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Cannabidiolic acid (CBD-a) and Cannabidiols (CBD’s)

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There are now around 111 known natural cannabinoids as reported in the scientific literature. In 2005, researchers from the University of Mississippi published a detailed review of the then 70 known cannabinoids. They have since isolated and described about 28 more cannabinoid derivatives, and a couple were reported by a group in Italy. In 2015, University of Mississippi scientists discovered seven new naturally occurring cannabinoids.
Cannabidiolic acid (CBD-a)
Until recently, CBD-a was thought to be a minor cannabinoid, only a small part of the overall cannabinoid profile. However, higher amounts have been seen in ruderalis strains and some recent hybrids have exhibited elevated levels of CBD-a, at potentially higher than THC-a. Just like THC-a, when heated, CBD-a decarboxylates; as THC-a becomes THC, so CBD-a becomes CBD. Like CBD, CBD-a is not psychoactive.
Cannabinoids, when heated (smoked, vaporised or baked into edibles) decarboxylate (decarboxylated forms might be produced biosynthetically and while drying, but acidic forms are the major product). Decarboxylation products are Δ9-THC, CBD and CBC. The ‘first cannabinoid’ also decarboxylates, from CBG-a to CBG.
CBD-a’s therapeutic and medicinal values include:
♋Anti-emetic (reduces vomiting and nausea),
♋Anti-bacterial agent (slows growth of bacteria),
♋Anti-inflammatory (reduces inflammation systemically),
♋Anti-proliferative (inhibits cancer cell growth).
And while there hasn’t been much research done on CBD-a yet, the research that has been done is quite promising. Using the search term, Cannabidiolic acid,Google Scholar returns over 400 results for 2015 alone (1,420 since 2014 [over 10,000 all told]) and Science.gov (US federal government resource) returns 520 results (from over 16,000).
Cannabidiolic Acid (CBD-a)
 
CBD-a requires a temperature of 120°C (248°F) to decarboxylate and the LD50 (lethal dose) is 5,000 mg/kg (for rats) with a toxic concentration in humans (Inhalation TCLo, Toxic Concentration Low) of 15,000 mg/kg.
Cannabidiol (CBD)

The flowers and leaves of some ‘industrial’ hemp strains may be a viable source of CBD, but hemp is by no means an optimal source. Hemp typically contains far less CBD than CBD-rich cannabis. Huge amounts of industrial hemp are required to extract small amounts of CBD, raising the risk of toxic contaminants (hemp is a ‘bio-accumulator’; drawing heavy metals from the soil). Single-molecule CBD synthesised in a lab or extracted and refined from industrial hemp lacks critical medicinal terpenes and secondary cannabinoids found in cannabis strains. These compounds interact with CBD and THC to enhance their therapeutic benefits.

CBD indirectly stimulates endogenous cannabinoid signalling by suppressing the enzyme ‘fatty acid amide hydroxylase’ (FAAH). This enzyme breaks down anandamide, a naturally occurring endogenous cannabinoid neurotransmitter, or ‘endogenous ligand’ which binds CB1 receptors which are concentrated in the brain and central nervous system. Because FAAH is responsible for breaking down anandamide, less FAAH means more anandamide (and greater CB1 activation) in the body for longer. By inhibiting the enzyme that metabolises and destroys anandamide, CBD enhances the body’s innate protective endocannabinoid response. At the same time, CBD powerfully opposes the action of THC at the CB1 receptor, thereby muting the psychoactive effects of THC. CBD also stimulates the release of 2-AG, another endocannabinoid that activates both CB1 and CB2 receptors. CB2 receptors are predominant in the peripheral nervous and immune systems.

