Cannabidiol (CBD) comes from the cannabis plant and is non-intoxicating. Notice that we did not say it is not psychoactive, since the definition of psychoactive means ‘affecting the mind’ and we know that CBD can affect our mood and alertness. In recent years, CBD has generated significant interest among scientists and physicians. How CBD exerts if impact, however, is still being sorted out in the lab. Being pleiotropic, it produces many effects through the more than 65 molecular targets that scientist have identified.
There are many receptors found on every cell membrane in the body, which act like gatekeepers to the sell. Ligands are the counterparts that fit into those receptors, similar to a lock and key. Cannabidiol is one of those ligands which also modulates several non-cannabinoid receptors and ion channels. It also acts through various receptor-independent pathways. Examples of this are delaying the reuptake of endogenous neurotransmitters such as anandamide and adenosine and enhancing or inhibiting the binding actions of certain G-protein coupled receptors.
The endocannabinoid system (ECS) is one of the many receptor systems in our bodies. It is present in all vertebrates (organisms with a back bone), therefore it is not unique to humans. The ECS is present on almost every cell type in the body, including the central nervous system, and it is thought to regulate appetite, pain sensation, mood, memory, and more. It is also thought to be important in regulating our immune system and inflammation.
The endocannabinoid system is composed of:
Two endocannabinoids (anandamide and 2-arachidonlyglycerol)
The enzymes that synthesize and degrade endocannabinoids.
Two receptors, CB1 and CB2 (cannabinoid type 1 and type 2 receptors)
There are over 100 cannabinoids documented in the cannabis plant, which consists of 3 species: Cannabis sativa, Cannabis indica, and Cannabis Ruderalis. Originally grown in the Western world, the sativa variants were grown for fiber, oil, and to feed animals. Hemp, which has less than 0.3% TCH, is no longer a controlled substance, and has a high CBD to THC ratio. Marijuana has a much higher THC content, generally between 2 and 20 percent.
“Medicinal preparation from the flowers and resin of Cannabis sativa have been used in China since ~2700 B.C. to treat menstrual disorder, gout, rheumatism, malaria, constipation, and absent-mindedness. In medieval times, Islamic physicians use cannabis to treat nausea and vomiting, epilepsy, inflammation, pain, and fever. Western medicine used cannabis widely in the 1800’s: before it was a common analgesic drug.” (Devinskiy et al., 2014)
At lower doses, the sympathetic system is activated, and those lower doses are thus considered ‘activating’. At these lower doses, the parasympathetic nervous system is decreased, leading to an increase in heart rate and mild increase in blood pressure. At higher doses, the parasympathetic system is activated, and the sympathetic system is decreased, resulting in lower blood pressure and slower heart rate.
CB1 receptors are mostly found on the cells of the central nervous system which consists of the brain, spinal cord, and peripheral nerves. THC is a partial agonist of the CB1 receptor, which means it only partially activates the receptor. CBD was once thought to be an inactive part of the cannabis plant since it did not cause the high associated with its use. It is still often described as being non-psychoactive, which was discussed above.
CB2 receptors are distributed amongst a majority of tissues, including the immune regulatory organs, including the spleen, tonsils, and thymus.
CBD indirectly increases the endocannabinoid anandamide by inhibiting the enzyme FAAH. FAAH job is to break down anandamide. By decreasing its breakdown, this leaves more anandamide available to interact with CB1 and CB2 receptors.
Several studies showed that cannabinoids down-regulate cytokine and chemokine production and, in some models, up-regulate T-regulatory cells as a mechanism to suppress inflammatory responses
Thanks to the work of Jose Alexandre Crippa and colleagues and the University of San Paulo in Brazil and King’s College in London, we know that CBD directly activates the 5-HT1A (hydroxytryptamine) serotonin receptor and conveys analgesic and anti-anxiety effect. This G-coupled protein receptor is involved in a wide range of biological and neurological processes, which include anxiety, addiction, appetite, sleep, pain perception, nausea, vomiting, and more.
5-HT1A is a member of the 5-HT receptor family, which are activated by serotonin. These receptors are found in both the central and peripheral nervous system and trigger various chemical cascades to produce an excitatory or inhibitory response, depending on the chemical context of the message.
