How does CBD affect the endocannabinoid system?
CBD, otherwise known as cannabidiol, is one of over 100 naturally occurring compounds in the cannabis plant called cannabinoids, accounting for roughly 40% of the plant’s extracts. Even though CBD has yet to be approved by the Food and Drug Administration (except for two rare forms of childhood epilepsy), many people say that they have experienced some pretty significant health benefits from incorporating it into their lives, from simple health perks like clearer skin, to some major claims regarding successful treatment of severe and chronic medical conditions. This large outcry has resulted in the mass production of CBD supplements in the form of CBD oil, and even the CBD Oil Act of 2016.
The legitimacy of these claims hasn’t been proved, nor have they been disproved. Due to the complex nature of the entire cannabis plant and its many components, as well as the medical applications that are already backed by science, homeopathic believers are not the only ones in support of using cannabidiol; researchers also believe that there may be more medicinal uses for CBD. There is still an overwhelming amount of research to do to fully explore the potential of CBD, but scientists are beginning to scratch the surface of how it works within the body. This is perhaps the first significant step in discovering what it really can- and can’t- do.
How CBD is Absorbed
Before CBD has the ability to influence the body’s various systems, it must first be introduced into the body via administration and absorption into the blood stream, where it can be circulated and affect cannabinoid receptors CB1 and CB2, and other receptors like 5HT1A and TRPV1. There are multiple ways to administer CBD, each with its own unique properties and variations of distribution, uptake, and elimination. CBD can be vaped (using a special vaporizing pen and CBD vape oil), ingested (through tinctures, capsules, and even sweets), and applied topically (with special lotions and creams).
Ingestion of CBD appeals to the largest demographic, as it is the most intuitive method of introduction to the body. CBD can be taken in the form of capsules, which is the best option for higher, more strictly regulated doses. It can also be taken in the form of teas, candies (like gummies), sweets, and other specialty snacks, which are all good options for careful and discrete use. Lastly, special CBD oils can be placed in the mouth beneath the tongue for sublingual absorption.
When CBD is ingested, it is absorbed through the lining of the stomach, where it enters into the hepatic portal system. From there, it’s carried through the portal vein into the liver, where the liver metabolizes the CBD molecules; what remains after this “first pass” metabolic process is then passed into the bloodstream. It is because of this process that ingestion isn’t considered the most optimal way of using CBD, even though it is perhaps the easiest, especially when administering very large doses to individuals that are new to using CBD.
Sublingual use of CBD involves ingesting, but not digesting. By holding the CBD oil beneath the tongue for a minute to a minute and a half before swallowing, the mucus membranes in the mouth are able to absorb the CBD and completely eliminate the degradation of the compounds by the digestive system and the liver’s “first pass” metabolic process. This allows the CBD to reach the bloodstream more quickly.
Vaping (the act of inhaling vaporized compounds) CBD oil has rapidly gained popularity, and for good reasons. When inhaled, the CBD compound is absorbed through the alveoli. Alveoli are sacs inside the lungs that allow oxygen and carbon dioxide to move between the lungs and the bloodstream. These provide quite a large surface area for absorption. Once absorbed through the alveoli, the molecules then immediately move into the bloodstream. Inhalation provides the highest bioavailability and fastest uptake of CBD into the body, making it especially useful for treating issues that have sudden acute onset.
With topical application of CBD, the compound actually never reaches the bloodstream because of the skin’s low permeability. The skin also has a low absorption rate for cannabinoids in particular, which limits its ability to influence certain systems. However, topical use still allows some interaction with the skin’s nearby cannabinoid receptors when it is heavily applied via absorption through the pores. Balms, lotions, and creams still have their place in CBD use, as they are helpful in treating isolated areas and treating a variety of troublesome skin conditions.
Though there are different methods of application, they are all mostly a means to the end result: absorption into the bloodstream. It is through the bloodstream that CBD has maximum efficacy as it circulates to different parts of the body. With that in mind, the choice of method of use primarily depends on personal preference and treatment goals, as well as accessibility to the different CBD products now available. Candies, for example, are widely available in places like California where all varieties of cannabis are legal, whereas they are hard to find in areas that do not have this same liberty.
The Endocannabinoid System
There are many aspects in which cannabidiol works when introduced to the body, most (if not all) of which would not be possible without our existing endocannabinoid system (ECS). Every animal with a backbone (vertebrae species) also has an endocannabinoid system, which is a molecular system that is responsible for many biological processes, primarily maintaining homeostasis (balance and harmony within the body). For example, maintaining a body temperature that is neither too hot nor too cold. There are three key components of the endocannabinoid system: cannabinoid receptors, endocannabinoids, and metabolic enzymes.