Several studies have documented CBD’s role as a PPAR-gamma agonist (peroxisome proliferator activated receptors, PPAR’s, a group of three nuclear receptors; PPAR-alpha, PPAR-gamma and PPAR-delta). Cannabidiol also promotes PPAR-alpha activity by inhibiting FAAH; the metabolic enzyme that breaks down several endogenous fatty acid compounds known as N-acylethanolamides. Two other N-acylethanolamides, N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), bind directly to PPAR-alpha. By suppressing the FAAH enzyme and increasing PEA and OEA levels, cannabidiol indirectly activates PPAR-alpha. Higher levels of PEA and OEA result in enhanced PPAR-alpha transmission. Deficient PPAR-alpha signalling has been linked to schizophrenia.
Whereas CBD does not bind to either of the two known cannabinoid receptors, it has been shown to directly interact with other, so-called ‘G-protein-coupled’ receptors, to confer its medicinal effect. CBD binds to the TRPV-1 receptor which is known to mediate pain perception, inflammation and body temperature. TRPV or ‘transient receptor potential cation channel subfamily V’ is referred to by scientists as the ‘vanilloid receptor’ (named after the vanilla bean). Vanilla contains eugenol, an essential oil that has antiseptic and analgesic properties which also helps unclog blood vessels. Historically, the vanilla bean has been used as a folk cure for headaches. Capsaicin (a vanilloid), the pungent compound in hot chilli peppers, is a well known activator of the TRVP-1 receptor. CBD is a TRPV-1 ‘agonist’ or stimulant and this seems to be one of the reasons why CBD-rich cannabis may be a particularly effective treatment for neuropathic pain.
There is also growing medical interest in the gene-regulating properties of CBD. In 2012, Israeli scientists identified more than 1,200 genes affected by CBD: 680 ‘gene transcripts’ were up-regulated (turned on) and 524 were down-regulated (turned off) by CBD in a probe that focused on CBD’s role in zinc homoeostasis. “The results show that CBD … affects the expression of genes involved in zinc homoeostasis and suggest that the regulation of zinc levels could have an important role through which CBD may exert its anti-oxidant and anti-inflammatory effects”, the Israeli research team concluded.
Studies indicate that CBD influences the expression of some genes by directly activating PPAR-gamma which has promising therapeutic implications, particularly with respect to cancer and metabolic disorders. PPAR’s are triggered by hormones, endogenous fatty acids and various nutritional compounds. When activated, PPAR’s bind to certain segments of DNA to promote or prevent transcription of specific genes. Many of the genes regulated by PPAR’s are involved in energy homoeostasis, lipid uptake and metabolism, insulin sensitivity and other metabolic functions. Big Pharma recognises the importance of these nuclear receptors. Thus far, two classes of pharmaceutical PPAR activators – fibrates and thiazolidinediones – have been approved by the US Food and Drug Administration.
CBD is usually taken orally as a cannabis-based concentrate or extract. However, compared to smoking or vaporising, ingesting cannabinoids orally poses a number of drawbacks, including inconsistent absorption and a delayed effect. Vaporising is considered a healthier alternative to smoking and decarboxylation is reached at 160-180°C (320-356°F). However, when vaporised, CBD produces dense vapour that can be irritating to the throat for some and generate significant coughing, with the vapours produced visibly different to the less dense vapours produced by THC.
Scientific and clinical studies underscore CBD’s potential as a treatment for a wide range of conditions. CBD’s therapeutic and medicinal values include:
Alzheimer’s Disease / Dementia / Memory Loss – CBD’s strong neuro-protective and anti-oxidative effects work together to counteract ageing in the brain,fighting off memory loss and dementia. In 2011, an Italian research team reported that PPAR-gamma activation degrades amyloid-beta plaque, a key molecule in the development of Alzheimer’s disease. Cardiovascular, autoimmune, neurological disorders, cancers and the ageing process itself are all thought to have free radicals as a causative agent. Further, they are implicated in the formation of protein amyloid plaques – plaques that can attack neural synapses and prevent normal chemical and electrical signalling. By binding up these free radicals, antioxidants can minimise the plaque formation cycle associated with the progression of Alzheimer’s disease.
