[45] which also occurs during pyrolysis (smoking).[46] The synthesis of cannabidiol has been accomplished by several research groups.[47][48][49]

Biosynthesis[edit]

Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the next to last step, where CBDA synthase performs catalysis instead of THCA synthase.[50]

Cannabidiol and THC biosynthesis[51]

Isomerism[edit]

Cannabidiol numbering
Cannabidiol's 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 2-(6-Isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
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 2-(6-Isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
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 2-(6-Isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
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 2-(6-Isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol.png
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 2-(6-Isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
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 2-(6-Isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
Δ6-Cannabidiol 3 2-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol Δ3-Cannabidiol 1 2 No Unscheduled 2-(6-Isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png

History[edit]

CBD was isolated from the cannabis plant in 1940, and its chemical structure was established in 1963.[6]

Society and culture[edit]

Names[edit]

Cannabidiol is the generic name of the drug and its INN.[52]

Food and beverage[edit]

cbd-infused cold brew coffee and tea from kickback cold brew
An example of CBD-infused cold brew coffee & tea on a grocery store shelf.

Food and beverage products containing CBD were introduced in the United States in 2017.[53] Similar to energy drinks and protein bars which may contain vitamin or herbal additives, food and beverage items can be infused with CBD as an alternative means of ingesting the substance.[54] In the United States, numerous products are marketed as containing CBD, but in reality contain little or none.[55] Some companies marketing CBD-infused food products with claims that are similar to the effects of prescription drugs have received warning letters from the Food and Drug Administration for making unsubstantiated health claims.[56]

Plant sources[edit]

Selective breeding of cannabis plants has expanded and diversified as commercial and therapeutic markets develop. Some growers in the U.S. succeeded in lowering the proportion of CBD-to-THC to accommodate customers who preferred varietals that were more mind-altering due to the higher THC and lower CBD content.[57] Hemp is classified as any part of the cannabis plant containing no more than 0.3% THC in dry weight form (not liquid or extracted form).[58]

Legal status[edit]

Non-psychoactivity[edit]

CBD does not appear to have any psychotropic ("high") effects such as those caused by ∆9-THC in marijuana, but may have anti-anxiety and anti-psychotic effects.[10] As the legal landscape and understanding about the differences in medical cannabinoids unfolds, it will be increasingly important to distinguish "medical marijuana" (with varying degrees of psychotropic effects and deficits in executive function) – from "medical CBD therapies” which would commonly present as having a reduced or non-psychoactive side effect profile.[10][59]

Various strains of "medical marijuana" are found to have a significant variation in the ratios of CBD-to-THC, and are known to contain other non-psychotropic cannabinoids.[60] 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 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.[61] Certain standards are required for legal growing, cultivating and producing the hemp plant. 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 a dry weight basis.[61]

United Nations[edit]

Cannabidiol is not scheduled under the Convention on Psychotropic Substances or any other UN drug treaty. In 2018, the World Health Organization recommended that CBD remain unscheduled.[15]

United States[edit]

In the United States, non-FDA approved CBD products are classified as Schedule I drugs under the Controlled Substances Act.[62] This means that production, distribution, and possession of non-FDA approved CBD products is illegal under federal law. In addition, in 2016 the Drug Enforcement Administration added "marijuana extracts" to the list of Schedule I drugs, which it defined as "an extract containing one or more cannabinoids that has been derived from any plant of the genus Cannabis, other than the separated resin (whether crude or purified) obtained from the plant."[63] Previously, CBD had simply been considered "marijuana", which is a Schedule I drug.[62][64]

In September 2018, following its approval by the FDA for rare types of childhood epilepsy,[13] Epidiolex was rescheduled (by the Drug Enforcement Administration) as a Schedule V drug to allow for its prescription use.[14] This change applies only to FDA-approved products containing no more than 0.1 percent THC.[14] This allows GW Pharmaceuticals to sell Epidiolex, but it does not apply broadly and all other CBD-containing products remain Schedule I drugs.[14] Epidiolex still requires rescheduling in some states before it can be prescribed in those states.[65][66]

