Cannabidiol

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Not to be confused with Cannabinol.
Cannabidiol
Cannabidiol.svg
Cannabidiol3Dan.gif
Systematic (IUPAC) name
2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
Clinical data
Trade names Epidiolex
AHFS/Drugs.com International Drug Names
Legal status
  • Schedule I (US)

Schedule II (Can)

(THC — Schedule/Level I; THC and CBD two main chemicals in cannabis)

Pharmacokinetic data
Bioavailability 13-19% (oral),[1] 11-45% (mean 31%; inhaled)[2]
Half-life 9 h[1]
Identifiers
CAS number 13956-29-1 YesY
ATC code None
PubChem CID 644019
ChemSpider 24593618 YesY
UNII 19GBJ60SN5 YesY
Chemical data
Formula C21H30O2 
Mol. mass 314.4636
Physical data
Melt. point 66 °C (151 °F)
Boiling point 180 °C (356 °F)
(range: 160–180 °C)[3]
 YesY (what is this?)  (verify)

Cannabidiol (CBD) is one of at least 85 active cannabinoids identified in cannabis.[4] It is a major phytocannabinoid, accounting for up to 40% of the plant's extract.[5] CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol (THC).[5] An orally-administered liquid containing CBD has received orphan drug status in the US, for use as a treatment for dravet syndrome, under the brand name Epidiolex.[6]

Clinical applications[edit]

The bud of a Cannabis sativa flower coated with trichomes

Antimicrobial actions[edit]

CBD absorbed transcutaneously may attenuate the increased sebum production at the root of acne, according to an untested hypothesis.[7]

Neurological effects[edit]

A 2010 study found that strains of cannabis containing higher concentrations of cannabidiol did not produce short-term memory impairment vs. strains with similar concentrations of THC, but lower concentrations of CBD. The researchers attributed this attenuation of memory effects to CBD's role as a CB1 antagonist. Transdermal CBD is neuroprotective in animals.[8]

Cannabidiol's strong antioxidant properties have been shown to play a role in the compound's neuroprotective and anti-ischemic effects.[9]

Psychotropic effect[edit]

CBD has anti-psychotic effects and may counteract the potential psychotomimetic effects of THC on individuals with latent schizophrenia;[5] some reports show it to be an alternative treatment for schizophrenia that is safe and well-tolerated.[10] Studies have shown CBD may reduce schizophrenic symptoms due to its apparent ability to stabilize disrupted or disabled NMDA receptor pathways in the brain, which are shared and sometimes contested by norepinephrine and GABA.[10][11] Leweke et al. performed a double blind, 4 week, explorative controlled clinical trial to compare the effects of purified cannabidiol and the atypical antipsychotic amisulpride on improving the symptoms of schizophrenia in 42 patients with acute paranoid schizophrenia. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale. While there was no statistical difference between the two treatment groups, cannabidiol induced significantly fewer side effects (extrapyramidal symptoms, increase in prolactin, weight gain) when compared to amisulpride.[12]

Studies have shown cannabidiol decreases activity of the limbic system[13] and decreases social isolation induced by THC.[14] Cannabidiol has also been shown to reduce anxiety in social anxiety disorder.[15][16]

Chronic cannabidiol administration in rats was found to produce anxiogenic-like effects, indicating that prolonged treatment with cannabidiol might incite anxiogenic effects.[17] Those results have been contested by,[18] and contradict [19] whose experimentation cover the same duration.

Cannabidiol has demonstrated antidepressant-like effects in animal models of depression.[20][21][22]

Dravet syndrome[edit]

Dravet syndrome is a rare form of epilepsy that is difficult to treat. Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare and 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.[23] While high profile and anecdotal reports of results from high-CBD/low-THC preparations have sparked interest in treatment with cannabinoids,[24] there is insufficient medical evidence to draw conclusions about their safety or efficacy.[24][25]

CBD-enhanced cannabis[edit]

Decades ago, selective breeding by growers in US dramatically lowered the CBD content of cannabis; their customers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.[26] To meet the demands of medical cannabis patients, growers are currently developing more CBD-rich strains.[27]

In November 2012, Tikun Olam, an Israeli medical cannabis facility announced a new strain of the plant which has only cannabidiol as an active ingredient, and virtually no THC, providing some of the medicinal benefits of cannabis without the euphoria.[28][29] The researchers said the cannabis plant, enriched with CBD, "can be used for treating diseases like rheumatoid arthritis, colitis, liver inflammation, heart disease and diabetes". Research on CBD enhanced cannabis began in 2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, a cannabinoid researcher, said "...Avidekel is thought to be the first CBD-enriched cannabis plant with no THC to have been developed in Israel".[30]

Industrial hemp[edit]

Several industrial hemp varieties can be legally cultivated in western Europe. They might seem to contain very small portion of cannabinoid, which is true in one sense. Nevertheless a variety such as "Fedora 17" has a cannabionoid profile consistently around 1% cannabidiol (CBD) with THC less than 0.1%.[31] 1% is little though for 1 kg of raw plant it yields 10 g of pure CBD.

