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===Cancer===
===Cancer===
The [[American Cancer Society]] says: "There is no available scientific evidence from controlled studies in humans that cannabinoids can cure or treat cancer."<ref name=Young_Riddle>{{Citation |last=Young |first=Saundra |date=15 Jan 2014 |title=3-year-old is focus of medical marijuana battle |publisher=[[CNN]] |url=http://www.cnn.com/2014/01/15/health/cannabis-landon-riddle/ |accessdate=2014-01-16 }}</ref> Laboratory experiments have been performed on the potential use of cannabinoids for cancer therapy but {{asof|2013|lc=y}} results have been contradictory and knowledge remains poor.<ref name=Cridge2013>{{medrs|date=March 2014}}{{cite journal |author=Cridge BJ, Rosengren RJ |title=Critical appraisal of the potential use of cannabinoids in cancer management |journal=Cancer Manag Res |volume=5 |issue= |pages=301–13 |year=2013 |pmid=24039449 |pmc=3770515 |doi=10.2147/CMAR.S36105}}</ref> Cannabinoids have been recommended for cancer pain but the adverse effects may make them a less than ideal treatment; two cannabinoid-based medicines have been approved as a backup remedy for nausea associated with [[chemotherapy]].<ref name=Borgelt2013>{{cite journal |author=Borgelt LM, Franson KL, Nussbaum AM, Wang GS |title=The pharmacologic and clinical effects of medical cannabis |journal=Pharmacotherapy |volume=33 |issue=2 |pages=195–209 |date=February 2013 |pmid=23386598 |doi=10.1002/phar.1187 |type=Review}}</ref>
The [[American Cancer Society]] says: "There is no available scientific evidence from controlled studies in humans that cannabinoids can cure or treat cancer."<ref name=Young_Riddle>{{Citation |last=Young |first=Saundra |date=15 Jan 2014 |title=3-year-old is focus of medical marijuana battle |publisher=[[CNN]] |url=http://www.cnn.com/2014/01/15/health/cannabis-landon-riddle/ |accessdate=2014-01-16 }}</ref> Laboratory experiments have been performed on the potential use of cannabinoids for cancer therapy but {{asof|2013|lc=y}} results have been contradictory and knowledge on cancer-curing cannabinoids remains limited, although there is considerable anecdotal evidence from those who stated they were cured of cancer on YouTube.<ref name=Cridge2013>{{medrs|date=March 2014}}{{cite journal |author=Cridge BJ, Rosengren RJ |title=Critical appraisal of the potential use of cannabinoids in cancer management |journal=Cancer Manag Res |volume=5 |issue= |pages=301–13 |year=2013 |pmid=24039449 |pmc=3770515 |doi=10.2147/CMAR.S36105}}</ref> Cannabinoids have been recommended for cancer pain but the adverse effects may make them a less than ideal treatment; two cannabinoid-based medicines have been approved as a backup remedy for nausea associated with [[chemotherapy]].<ref name=Borgelt2013>{{cite journal |author=Borgelt LM, Franson KL, Nussbaum AM, Wang GS |title=The pharmacologic and clinical effects of medical cannabis |journal=Pharmacotherapy |volume=33 |issue=2 |pages=195–209 |date=February 2013 |pmid=23386598 |doi=10.1002/phar.1187 |type=Review}}</ref>


===Dravet syndrome===
===Dravet syndrome===

Revision as of 05:28, 28 June 2014

Not to be confused with Cannabinol.
Cannabidiol
Clinical data
Trade namesEpidiolex
AHFS/Drugs.comInternational Drug Names
ATC code
  • None
Legal status
Legal status
  • Schedule I (US)

Schedule II (Can)

(THC - Schedule/Level I; THC and CBD two main chemicals in cannabis)
Pharmacokinetic data
Bioavailability13-19% (oral),[1] 11-45% (mean 31%; inhaled)[2]
Elimination half-life9 h[1]
Identifiers
  • 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
CAS Number
PubChem CID
ChemSpider
UNII
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)[3]
  • 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
  (verify)

Cannabidiol (CBD) is one of at least 60 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

The bud of a Cannabis sativa flower coated with trichomes

Antimicrobial actions

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

Neurological effects

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]

Parkinson's disease

It has been proposed that CBD may help people with Parkinson's disease, but promising results in animal experiments were not confirmed when CBD was trialled in humans.[10]

