There has been little high-quality research into the use of cannabidiol for epilepsy. The limited available evidence primarily focuses on refractory epilepsy in children. Using medical-grade cannabidiol in combination with conventional medication has shown some promise for reducing seizure frequency and improving quality of life. While cannabidiol treatment is generally well tolerated, it is also associated with some minor adverse effects.
Preliminary research on other possible therapeutic uses for cannabidiol include several neurological disorders, but the findings have not been confirmed by sufficient high-quality clinical research to establish such uses in clinical practice.
Preliminary research indicates that cannabidiol may reduce adverse effects of THC, particularly those causing intoxication and sedation, but only at high doses. Safety studies of cannabidiol showed it is well tolerated, but may cause tiredness, diarrhea, or changes in appetite as common adverse effects. Epidiolex documentation lists sleepiness, insomnia and poor quality sleep, decreased appetite, diarrhea, and fatigue.
Nabiximols (brand name Sativex) is a patented medicine containing CBD and THC in equal proportions. The drug was approved by Health Canada in 2005 for prescription to treat central neuropathic pain in multiple sclerosis, and in 2007 for cancer related pain. In New Zealand, Sativex is "approved for use as an add-on treatment for symptom improvement in people with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication."
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, which also occurs during pyrolysis (smoking). The synthesis of cannabidiol has been accomplished by several research groups.
CBD was first studied in 1940 from Minnesota wild hemp and EgyptianCannabis indica resin. The chemical formula of CBD was proposed from a method for isolating it from wild hemp. Its structure and stereochemistry were determined in 1963.
An example of CBD-infused cold brew coffee & tea in a Los Angeles grocery.
Food and beverage products containing CBD were introduced in the United States in 2017.[dubious – discuss] Hemp seed ingredients which do not naturally contain THC or CBD (but which may be contaminated with trace amounts on the outside during harvesting) were declared by the FDA as GRAS in December 2018. CBD itself has not been declared GRAS, and under U.S. federal law is illegal to sell as a food, dietary supplement, or animal feed. State laws vary considerably as non-medical cannabis and derived products have been legalized in some jurisdictions in the 2010s.
Similar to energy drinks and protein bars which may contain vitamin or herbal additives, food and beverage items can be infused with CBD as an alternative means of ingesting the substance. In the United States, numerous products are marketed as containing CBD, but in reality contain little or none. Some companies marketing CBD-infused food products with claims that are similar to the effects of prescription drugs have received warning letters from the Food and Drug Administration for making unsubstantiated health claims. In February 2019, the New York City Department of Health announced plans to fine restaurants that sell food or drinks containing CBD, beginning in October 2019.
Selective breeding of cannabis plants has expanded and diversified as commercial and therapeutic markets develop. Some growers in the US succeeded in lowering the proportion of CBD-to-THC to accommodate customers who preferred varietals that were more mind-altering due to the higher THC and lower CBD content. In the US, hemp is classified by the federal government as cannabis containing no more than 0.3% THC by dry weight. This classification was established in the 2018 Farm Bill and was refined to include hemp-sourced extracts, cannabinoids, and derivatives in the definition of hemp.
CBD does not appear to have any psychotropic ("high") effects such as those caused by ∆9-THC in marijuana, but may have anti-anxiety and anti-psychotic effects. As the legal landscape and understanding about the differences in medical cannabinoids unfolds, experts are working to distinguish "medical marijuana" (with varying degrees of psychotropic effects and deficits in executive function) – from "medical CBD therapies” which would commonly present as having a reduced or non-psychoactive side-effect profile.
