Endocannabinoid regulation of brain cell firing
Brain cells (neurons) talk by sending electrochemical gestures to each other. Each neuron must heed to its partners to choose whether it will fire off its signal at any time. However, neurons don’t like to be overwhelmed. If they get overloaded by signals, it can be poisonous.
Endocannabinoid Regulation of Inflammation
Swelling is a natural protective response the immune system has in reaction to infection or physical harm. The purpose of inflammation is to remove germs or damaged tissue. The inflamed part creates fluid and immune cells move into the area. Their goal is to work and return things to normal conditions.
It’s critical that inflammation restricts the location of harm and doesn’t continue longer than needed, which can cause damage. Chronic inflammation and autoimmune diseases are instances of the immune system getting triggered improperly. When that happens, the inflammatory reaction lasts too long. This causes chronic inflammation or gets guided toward healthy cells, which is known as autoimmunity.
What are Cannabinoid Receptors?
Cannabidiol (CBD), a non-intoxicating part of the cannabis plant, has created significant attention among scientists and physicians recently—but how CBD expels its therapeutic impact on a molecular level is under study. Cannabidiol is a pleiotropic drug in that it creates many effects through many molecular pathways. Scientific research has identified more than 65 molecular targets of CBD.
Even though CBD has little binding affinity for both cannabinoid receptors (CB1 and CB2), cannabidiol modulates multiple non-cannabinoid receptors and ion channels. CBD also moves through various receptor-independent pathways by slowing the “reuptake” of endogenous neurotransmitters (such as anandamide and adenosine) and increasing or prohibiting the binding action of specific G-protein coupled receptors. Here are some of the ways that CBD presents its various therapeutic effects.
SEROTONIN RECEPTORS
CBD directly triggers the 5-HT1A (hydroxytryptamine) serotonin receptor at heavy concentrations, thereby creating an anti-anxiety effect. This G-coupled protein receptor is involved in a range of biological and neurological processes, including anxiety, addiction, appetite, sleep, pain perception, nausea, and vomiting.
5-HT1A is a part of the group of 5-HT receptors, which the neurotransmitter serotonin triggers. These receptors live in both the central and peripheral nervous systems. 5-HT receptors activate multiple intracellular cascades of chemical messages to create either an excitatory or inhibitory response, depending on the message’s chemical context.
CBDA [Cannabidiolic acid], the raw, unheated version of CBD present in the cannabis plant, also has a strong affinity for the 5-HT1A receptor (even more so than CBD). Preclinical studies indicate that CBDA is a potent anti-emetic, more robust than either CBD or THC, which also have anti-nausea properties.
VANILLOID RECEPTORS
CBD directly interacts with various ion channels to confer a therapeutic effect. 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 with antiseptic and analgesic properties; it also helps unclog blood vessels. Historically, the vanilla bean is a folk cure for headaches. CBD binds to TRPV1, which can influence pain perception. Capsaicin—the pungent compound in hot chili peppers—activates the TRPV1 receptor. Anandamide, the endogenous cannabinoid, is also a TRPV1 agonist.
GPR55—ORPHAN RECEPTORS
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 is an “orphan receptor” because scientists are still unsure if it belongs to a more prominent receptors family. GPR55 lives 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.
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.
PPARS – NUCLEAR RECEPTORS
Activation of the receptor known as PPAR-gamma has an anti-proliferative effect and 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 why cannabidiol, a PPAR-gamma agonist, may be a helpful remedy for Alzheimer’s patients.
PPAR receptors also regulate genes involved in energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions. People with diabetes, accordingly, may benefit from a CBD-rich treatment regimen.
What are phytocannabinoids?
There are three general categories of cannabinoids:
- Phytocannabinoids: Cannabinoids produced by plants.
- Endogenous cannabinoids (endocannabinoids): Cannabinoids produced naturally by living animals (humans included) that interact with the body’s endogenous cannabinoid (endocannabinoid) system.
- Synthetic cannabinoids: Cannabinoids developed by humans in a laboratory.
While many people have heard about compounds found in cannabis – such as THC and CBD –many are surprised to learn that certain cannabinoids can be found naturally in our bodies. These are endocannabinoids. As a pivotal component of the endocannabinoid system, endocannabinoids help us operate at our best. When our endocannabinoid system functions appropriately, our bodies maintain homeostasis – the optimal state for our cells and tissues to function.