Analgesic – relieves pain, including chronic and neuropathic.
Anti-bacterial agent – slows growth of bacteria.
♋ Anti-inflammatory – reduces inflammation systemically. “CBD affects the expression of genes involved in zinc homoeostasis and suggest that the regulation of zinc levels could have an important role through which CBD may exert its anti-oxidant and anti-inflammatory effects,” an Israeli research team concluded. Nutritional factors also influence PPAR signalling. At the 2013 International Cannabinoid Research Society Conference, Wageningen University (Netherlands) reported that the omega-3 fatty acid derivative docosahexaenoyl ethanolamine (DHEA) acts as an inhibitor of the COX-2 enzyme. So does CBD; this is one of the major reasons why CBD has potent anti-inflammatory properties. COX-2 is an enzyme that creates prostaglandins, a class of inflammatory compounds. Aspirin and all the other non-steroidal anti-inflammatory drugs are COX inhibitors.
♋ Anti-oxidant – prevents the damage of oxidation to other molecules in the body. The antioxidant properties of CBD exceed the antioxidant potency of either Vitamin C or E. CBD has been shown to be a potent anti-oxidant that mitigates the negative effects of oxygen free radicals. When combined with THC, the anti-oxidant properties of CBD grow even stronger. Once again, whole-plant cannabis therapeutics have been shown to be far greater than the sum of the herb’s individual medicinal components.
Angiogenesis (development of new blood vessels). According to a 2008 report by the University of Rome, both PPAR-alpha and PPAR-gamma agonists regulate angiogenesis, the creation of new blood vessels, particularly capillaries. In cancerous tumours, dysregulated angiogenesis leads to new blood vessels which provide tumours with nutrients, helping them to grow and metastasise. By directly activating PPAR-gamma and indirectly promoting PPAR-alpha activity, CBD may inhibit tumour angiogenesis. Three major complications associated with Diabetes Mellitus – retinopathy, neuropathy and nephropathy are all worsened by aberrant angiogenesis. Although numerous PPAR agonists have shown efficacy in preventing retinal angiogenesis, some studies report that activating PPAR’s can amplify angiogenesis. But the overall scientific consensus seems to be that PPAR-alpha and PPAR-gamma agonists prevent angiogenesis.
♋ Anti-diabetic – CBD is the only cannabinoid identified that helps lower blood sugar levels.
♋ Anti-emetic – reduces vomiting and nausea.
Anti-epileptic – reduces seizures and convulsions. In October 2013, the US FDA approved two clinical trials assessing the therapeutic uses of CBD in treating intractable epilepsy in children (Dravet Syndrome). The CBD preparations were made by British pharmaceutical company GW Pharmaceuticals. Dravet is a rare seizure disorder wherein children usually suffer their first intractable seizure before their first birthday and in exceptional cases seizures can last over 24 hours. In Australia, whole, organic cannabis extracts for intractable forms of epilepsy have been formulated from high-CBD cannabis strains that also include THC (‘Entourage Effect’).
♋ Anti-insomnia – aids with sleep.
♋ Anti-ischemic – CBD is the only cannabinoid identified that reduces the risk of artery blockage.
♋ Anti-proliferative – inhibits the growth of tumours / cancer cells. A study published in 2007 showed that CBD inhibited a particular gene, Id-1, which is responsible for the growth of cancer cells in the body. By inhibiting this gene CBD shuts down the growth of cancer cells, potentially stopping or even reversing tumour growth. Researchers at the California Pacific Medical Center have shown that CBD reduces brain cancer and breast cancer cell proliferation and metastasis by inhibiting the expression of the Id-1 gene. GPR55, a G protein-coupled receptor that some researchers postulate may actually be a third cannabinoid receptor type (CB-3?), when activated, promotes cancer cell proliferation, according to a 2010 study by researchers at the Chinese Academy of Sciences. CBD is a GPR55 antagonist, as University of Aberdeen discovered, also in 2010. By blocking GPR55 signalling, CBD might act to decrease both bone re-absorption and cancer cell proliferation. This is one of many molecular pathways through which CBD exerts an anti-cancer effect. Best results were obtained when CBD was administered in combination with THC. ID-1 expression is implicated in several kinds of aggressive cancer.