Psychotropic effect

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.[11] 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.[11][12] 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.[13]

Studies have shown cannabidiol decreases activity of the limbic system[14] and decreases social isolation induced by THC.[15] Cannabidiol has also been shown to reduce anxiety in social anxiety disorder.[16][17] However, chronic cannabidiol administration in rats was recently found to produce anxiogenic-like effects, indicating that prolonged treatment with cannabidiol might incite anxiogenic effects.[18]

Cannabidiol has demonstrated antidepressant-like effects in animal models of depression.[19][20][21]

Cancer

The American Cancer Society says: "There is no available scientific evidence from controlled studies in humans that cannabinoids can cure or treat cancer."[22] Laboratory experiments have been performed on the potential use of cannabinoids for cancer therapy but as of 2013 results have been contradictory and knowledge on cancer-curing cannabinoids remains limited, although there is considerable anecdotal evidence from those who stated they were cured of cancer on YouTube.[23] Cannabinoids have been recommended for cancer pain but the adverse effects may make them a less than ideal treatment; two cannabinoid-based medicines have been approved as a backup remedy for nausea associated with chemotherapy.[4]

Dravet syndrome

See also: Charlotte's Web (cannabis)

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.[24] While high profile and anecdotal reports have sparked interest in treatment with cannabinoids,[25] there is insufficient medical evidence to draw conclusions about their safety or efficacy.[25][26]

CBD-enhanced cannabis

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.[27] To meet the demands of medical cannabis patients, growers are currently developing more CBD-rich strains.[28]

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.[29][30] 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".[31]

Pharmacology

Pharmacodynamics

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,[19][36] anxiolytic,[36][37] and neuroprotective[38][39] effects. Cannabidiol is an allosteric modulator of μ and δ-opioid receptors.[40] Cannabidiol's pharmacologial effects have also been attributed to PPAR-γ receptor agonism and intracellular calcium release.[5]

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

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.[44][45][46]

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.

Chemistry

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

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]

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:

The DEA Drug Schedule classifies synthetic THC (Tetrahydrocannabinol) as a schedule III substance (eg Marinol); while the natural marijuana plant is listed as Schedule I. Cannabidiol is not named specifically on the list.[55] However the CSA does mention all natural Phytocannabinoids in Schedule 1 Code 7372, which would include CBD.[55]

Marijuana (along with all of its cannabinoids) is defined by 21 U.S.C. §802(16), which is part of the Controlled Substances Act.[56][57][58] There is an exemption for certain Hemp products produced abroad. Under this exception, what are known as industrial hemp-finished products are legally imported into the United States each year. Hemp finished products which meet the specific definitions including hemp oil which may contain cannabidiol are legal in the United States but aren't used for getting high.[59]

Some cannabidiol oil is derived from marijuana and therefore contains higher levels of THC.[60] This type of cannabidiol oil would be considered a Schedule I as a result of the THC present.[60]

US patent

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]

"Oxidative associated diseases include, without limitation, free radical associated diseases, such as ischemia, ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial ischemia or infarction, cerebrovascular accidents (such as a thromboembolic or hemorrhagic stroke) that can lead to ischemia or an infarct in the brain, operative ischemia, traumatic hemorrhage (for example a hypovolemic stroke that can lead to CNS hypoxia or anoxia), spinal cord trauma, Down's syndrome, Crohn's disease, autoimmune diseases (e.g. rheumatoid arthritis or diabetes), cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia, undesired cellular apoptosis, radiation sickness, and others. The present invention is believed to be particularly beneficial in the treatment of oxidative associated diseases of the CNS, because of the ability of the cannabinoids to cross the blood brain barrier and exert their antioxidant effects in the brain. In particular embodiments, the pharmaceutical composition of the present invention is used for preventing, arresting, or treating neurological damage in Parkinson's disease, Alzheimer's disease and HIV dementia; autoimmune neurodegeneration of the type that can occur in encephalitis, and hypoxic or anoxic neuronal damage that can result from apnea, respiratory arrest or cardiac arrest, and anoxia caused by drowning, brain surgery or trauma (such as concussion or spinal cord shock)."[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]

References

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  33. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/sj.bjp.0707442, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/sj.bjp.0707442 instead.
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  • Project CBD Non-profit educational service dedicated to promoting and publicizing research into the medical utility of cannabidiol.
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