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| Clinical data | |
|---|---|
| Trade names | Sativex (with THC), Epidiolex |
| Synonyms | CBD |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration |
Inhalation (smoking, vaping), buccal (aerosol spray), oral (solution)[1][2][3] |
| Drug class | Cannabinoid |
| ATC code |
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| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | • Oral: 13–19%[4] • Inhaled: 31% (11–45%)[5] |
| Elimination half-life | 9 hours[4] |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| ChEBI | |
| ECHA InfoCard | 100.215.986  |
| Chemical and physical data | |
| Formula | C21H30O2 |
| Molar mass | 314.464 g/mol |
| 3D model (JSmol) | |
| Melting point | 66 °C (151 °F) |
| (verify) | |
| Part of a series on |
| Cannabis |
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Cannabidiol (CBD) is a naturally occurring cannabinoid constituent of cannabis. It was discovered in 1940 and initially thought not to be pharmaceutically active.[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] As of 2018 in the United States, Food and Drug Administration approval of cannabidiol as a prescription drug for medical uses has been limited to two rare forms of childhood epilepsy.[10][11]
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 sleepiness, 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][12][13] CBD has been found to interact with a variety of different biological targets, including cannabinoid receptors and other neurotransmitter receptors.[7][14] The mechanism of action of CBD in terms of its psychoactive and therapeutic effects is not fully clear.[7]
Medical uses
Multiple sclerosis pain
Nabiximols (brand 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.[15] It is also prescribed in Sweden.[16][17]
Epilepsy
Medical reviews published in 2017 and 2018 incorporating numerous clinical trials concluded that cannabidiol is an effective treatment for certain types of childhood epilepsy.[18][19] 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.[11]
Other Uses
Considerable preliminary research has been done on other possible therapeutic uses for cannabidiol, but the findings have not been confirmed by sufficient high-quality clinical research to establish such uses in clinical practice.[7][20][21][22][23]
Side effects
Studies of cannabidiol safety indicate it is well-tolerated, but may cause tiredness, diarrhea, or changes in appetite as common adverse effects.[24] Epidiolex documentation lists sleepiness but also insomnia, sleep disorder and poor quality sleep, decreased appetite, diarrhea, fatigue, malaise, and others.[3]
Interactions
There is preclinical (rodent) 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.[25][26] A small clinical trial reported that CBD partially inhibits the CYP2C catalyzed hydroxylation of THC to 11-OH-THC.[27]
Pharmacology
Pharmacodynamics
Cannabidiol has very low affinity for the cannabinoid CB1 and CB2 receptors but is said to act as an indirect antagonist of these receptors.[28][29] At the same time, it may potentiate the effects of THC by increasing CB1 receptor density or through another CB1 receptor-related mechanism.[30]
Cannabidiol has been found to act as an antagonist of the GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain.[31] It has also been found to act as an inverse agonist of the GPR3, GPR6, and GPR12.[14] Although currently classified as orphan receptors, these receptors are most closely related phylogeneticaly to the cannabinoid receptors.[14] In addition to orphan receptors, CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist,[32] and this action may be involved in its antidepressant,[33][34] anxiolytic,[34][35] and neuroprotective effects.[36][37] It is an allosteric modulator of the μ- and δ-opioid receptors as well.[38] 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.[39]
Pharmacokinetics
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 9 hours.[4]
Chemistry
Cannabidiol is insoluble in water but soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid.[40] In strongly basic media and the presence of air, it is oxidized to a quinone.[41] Under acidic conditions it cyclizes to THC.[42] The synthesis of cannabidiol has been accomplished by several research groups.[43][44][45]
Biosynthesis
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.[46]
Isomerism
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History
CBD was isolated from the cannabis plant in 1940 independently by Adams and Todd and their colleagues.[6] They assessed CBD and considered it to be biologically inactive.[6] The chemical structure of CBD was fully established in 1963 by Mechoulam and Shvo.[6]
Society and culture
Names
Cannabidiol is the generic name of the drug and its INN.[48]
Food and beverage
Food and beverage products containing CBD were introduced in the United States in 2018.[49] 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.[50] In the United States, numerous products are marketed as containing CBD, but in reality contain little or none.[51] 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.[52]
Plant sources
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.[53] To meet the demands of medical cannabis users, growers have also developed more CBD-dominant strains.[54] Cultural discussions and references to clinical studies that include CBD have influenced the demand for CBD-dominant products. 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).[55]
Legal status
Non-psychoactivity
CBD does not appear to have any psychoactive ("high") effects such as those caused by ∆9-THC in marijuana, but may have anti-anxiety and anti-psychotic effects.[12] 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.[12][56]
Various breeds/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.[57] 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.[citation needed]
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. 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.[58]
United Nations
Cannabidiol is not scheduled by the Convention on Psychotropic Substances.
