(Editor’s note: This article is meant to be read in the context of the other pieces in our SCIENCE section. If you’d like a less science-heavy, more simplified take on how CBD works, you might want to check out “Simplified: What Is CBD, and How Does It Work?”)

Cannabidiol (CBD) is a complex chemical compound, and scientists are still studying the way it works throughout the body. It is a pleiotropic compound, meaning that CBD produces multiple effects across multiple molecular pathways.

CBD, FABPs, and the endocannabinoid system

CBD is fat-soluble and binds with fatty acid binding proteins (FABPs) to travel through cell membranes so that it can interact with various receptor targets. Our own endocannabinoids, anandamide and 2-AG, also require FABPs for intracellular travel. When taken into the body, CBD “competes” with endocannabinoids for access to these FABP transporters. Anandamide uses FABPs to enter cells, where it is metabolized by the enzyme fatty acid amide hydrolase (FAAH) as part of its natural life cycle. By reducing FABP availability for anandamide to move into the cells and be broken down, CBD delays its metabolism, leaving more of the endocannabinoid in the system, thereby improving the ECS “tone.” As an anandamide reuptake/breakdown inhibitor, CBD is shown to offer potential neuroprotective benefits by maintaining higher endocannabinoid levels in the system.

Although CBD is a cannabinoid, and works with the endocannabinoid system (ECS), it does not bind with the ECS receptors in the way that THC, for example, does. CBD acts on these receptors indirectly, and is said to be an antagonist of CB1 agonists (meaning it suppresses compounds that activate CB1 receptors). This is why CBD’s effects when it comes to the ECS are often categorized as being “opposite” those of THC.

CBD and 5-HT1A receptors

CBD does, however, activate several other noncannabinoid receptors and ion channels in the body. One of the most exciting discoveries in recent years is that CBD can directly affect the hydroxytryptamine (5-HT1A) serotonin receptor, another G-protein-coupled receptor (the CB1 and CB2 receptors are also of this type) that contributes to a vast range of physiological processes such as anxiety, withdrawal and addiction, sleep, pain response, appetite, vomiting, and nausea. The 5-HT1A receptor is part of the 5-HT receptor family that is found throughout the nervous system and activated by the neurotransmitter serotonin. CBD’s ability to target and enhance these serotonin receptors gives it remarkable therapeutic promise. Roger Pertwee, a pharmacologist from the University of Aberdeen, has stated that CBD’s relationship with these receptors “supports the possibility that it could be used to ameliorate disorders that include: opioid dependence, neuropathic pain, depression and anxiety disorders, nausea and vomiting (e.g., from chemotherapy), and negative symptoms of schizophrenia.” He does warn that many of the studies done on CBD and serotonin receptors have been on animals or in vitro (meaning “in the glass”—test tube studies) and that more clinical validation is needed, but there is mounting evidence that CBD does indeed have the effects described here. Cannabidiolic acid (CBDa), which is the raw precursor to CBD—occurring naturally in the cannabis plant before heating/processing—is also shown to have an affinity for the 5-HT1A receptor, perhaps even more so than CBD.

CBD and TRPV1

CBD also binds to transient receptor potential cation subfamily V (TRPV1) receptors, part of a family of receptors that interact with many medicinal herbs. The TRPV1 receptor is involved in pain perception, inflammation, and body temperature. TRPV1 also acts as an ion channel—meaning that it acts as a kind of “pore” in cell membranes, allowing the selective passing of ions in or out of cells. TRPV1 is also called a vanilloid receptor, so named after the vanilla bean. Vanilla has long been used as a plant medicine, and has been said to be a folk remedy for headaches. It contains eugenol, an essential oil that has antiseptic and analgesic properties, and which has been shown to interact with TRPV1s. Capsaicin, found in hot peppers, is another noncannabinoid that activates TRPV1s, and the endocannabinoid anandamide also works on these receptors.

Have you checked out our CBD tincture reviews?

CBD and GPR55

Another noncannabinoid receptor that CBD can affect is the G-protein-receptor GPR55, which some scientists call an “orphan” receptor, as it’s still undetermined if this is part of a larger receptor family. GPR55 is largely found in the brain, and especially in the cerebellum. It’s known to play an important role in bone reabsorption, bone density, and blood pressure control. A 2010 study from the Chinese Academy of Sciences showed that GPR55 can be a culprit for cancer cell growth when activated. Overactive GPR55 signaling has also been implicated in osteoporosis. CBD is actually an antagonist of the GPR55 receptor, meaning it has a deactivating effect. By interacting with GPR55 receptors, CBD can have great medical value in decreasing both the bone reabsorption associated with osteoporosis, and the proliferation of cancer cells.