Various strains of "medical marijuana" are found to have a significant variation in the ratios of CBD-to-THC, and are known to contain other non-psychotropic cannabinoids. Any psychoactive marijuana, regardless of its CBD content, is derived from the flower (or bud) of the genus Cannabis. As defined by U.S. federal law, non-psychoactive hemp (also commonly-termed industrial hemp), regardless of its CBD content, is any part of the cannabis plant, whether growing or not, containing a ∆-9 tetrahydrocannabinol concentration of no more than 0.3% on a dry-weight basis. Certain standards are required for legal growing, cultivating, and producing the hemp plant. The Colorado Industrial Hemp Program registers growers of industrial hemp and samples crops to verify that the dry-weight THC concentration does not exceed 0.3%.
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.
Following a change in legislation in 2017, CBD was changed from a schedule 9 drug to a schedule 4 drug, meaning that it is legally available in Australia.
In October 2018, cannabidiol became legal for recreational and medical use.
In 2019, the European Commission announced that CBD and other cannabinoids would be classified as "novel foods", meaning that CBD products would require authorization under the EU Novel Food Regulation stating: because "this product was not used as a food or food ingredient before 15 May 1997, before it may be placed on the market in the EU as a food or food ingredient, a safety assessment under the Novel Food Regulation is required." The recommendation – applying to CBD extracts, synthesized CBD, and all CBD products, including CBD oil – was scheduled for a final ruling by the European Commission in March 2019. If approved, manufacturers of CBD products would be required to conduct safety tests and prove safe consumption, indicating that CBD products would not be eligible for legal commerce until at least 2021.
Cannabidiol is listed in the EU Cosmetics Ingredient Database (CosIng). However, the listing of an ingredient, assigned with an INCI name, in CosIng does not mean it is to be used in cosmetic products or is approved for such use.
Several industrial hemp varieties can be legally cultivated in Western Europe. A variety such as "Fedora 17" has a cannabinoid profile consistently around 1%, with THC less than 0.3%.
CBD is classified as a medical product in Sweden.
In 2017 the government made changes to the regulations so that restrictions would be removed, which meant a doctor was able to prescribe cannabidiol to patients.
The passing of the Misuse of Drugs (Medicinal Cannabis) Amendment Act in December 2018 means cannabidiol is no longer a controlled drug in New Zealand, but is a prescription medicine under the Medicines Act provided the product contains no more than two percent THC of total CBD.
Cannabidiol, in an oral-mucosal spray formulation combined with delta-9-tetrahydrocannabinol, is a product available (by prescription only until 2017) for relief of severe spasticity due to multiple sclerosis (where other anti-spasmodics have not been effective).
Until 2017, products containing cannabidiol marketed for medical purposes were classed as medicines by the UK regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA) and could not be marketed without regulatory approval for the medical claims. As of 2018[update], cannabis oil is legal to possess, buy, and sell in the UK, providing the product does not contain more than 0.3% THC and is not advertised as providing a medicinal benefit.
In January 2019, the UK Food Standards Agency indicated it would regard CBD products, including CBD oil, as a novel food in the UK, having no history of use before May 1997, and indicating such products must have authorization and proven safety before being marketed.
As of April 2019[update], CBD extracted from marijuana remains a Schedule I Controlled Substance, and is not approved as a prescription drug, dietary supplement, or allowed for interstate commerce in the United States. CBD derived from hemp (with 0.3% THC or lower) was delisted as a federally scheduled substance by the 2018 Farm Bill. FDA regulations still apply: hemp CBD is legal to sell as a cosmetics ingredient, but despite a common misconception, because it is an active ingredient in an FDA-approved drug, cannot be sold under federal law as an ingredient in food, dietary supplements, or animal food. It is a common misconception that the legal ability to sell hemp (which may contain CBD) makes CBD legal.
In September 2018, following its approval by the FDA for rare types of childhood epilepsy, Epidiolex was rescheduled (by the Drug Enforcement Administration) as a Schedule V drug to allow for its prescription use. This allows GW Pharmaceuticals to sell Epidiolex, but it does not apply broadly and all other CBD-containing products remain Schedule I drugs. Epidiolex still requires rescheduling in some states before it can be prescribed in those states.