Extraction can be done with olive oil, ethanol, or CO2, among other solvents.

Hemp world production is around 30000 tonnes per year.

Pharmacology[edit]

Pharmacodynamics[edit]

Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists.[9] 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.[32] It is also an inverse agonist of CB2 receptors.[9][33] Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[34] Cannabidiol has also been shown to act as a 5-HT1A receptor agonist,[35] an action which is involved in its antidepressant,[20][36] anxiolytic,[36][37] and neuroprotective[38][39] effects. Cannabidiol is an allosteric modulator of μ and δ-opioid receptors.[40] Cannabidiol's pharmacological effects have also been attributed to PPAR-γ receptor agonism and intracellular calcium release.[5]

Pharmacokinetic interactions[edit]

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.[41][42] Despite this the available evidence in humans suggests no significant effect of CBD on THC plasma levels.[43]

Pharmaceutical preparations[edit]

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.[44][45][46]

Isomerism[edit]

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 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

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

See also: Tetrahydrocannabinol#Isomerism, Abnormal cannabidiol.

Chemistry[edit]

Cannabidiol is insoluble in water but soluble in organic solvents, such as pentane. At room temperature it is a colorless crystalline solid.[47] In strongly basic medium and the presence of air it is oxidized to a quinone.[48] Under acidic conditions it cyclizes to THC.[49] The synthesis of cannabidiol has been accomplished by several research groups.[50][51][52]

Biosynthesis[edit]

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.[53]

Legal status[edit]

Cannabidiol is not scheduled by the Convention on Psychotropic Substances.

Cannabidiol is a Schedule II drug in Canada.[54]

Cannabidiol's legal status in the United States:

While the DEA Drug Schedule classifies THC (Tetrahydrocannabinols) and marijuana as Schedule I, cannabidiol is not found on the list.[55] Other synthetic cannabinoids such as JWH-019,073,081,122,200,203,250,398 are also listed in Schedule I, but cannabidiol is absent.[55]

Marijuana is defined by 21 U.S.C. §802(16), which is part of the Controlled Substances Act. The mature stalks and seeds of the Cannabis sativa L. plant, as well as products derived from the mature stalks and seeds are explicitly exempt from classification as marijuana.[56][57][58] Under this exception, what are known as industrial hemp-finished products are legally imported into the United States each year.[59] Hemp finished products, including hemp oil high in cannabidiol, are legal in the United States for this reason.

Some cannabidiol oil is derived from marijuana and is therefore high in THC.[60] This type of cannabidiol oil would be considered a Schedule I as a result. However, cannabidiol derived from industrial hemp is legal and unscheduled itself.[60] In other words, cannabidiol's legal status depends on where it is derived from, as cannabidiol itself is not scheduled.[56]

US patent[edit]

In October 2003, U.S. patent #6630507 entitled "Cannabinoids as antioxidants and neuroprotectants" was assigned to "The United States Of America As Represented By The Department Of Health And Human Services." The patent was filed in April 1999 and listed as the inventors: Aidan J. Hampson, Julius Axelrod, and Maurizio Grimaldi, who all held positions at the National Institute of Mental Health (NIMH) in Bethesda, MD, which is part of the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). The patent mentions cannabidiol's ability as an antiepileptic, to lower intraocular pressure in the treatment of glaucoma, lack of toxicity or serious side effects in large acute doses, its neuroprotectant properties, its ability to prevent neurotoxicity mediated by NMDA, AMPA, or kainate receptors; its ability to attenuate glutamate toxicity, its ability to protect against cellular damage, its ability to protect brains from ischemic damage, its anxiolytic effect, and its superior antioxidant activity which can be used in the prophylaxis and treatment of oxidation associated diseases.[61]

On November 17, 2011, the Federal Register published that the National Institutes of Health of the United States Department of Health and Human Services was "contemplating the grant of an exclusive patent license to practice the invention embodied in U.S. Patent 6,630,507" to the company KannaLife based in New York, for the development and sale of cannabinoid and cannabidiol based therapeutics for the treatment of hepatic encephalopathy in humans.[62][63][64]

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External links[edit]

  • Project CBD Non-profit educational service dedicated to promoting and publicizing research into the medical utility of cannabidiol.