Originally published in O’Shaughnessy’s.
Cannbidiol (CBD), a non-psychoactive component of the marijuana plant, has generated significant interest among scientists and physicians in recent years—but how CBD exerts its therapeutic impact on a molecular level is still being sorted out. Cannabidiol is a pleiotropic drug in that it produces many effects through multiple molecular pathways. CBD acts through various receptor-independent channels and by binding with a number of non-cannabinoid receptors and ion channels.
Here are some of the ways that CBD confers its therapeutic effects.
CBD and FAAH
Unlike psychoactive THC, CBD has little binding affinity to either the CB1 or CB2 cannabinoid receptors. Instead, CBD indirectly stimulates endogenous cannabinoid signaling by suppressing the enzyme fatty acid amide hydroxylase (FAAH)—the enzyme that breaks down anandamide, the first endocannabinoid discovered in the mammalian brain in 1992.
Whereas the cannabinoid molecules found in cannabis are considered “exogenous ligands” to the cannabinoid (CB) receptor family, anandamide is an “endogenous” cannabinoid ligand—meaning it binds to one or more cannabinoid receptors and is found naturally inside the mammalian brain and body. Anandamide favors the CB1 receptor, which is concentrated in the brain and central nervous system. Because FAAH is involved in the metabolic breakdown of anandamide, less FAAH means more anandamide remains present in the body for a longer duration. More anandamide means greater CB1 activation.
CBD enhances endocannabinoid tone by supressing FAAH.
By inhibiting the enzyme that metabolizes and degrades anandamide, CBD enhances the body’s innate protective endocannabinoid response. At the same time, CBD 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 receptor. CB2 receptors are predominant in the peripheral nervous system and the immune system.
The Vanilloid Receptor
While CBD has little binding affinity for either of the two cannabinoid receptors, it has been shown to directly interact with other “G-protein-coupled” receptors and ion channels to confer a therapeutic effect. CBD, for example, binds to the TRPV-1 receptor, which is known to mediate pain perception, inflammation and body temperature.
TRPV is the technical abbreviation for “transient receptor potential cation channel subfamily V.” There are several dozen TRP receptor variants or subfamilies that mediate the effects of a wide range of medicinal herbs.
Scientists also refer to TRPV-1 as the “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 is a TRPV-1 “agonist” or stimulant. This is likely one of the reasons why CBD-rich cannabis is an effective treatment for neuropathic pain.
Capsaicin—the pungent compound in hot chili peppers—activates the TRVP-1 receptor. Anandamide, the endogenous cannabinoid, is also a TRPV-1 agonist.
The Serotonin Receptor
Jose Alexandre Crippa and his colleagues at the University of San Paulo in Brazil and at the 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, thereby conferring an anti-depressant effect. This receptor is implicated in a range of biological and neurological processes, including (but not limited to) anxiety, addiction, appetite, sleep, pain perception, nausea and vomiting.
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.
CBD triggers an inhibitory response that slows down 5-HT1A signaling. In comparison, LSD, mescaline, magic mushrooms, and several other hallucinogenic drugs activate a different type of 5-HT receptor that produces an excitatory response.
The Adenosine Receptor
CBD’s anxiolytic (anti-anxiety) properties may in part be attributable to its activation of the adenosine receptor. 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. They down-regulate the release of other neurotransmitters such as dopamine and glutamate.
Whereas cannabidiol activates the TRPV-1 vanilloid receptor, the A2A adenosine receptor, and the 5-HT1A serotonin receptor, 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 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, as University of Aberdeen scientist Ruth Ross disclosed at the 2010 conference of the International Cannabinoid Research Society in Lund, Sweden.
By blocking GPR55 signaling, CBD may act to decrease both bone reabsorption and cancer cell proliferation.
CBD also exerts an anti-cancer effect by activating PPARs [peroxisome proliferator activated receptors] that are situated on the surface of the cell's nucleus. Activation of the 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, a key molecule linked to the development of Alzheimer’s disease. This is one of the reasons why cannabidiol, a PPAR-gamma agonist, may be a useful remedy for Alzheimer’s patients.
PPAR receptors also regulate genes that are involved in energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions. Diabetics, accordingly, may benefit from a CBD-rich treatment regimen.
CBD’s enzyme-mediated activation of the PPAR-alpha receptor may have antipsychotic effects. Polymorphisms or mutations in the gene encoding PPAR-alpha can result in deficient PPAR-alpha signaling, which has been linked to schizophrenia. PPAR-alpha activation is both anti-inflammatory and can decrease dopamine release, thereby minimizing schizophrenic symptoms.