There has been little high-quality research into the use of cannabidiol for epilepsy. The limited available evidence primarily focuses onrefractoryepilepsy in children.Using medical-grade cannabidiol in combination with conventional medication has shown some promise for reducing seizure frequency and improvingquality of life.While cannabidiol treatment is generally well tolerated, it is also associated with some minoradverse 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 reduceadverse effectsof THC, particularly those causing intoxication andsedation, 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,insomniaand poor quality sleep, decreased appetite, diarrhea, and fatigue.
Context: Chronic pain is highly prevalent in most of the industrialized nations around the world. Despite the documented adverse effects, opioids are widely used for pain management. Cannabinoids, and specifically Cannabidiol, is proposed as an opioid alternative, having comparable efficacy with better safety profile.Objectives: We aim to investigate the impact of full hemp extract cannabidiol (CBD) on opioid use and quality of life indicators among chronic pain patients.Methods: An initial sample of 131 patients was recruited from a private pain management center's investigative population. Ninety-seven patients completed the 8-week study. The primary inclusion criteria included patients between 30 and 65 years old with chronic pain who have been on opioids for at least 1 year. Data were collected at three different time points: baseline, 4, and 8 weeks. Opioid and other medication use were evaluated via the medication and psychiatric treatment receipt. Improvement was evaluated using four indices: Pain Disability Index (PDI-4); Pittsburgh Sleep Quality Index (PSQI), Pain Intensity and Interference (PEG); and Patient Health Questionnaire (PHQ-4).Results: Over half of chronic pain patients (53%) reduced or eliminated their opioids within 8 weeks after adding CBD-rich hemp extract to their regimens. Almost all CBD users (94%) reported quality of life improvements. The results indicated a significant relationship between CBD and PSQI (p = 0.003), and PEG (p = 0.006). There was a trend toward improvement but no significant relationship between CBD use and PHQ and PDI.Conclusion: CBD could significantly reduce opioid use and improve chronic pain and sleep quality among patients who are currently using opioids for pain management.Key Message: This is a prospective, single-arm cohort study for the potential role of cannabinoids as an alternative for opioids. The results indicate that using the CBD-rich extract enabled our patients to reduce or eliminate opioids with significant improvement in their quality of life indices.
Nabiximols(brand nameSativex) is a patented medicine containing CBD and THC in equal proportions. The drug was approved by Health Canada in 2005 for prescription to treat centralneuropathic paininmultiple 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 aspentane. At room temperature, it is a colorless crystalline solid.In strongly basic media and the presence of air, it is oxidized to aquinone.Under acidic conditions it cyclizes to THC,which also occurs duringpyrolysis(smoking).The synthesis of cannabidiol has been accomplished by several research groups.
Cannabidiol's 7 double bond isomers and their 30 stereoisomersshow
CBD was first studied in 1940 fromMinnesotawild hempandEgyptianCannabis indicaresin.The chemical formula of CBD was proposed from a method for isolating it from wild hemp.Its structure andstereochemistrywere determined in 1963.
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 theFDAasGRASin 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.
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 genusCannabis. As defined by U.S. federal law, non-psychoactive hemp (also commonly-termedindustrial 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%.
As of April 2019, CBD extracted from marijuana remains aSchedule I Controlled Substance,and is not approved as aprescription 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 the2018 Farm Bill. FDA regulations still apply: hemp CBD is legal to sell as a cosmetics ingredient, but despite acommon 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 allowsGW Pharmaceuticalsto 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 aCNNprogram that featuredCharlotte's Web cannabisbrought 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 the30 statesthat 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 FDAinvestigational new drugevaluation, and is not considered legal as adietary supplementor food ingredient as of December 2018.Federal illegality has made it difficult historically to conduct research on CBD.CBD is openly sold inhead shopsandhealth food storesin some states where such sales have not been explicitly legalized.
The2014 Farm Billlegalized the sale of "non-viable hemp material" grown within states participating in the Hemp Pilot Program.This legislation definedhempas 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, CDB 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 48warning lettersto 23 American manufacturers of CBD products for false advertising and illegal interstate marketing of CBD as an unapproveddrugto treat diseases, such as cancer,osteoarthritis, symptoms ofopioid withdrawal, Alzheimer's disease, andpetdisorders.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."
^Jump up to: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.
^Jump up to: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.
^Jump up to: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.
^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.
^Jump up to: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.
^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.