Cannabidiol (INN;[122] abbreviated as: CBD) is one of at least 113 active cannabinoids identified in cannabis.[124][126] It is a major phytocannabinoid, accounting for up to 40% of the plant's extract.[128]

CBD does not appear to have any intoxicating effects such as those caused by tetrahydrocannabinol (THC) in cannabis, but may have a downregulating impact on disordered thinking and anxiety.[131]

Medical uses

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.[74][75]

Addiction treatment

In 2015 a case study on CBD and addictive use of marijuana was published. A bipolar man who had a daily marijuana addiction was given CBD along with his regiment of medication and reported less anxiety and no marijuana use.[132] A 2015 systematic review of studies on CBD and addiction (five on humans, nine on animals) found that CBD acts on neurotransmittors involved in addiction; animal studies showed some relation in opioid and psychostimulant addiction and human studies showed beneficial effects for tobacco and cannabis dependence. However, the anti-addictive properties displayed might be due to CBD's protective effect on stress and neurotoxicity, the review also mentions the need for more research.[134]

Adverse effects

CBD safety in humans has been studied in multiple small studies, suggesting that it is well tolerated at doses of up to 1,500 mg/day (p.o.) or 30 mg (i.v.).[136] Daily doses of CBD (700 mg) for 6 weeks did not induce any toxicity in patients being treated for Huntington's disease.[139]

Interactions

There is 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.[140][142] Despite this, the available evidence in humans suggests no significant effect of CBD on THC plasma levels.[144]

Pharmacology

Pharmacodynamics

Cannabidiol has very low affinity for the cannabinoid CB1 and CB2 receptors but acts as an indirect antagonist of these receptors.[146][148] It may potentiate THC's effects by increasing CB1 receptor density or through another CB1 receptor-related mechanism.[151] Cannabidiol may also extend the duration of the effects of THC via inhibition of the cytochrome P450, CYP3A and CYP2C enzymes.[44]

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.[153] It has also been shown to act as a 5-HT1A receptor partial agonist,[156] and this action may be involved in the antidepressant,[158][161] anxiolytic,[161][164] and neuroprotective[166][168] effects of cannabidiol. It is an allosteric modulator of the μ- and δ-opioid receptors as well.[170] Cannabidiol's pharmacological effects have additionally been attributed to PPARγ agonism and intracellular calcium release.[128]

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.[128] It has also been speculated that some of the metabolites of CBD have pharmacological effects that contribute to the biological activity of CBD.[171]

Recently, cannabidiol has been identified as a novel inverse agonist of the GPR12.[173]

Chemistry

Cannabidiol is insoluble in water but soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid.[122] In strongly basic media and the presence of air, it is oxidized to a quinone.[122] Under acidic conditions it cyclizes to THC.[122] The synthesis of cannabidiol has been accomplished by several research groups.[122][122][122]

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.[122]

 

Isomerism

 
7 double bond isomers and their 30 stereoisomers
Formal numberingTerpenoid numberingNumber of stereoisomersNatural occurrenceConvention on Psychotropic Substances ScheduleStructure
Short nameChiral centersFull nameShort nameChiral centers
Δ5-cannabidiol1 and 32-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ4-cannabidiol1 and 34Nounscheduled 
Δ4-cannabidiol1, 3 and 62-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ5-cannabidiol1, 3 and 48Nounscheduled 
Δ3-cannabidiol1 and 62-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ6-cannabidiol3 and 44 ?unscheduled 
Δ3,7-cannabidiol1 and 62-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediolΔ1,7-cannabidiol3 and 44Nounscheduled 
Δ2-cannabidiol1 and 62-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ1-cannabidiol3 and 44Yesunscheduled 
Δ1-cannabidiol3 and 62-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ2-cannabidiol1 and 44Nounscheduled 
Δ6-cannabidiol32-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ3-cannabidiol12Nounscheduled 

Based on: .

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.[91] To meet the demands of medical cannabis patients, growers are currently developing more CBD-dominant strains.[92]

In the United States a number of products are marketed as containing CBD, but in reality contain little or none; in 2016 the FDA sent 16 warning letters to manufacturers making such false claims.[188]

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.[131] 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".[131][190]

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.[193] 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.[102]

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.[194] This means that production, distribution and possession of CBD is illegal under federal law. In 2016, the Drug Enforcement Administration added "marihuana 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."[195] Previously, CBD had simply been considered "marihuana," which is also a Schedule I drug.[194][196]

A CNN program that featured Charlotte's Web cannabis in 2013 brought increased demand for CBD-dominant cannabis across the US. Legislation was passed in Kentucky in 2013 to promote Hemp farming in that state as an economic development program to help tobacco farmers who were losing markets for their crops; the state lobbied for and was able to win a provision in the Agricultural Act of 2014 that legalized hemp production in states like Kentucky.[104][126]

As of 2017, at least 31 states had legalized industrial hemp production, including: California, Colorado, Indiana, Maine, Montana, North Carolina, North Dakota, Oregon, South Carolina, Tennessee, Vermont, and West Virginia. 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.[126][126][126]

In the state of Utah, people possessing CBD-dominant hemp extract are exempt from penalties for possession or use of hemp extract under the Controlled Substances Act if they have a neurologist sign an application for a Hemp Extract Registration Card.[126] The neurologist indicates if the patient exhibits signs of intractable epilepsy or if the patient may receive benefit from the use of hemp extract. The law requires the neurologist to keep and transmit data for the Utah Department of Health database of neurologist evaluations.[126] The individual possessing the hemp extract must also obtain the hemp extract's certificate of analysis from the seller.[126]

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.[126]

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.[126]

Canada

Cannabidiol is a Schedule II drug in Canada. As such, it is only available with a prescription.[126]

Europe

Cannabidiol is listed in the EU Cosmetics Ingredient Database.[113]

Cannabidiol is listed in the EU Novel Food Catalogue.[203] 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.[204]

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%.[205]

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.

Sweden

CBD is not classified in Sweden.

Sativex (CBD and THC) is a prescription product available for relief of severe spasticity due to multiple sclerosis.[206][207]

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).[112]

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.[208]

Switzerland

While THC remains illegal, CBD is not subjected by the Swiss Narcotic Acts because this substance does not produce a comparable psychoactive effect.[209] Cannabis products containing less than 1% THC can be sold and purchased legally.[210]

Research

Anecdotal reports and early studies suggested that CBD may be of value in treating epilepsy, but the quality of the studies were too poor to draw definitive conclusions.[211][212] A 2014 Cochrane review included four randomized controlled trials, but all were of poor quality.[213] As of 2014 plans were underway to conduct double-blinded, randomized studies of CBD in Dravet syndrome and other treatment-resistant epilepsies.

Dravet syndrome (aka myoclonic epilepsy of infancy or SMEI) is a rare form of epilepsy that begins in infancy and is difficult to treat.[16]

Some cannabis/hemp extract preparations containing CBD are marketed as and claim efficacy against Dravet syndrome. One such preparation is marketed under the tradename Charlotte's Web Hemp Extract.[215][20]

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.[10][22][78] Epidiolex received orphan drug status in the United States for treatment of Dravet syndrome in July 2015.[74][74]

See also