Recently, Cannabidiol (CBD) has gained a lot of buzz in the medical field. A lot of medical scientists and physicians have become interested in the application of CBD on treating different kinds of conditions due to its therapeutic properties. CBD is a non-intoxicating component that can be found in a cannabis plant. Its mechanisms on a molecular level are still being studied by numerous researchers in order to fully know its therapeutic capabilities. Since cannabidiol is considered a pleiotropic drug, it produces a lot of effects through different molecular pathways in the body and as of now, there are more than 65 molecular targets of CBD that has been identified in the scientific literature.
CBD has only a small affinity for the two cannabinoid receptors which are CB1 and CB2 but cannabidiol modulates a lot of other non-cannabinoid receptors and ion channels in the body. CBD also exerts its effects via different receptor-independent pathways. One example of these is by delaying the “reuptake” of different endogenous transmitters like anandamide and adenosine and by acting on certain G-protein coupled receptors in order to enhance or inhibit their binding properties.
Listed below are some of the ways that CBD can manifold its therapeutic effects.
Pioneering research about CBD and the neural correlates of anxiety has been undertaken by Jose Alexandre Crippa and some of his colleagues from the University of Sao Paulo in Brazile and King’s College in London. They found out that at high concentrations of CBD, the 5-HT1A (hydroxytryptamine) serotonin receptor is activated by CBD resulting in an anti-anxiety effect. This receptor is also involved in different biological and neurological processes including (but bnot limited to) anxiety, addiction, appetite, sleep, pain perception, nausea, and vomiting.
5-HT1A is included in the family of the 5-HT receptors that are activated by a neurotransmitter called serotonin. This family of receptors can be found in the central and peripheral nervous system and works by triggering different intracellular cascades in order to produce various chemical messages that results to an excitatory or inhibitory response depending on the chemical composition of the message.
The raw and unheated version of CBD that can be found in the cannabis plant is called CBDA or Cannabidiolic acid. This component has a strong affinity for the 5-HT1A receptor which is even stronger than that of CBD. Preclinical studies have shown that the CBDA hs a strong potential as a more effective anti-emetic than CBD or THC, both of which have anti-nausea properties.
CBD interacts with different ion channels in the body in order to produce therapeutic effects. An example of this is the TRPV1 receptors which also functions as ion channels. The CBD binds with the TPRV1 receptors which are known to mediate the perception of pain, inflammation and the temperature of the body.
TRPV stands for “transient receptor potential cation channel subfamily V” and is one of the many TRP (pronounced as “trip”) receptor variants or subfamilies that can influence the effects of different kinds of medicinal herbs.
TRPV1 is also called the “vanilloid receptor” by some scientist. Name after the vanilla bean which has an essential oil called eugenol that has antiseptic and analgesic properties. Aside from those, vanilla can also help unclog blood vessels. Vanilla has been used in different folk medicines throughout history as a cure for headaches.
The binding of CBD to TRPV1 can influence the perception of pain.
A pungent compound found in chili peppers called Capsaicin can also activate the TRPV1 receptor. The endogenous cannabinoid called Anandamide is also an agonist of TRPV1.
It is now known that cannabidiol directly activates the 5-HT1A receptor and various TRPV ion channels. Studies have shown that a G-protein-coupled receptor, on the other hand, is blocked or deactivated by cannabidiol. This receptor is known as GPR55.
Scientists have called GPR55 as an “orphan receptor” since scientists have not yet identified if it belongs to a larger family of receptors. The GPR55 is widely available in the brain especially in the cerebellum and is involved in different physiological processes such as modulating blood pressure and bone density.
GPR55 is known to promote that function of osteoclasts which are involved in bone reabsorption. It has been shown that GPR55 receptor that is overactive in signaling is associated with a bone condition called osteoporosis.
Based on a study in 2010 by researchers from the Chinese Academy of Sciences based in Shanghai, activated GPR55 receptor promotes the proliferation of different cancer cell and this receptor has been expressed in different types of cancer.
On the 2010 International Cannabinoid Research Society conference in Lund, Sweden, Ruth Ross, a scientist from the University of Aberdeen, exclaimed that CBD is a GPR55 antagonist. CBD works by blocking the signals of GPR55 which may lead to a decrease in bone reabsorption and a decrease in the proliferation of cancer cells.
PPARS – NUCLEAR RECEPTORS
CBD also activates PPARs also called peroxisome proliferator-activated receptors located on the surface of the cell nucleus thereby exerting its anti-cancer effects. The activation of PPAR-gamma is known to have an anti-proliferative effect and the ability to induce the regression of tumors in the cancer cell line in the human lungs. The activation of this receptor works by degrading a key molecule linked to the development of Alzheimer’s disease called beta-amyloid plaque. This is one of the reasons why it has been said the cannabidiol may be useful for patients with Alzheimer’s due to it being an agonist of the PPAR-gamma receptor.
Aside from those mentioned above, PPAR receptors are also involved in regulating genes associated with energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions of the body. According to this, diabetic patients may benefit from a treatment regimen rich with CBD.
CBD AS A REUPTAKE INHIBITOR
So how does CBD which is an exogenous plant compound able to find its way through the human body and bind to a nuclear receptor?
First, it rides with a fatty acid binding protein (FABP) in order to pass through the cell membrane. FABP chaperones various lipid molecules directly into the interior of the cell and also escort tetrahydrocannabinol (THC) and anandamide and 2AG, which are endocannabinoids functioning as the brain’s own marijuana-like molecules, into their own respective target areas in the cell. CBD and THC are both acting on receptors found in the surface of the nucleus which are involved in regulating gene expression and the activity of the mitochondria.
Scientists from the Stony Brook University have shown in their studies that CBD inhibits the reuptake and breakdown of anandamide which increases the endocannabinoid levels in the synapses of the brain. The enhancement of the endocannabinoids via reuptake inhibition may be the reason why CBD has neuroprotective effects against seizures and other therapeutic effects.
The anti-inflammatory and anti-anxiety effects of CBD can be partly attributed to the inhibition of the reuptake of adenosine. CBD is able to boost the levels of the adenosine in the brain by delaying the reuptake of the neurotransmitter since the brain regulates the activity of the adenosine receptors. A1A and A2A adenosine receptor are significant in cardiovascular function by regulating the oxygen consumption of the myocardial and the coronary blood flow. These receptors have wide anti-inflammatory effects throughout the whole body.
CBD AS AN ALLOSTERIC MODULATOR
The CBD can also enhance or inhibit the ability of a receptor to transmit a signal by changing its shape since CBD is also an allosteric receptor modulator.
Researches done by scientists from Australia have shown that CBD is a “positive allosteric modulator” of the GABA-A receptor. This means that CBD enhances the binding affinity of the GABA-A receptor for its major endogenous agonist which is the gamma-aminobutyric acid (GABA). GABA is found in the central nervous system of mammals and is considered as its main inhibitory neurotransmitter.
CBD has been also shown as a “negative allosteric modulator” of the cannabinoid CB1 receptor by Canadian scientists. The CB1 receptor can be found in the brain and central nervous system. Although cannabidiol does not directly bind with this receptor unlike THC, CBD interacts with it allosterically changing its shape in a way that weakens the binding capability of the CB1 receptor to THC.
CBD lowers the THC psychoactive ability since it is a negative allosteric modulator of the CB1 receptor. This means the users don’t get the usually get as “high” when using cannabis products rich in CBD compared to medicines rich in THC. Products rich in THC and have little THC component can have a lot of therapeutic benefits without getting its users “high” or have a dysphoric effect.