We now know that Cannabidiol (CBD) is an amazing chemical for its many brain-related benefits. Put simply, it is the Legal and Non-Hallucinatory Component of the drug Marijuana (dope, hashish, weed, etc) And, we are learning how and why it works beneficially through our emerging understanding of how the brain works, and how it is a substance whose chemical make-up closely mimics an important brain chemical.
Cannabidiol (CBD) What We Know and What We Don’t
It 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. As of 2019, clinical research on CBD included studies related to anxiety, cognition, movement disorders, and pain, but there is insufficient high-quality evidence that cannabidiol is effective for these conditions.
Keep reading to find out: “What is Cannabidiol (CBD)?”
How to Take Cannabidiol Tablets
Cannabidiol can be taken in multiple ways, including by inhalation of cannabis smoke or vapour, as an aerosol spray into the cheek, and by mouth. It may be supplied as CBD oil containing only CBD as the active ingredient (excluding tetrahydrocannabinol [THC] or terpenes), CBD-dominant hemp extract oil, capsules, dried cannabis, or 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[update], the mechanism of action for its biological effects has not been determined.
In the United States, the cannabidiol drug Epidiolex has been approved by the Food and Drug Administration
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 under federal law to prescribe for medical use or to use as an ingredient in dietary supplements or other foods.
Cannabidiol is the generic name of the drug and its INN. As of 2019 there was been limited high-quality evidence for cannabidiol having a neurological effect in people.
Prescription Cannabidiol (Epidiolex)
In the United States, prescription cannabidiol (Epidiolex) is indicated for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex in people one year of age and older. While Epidiolex treatment is generally well tolerated, it is associated with minor adverse effects, such as gastrointestinal upset, decreased appetite, lethargy, sleepiness and poor sleep quality.
CBD Use as an Adjunctive Therapy of Seizures
In the European Union, cannabidiol (Epidyolex) is indicated for use as adjunctive therapy of seizures associated with Lennox Gastaut syndrome (LGS) or Dravet syndrome (DS), in conjunction with clobazam, for people two years of age and older. In 2020, the label for Epidiolex in the U.S. was expanded to include seizures associated with tuberous sclerosis complex. Epidiolex/Epidyolex is the first prescription formulation of plant-derived cannabidiol approved by regulatory bodies in the U.S. and Europe.
In 2020, the label for Epidiolex in the U.S. was expanded to include treatment of seizures associated with tuberous sclerosis complex.
Research on Possible Benefits of CBD to certain Neurological Disorders
Research on other uses for cannabidiol includes several neurological disorders, but the findings have not been confirmed 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.
Many claims are made for the therapeutic benefit of cannabidiol that is not backed by sound evidence. Some claims – for example that cannabidiol can be used to treat cancer – fall into the realm of pseudoscience.
What We’re Working to Find Out About Products Containing Cannabis or Cannabis-derived Compounds, Including CBD
Cannabidiol does not appear to have any intoxicating effects (i.e. “getting high”) such as those caused by ∆9-THC in marijuana, but it is under preliminary research for its possible anti-anxiety and anti-psychotic effects. As the legal landscape and understanding about the differences in medical cannabinoids unfold, 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.
FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)
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 US 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.
Standards for High Quality Natural CBD are Lacking
Certain standards are required for legal growing, cultivating, and producing the hemp plant, but there are no federal standards for quality being enforced in the hemp industry. Certain state regulations are in place, but vary state to state. For instance, 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%. This is essential to the definition of What is Cannabidiol (CBD).
CBD May Reduce Adverse Effects of THC Use
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.
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 manner. In vitro, cannabidiol inhibited 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.
Unanswered Questions About the Science, Safety, and Quality
The number of research projects and scientific publications on Cannabidiol and other cannabinoids in pets, surged in the late 2010's.
As of December 2020, there are no hemp-derived, cannabinoid-rich registered veterinary medicinal products in any of the major regions (see Legal status across countries).
In the USA and other territories, there are, however, numerous veterinary nutraceutical products available OTC. The lack of clarity in the regulations governing veterinary hemp food supplements allows for products of questionable quality to flood the market, 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
CBD's ability to help regulate the Endocannabinoid System, and reduce the release of excitatory neurotransmitters would result in a retrograde inhibitory signal that lessens chronic pain responses. Studies in dogs suffering from chronic pain associated with osteoarthritis showed an increase in the level of activity in animals receiving CBD-rich food supplements.
The nature of these products means that since the outcome of each study is dose, strain, product and presentation-specific they should not be generalized. Still, most researchers coincide in that although more research is needed, cannabinoids have shown to be a valuable resource in canine chronic pain management.
Is CBD Safe for Pets Including Dogs?
From the results seen in humans with drugs such as Epidyolex and Sativex, scientific studies and reviews, 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. Further research in this area is required before any clear conclusion could be drawn.
As in humans, some results on CBD helping manage some forms of anxiety in dogs have been reported.
The oral bioavailability of CBD varies greatly across species and it is linked to the presentation and the time of administration. A 24-h kinetic examination in dogs showed that the absorption of the cannabidiolic acid (CBDA) does occur and that this molecule is absorbed at least twice as well as CBD post oral ingestion.
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, suggesting that canine and human CBD metabolic route might be somewhat different.
Increases in Alkaline Phosphatase (ALP) have been reported in various canine studies. A 39-week study in dogs evaluating doses of 0, 10, 50 and 100mg of CBD/kg reported an increase of up to 8x in the ALP in the 100mg/Kg group; and of up to 1.5x in Alanine Aminotransferase (ALT) in the 50mg/Kg and 100mg/Kg groups. However, there were no clinical signs associated with these results.
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 GPR3, GPR6, and GPR12. CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist. It is an allosteric modulator of the m- and d-opioid receptors as well. The pharmacological effects of CBD may involve PPARg agonism, inhibition of voltage-gated cation channels, and intracellular calcium release.
Oral Bioavailability of Cannabidiol
The oral bioavailability of cannabidiol 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 the cytochrome P450 enzymes CYP2B6, CYP2C19, CYP2D6, CYP2J2, and CYP3A4, and by the isoenzymes UGT1A7, UGT1A9, and UGT2B7. CBD may have a wide margin in dosing.
CBD Was Approved by Health Canada in 2005 to Treat Central Neuropathic Pain in Multiple Sclerosis
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.
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.”
An Orally Administered Cannabidiol Solution Approved by FDA for 2 Rare Forms of Childhood Epilepsy
Epidiolex is an orally administered cannabidiol solution. It was approved in 2018 by the US Food and Drug Administration (FDA) for treatment of two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, and seizures associated with tuberous sclerosis complex. In the U.S., it is approved in these indications for patients one year of age and older.
What is Cannabidiol (CBD) Chemical Physics
At room temperature, cannabidiol 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, but not during combustion (smoking). The synthesis of cannabidiol has been accomplished by several research groups.
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.
Efforts to isolate the active ingredients in cannabis were made in the 19th century. Cannabidiol 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.
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