United States
In the United States, cannabidiol is a Schedule I drug under the Controlled Substances Act.[59] This means that production, distribution and possession of CBD is illegal under federal law. 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."[60] Previously, CBD had simply been considered "marijuana", which is also a Schedule I drug.[59][61] In June 2018, the FDA approved oral use of CBD as an anti-seizure drug in treating rare types of childhood epilepsy.[11] This is a contradiction as Schedule I substances by definition have no accepted medical use.
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.[62][63] Since then, 16 states have passed laws to allow for the use of CBD products (not exceeding a specified concentration of THC) for the treatment of certain medical conditions.[64] 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.[64] Of these 30 states, eight have legalized the use and sale of cannabis products without requirement for a doctor's recommendation.[64]
Although most states restrict the use of CBD products to certain medical conditions, manufacturers of CBD claim their products are derived from industrial hemp, and therefore legal for anyone to use.[65] A number of these manufacturers ship CBD products to all 50 states, which the federal government has so far not intervened in.[66][67] CBD is also openly sold in head shops, health food stores, chiropractor clinics, optometrist offices, doctors offices and pharmacies in some states where such sales have not been explicitly legalized.[65][68]
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). 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.[69]
New Zealand
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.[70]
Canada
Cannabidiol is a Schedule II drug in Canada. As such, it is only available with a prescription.[71] It is available as a spray, called Sativex produced by GW Pharmaceuticals in the UK, for use in multiple sclerosis. The Canadian Government announced that October 17, 2018 is the date when marijuana can be consumed recreationally without criminal penalties,[72] indicating that various cannabidiol products will be freely available to adult consumers.
Europe
Cannabidiol is listed in the EU Cosmetics Ingredient Database (CosIng).[73] 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.[74]
Cannabidiol is listed in the EU Novel Food Catalogue.[75] 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.[76]
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%.[77]
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
CBD is classified as a medical product in Sweden.[78]
United Kingdom
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).[79]
As of 31 December 2016, products containing cannabidiol that are marketed for medical purposes are classed as medicines by the UK regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA) and cannot be marketed without regulatory approval for the medical claims.[80]
Switzerland
While THC remains illegal, CBD is not subject to the Swiss Narcotic Acts because this substance does not produce a comparable psychoactive effect.[81] Cannabis products containing less than 1% THC can be sold and purchased legally.[82]
Research
A 2016 review of animal studies indicated that cannabidiol has potential as an anxiolytic for relief of anxiety-related disorders and fear.[13] 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.[83][84][85]
See also
References
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Further reading[edit]
- Keating GM (April 2017). "Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity". Drugs. 77 (5): 563–574. doi:10.1007/s40265-017-0720-6. PMID 28293911.
- Colizzi M, Bhattacharyya S (2017). "Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition". Curr Addict Rep. 4 (2): 62–74. doi:10.1007/s40429-017-0142-2. PMC 5435777 . PMID 28580227.
- Iffland K, Grotenhermen F (2017). "An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies". Cannabis Cannabinoid Res. 2 (1): 139–154. doi:10.1089/can.2016.0034. PMC 5569602 . PMID 28861514.
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