In 2013 a CNN program that featured Charlotte's Web cannabis brought increased attention to the use of CBD in the treatment of seizure disorders. Since then, 16 states have passed laws to allow the use of CBD products with a doctor's recommendation (instead of a prescription) for treatment of certain medical conditions. This is in addition to the 30 states that have passed comprehensive medical cannabis laws, which allow for the use of cannabis products with no restrictions on THC content. Of these 30 states, eight have legalized the use and sale of cannabis products without requirement for a doctor's recommendation.
Some manufacturers ship CBD products nationally, an illegal action which the FDA did not enforce in 2018, with CBD remaining the subject of an FDA investigational new drug evaluation, and is not considered legal as a dietary supplement or food ingredient as of December 2018[update]. Federal illegality has made it difficult historically to conduct research on CBD. CBD is openly sold in head shops and health food stores in some states where such sales have not been explicitly legalized.
The 2014 Farm Bill legalized the sale of "non-viable hemp material" grown within states participating in the Hemp Pilot Program. This legislation defined hemp as cannabis containing less than 0.3% of THC delta-9, grown within the regulatory framework of the Hemp Pilot Program. The 2018 United States farm bill allowed for interstate commerce of hemp derived products, though these products still fall under the purview of the FDA.
State and local governments may also regulate CBD. For example, the Massachusetts Department of Agricultural Resources issued a rule in June 2019 aligning state CBD regulations with FDA regulations. This means that although recreational marijuana is legal in the state, CBD cannot legally be sold in food or as a dietary supplement under state law.
FDA warning letters
From 2015 to July 2019, the FDA issued 48 warning letters to 23 American manufacturers of CBD products for false advertising and illegal interstate marketing of CBD as an unapproved drug to treat diseases, such as cancer, osteoarthritis, symptoms of opioid withdrawal, Alzheimer's disease, and pet disorders. The FDA said that the letters were issued to enforce action against companies that were deceiving consumers by marketing illegal products for which there was insufficient evidence of safety and efficacy to treat diseases. In July 2019, the FDA stated: "Selling unapproved products with unsubstantiated therapeutic claims — such as claims that CBD products can treat serious diseases and conditions — can put patients and consumers at risk by leading them to put off important medical care. Additionally, there are many unanswered questions about the science, safety, effectiveness and quality of unapproved products containing CBD."
While THC remains illegal, CBD is not subject to the Swiss Narcotic Acts because this substance does not produce a comparable psychoactive effect. Cannabis products containing less than 1% THC can be sold and purchased legally.
^ abScuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G (May 2009). "Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders". Phytotherapy Research (Review). 23 (5): 597–602. doi:10.1002/ptr.2625. PMID18844286.
^ abcdPisanti S, Malfitano AM, Ciaglia E, Lamberti A, Ranieri R, Cuomo G, Abate M, Faggiana G, Proto MC, Fiore D, Laezza C, Bifulco M (July 2017). "Cannabidiol: State of the art and new challenges for therapeutic applications". Pharmacol. Ther. 175: 133–150. doi:10.1016/j.pharmthera.2017.02.041. PMID28232276.
^Aizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, Navarro P, Etxebarria N, Usobiaga A (February 2016). "Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes". Journal of Natural Products. 79 (2): 324–31. doi:10.1021/acs.jnatprod.5b00949. PMID26836472.
^ abcStockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, Herkes GK, Farrell M, Degenhardt L (July 2018). "Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence". J. Neurol. Neurosurg. Psychiatry. 89 (7): 741–753. doi:10.1136/jnnp-2017-317168. PMID29511052.
^Silva TB, Balbino CQ, Weiber AF (May 1, 2015). "The relationship between cannabidiol and psychosis: A review". Annals of Clinical Psychiatry. 27 (2): 134–41. PMID25954940.
