Cannabidiol (CBD) is a compound with significant medical benefits (to relieve conditions like inflammation, pain, anxiety, psychosis, seizures, spasms, arthritis, diabetes, alcoholism, MS, chronic pain, schizophrenia, PTSD, depression, antibiotic-resistant infections, and epilepsy) in addition to its anti-cancer properties. It is a non-psychoactive component, and it doesn’t give you the “high” feeling, often associated with the psychoactivity of THC. Plus, it is safe even at high doses. However, how CBD exerts its therapeutic effect on a molecular level is still being researched as it is a pleiotropic drug, producing many effects through multiple molecular pathways. Furthermore, more than 65 molecular targets of CBD have already been identified.
Although CBD has little binding affinity for CB1 and CB2 receptors, it modulates multiple non-cannabinoid receptors as well as ion channels, acting through receptor-independent pathways. For instance, CBD delays the reuptake of endogenous neurotransmitters (e.g., anandamide and adenosine), and enhances or inhibits the binding action of certain G protein-coupled receptors (GPCRs).
- Serotonin Receptors
According to this research conducted by the University of São Paulo and King’s College London, CBD directly activates the 5-hydroxytryptamine (5-HT1A) serotonin receptor, a member of the family of 5-HT receptors that can be activated by the neurotransmitter serotonin, and effectively confers an anti-anxiety effect. The G protein-coupled receptor is implicated in a range of biological and neurological processes: anxiety, addiction, appetite, sleep, pain perception, nausea and vomiting. 5-HT receptors, in the central and peripheral nervous systems, trigger several intracellular cascades of chemical messages to produce either an excitatory or inhibitory response, depending on the chemical context of the message.
Cannabidiolic acid (CBDA), a chemical compound found in the resin glands (trichomes) of raw cannabis plants, has a stronger affinity for the 5-HT1A receptor than CBD. CBDA is a potent anti-emetic with anti-nausea properties.
- Vanilloid Receptors
By directly interacting with various ion channels, CBD can confer a therapeutic effect.
CBD binds to TRPV1 (transient receptor potential cation channel subfamily V member 1) receptors, which also function as ion channels and can influence pain perception. Known to relieve pain perception, inflammation and body temperature, TRPV1 is one of the TRP receptor variants or subfamilies that mediate the effects of a wide range of medicinal herbs.
Named after the flavorful vanilla bean, often used as a folk cure for headaches, TRPV1 is called a vanilloid receptor due to eugenol (an essential oil with antiseptic and analgesic properties that also helps to unclog blood vessels) that vanilla contains.
On a side note, capsaicin (the pungent substance in hot chili peppers) activates the TRVP1 receptor, and anandamide (the endogenous cannabinoid) is also a TRPV1 agonist.
- Orphan Receptors: GPR55
Additionally, CBD functions as an antagonist that blocks or deactivates GPR55 (G protein-coupled receptor), nicknamed an orphan receptor since it’s still uncertain whether it belongs to a larger family of receptors. Widely expressed in the brain, especially in the cerebellum, it is largely involved in modulating blood pressure and bone density – along with other physiological processes.
GPR55 also promotes osteoclast cell function, facilitating bone reabsorption, and overactive GPR55 receptor signaling is associated with osteoporosis. Based on a study by the Chinese Academy of Sciences, GPR55 promotes cancer cell proliferation as this receptor is expressed in various types of cancer. Another study also clarifies that CBD is a GPR55 antagonist, and by blocking GPR55 signaling, CBD may act to decrease bone reabsorption and cancer cell proliferation.
- Nuclear Receptors: PPARs
By activating peroxisome proliferator-activated receptors (PPARs) situated on the surface of the cell’s nucleus, CBD can confer an anti-cancer effect. Once the receptor known as PPAR-gamma is active, it can bring about an anti-proliferative effect and an ability to induce tumor regression in human lung cancer cell lines since it degrades amyloid-beta plaque, a key molecule crucially involved in the development of Alzheimer’s disease. That said, there is a possibility of cannabidiol, a PPAR-gamma agonist, helping those who suffer from AD.
As PPAR receptors also regulate genes involved in metabolic functions including energy homeostasis, lipid uptake, and insulin sensitivity, CBD could also help diabetics.
- As a Reuptake Inhibitor
CBD passes through the cell membrane by hitching a ride with a fatty acid-binding protein (FABP) that chaperones some lipid molecules into the cell’s interior. The intracellular transport molecules guide tetrahydrocannabinol (THC), as well as the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) – across the membrane to numerous targets within the cell. Both CBD and THC regulate receptors on the surface of the nucleus, controlling gene expression and mitochondrial activity.
CBD has a strong affinity for three kinds of FABPs and competes with endocannabinoids (which are fatty acids) for the same transport molecules. Once it goes inside the cell, a natural molecular life cycle occurs where anandamide (also known as N-arachidonoylethanolamine or AEA) is broken down by fatty acid amide hydrolase (FAAH), a member of the serine hydrolase family of enzymes. However, it turns out that CBD interferes with this process by reducing AEA’s access to FABP transport molecules and delaying endocannabinoid passage into the cell’s interior. A study conducted by Stony Brook University proves, moreover, that CBD functions as an AEA’s reuptake and breakdown inhibitor by raising endocannabinoid levels in the brain’s synapses – meaning that CBD confers neuroprotective effects against seizures and other conditions due to reuptake inhibition enhancing endocannabinod tone.
Additionally, adenosine reuptake inhibitors partially cause CBD to confer anti-inflammatory and anti-anxiety effects because CBD delays the reuptake of this neurotransmitter and raises adenosine levels in the brain that regulates adenosine receptor activity.
When it comes to cardiovascular function, A1A and A2A adenosine receptors, having broad anti-inflammatory effects, regulates myocardial oxygen consumption and coronary blood flow.
- As a Positive/Negative Allosteric Modulator
CBD can also change the shape of the receptor to enhance or inhibit how a receptor transmits a signal.
A study reports that CBD interacts with the GABA-A receptor while enhancing the receptor’s binding affinity for its principal endogenous agonist, gamma-Aminobutyric acid (GABA), the key inhibitory neurotransmitter in the mammalian central nervous system. GABA receptor transmission mediates the sedating effects of benzodiazepines and diazepam, and by changing the shape of the GABA-A receptor to amplify the natural calming effect of GABA, CBD reduces anxiety, accordingly.
Although cannabidiol doesn’t bind to the CB1 receptor directly (unlike THC), another study emphasizes that CBD interacts allosterically with CB1 and changes the shape of the receptor, weakening CB1’s ability to bind with THC – and lowers the psychoactivity of THC (the “high”), meaning that CBD is actually anti-psychoactive.