Unfortunately, the body does not always function the way nature intended. An autoimmune disease, for example, occurs when the immune system attacks healthy organs and tissues instead of attacking bacteria, viruses, or other sources of infection. Similarly, in some cases, the body lacks the average level of endocannabinoids for proper functionality. When this happens, it may be beneficial to get cannabinoids from an outside source.
Phytocannabinoids are naturally-occurring cannabinoids found in the Cannabis Sativa plant. As it stands, over 100 of them exist. These cannabinoids exist in other plants as well, such as the Echinacea Purpure. However, 113 compounds are unique to the Cannabis plant. These natural, plant-derived cannabinoids can help create proper homeostasis within the body by promoting balance in the endocannabinoid system.
A lesser-known fact is that scientists found phytocannabinoids in the ECS in mammals. Current studies focus on how these plant molecules aid in medicine, both on their own and through synthetic formats.
The most common and well-known plant-based compounds are tetrahydrocannabinol (THC) and cannabidiol (CBD). They are popular because of their potential therapeutic benefits. THC alleviates chronic pain, muscle spasms, and inflammation, while CBD has shown to help with various mental and physiological ailments in mammals.
HOW ARE PHYTOCANNABINOIDS DIFFERENT?
Phytocannabinoids are found in plants, while endocannabinoids live within mammal bodies. The prefix “Phyto” signifies that they are plant-derived in the former, while “endo” reveals the latter’s endogenous nature.
Recently, phytocannabinoids exist in several plant species different from cannabis, including Echinacea purpurea, Echinacea Angustifolia, Echinacea pallida, Acmella oleracea, Helichrysum umbraculigerum, and Radula marginata. According to the definition, these molecules are phytocannabinoids show binding affinity at cannabinoid receptors, but they show chemical structures far different from THCs.
All of the plants within the cannabis genus contain “phytocannabinoids,” and there are dozens of different ones. The most well-known are THC and CBD. THC is the only one that gets you “high.”
The leaves and flowers of marijuana plants make joints and edibles because they typically contain 15-20% THC. CBD oils come from the hemp plants, which includes, at most, 0.3% THC. That’s why CBD oils don’t get you high.
According to a recent review19, out of more than 545 metabolic constituents identified from Cannabis20, 144 have been isolated and identified as phytocannabinoids. Phytocannabinoids fall into the following 11 subclasses according to their chemical structures:
- cannabigerol (CBG, 1)
- (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC, 2)
- cannabidiol (CBD, 3)
- cannabichromene (CBC, 4)
- cannabinol (CBN, 5)
- (-)-Δ8-trans-tetrahydrocannabinol (Δ8-THC, 6)
- cannabicyclol (CBL, 7)
- cannabidiol (CBND, 8)
- cannabielsoin (CBE, 9)
- cannabitriol (CBT, 10)
- miscellaneous types
Scientists recognize the endocannabinoid system for its involvement in uterine function. Estrogen, for example, has been shown to regulate the expression of FAAH, the primary protein tasked with breaking down anandamide, the first endogenous cannabinoid compound identified in the mammalian brain.
Aberrant signaling by endocannabinoids and their molecular cousins, the prostaglandins, occurs in menstrual pain and heavy bleeding. New research from scientists in Italy, Britain, and Qatar adds to how we understand these conditions by probing the connection between endocannabinoid levels and preterm birth, meaning delivery before the 37th week of pregnancy.
The scientists measured the levels of FAAH and anandamide (AEA), along with two related lipids, called PEA and OEA, in 217 women at risk for preterm birth. Plasma AEA increases during pregnancy until labor, so the researchers hoped to find a threshold that could predict preterm birth.
They found that an AEA concentration above 1.095 nanomolar (nM) was a valuable predictor of preterm birth. The specificity (valid negative rate) was 87%, meaning they will only miss about 1-in-10 cases using this threshold. On the other hand, the sensitivity (true positive) was only 26%, meaning 3-in-4 results are false positives.
The authors conclude that using anandamide as a marker was more accurate and less invasive than current testing methods. PEA could also be a marker for preterm birth, but FAAH and OEA levels were not well correlated.
Future research should replicate this diagnostic threshold prospectively.
Another recent study suggested that AEA levels are generally around 0.6-0.8 nM in the blood, but this fluctuates to some degree throughout the day. So, blood needs to collect consistently.