Cannabidiol

Not to be confused with Cannabinol.

Cannabidiol

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	CA: Schedule II US: Unscheduled
Pharmacokinetic data
Bioavailability	13-19% (oral), 11-45% (mean 31%; inhaled)
Biological half-life	9 h
Identifiers
CAS Number	13956-29-1 Y
ATC code	None
PubChem	CID: 644019
IUPHAR/BPS	4150
ChemSpider	24593618 Y
UNII	19GBJ60SN5 Y
Chemical data
Formula	C21H30O2
Molecular mass	314.4636
SMILES Oc1c(c(O)cc(c1)CCCCC)[C@@H]2\C=C(/CC[C@H]2\C(=C)C)C
InChI 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 Y Key:ZTGXAWYVTLUPDT-ZWKOTPCHSA-N Y
Physical data
Melting point	66 °C (151 °F)
Boiling point	180 °C (356 °F) (range: 160–180 °C)
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Cannabidiol (CBD) is one of at least 85 active cannabinoids identified in cannabis. It is a major phytocannabinoid, accounting for up to 40% of the plant's extract. CBD is considered to have a wider scope of potential medical applications than tetrahydrocannabinol (THC).

Research

The bud of a Cannabis sativa flower coated with trichomes bearing cannabidiol and other cannabinoids

Neurological effects

Cannabidiol has been seen to be an anticonvulsant in animals, but controlled studies in humans are lacking. Randomized trials in treatment-resistant epilepsy syndromes are planned in 2015.

Transdermal CBD is neuroprotective in animals.

Dravet syndrome

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. A number of high profile and anecdotal reports have sparked interest in treatment of Dravet snydrome with CBD. GW Pharmaceuticals is seeking FDA approval to market a formulation of CBD, under the tradename Epidiolex, as a treatment for Dravet syndrome. Epidiolex was granted fast-track status and is in late stage trials following positive early results from the drug. Some cannabis extract preparations containing CBD are marketed as dietary supplements and claim efficacy against Dravet Syndrome. One such preparation is marketed under the tradename Charlotte's web.

Psychotropic effect

A 2014 Cochrane Review concluded that the evidence is insufficient to conclude that CBD has anti-psychotic effects Others have concluded it may have antipsychotic effects and may counteract the potential psychotomimetic effects of THC on individuals with latent schizophrenia; some reports show it to be an alternative treatment for schizophrenia that is safe and well-tolerated. 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. Studies have shown cannabidiol decreases activity of the limbic system and decreases social isolation induced by THC in rats.

Chronic cannabidiol administration in rats was found to produce reactions suggesting anxiety, indicating that prolonged treatment with cannabidiol might lead to anxiety. Those results have been contested by Gururajan, and contradict Réus, whose experimentation cover the same duration.

CBD-enhanced cannabis

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

Industrial hemp

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%.

Extraction can be done with olive oil, ethanol, or CO₂, and other nonpolar to semipolar solvents.

Pharmacodynamics

Cannabidiol has a very low affinity for CB₁ and CB₂ receptors but acts as an indirect antagonist of their agonists. 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. It may also extend the duration of the effects of THC via inhibition of the cytochrome P-450-3A and 2C enzymes.

Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen. Cannabidiol has also been shown to act as a 5-HT_1A receptor partial agonist, an action which may be involved in its antidepressant, anxiolytic, and neuroprotective effects. Cannabidiol is an allosteric modulator of μ and δ-opioid receptors. Cannabidiol's pharmacological effects have also been attributed to PPAR-γ receptor agonism and intracellular calcium release.

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.

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. Despite this the available evidence in humans suggests no significant effect of CBD on THC plasma levels.

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.

Epidiolex is an oil formulation of CBD extracted from the cannabis plant undergoing clinical trials for refractory epilepsy syndromes.

Isomerism

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. In strongly basic media and the presence of air, it is oxidized to a quinone. Under acidic conditions it cyclizes to THC. The synthesis of cannabidiol has been accomplished by several research groups.

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.

Legal status

Cannabidiol is not scheduled by the Convention on Psychotropic Substances.

Legal status in Canada

Cannabidiol is a Schedule II drug in Canada. The newly installed Trudeau government has made full legalization a priority.

Legal status in the United States

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 nor in any of the other schedules, However, public statements by the Drug Enforcement Administration have long represented cannabidiol as Schedule I.

The drug Schedules list "Tetrahydrocannabinols" and "marihuana" both as Schedule I drugs under the Controlled Substances Act, cannabidiol is not 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. Under current legislation, Cannabidiol as a singular substance does not fall under the criteria set forth under these guidelines, and is currently regarded as GRAS, or "Generally Regarded As Safe" by default.

• "Marijuana" has a DEA Drug Code of 7360 (distinct from cannabidiol's Drug Code of 7372) and is defined by the CSA as "all parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin." Exempted from regulation under the definition are "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 such plant which is incapable of germination." A DEA Interpretive Rule published in 2001 states that the "definition of marijuana was intended to include those parts of marijuana which contain THC and to exclude those parts which do not. ... The legislative history is absolutely clear that Congress meant to outlaw all plants popularly known as marijuana to the extent those plants possessed THC." Cannabidiol isolated by extraction from marijuana sources does not contain THC, and synthetically produced cannabidiol does not contain THC either. It therefore stands to reason that cannabidiol is not covered under the prohibition on marijuana.
• "Tetrahydrocannabinols" listed under Schedule I of the CSA are unlikely to include cannabidiol. Tetrahydrocannabinols are defined as follows:

Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation, which contains any quantity of the following hallucinogenic substances, or which contains any of its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation (for purposes of this paragraph only, the term "isomer" includes the optical, position and geometric isomers):

• (31) Tetrahydrocannabinols (DEA Drug Code: 7370)
  • Meaning tetrahydrocannabinols naturally contained in a plant of the genus Cannabis (cannabis plant), as well as synthetic equivalents of the substances contained in the cannabis plant, or in the resinous extractives of such plant, and/or synthetic substances, derivatives, and their isomers with similar chemical structure and pharmacological activity to those substances contained in the plant, such as the following:
    • 1 cis or trans tetrahydrocannabinol, and their optical isomers
    • 6 cis or trans tetrahydrocannabinol, and their optical isomers
    • 3,4 cis or trans tetrahydrocannabinol, and its optical isomers
    • (Since nomenclature of these substances is not internationally standardized, compounds of these structures, regardless of numerical designation of atomic positions covered.)

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), 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) to ban various cannabinoids, cathinones, and phenethylamines. The part adding to Schedule I various "cannabimimetic agents" which include molecules more closely resembling so-called "classically" structured cannabinoids reads as follows:

(d)

(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.

(2) In paragraph (1):

(A) The term "cannabimimetic agents" means any substance that is a cannabinoid receptor type 1 (CB1 receptor) agonist as demonstrated by binding studies and functional assays within any of the following structural classes:

(i) 2-(3-hydroxycyclohexyl)phenol with substitution at the 5-position of the phenolic ring by alkyl or alkenyl, whether or not substituted on the cyclohexyl ring to any extent.

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"), 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. 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." Under this exception, what are known as industrial hemp-finished products are legally imported into the United States each year. 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.

External links

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