Cannabinoid receptors are located throughout the body, on the surface of the cells. These receptors are responsible for monitoring conditions outside of the cells, and communicating any changing information to the inside of the cells. Once the information is received, this starts the corresponding appropriate cellular response. The two primary receptors are called the CB1 and CB2 receptors, with CB1 being the most plentiful within the central nervous system, including neurons in the brain. These CB1 receptors are what interacts with CBD’s sister compound THC, producing a “high” (of course, unlike THC, CBD does not contain any psychoactive properties). CB2 receptors, on the other hand, are more abundant external of the central nervous system, like the immune system (though both CB1 and CB2 are seen throughout the whole body and not limited to one location).
Endocannabinoids, another primary component of the endocannabinoid system, are molecules that bind to and activate the cannabinoid receptors. This process is very much like the binding and activating seen with the introduction of plant sources of cannabinoids, but these are produced naturally within the body. The two major endocannabinoids are called anandamide and 2-AG. These are synthesized in the body on-demand; they are produced at the exact time and the exact amount needed, versus being obtained from an external source and stored for later use.
The third major component of the endocannabinoid system entails metabolic enzymes. These enzymes break down and destroy remaining endocannabinoids once they are used, ensuring that the endocannabinoids are available when needed, but not present longer than necessary. There are two primary enzymes; FAAH, which breaks down anandamide, and MAGL, which breaks down 2-AG. This makes endocannabinoids unique and sets them apart from other molecular signals, like hormones, which can be present in the body much longer, or stored for later use.
These three components of the endocannabinoid system are present throughout the body, and can be found in nearly all major systems that control biological processes. When different stimuli affects the body and throws it out of its known state of balance, these components react, and attempt to restore the body’s homeostasis. In regards to the central nervous system, the endocannabinoid system can prompt the creation of endocannabinoids that then send necessary signals to other parts of the brain. These signals will relay important information, communicating certain actions (or inaction) that correct issues causing the imbalance. Outside of the central nervous system, the ECS seems to affect things like the immune system. Research shows that endocannabinoids are produced when immune cells are activated, so they may be able to help regulate the immune response and act as an anti-noninflammatory. This is promising for reducing chronic, damaging inflammation in the body, such is the case with auto-immune disorders.
CBD Within the Body: Anxiety
While cannabinoids interact with the endocannabinoid system, the interaction can differ from compound to compound, system to system. THC, for example, binds to the CB1 and CB2 receptors, whereas CBD doesn’t have much of a binding effect. Instead, CBD modulates various non-cannabinoid receptors and ion channels. It also acts through several receptor-independent pathways, an example of which is its delayed re-absorption of endogenous neurotransmitters (like the previously mentioned anandamide or adenosine), and by either increasing or decreasing the binding actions of some G-protein coupled receptors.
One area of study on the use of CBD is on how it affects 5-HT1A serotonin receptor, which is G-protein coupled and in the family of 5-HT receptors. The 5-HT receptors are activated by the neurotransmitter serotonin. This type of receptor is found throughout the body in both the central and peripheral nervous systems, responsible for precipitating various intracellular chains of chemical messages in order to produce an excitatory or inhibitory response (depending on the content of the message). The 5-HT1A receptor in particular is involved in a variety of neurological and biological processes, like pain perception, sleep, appetite, anxiety, addiction, nausea, and vomiting. A study conducted by Jose Alexandre Crippa shows the effects of CBD specifically on anxiety. With a high enough concentration, CBD can activate the 5-HT1A serotonin receptor, which presents an anti-anxiety effect.
CBD Within the Body: Pain
Though cannabidiol does not bind to the CB1 or CB2 receptors the way its sister compound THC does, CBD has been found to bind to others, like the TRPV1 receptor. This receptor helps to maintain proper body temperature, and mediate pain as well as inflammation. The TRPV1 receptor is just one variant of several dozen TRP receptors that mediate the healthful effects of different plants, including cannabis. An additional example is the capsaicin found in a variety of hot peppers. Capsaicin also interacts with the TRPV1 receptor, activating it, which has a direct effect on inflammation and correlated pain; this is a similar effect that CBD has when it binds to the same receptor.
CBD Within the Body: Cancer
In addition to prompting the physiological response when interacting with the 5-HT1A and TRPV1 receptors (the substances that have these effects are called agonists), CBD also activates PPAR nuclear receptors. These receptors are found on the surface of the cell’s nucleus. The activation of one of these receptors, called the PPAR-Gamma, has shown promising anti-proliferation and tumor regression effects, which provides scientists hopeful possibilities when it comes to the treatment of cancer.