CBD and adenosine

Another influence CBD has is on the neurotransmitter adenosine and adenosine receptors A1A and A2A. As with the endocannabinoid anandamide, CBD works to inhibit the reuptake/breakdown of adenosine, thereby boosting levels of this neurotransmitter in the brain. The presence of adenosine is what influences the activity of the A1A and A2A adenosine receptors, which control the release of glutamate and dopamine. Glutamate levels are closely connected to cognition, learning, and excitatory signals in the brain. Dopamine is connected to motor function, motivation, and cognition. The A1A and A2A adenosine receptors play an important role in cardiovascular functioning, inflammation response (A2A), and also mood. CBD’s inhibition of adenosine reuptake ultimately leads to anti-inflammatory and anti-anxiety effects.

CBD and GABA

CBD’s ability to modulate the GABA-A receptor also plays a role in its anti-anxiolytic effects. Gamma-aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the central nervous system. Benzodiazepines (anti-anxiety medications like Xanax, Valium, etc.) work via the GABA-A receptors to have a sedative effect. CBD is shown to be an allosteric receptor modulator, meaning it can change the shape of the receptor it interacts with to drive or inhibit signal transmission. When it comes to the GABA-A receptor, CBD is seen as a “positive allosteric modulator,” meaning it increases the receptor’s affinity for its main agonist (activator), the neurotransmitter GABA. By changing the shape of the GABA-A receptor, CBD boosts the soothing effects of GABA in the body. Read our piece in the CONDITIONS section for more specifics on CBD and anxiety.

We’ve already talked about CBD inhibiting reuptake of anandamide at the CB1 ECS receptor sites, but it is also worth noting here that CBD is actually a “negative allosteric modulator” of the CB1 receptor—it does in fact also change the shape of the CB1 receptor, and this is in part what weakens the effects of THC; because THC binds directly with CB1, a change in this key/lock binding mechanism makes it more difficult for THC and CB1 receptors to interact.

CBD and PPARs

Some of the most exciting CBD innovations center around CBD’s ability to activate, or bind with, peroxisome proliferator activated receptors (PPARs), and specifically with the PPAR-gamma receptors, on cell nuclei. Activating these receptors has been proven to slow the proliferation of tumors and even to induce tumor regression in human lung cancer cells. Activation has also been shown to degrade amyloid-beta plaque, which is a key factor in the development of Alzheimer’s disease. PPARs are also involved in regulating lipid uptake and insulin sensitivity. Its interaction with PPARs and specifically as a PPAR-gamma agonist is one way in which CBD seems to work therapeutically in fighting cancer, Alzheimer’s disease, and diabetes

CBD, ID-1, and cancer

A final word about CBD’s arsenal of therapeutic gifts: CBD (and THC) has increasingly been shown to not only aid in symptoms associated with cancer and traditional cancer therapy (nausea, fatigue, appetite loss, etc.), but also appears to have a direct effect on various types of tumors. At the California Pacific Medical Center (CPMC), a doctor named Sean McAllister has been at the forefront of research on cannabinoids and their effects on cancer for the last 10 years. In 2007, he published a review on how CBD specifically is able to destroy malignant breast cancer tumors by “switching off” the ID-1 gene, a protein compound that has been implicated in cancer cell proliferation. ID-1 seems to play a role in cell growth and differentiation during embryonic development, but it deactivates thereafter. However, ID-1 is “re-expressed” in several types of aggressive cancers, pushing malignant cells to multiply and metastasize. McAllister and colleagues believe that CBD’s ability to restore ID-1 back to its “off” state is a potential breakthrough when it comes to cancer treatment. CBD’s other properties also reveal it to be a potentially effective complement to chemotherapy, as CBD can offset the effects of chemo drugs and possibly allow for cutting their dosages (and therefore toxicity) down without losing benefits.

Final thoughts on how CBD works

What we know about the workings of CBD thus far is quite inspiring, and also complex. Truth be told, we are still far from understanding all of the intricacies of how CBD works and the numerous pathways with which it interacts. It’s important to acknowledge that many CBD studies are on animals or in vitro, but increasingly, clinical trials are proving its medical value in humans with a vast array of health conditions. Visit CONDITIONS for more specifics on how CBD works in relation to specific diseases.


RESOURCES:

https://www.ncbi.nlm.nih.gov/pubmed/24923339
https://www.alchimiaweb.com/blogfr/wp-content/uploads/2016/06/Cannabidiol-as-a-Potential-Treatment-for-Anxiety-Disorders-Neurotherapeutics-2015.pdf
http://bjp.rcpsych.org/content/197/4/285
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645550/
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737440/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604182/
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https://www.projectcbd.org/science/genetics/cbd-ppars-and-gene-expression
https://www.nature.com/bjc/journal/v95/n2/abs/6603236a.html
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2 COMMENTS

    • Hi Doyle, we’re glad you like what you’ve read here, and thanks for your question. You might mean “hempseed oil” when you say hemp oil – that’s made from the seeds of hemp plants. While it has some value as a health supplement, containing various nutrients and being rich in fatty acids, it has little to do with the extracted oils that make up most CBD formulations. These come from a different part of the hemp cannabis plant, and are treated and processed differently. To learn more, you might check out some of our BASICS articles, like “What Is CBD”, or if you really want to get into hemp, check out “A History of CBD and Hemp”. Hopefully this helps, but let us know if you have more questions!

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