CBDA (Cannabidiolic acid) is the raw, unheated version of CBD and was also thought to be inactive but it is now known it has a high affinity for the 5-HT1A Receptor (even more than CBD). Preclinical studies also indicate that CBDA is a potent anti-emetic. Unrelated to Serotonin, results of the current investigation revealed that CBDA inhibits migration of the highly invasive MDA-MB-231 human breast cancer cells, apparently through a mechanism involving inhibition of cAMP-dependent protein kinase A, coupled with an activation of the small GTPase, RhoA.
CBD interacts with various ion channels to give therapeutic effects, including its interaction with the TRPV1 receptor, which also functions as an ion channel. This receptor/ion channel is known to mediate pain perception, inflammation, and body temperature.
TRPV is the technical abbreviation for “transient receptor potential cation channel subfamily V.” It is one of sever dozen TRP (pronounced ‘trip’) receptor subfamilies that mediate the effects of a wide range of medicinal herbs. It is called a vanilloid receptor, named after the vanilla bean, which contains eugenol, an essential oil that has antiseptic and analgesic properties. Vanilla bean has been used historically as a folk cure for headaches.
CBD binds TRPV1, which can influence pain perception. Capsaicin (pungent compound in hot chili peppers) also activates TRVP1 receptors. Anandamide, the endogenous cannabinoid, is also an agonist of TRPV1 receptors.
GPR55 ORPAN RECEPTORS
Some studies indicate that CBD functions as an antagonist that blocks, or deactivates, the G protein-coupled receptor known as GPR55. It has been dubbed an ‘orphan receptor’ because scientist are still unsure if it belongs to a larger family of receptors. GPR55 is expressed in the brain, especially the cerebellum. It’s thought to be involved in modulating blood pressure and bone destiny, among other physiological processes.
When GPR55 is activated, it promotes cancer cell proliferation according to a 2010 study by researchers at the Chinese Academy of Sciences in Shanghai. It is expressed in various types of cancer. CBD is a GPR55 antagonist. By blocking GPR55, CBD may act to decrease both bone resorption and cancer cell proliferation.
PPARS NUCLEAR RECEPTORS
CBD may also exert anti-cancer effects by activating PPARs (peroxisome proliferator activated receptors) that are on the surface of the cells nucleus. By activating PPAR-gamma, anti-proliferative effects are promoted, as well as the ability to induce tumor regression in cancer cell lines. PPAR-gamma activation degrades amyloid-beta plaque, which is a key molecule linked to the development of Alzheimer’s disease. PPAR receptors also regulate genes involved in energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic function, which could mean benefits for those with diabetes.
CBD AS A REUPTAKE INHIBITOR
CBD must first pass through the cell membrane by utilizing a fatty acid binding protein (FABP), which helps transport various lipid molecules into the cell’s interior. They also transport TCH and the other endocannabinoids, anandamide and 2AG. CBD and THC both modulate receptors on the surface of the nucleus that regulate gene expression and mitochondrial activity.
CBD may also exert anti-cancer effects by activating PPAR on the surface of the cell nucleus, since it has a strong affinity for three kinds of FABP. Once inside the cell, anandamide is broken down by fatty acid amide hydrolase (FAAH), an enzyme, as part of is life cycle. CBD interferes with this process by reducing anandamide’s access to FABP transport molecules, thus delaying endocannabinoid passage into the cell’s interior.
Researchers at Stony Brook University state that CBD functions as an anandamide reuptake inhibitor, which leads to increased levels of anandamide. Reuptake inhibition may be a key mechanism by which CBD confers neuroprotective effects against seizure, as well as other health benefits.
The anti-inflammatory and anti-anxiety effects are attributed to its inhibition of adenosine reuptake. By delaying adenosine reuptake, levels are boosted in the brain. A1A and A2A adenosine receptors play significant roles in cardiovascular function, regulating myocardial oxygen consumption, and coronary blood flow.
CBD AS AN ALLOSTERIC MODULATOR
CBD also acts as an allosteric modulator, which means it can enhance OR inhibit how a receptor transmits signal by changing the shape of the receptor. Some Australian scientists report that CBD acts as a positive allosteric modulator of the GABA-A receptor, which means it enhances the receptors binding affinity for gammaAminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system. The sedating effects of medications alike Valium and other benzodiazepines are mediated by GABA receptors transmission. By changing the shape of the GABA-A receptor the natural calming effects of GABA are amplified, thus CBD reduces anxiety.
CBD also acts as a negative allosteric modulator of the CB1 receptor. CBD does not bind the CB1 receptor directly, but it does interact allosterically and changes the shape of the CB1 receptor which weakens CB1’s ability to bind THC. This leads to a decreased high when using CBD rich cannabis.