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Cannabidiol (CBD) is one of at least 85 active [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). 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]
Cannabidiol has been seen to be anticonvulsant in animals, but controlled studies in humans are lacking.[7] Randomized trials in treatment-resistant epilepsy syndromes are planned in 2015.
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]
Dravet syndrome is a rare form of epilepsy that is difficult to treat. It is a 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.[10] While high profile and anecdotal reports of results from high-CBD/low-THC preparations have sparked interest in treatment with cannabinoids,[11] there is insufficient medical evidence to draw conclusions about their safety or efficacy.[11][12]
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.[13] 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.[13][14] 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.[15] A phase 2 study of 88 schizophenic patients who failed to respond to a first-line anti-psychotic had cannabidol(or placebo) added on.[16] Cannabidiol improved positive and cognitive symptoms over six weeks with no severe adverse effects.
Studies have shown cannabidiol decreases activity of the limbic system [17] and decreases social isolation induced by THC.[18] Cannabidiol has also been shown to reduce anxiety in social anxiety disorder.[19][20]
Chronic cannabidiol administration in rats was found to produce reactions suggesting anxiety, indicating that prolonged treatment with cannabidiol might lead to anxiety.[21] Those results have been contested by Gururajan,[22] and contradict Réus,[23] whose experimentation cover the same duration.
Cannabidiol has demonstrated antidepressant-like effects in animal models of depression.[24][25][26]
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.[27] To meet the demands of medical cannabis patients, growers are currently developing more CBD-rich strains.[28]
Charlotte's Web, a cannabis plant, was developed in 2011 by crossbreeding a strain of marijuana with industrial hemp. This process created a variety with less tetrahydrocannabinol (THC) and more cannabidiol (CBD) than typical varieties of cannabis in the US (see Charlotte's Web in the section above).
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] In February 2014, a patent application was filed for a cannabis plant named 'avidekel'.[32]
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%.[33]
Extraction can be done with olive oil, ethanol, or CO2, and other nonpolar to semipolar solvents.
Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists.[9][34] 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.[35] It may also extend the duration of the effects of THC via inhibition of the cytochrome P-450-3A and 2C enzymes.[36]
Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[37] Cannabidiol has also been shown to act as a 5-HT1A receptor agonist,[38] an action which may be involved in its antidepressant,[24][39] anxiolytic,[39][40] and neuroprotective[41][42] effects. Cannabidiol is an allosteric modulator of μ and δ-opioid receptors.[43] Cannabidiol's pharmacological effects have also been attributed to PPAR-γ receptor agonism and intracellular calcium release.[5]
Research suggests that CBD may exert some of its pharmacological action through its inhibition of FAAH, which may in turn increase the levels of endocannabinoids, such as anandamide, produced by the body.[44]
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.[45][46] Despite this the available evidence in humans suggests no significant effect of CBD on THC plasma levels.[47]
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.[48][49][50]
Epidiolex is an oil formulation of CBD extracted from the cannabis plant undergoing clinical trials for refractory epilepsy syndromes.[51]
Based on: , Arizona University 1987Synthesis of delta-3-cannabidiol and the derived rigid analogsNagaraja, Kodihalli Nanjappa, .
See also: Tetrahydrocannabinol#Isomerism, Abnormal cannabidiol.
Cannabidiol is insoluble in water but soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid.[52] In strongly basic media and the presence of air, it is oxidized to a quinone.[53] Under acidic conditions it cyclizes to THC.[54] The synthesis of cannabidiol has been accomplished by several research groups.[55][56][57]
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.[58]
Cannabidiol is not scheduled by the Convention on Psychotropic Substances.
Cannabidiol is a Schedule II drug in Canada.[59]
The legal status of Cannabidiol in the United States at the federal level is not immediately clear. The Controlled Substances Act (CSA) does not specifically list cannabidiol in Schedule I[60] nor in any of the other schedules,[61] however it appears that the Drug Enforcement Administration (DEA) presumes to assert authority to regulate cannabidiol as a Schedule I controlled substance.[62][63] The legal basis for that presumed authority is unclear.
The drug Schedules list "Tetrahydrocannabinols" and "marihuana" both as Schedule I drugs under the Controlled Substances Act,[60] however cannabidiol is unlikely to be considered as a Schedule I drug on the basis of being covered by the listing of "Marihuana" or by the listing of "Tetrahydrocannabinols" under Schedule I of the CSA.
Since cannabidiol is chemically not a tetrahydrocannabinol (nor indeed a "cannabinol" of any kind) and cannabidiol has a DEA Drug Code of 7372 (distinct from Tetrahydrocannabinols' designated Drug Code of 7370),[62] it stands to reason that cannabidiol is not considered one of the drugs placed into Schedule I under the listing of "Tetrahydrocannabinols" in the CSA.
Furthermore, cannabidiol was not placed into Schedule I when The Controlled Substances Act was amended in July 2012 with the US Congress' passing of the Synthetic Drug Abuse Prevention Act of 2012 (SDAPA) (which came into effect on January 4, 2013[66])[67] to ban various cannabinoids, cathinones, and phenethylamines.[60] The part adding to Schedule I various "cannabimimetic agents" which include molecules more closely resembling so-called "classically" structured cannabinoids reads as follows:
(1) Unless specifically exempted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of cannabimimetic agents, or which contains their salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation.
Cannabidiol, while being a more "classically structured" cannabinoid (not like the much more recently discovered cannabinoid receport agonists with indole rings such as many of the JWH- and AM- named series), was not on the list of specifically newly banned cannabinoids (even among those with a more so-called "classic structure"),[66][60] and it does not fall into the category of unlisted cannabinoids which are caught by the definition above for several reasons. Primarily, CBD is not a CB1 agonist; it is a CB1 antagonist.[68][69] Also, unlike CP 47,497's homologues and similar synthetic "classical structured cannabinoids" which the above definition was written carefully to include, the cannabidiol molecule has a cyclohexene ring where the amended law requires a cyclohexane ring, and further cannabidiol does not have the required 3-hydroxyl moiety bonded to its cyclohexenyl functional group where the law requires a hydroxyl moiety bonded to the 3- position of a cyclohexyl functional group.
Extracts and concentrates of hemp products which are high in cannabidiol content are very likely legal under US federal law as long as they meet certain requirements. Marihuana is defined by 21 U.S.C. §802(16), which is part of the Controlled Substances Act, and it has a DEA Number / Drug Code of 7360. Exempted from regulation under the definition of marihana is "the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of any such plant which is incapable of germination."[64][70][71] Under this exception, what are known as industrial hemp-finished products are legally imported into the United States each year.[72] Hemp finished products, including hemp oil and extracts of hemp products which are high in cannabidiol, are legal in the United States for this reason.
It should be noted that despite the legal ambiguity, the DEA requires researchers and clinical practitioners working with purified CBD extracts to possess a Schedule I license with endorsement for DEA Drug Code 7360 (Cannabis/Marijuana). Commercial and governmental suppliers of CBD for research purposes likewise require affirmation of Schedule I licensing by the purchaser. [73]
Methamphetamine, Amphetamine, Migraine, Ergotamine, Norepinephrine
5-Carboxamidotryptamine, 5-Methoxytryptamine, Metitepine, Lysergic acid diethylamide, Methysergide
Tetrahydrocannabinol, Cannabis, Cannabidiol, Kava, Anandamide