Cannabidiol
Cannabidiol (CBD) (/kæ.nə.bə.ˈdaɪ.əl/) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract.[16] As of 2022, clinical research on CBD included studies related to the treatment of anxiety, addiction, psychosis, movement disorders, and pain, but there is insufficient high-quality evidence that cannabidiol is effective for these conditions.[17][18][19][20] CBD is also sold as a herbal dietary supplement promoted with unproven claims of particular therapeutic effects.[21]
Not to be confused with cannabinol or cannabinodiol.Clinical data
Epidiolex, Epidyolex
CBD, cannabidiolum, (−)-cannabidiol[1]
- EU EMA: by INN
- US DailyMed: Cannabidiol
- AU: B2[2]
Low[3]
- AU: S3 (Pharmacist only)
- BR: Synthetic: C3; Oil with <0,2% THC: B1; Oil <30mg/ml THC and <30mg/ml CBD: A3.[10]
- CA: Unscheduled
- UK: General sales list (GSL, OTC)[11]
- US: Unscheduled if derived from hemp with less than 0.3% D9-THC but may be considered Schedule I if a component of marijuana with more than 0.3% D9-THC.[8][9]
- EU: Rx-only[12]
18–32 hours[15]
C21H30O2
314.469 g·mol−1
66 °C (151 °F)
Insoluble
Cannabidiol can be taken internally in multiple ways, including by inhaling cannabis smoke or vapor, oral, and as an aerosol spray into the cheek.[4][5] It may be supplied as CBD oil containing only CBD as the active ingredient (excluding THC or terpenes), CBD-dominant hemp extract oil, capsules, dried cannabis, or prescription liquid solution.[7][19] CBD does not have the same psychoactivity as THC,[22][23] and can modulate the psychoactive effects of THC on the body if both are present.[16][22][24][25] CBD heated to 250–300 °C may partially be converted into THC.[26]
In the United States, the cannabidiol drug Epidiolex was approved by the Food and Drug Administration (FDA) in 2018 for the treatment of two epilepsy disorders.[7] While the 2018 United States Farm Bill removed hemp and hemp extracts (including CBD) from the Controlled Substances Act, the marketing and sale of CBD formulations for medical use or as an ingredient in dietary supplements or manufactured foods remains illegal under FDA regulation, as of 2024.[27][28]
Veterinary medicine[edit]
Research[edit]
The number of research projects and scientific publications on cannabidiol and other cannabinoids in pets surged in the late 2010s; nonetheless, as of December 2020, there were no hemp-derived, cannabinoid-rich registered veterinary medicinal products in any of the major regions (see #Legal status).
In the US and other territories there are, however, numerous veterinary nutraceutical products available over the counter (OTC). The lack of clarity in the regulations governing veterinary hemp food supplements allows for products of questionable quality to flood the market,[63][64] which may pose a risk to the wellbeing of pets and owners.
To understand better the benefits of CBD and associated compounds for the quality of life of animals, companies specialized in CBD products for animals have been funding research projects.[65][66][67][68]
Canine osteoarthritis[edit]
CBD's ability to help regulate the endocannabinoid system[69][70][71] and reduce the release of excitatory neurotransmitters could result in a retrograde inhibitory signal that lessens chronic pain responses. Studies in dogs with chronic pain associated with osteoarthritis showed an increase in level of activity in animals receiving CBD-rich food supplements.[72][73][74][66]
Epilepsy[edit]
From the results seen in humans with drugs such as Epidiolex and Sativex in scientific studies and reviews,[75] it could be expected that CBD-based products would be helpful to manage seizures in dogs. However, despite the numerous case reports presented by veterinary neurologists supporting the benefits of CBD as adjunctive therapy, as of December 2020, published controlled studies have not shown a statistically significant decrease in the number of seizures across the groups receiving CBD.[65][67]
Pharmacokinetics[edit]
The oral bioavailability of CBD varies greatly across species and it is linked to the presentation and the time of administration.[76][68][77] A 24-hour kinetic examination in dogs showed that the absorption of the cannabidiolic acid (CBDA) does occur, and that this molecule is absorbed least twice as well as CBD post oral ingestion.[76][68][78]
It was found that the major metabolites of CBD in humans (7-OH-CBD and 7-COOH-CBD) are not prevalent in dogs, while 6-OH-CBD was found to be the primary metabolite in dogs receiving a CBD-enriched cannabis-derived herbal extract,[79] suggesting that canine and human CBD metabolic route might be somewhat different.[77]
Pharmacology[edit]
Possible mechanisms[edit]
As of 2024, the cellular effects and mechanisms of cannabidiol in vivo are unknown,[7][12] as research to date has been inconclusive and based on laboratory studies.[80] The anticonvulsant effects provided by cannabidiol (Epidiolex) in people with certain forms of epilepsy do not appear to involve cannabinoid receptors.[7] A possible mechanism for the effects of cannabidiol on seizures is by affecting the neuronal movement of calcium in brain structures involved in the excessive electrical activity of seizures.[12]
Pharmacodynamics[edit]
In vitro, cannabidiol has low affinity for, and acts as a negative allosteric modulator on the CB1 cannabinoid receptor[81][82]
Cannabidiol may be an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor shown by in vitro studies to be widely distributed in the brain.[80][83][84] Cannabidiol may interact with various neurotransmitters, such as serotonin, dopamine, and GABA.[80][83][85]
Pharmacokinetics[edit]