A CNN program that featured Charlotte's Web cannabis in 2013 brought increased attention to the use of CBD in the treatment of seizure disorders.[67][68] Since then, 16 states have passed laws to allow the use of CBD products with a doctor's recommendation (instead of a prescription) for treatment of certain medical conditions.[69] This is in addition to the 30 states that have passed comprehensive medical cannabis laws, which allow for the use of cannabis products with no restrictions on THC content.[69] Of these 30 states, eight have legalized the use and sale of cannabis products without requirement for a doctor's recommendation.[69]

Some manufacturers ship CBD products nationally, an illegal action which the FDA has not enforced in 2018, with CBD remaining as the subject of an FDA investigational new drug evaluation and is not considered legal as a dietary supplement or food ingredient as of November 2018.[70] CBD is openly sold in head shops and health food stores in some states where such sales have not been explicitly legalized.[71][72]

The 2014 Farm Bill[73], legalized the sale of "non-viable hemp material" grown within states participating in the Hemp Pilot Program[74]. This legislation defined hemp as cannabis containing less than 0.3% of THC delta-9, grown within the regulatory framework of the Hemp Pilot Program. This has led many to insist that CBD manufactured from hemp, is legal in all 50 states and exempts its oversight by the DEA as a controlled substance[75]. The 2018 Farm Bill is anticipated to provide further clarity regarding hemp regulations[76].

Australia[edit]

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). A schedule 4 drug under the SUSMP is Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription.[77]

New Zealand[edit]

Cannabidiol is currently a class B1 controlled drug in New Zealand under the Misuse of Drugs Act. It is also a prescription medicine under the Medicines Act. In 2017 the rules were changed so that anyone wanting to use it could go to the Health Ministry for approval. Prior to this, the only way to obtain a prescription was to seek the personal approval of the Minister of Health.

Associate Health Minister Peter Dunne said restrictions would be removed, which means a doctor will now be able to prescribe cannabidiol to patients.[78]

Canada[edit]

On October 17, 2018, cannabidiol became legal for recreational and medical use.[79][80]

Europe[edit]

Cannabidiol is listed in the EU Cosmetics Ingredient Database (CosIng).[81] However, the listing of an ingredient, assigned with an INCI name, in CosIng does not mean it is to be used in cosmetic products nor approved for such use.[82]

Cannabidiol is listed in the EU Novel Food Catalogue.[83] This listing only applies to isolated or synthetic CBD, not to crude hemp extracts or tinctures naturally containing CBD.

The European Industrial Hemp Association has issued a position paper suggesting regulatory framework in EU.[84]

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%.[85]

Although the World Health Organization listed Cannabidiolum in a list of International Nonproprietary Names for Pharmaceutical Substances (INN) on 30 June 2016. French and Spanish versions wrongly mention agonist action of CBD on cannabinoid receptors while the English version says CBD is a cannabinoid receptor antagonist.[citation needed]

Sweden[edit]

CBD is classified as a medical product in Sweden.[86]

United Kingdom[edit]

Cannabidiol, in an oral-mucosal spray formulation combined with delta-9-tetrahydrocannabinol, was a prescription product available for relief of severe spasticity due to multiple sclerosis (where other anti-spasmodics have not been effective).[87]

Until 2017, products containing cannabidiol that are marketed for medical purposes were classed as medicines by the UK regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA) and could not be marketed without regulatory approval for the medical claims.[88][89] CBD oil with THC content not exceeding 0.2% was legalized throughout the UK in 2017.[citation needed] Cannabis oil, however, remained illegal to possess, buy and sell.[90]

Switzerland[edit]

While THC remains illegal, CBD is not subject to the Swiss Narcotic Acts because this substance does not produce a comparable psychoactive effect.[91] Cannabis products containing less than 1% THC can be sold and purchased legally.[92]

Research[edit]

A 2016 review of animal studies indicated that cannabidiol has potential as an anxiolytic for relief of anxiety-related disorders and fear.[11] Reviews of preliminary research showed cannabidiol has potential for improving addictive disorders and drug dependence, although as of 2016, they indicated limited high-quality evidence for anti-addictive effects in people.[93][20][94]

See also[edit]

References[edit]

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Further reading[edit]