^Fischer B, Russell C, Sabioni P, van den Brink W, Le Foll B, Hall W, Rehm J, Room R (August 2017). "Lower-Risk Cannabis Use Guidelines: A Comprehensive Update of Evidence and Recommendations". American Journal of Public Health. 107 (8): e1–e12. doi:10.2105/AJPH.2017.303818. PMID28644037.
^Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, Gunasekaran N, Karl T, Long LE, Huang XF, Liu K, Arnold JC, McGregor IS (November 2011). "Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats". Psychopharmacology. 218 (2): 443–457. doi:10.1007/s00213-011-2342-0. PMID21667074.
^Nadulski T, Pragst F, Weinberg G, Roser P, Schnelle M, Fronk EM, Stadelmann AM (December 2005). "Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract". Ther Drug Monit. 27 (6): 799–810. doi:10.1097/01.ftd.0000177223.19294.5c. PMID16306858.
^Laun AS, Shrader SH, Brown KJ, Song ZH (June 2018). "GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol". Acta Pharmacol. Sin. 40 (3): 300–308. doi:10.1038/s41401-018-0031-9. PMID29941868.
^Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (February 2006). "Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 372 (5): 354–61. doi:10.1007/s00210-006-0033-x. PMID16489449.
^Cite error: The named reference Ohlsson1986 was invoked but never defined (see the help page).
^Gaoni Y, Mechoulam R (1966). "Hashish—VII The isomerization of cannabidiol to tetrahydrocannabinols". Tetrahedron. 22 (4): 1481–1488. doi:10.1016/S0040-4020(01)99446-3.
^Küppers, F.J.E.M.; Bercht, C.A.L.; Salemink, C.A.; Lousberg, R.J.J.Ch.; Terlouw, J.K.; Heerma, W. (1975), "Cannabis—XV: Pyrolysis of cannabidiol. Structure elucidation of four pyrolytic products", Tetrahedron, 31 (13–14): 1513–1516, doi:10.1016/0040-4020(75)87002-5
^Petrzilka T, Haefliger W, Sikemeier C, Ohloff G, Eschenmoser A (March 1967). "[Synthesis and optical rotation of the (-)-cannabidiols]". Helvetica Chimica Acta. 50 (2): 719–23. doi:10.1002/hlca.19670500235. PMID5587099.
^Gaoni Y, Mechoulam R (1985). "Boron trifluoride etherate on alumuna — a modified Lewis acid reagent. An improved synthesis of cannabidiol". Tetrahedron Letters. 26 (8): 1083–1086. doi:10.1016/S0040-4039(00)98518-6.
^Kobayashi Y, Takeuchi A, Wang YG (June 2006). "Synthesis of cannabidiols via alkenylation of cyclohexenyl monoacetate". Organic Letters. 8 (13): 2699–702. doi:10.1021/ol060692h. PMID16774235.
^Taura F, Sirikantaramas S, Shoyama Y, Yoshikai K, Shoyama Y, Morimoto S (June 2007). "Cannabidiolic-acid synthase, the chemotype-determining enzyme in the fiber-type Cannabis sativa". FEBS Letters. 581 (16): 2929–34. doi:10.1016/j.febslet.2007.05.043. PMID17544411.
^ abAdams, Roger; Hunt, Madison; Clark, J. H. (1940). "Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. I". Journal of the American Chemical Society. 62 (1): 196–200. doi:10.1021/ja01858a058. ISSN0002-7863.
^Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (October 2009). "Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb". Trends in Pharmacological Sciences. 30 (10): 515–27. doi:10.1016/j.tips.2009.07.006. PMID19729208.
^ ab"Industrial hemp". Department of Agriculture, State of Colorado. 2018. Retrieved September 14, 2018.
^Fournier G, Beherec O, Bertucelli S (2003). "Intérêt du rapport Δ-9-THC / CBD dans le contrôle des cultures de chanvre industriel" [The advantage of the Δ-9-THC / CBD ratio in the control of industrial hemp crops]. Annales de Toxicologie Analytique (in French). 15 (4): 250–59. doi:10.1051/ata/2003003.