The interaction of CBD with the PPAR-Gamma receptors may have other beneficial effects, like the treatment of Alzheimer’s. As a result of activating these receptors, degradation of amyloid-beta plaque begins to take place. This plague has been tied to the development of Alzheimer’s, so the elimination of it via the PPAR-Gamma degradation response may prove to be an effective treatment.
The Interactive and Binding Process of CBD
So, now we know of a few ways CBD interacts with and binds to certain receptors throughout the human body. How, exactly, this takes place is interesting when you consider that this is a plant compound that is completely exogenous (external of us). To interact and bind with the nuclear receptors, the compound has to first grab on to a fatty acid binding protein, essentially “hitchhiking” along. These proteins are responsible for transporting assorted lipid molecules into the inside of the cell. These same lipid molecules also transport other compounds like THC and endogenous cannabinoids like anandamide and 2AG past the membrane to the cell’s interior.
As CBD has to use the same molecules as our own existing endocannabinoids to reach the center of the cell, it actually competes with them for transport. As mentioned in the section about the endocannabinoid system, the human body has metabolic enzymes that break down our endocannabinoids after they are deemed no longer needed for a particular function in that instance; these are in the center of the cell, and the breakdown process begins once the endocannabinoids pass to the center. CBD, however, interferes with this metabolic process. It reduces our endocannabinoid’s access to transport, which means they can’t reach the center of cell, resulting in the delayed ability to begin the break-down process. In turn, this raises the level of endocannabinoids in the brain’s synapses. The inhibited reuptake of this, along with other compounds, thus the increase in the presence of endocannabinoids, is what appears to result in beneficial, perhaps considered medicinal, effects.
In addition to CBD’s inhibiting effect on endocannabinoids, it can also alter receptors by either inhibiting or enhancing the receptor’s ability to transmit signals; this is done by changing the shape of the receptor, thus changing signal transmission. Scientists in Australia have discovered that CBD interacts with the GABA-A receptor, resulting in an enhanced binding ability for its chief endogenous agonist, GABA. GABA (or gamma-Aminobutyric acid) is the primary inhibitory neurotransmitter in our central nervous system. Just as certain sedative pharmaceuticals like benzodiazepines (Xanax and Valium, for example) are mediated by GABA receptor transmission, CBD has a similar anxiety-reducing effect by changing the shape of the GABA-A receptor. This change results in the amplification of the calming effects of GABA, thus reduced anxiety.
As with any chemical reaction within the human body, while there may be a overplus of potential benefits, there can be some less-than-desirable effects as well. By now, it’s obvious that this level of biochemistry is quite complex, and even with a solid understanding, the various effects and processes hard hard to identify. With that said, what certainly can be seen are the outcomes and results of studies and clinical trials, which form the basis of what scientists have documented as side effects.
After a number of human-applicable trials on animals, CBD has been found to have fewer side effects and to a lesser severity than other conventional medications, making it a safer, more favorable option. Most of the studies in which side effects were seen were done for the treatment of psychotic disorders and epilepsy with CBD. The most common side effects in these studies were concluded to be changes in appetite (and weight as a result), tiredness, and diarrhea.
Many, many years ago, scientists actually thought that the CBD compound was completely inactive in humans, and thus would have no medicinal applications. As a result, most of the research done then was centered around the THC compound for its prolific use as a psychoactive drug. Today, scientists know that CBD is actually quite an impressive compound and has many effects on people. They are regularly researching, studying, and learning about CBD and how it affects different receptors throughout the body to promote homeostasis and healing. So far in just the past decade alone there have been studies that have produced results that are hopeful in reducing anxiety and depression, reducing the perception of pain, reducing or eliminating seizures, fighting certain kinds of cancer, and providing anti-inflammatory effects. There is also promising research that shows CBD can be neuroprotective, which means it could be beneficial in treating cognitive degradation conditions like Alzheimer’s.
For every answered question science discovers about CBD, several more unanswered questions are born. The research thus far is overwhelmingly positive, though- afterall, why would people have an endocannabinoid system that reacts positively to exogenous cannabinoid compounds to begin with, if not for our benefit? Even so, there are many things to consider, even with the assumption that CBD can have positive effects. For example, is CBD overdose possible? If so, what are the overdose risks? What are the overdose effects? What are the long-term treatment results? Can CBD really be used by anyone, or might some people have extremely negative reactions? What about other mammals, can it benefit them as well? Scientists are working tirelessly to answer these questions alongside many more, and while the cannabis plant has actually been used for medicinal treatment for centuries, only the future holds answers that are truly absolute.