Anti-psioratic – CBD is the only cannabinoid identified to treat psoriasis.

♋ Anti-psychotic – tranquilising effects relieve symptoms of psychosis; two terpenoids, Linalool and Myrcene, also help. CBD is a powerful anti-psychotic currently being considered for use in treating schizophrenia and other psychoses. CBD appears to have a very similar chemical profile to certain atypical anti-psychotic drugs. PPAR-alpha agonists in particular are indicated as an adjunct treatment for schizophrenia. Polymorphisms or mutations in the gene encoding PPAR-alpha are associated with schizophrenia. Furthermore, PPAR-alpha activation is both anti-inflammatory and can decrease dopamine release, thereby minimising schizophrenic symptoms. This may help to explain how and why CBD has anti-psychotic effects.

♋ Anti-spasmodic – suppresses muscle spasms.

♋ Anxiolytic (anti-anxiety) / Anti-depressant – CBD is the only cannabinoid identified that relieves anxiety, but two terpenoids also help (Linalool and Limonene). CBD may exert its anti-anxiety effect by activating adenosine receptors. Adenosine receptors play significant roles in cardiovascular function, regulating myocardial oxygen consumption and coronary blood flow. The adenosine (A2A) receptor has broad anti-inflammatory effects throughout the body. Adenosine receptors also play a significant role in the brain as they down-regulate release of other neurotransmitters (dopamine and glutamate). CBD also stimulates the 5-HT1a (hydroxytryptamine) receptor in the brain involved in the re-uptake of serotonin and other processes that aid depression and anxiety. The anti-depressant properties of CBD are very similar to the trycyclic anti-depressant Imipramine (also being evaluated for panic disorder). At the University of San Paulo in Brazil and King’s College in London, pioneering research into CBD and the neural correlates of anxiety have been studied. At high concentrations, CBD directly activates the 5-HT1A serotonin receptor, thereby conferring an anti-depressant effect. This receptor is implicated in a range of biological and neurological processes, including, but not necessarily limited to, anxiety, addiction, appetite, sleep, pain perception, nausea and vomiting. 5-HT receptors are activated by the neurotransmitter serotonin, found in both the central and peripheral nervous systems. 5-HT receptors trigger various intracellular cascades of chemical messages to produce either an excitatory or inhibitory response, depending on the chemical context of the message. CBD triggers an inhibitory response that slows down 5-HT1A signalling. In comparison, LSD, mescaline, magic mushrooms and several other hallucinogenic drugs activate a different type of 5-HT receptor that produces an excitatory response.
♋ Bone Stimulant – promotes bone growth. Some studies indicate that CBD may function as an antagonist that blocks, or deactivates, GPR55 which is widely expressed in the brain, especially in the cerebellum. It is involved in modulating blood pressure and bone density. GPR55 promotes osteoclast cell function, which facilitates bone re-absorption; over-active GPR55 receptor signalling is associated with osteoporosis.
♋ Immunosuppressive – CBD is the only cannabinoid identified that reduces function in the immune system.
Inflammatory Bowel Disease (Syndrome) / Crohn’s Disease – CBD shows a lot of promise for controlling the inflammatory responses and discomfort caused by Crohn’s disease and IBD/IBS. CBD has so much potential to regulate these diseases that it is being considered for a new class of IBD drugs.
♋ Intestinal Anti-prokinetic – CBD is the only cannabinoid identified that reduces small intestine contractions.
Neuroprotective – slows damage to the nervous system and brain.
Obesity and Metabolic Syndrome – most genes regulated by PPAR’s (peroxisome proliferator activated receptors) are involved with lipid metabolism and energy storage. PPAR activation typically promotes glycolysis (glucose breakdown), lipolysis (lipid breakdown) and insulin sensitivity. These properties make PPAR activation a promising treatment for Type II Diabetes and obesity. The PPAR-activating drugs, fibrates and thiazolidinediones (PPAR-alpha agonists and PPAR-gamma agonists, respectively) have been approved to treat dyslipidemia (obesity) and insulin insensitivity in Type II Diabetics by the US FDA.
♋ Vasorelaxant – CBD is the only cannabinoid identified that reduces vascular tension.
List of Conditions treatable with Cannabidiol (Project CBD)

A search for ‘Cannabidiol’ in the US National Library of Medicine National Institutes of Health website, ‘PubMed’, returns 1,341 results. If you need more examples of research into CBD, check out Cannabis Research A-Z and/or CBD Research and Studies from ‘Medical Jane’.
This is Part 2 of a four-part series on a lot of what is currently known about cannabinoids and covers one of the three major branches; Cannabidiols (CBD’s) including Cannabidiolic acid (CBD-a). Part 1 covered CBG-a, The Precursor, and CBG. Part 3 will cover another of the three major branches of cannabinoids; Cannabichromenes (CBC’s), including Cannabichromenic acid (CBC-a).


Reference sources included;

Study:New Cannabinoids Discovered
Safety Data Sheet-CBDa
A Chemotaxonomic Analysis of Cannabinoid Variation in Cannabis (Cannabaceae)
How Cbd Works Within Cells
Cannabinoid Profile CBDa
Cannabinoid Profile – CBD
How CBD Works

GPR55 
Cannabinoid Profile CBG
Granny Storm Crows List 2015

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