Our body’s endocannabinoid system was found to be directly involved in the processes that keep our bodies balanced day to day, including: appetite, pain sensation, mood, memory, immune system functions, and inflammation control. Essentially, the system helps to manage homeostasis, balancing our body’s natural conditions. This system is made up of receptors that are located in the brain and nervous systems throughout the body.
The reason that (phyto) cannabinoids have effects within the body is, in large part, because we have an endocannabinoid system (ECS) that they can interact with.
It’s important to remember that molecules like cannabinoids and other neurotransmitters rarely interact with only one receptor type; they often interact with many. The plant-based cannabinoid CBD illustrates this nicely, as it interacts with numerous receptor types in the brain. So, while plant cannabinoids may activate the same cannabinoid receptors as endocannabinoids, they will likely interact with several other receptors and therefore have distinct effects.
CBD is also interesting because it can affect overall levels of endocannabinoids in the brain, referred to as “endocannabinoid tone.” CBD inhibits the FAAH enzyme, which breaks down anandamide. Thus, CBD can increase anandamide levels by preventing FAAH from breaking it down.
The body creates its own cannabinoids, called endocannabinoids, to help support this regulatory system. CBD supplements these naturally created endocannabinoids to keep the receptors working at optimal capacity. Similar to how we use vitamin C to kick start our immune system, CBD acts as a kick starter to help the functions of the body’s central regulatory system, which is the ECS.
Cannabidiol (CBD), a non-intoxicating component of the cannabis plant, has generated significant interest among scientists in recent years—but how CBD exerts its wellness impact on a molecular level is still being fully figured out. Cannabidiol is a pleiotropic substance in that it produces many effects through multiple molecular pathways. The scientific literature has identified more than 65 molecular targets of CBD.
Although CBD has little binding affinity for either of the two cannabinoid receptors (CB1 and CB2), cannabidiol modulates several non-cannabinoid receptors and ion channels. CBD also acts through various receptor-independent pathways—for example, by delaying the “reuptake” of endogenous neurotransmitters (such as anandamide and adenosine) and by enhancing or inhibiting the binding action of certain G-protein coupled receptors.
Here are some of the ways that CBD confers its manifold wellness benefits.
Jose Alexandre Crippa and his colleagues at the University of San Paulo in Brazil and King’s College in London have conducted pioneering research into CBD and the neural correlates of anxiety. At high concentrations, CBD directly activates the 5-HT1A (hydroxytryptamine) serotonin receptor. This G-coupled protein receptor is implicated in a range of biological and neurological processes..
5-HT1A is a member of the family of 5-HT receptors, which 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.
CBDA [Cannabidiolic acid], the raw, unheated version of CBD that is present in the cannabis plant, also has a strong affinity for the 5-HT1A receptor (even more so than CBD).
CBD directly interacts with various ion channels. CBD, for example, binds to TRPV1 receptors, which also function as ion channels. TRPV1 is known to mediate pain perception, inflammation and body temperature.
TRPV is the technical abbreviation for “transient receptor potential cation channel subfamily V.” TRPV1 is one of several dozen TRP (pronounced “trip”) receptor variants or subfamilies that mediate the effects of a wide range of medicinal herbs.
Scientists also refer to TRPV1 as a “vanilloid receptor,” named after the flavorful vanilla bean. Vanilla contains eugenol, an essential oil that has antiseptic and analgesic properties; it also helps to unclog blood vessels. Historically, the vanilla bean has been used as a folk cure for headaches.
CBD binds to TRPV1, which can influence pain perception.
Capsaicin—the pungent compound in hot chili peppers—activates the TRVP1 receptor. Anandamide, the endogenous cannabinoid, is also a TRPV1 agonist.
Whereas cannabidiol directly activates the 5-HT1A serotonin receptor and several TRPV ion channels, some studies indicate that CBD functions as an antagonist that blocks, or deactivates, another G protein-coupled receptor known as GPR55.
GPR55 has been dubbed an “orphan receptor” because scientists are still not sure if it belongs to a larger family of receptors. GPR55 is widely expressed in the brain, especially in the cerebellum. It is involved in modulating blood pressure and bone density, among other physiological processes.
GPR55 promotes osteoclast cell function, which facilitates bone reabsorption. Overactive GPR55 receptor signaling is associated with osteoporosis.
GPR55, when activated, also promotes cancer cell proliferation, according to a 2010 study by researchers at the Chinese Academy of Sciences in Shanghai. This receptor is expressed in various types of cancer.
CBD is a GPR55 antagonist.
PPARs – nuclear receptors
CBD also infers effects by activating PPARs [peroxisome proliferator activated receptors] that are situated on the surface of the cell’s nucleus. Activation of this receptor known as PPAR-gamma, has an anti-proliferative effect as well as an ability to induce tumor regression in human lung cancer cell lines. PPAR-gamma activation degrades amyloid-beta plaque. This is one of the reasons why cannabidiol, a PPAR-gamma agonist, may be a useful supplement for wellness.
PPAR receptors also regulate genes that are involved in energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions.
CBD as a reuptake inhibitor
How does CBD, an exogenous plant compound, get inside a human cell to bind to a nuclear receptor? First it has to pass through the cell membrane by hitching a ride with a fatty acid binding protein (FABP), which chaperones various lipid molecules into the cell’s interior. These intracellular transport molecules also escort, the endocannabinoids anandamide and 2AG, across the membrane to several targets within the cell. CBD modulates receptors on the surface of the nucleus, which regulate gene expression and mitochondrial activity.
Cannabidiol, it turns out, has a strong affinity for three kinds of FABPs, and CBD competes with our endocannabinoids, which are fatty acids, for the same transport molecules. Once it is inside the cell, anandamide is broken down by FAAH [fatty acid amide hydrolase], a metabolic enzyme, as part of its natural molecular life cycle. But CBD interferes with this process by reducing anandamide’s access to FABP transport molecules and delaying endocannabinoid passage into the cell’s interior.
According to a team of Stony Brook University scientists, CBD functions as an anandamide reuptake and breakdown inhibitor, thereby raising endocannabinoid levels in the brain’s synapses. Enhancing endocannabinod tone via reuptake inhibition may be a key mechanism whereby CBD confers huge wellness benefits.
CBD as an allosteric modulator
CBD also functions as an allosteric receptor modulator, which means that it can either enhance or inhibit how a receptor transmits a signal by changing the shape of the receptor.
Australian scientists report that CBD acts as a “positive allosteric modulator” of the GABA-A receptor. In other words, CBD interacts with the GABA-A receptor in a way that enhances the receptor’s binding affinity for its principal endogenous agonist, gamma-Aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. The sedating effects of Valium and other Benzos are mediated by GABA receptor transmission.
Canadian scientists have identified CBD as a “negative allosteric modulator” of the cannabinoid CB1 receptor, which is concentrated in the brain and central nervous system. While cannabidiol doesn’t bind to the CB1 receptor directly, CBD interacts allosterically with CB1 and changes the shape of the receptor, limiting other cannabinoids ability to bind with it.