The oral bioavailability of cannabidiol is approximately 6% in humans, while its bioavailability via inhalation is 11 to 45% (mean 31%).[13][14] The elimination half-life of cannabidiol in blood is 56 to 61 hours after oral doses twice per day over 7 days.[7] Cannabidiol is metabolized in the liver as well as in the intestines by cytochrome P450 enzymes.[7][83]
Pharmaceutical preparations[edit]
Nabiximols (brand name Sativex), an oromucosal spray made of a complex botanical mixture containing cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), and additional cannabinoid and non-cannabinoid constituents from cannabis sativa plants, was approved by Health Canada in 2005, to treat central neuropathic pain in multiple sclerosis, and in 2007, for cancer-related pain.[86] 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."[87]
Epidiolex (Epidyolex in Europe) is an orally administered cannabidiol solution.[7][12] It was approved in 2018 for treatment of two rare forms of childhood epilepsy, Lennox–Gastaut syndrome and Dravet syndrome, and seizures associated with tuberous sclerosis complex.[7][12] In the US, it is approved in these indications for people one year of age and older.[7]
Labeling and advertising[edit]
Studies conducted by the FDA from 2014 through 2019 have determined that a majority of CBD products are not accurately labeled with the amount of CBD they contain.[99] For example, a 2017 analysis of cannabidiol content in oil, tincture, or liquid vape products purchased online in the United States showed that 69% were mislabeled, with 43% having higher and 26% having lower content than stated on product labels.[100][54] In 2020, the FDA conducted a study of 147 CBD products and found that half contained THC.[99][101]
From 2015 to November 2022, the FDA issued dozens of warning letters to 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.[55] Chemical analysis of CBD products found that many did not contain the levels of CBD claimed in advertising.[55]
In December 2020, the Federal Trade Commission initiated a law enforcement crackdown on American companies marketing CBD products as unapproved drugs.[102][103] The warning also applied to hemp CBD capsules and oil that were being marketed illegally while not adhering to the federal definition of a dietary supplement.[103]
Legal status[edit]
Australia[edit]
Prescription medicine (Schedule 4) for therapeutic use containing two percent (2.0%) or less of other cannabinoids commonly found in cannabis (such as ∆9-THC). A Schedule 4 drug under the SUSMP is a 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.[122]
In June 2020, the Australian Therapeutic Goods Administration (TGA) published a consultation on a proposal to pave the way to make "low dose" CBD available to consumer/patients via pharmacists only through moving products from Schedule 4 to 3.[123] Any products sold would need to have their safety, quality and efficacy pre-assessed by the TGA and be formally approved for sale (details to be outlined by TGA). They would be made available to over 18s only, with the maximum daily dose of 60 mg/day, up to 2% THC finished product allowed, 30-day maximum supply, plant-derived or synthetic. This proposal is based on an initial literature review on the safety of low dose CBD published by the TGA in April 2020.[124] Epidyolex was approved for the adjunctive therapy of seizures associated with Lennox–Gastaut syndrome or with Dravet syndrome in September 2020.[2]
Bulgaria[edit]
In 2020, Bulgaria became the first country in the European Union to allow retail sales of food products and supplements containing CBD, despite the ongoing discussion within the EU about the classification of CBD as a novel food.[125] However, there exists a legal gap because of the lack of a legally-permissible minimum amount of THC in the products containing cannabinoids.[126]
Canada[edit]
In October 2018, cannabidiol became legal for recreational and medical use by the federal Cannabis Act.[127][128][129] As of August 2019, CBD products in Canada could only be sold by authorized retailers or federally licensed medical companies, limiting their access to the general public.[130] Nonetheless, with online delivery services and over 2,600 authorized cannabis retail stores as of October 2021, accessibility has steadily increased over time.[131][132] The Canadian government states that CBD products "are subject to all of the rules and requirements that apply to cannabis under the Cannabis Act and its regulations."[127] It requires "a processing licence to manufacture products containing CBD for sale, no matter what the source of the CBD is, and that CBD and products containing CBD, such as cannabis oil, may only be sold by an authorized retailer or licensed seller of medical CBD."[127] Edible CBD products were scheduled to be permitted for sale in Canada on October 17, 2019, for human consumption.[127]
As of August 2020, it was still illegal to carry cannabis and cannabis-derived products (including products containing CBD) across the Canadian border. If one carries any amount of cannabis for any purpose (including medical), it needs to be declared to the Canada Border Services Agency. Not declaring it is a serious criminal offence.[133]
Czech Republic[edit]
As of May 2023, the State Agricultural and Food Inspection of the Czech Republic is putting together broad regulations regarding a ban on CBD products.[134] They will make it illegal to sell products containing cannabidiol and other cannabinoids derived from hemp, as a result of EU Novel Food Regulation. In case of Czech Republic, European Industrial Hemp Association has submitted an official request to the Czech Republic to recognize natural hemp extracts with cannabinoids as traditional food.[135]