Cannabidoil

Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants and accounts for up to 40% of the plant's extract. In 2018, clinical research on cannabidiol included preliminary studies of anxietycognitionmovement disorders, and pain.

Cannabidiol can be taken into the body in multiple ways, including by inhalation of cannabis smoke or vapor, as an aerosol spray into the cheek, and by mouth. It may be supplied as CBD oil containing only CBD as the active ingredient (no included tetrahydrocannabinol [THC] or terpenes), a full-plant CBD-dominant hemp extract oil, capsules, dried cannabis, or as a prescription liquid solution. CBD does not have the same psychoactivity as THC, and may change the effects of THC on the body if both are present. As of 2018, the mechanism of action for its biological effects has not been determined.

In the United States, the cannabidiol drug Epidiolex was approved by the Food and Drug Administration in 2018 for the treatment of two epilepsy disorders. Since cannabis is a Schedule I controlled substance in the United States, other CBD formulations remain illegal to prescribe for medical use or to use as an ingredient in foods or dietary supplements.

Medical uses

Epilepsy

See also: Charlotte's web (cannabis)

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.

In the United States, the cannabidiol drug Epidiolex was approved by the Food and Drug Administration (FDA) in 2018 for treatment of epilepsy associated with Lennox–Gastaut syndrome or Dravet syndrome in patients 2 years of age and older.

Other uses

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. In October 2019, the FDA issued an advisory warning that the effects of CBD during pregnancy or breastfeeding are unknown, indicating that the safety, doses, interactions with other drugs or foods, and side effects of CBD are not clinically defined, and may pose a risk to the mother and infant.

Side effects

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.

Potential interactions

Laboratory evidence indicated that cannabidiol may reduce THC clearance, increasing plasma concentrations which may raise THC availability to receptors and enhance its effect in a dose-dependent mannerIn vitro, cannabidiol inhibited receptors affecting the activity of voltage-dependent sodium and potassium channels, which may affect neural activity. A small clinical trial reported that CBD partially inhibited the CYP2C-catalyzed hydroxylation of THC to 11-OH-THC. Little is known about potential drug interactions, but CBD-mediates a decrease in clobazam metabolism.

Pharmacology

Pharmacodynamics

Cannabidiol has low affinity for the cannabinoid CB1 and CB2 receptors, although it can act as an antagonist of CB1/CB2 agonists despite this low affinity. Cannabidiol may be an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It also may act as an inverse agonist of GPR3GPR6, and GPR12. CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist. It is an allosteric modulator of the μ- and δ-opioid receptors as well. The pharmacological effects of CBD may involve PPARγ agonism and intracellular calcium release.

Pharmacokinetics

The oral bioavailability of CBD is approximately 6% in humans, while its bioavailability via inhalation is 11 to 45% (mean 31%). The elimination half-life of CBD is 18–32 hours. Cannabidiol is metabolized in the liver as well as in the intestines by CYP2C19 and CYP3A4 enzymes, and UGT1A7UGT1A9, and UGT2B7 isoforms. CBD may have a wide margin in dosing.

Pharmaceutical preparations

Nabiximols (brand name Sativex), a patented medicine containing CBD and THC in equal proportions, was approved by Health Canada in 2005 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."

Epidiolex is an orally administered cannabidiol solution. It was approved in 2018 by the US Food and Drug Administration for treatment of two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome.

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, which also occurs during pyrolysis (smoking). The synthesis of cannabidiol has been accomplished by several research groups.

Biosynthesis

Cannabidiol and THC biosynthesis

Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the next to last step, where CBDA synthase performs catalysis instead of THCA synthase.

Isomerism

See also: Tetrahydrocannabinol § Isomerism, and Abnormal cannabidiol

Cannabidiol numbering

Cannabidiol's 7 double bond isomers and their 30 stereoisomers show

History

Efforts to isolate the active ingredients in cannabis were made in the 19th century. CBD was studied in 1940 from Minnesota wild hemp and Egyptian Cannabis 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.

Society and culture

Names

Cannabidiol is the generic name of the drug and its INN.

Food and beverage

cbd-infused cold brew coffee and tea from kickback cold brew

An example of beverages claiming to contain CBD in a Los Angeles grocery.

Food and beverage products containing CBD were introduced in the United States in 2017. 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.

Plant sources

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.

Non-psychoactivity

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%.

CBD and sport

CBD has been used by athletes and sportspeople in different disciplines. UKAD says that, "CBD is not currently listed on the World Anti-Doping Agency’s Prohibited List. As a result, it is permitted to use in sport. All other cannabinoids (including but not limited to cannabis, hashish, marijuana, and THC) are prohibited in-competition. The intention of the regulations is to prohibit cannabinoids that activate the same receptors in the brain as activated by THC."

Legal status

United Nations

Cannabidiol is not scheduled under the Convention on Psychotropic Substances or any other UN drug treaties. In 2018, the World Health Organization recommended that CBD remain unscheduled.

 

United States

As of October 2019, CBD extracted from marijuana remains a Schedule I Controlled Substance, and is not approved as a prescription drugdietary supplement, or allowed for interstate commerce in the United States. CBD derived from hemp (with 0.3% THC or lower) is legal to sell as a cosmetics ingredient but 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 physician'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 physician's recommendation. As of October 2019, CBD was not a FDA-approved drug eligible for interstate commerce.

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 October 2019. 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.

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.

2018 Farm Bill and hemp

The 2014 Farm Bill legalized the sale of "non-viable hemp material" grown within states participating in the Hemp Pilot Program which defined hemp as cannabis containing less than 0.3% of THC. Although the 2018 United States Farm Bill led some states to interpret the bill as enabling private farmers to grow hemp for extraction and retail of CBD, federal agencies – including the FDA and DEA – retained regulatory authority over hemp-derived CBD as a Schedule I substance. By federal law, private enterprises developing hemp-derived CBD are obligated to cultivate hemp exclusively for industrial purposes, which involve the fiber and seed, but not the flowering tops which contain THC and CBD. Hemp CBD products may not be sold into general commerce, but rather are allowed only for research. The 2018 Farm Bill requires that research and development of CBD for a therapeutic purpose would have to be conducted under notification and reporting to the FDA.

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."

In October 2019, the FDA and Federal Trade Commission announced a joint warning to a Florida supplements company marketing CBD products as unapproved drugs to treat childhood autismattention-deficit hyperactivity disorderParkinson’s diseaseAlzheimer’s diseaseacne, and infant teething and ear aches. 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.

Mislabeling and poisoning

A 2017 analysis of CBD 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.

As of September 2019, 1,085 people contacted US poison control centers about CBD-induced illnesses, doubling the number of cases over the 2018 rate and increasing by 9 times the case numbers of 2017. Of cases reported in 2019, more than 33% received medical attention and 46 people were admitted to a hospital intensive care unit.

 

Research

As of 2019, there was only limited high-quality evidence for cannabidiol having a neurological effect in people, mainly due to the weak design and small number of subjects in randomized controlled trials.