What Is Cannabis Receptor GPR55 and How Does It Promote CBD Benefits?

No, GPR55 was not in Star Wars. It’s not a cousin to R2-D2 or C-3PO. But, given its prominent role in CBD benefits, GPR55 has been getting an increasing amount of attention in the cannabis and science communities.

So, what the heck is “GPR55” and why is so important? Actually, it’s an abbreviation for G protein-coupled receptor 55. (In humans, this G protein-coupled receptor is encoded by the GPR55 gene.) Along with GPR119 and GPR18, scientists have identified it as a possible novel cannabinoid receptor.

However, a growing body of evidence demonstrating the importance of GPR55 has led more and more scientists to believe GPR55 may be the third most important cannabis receptor after CB1 and CB2 (more on this in the next section).

I know, I know… this sounds awfully nerdy and scientific, but I’ll try to break it down in more simple terms in this article. But, first, to truly understand and appreciate GPR55, you’ll need some foundational knowledge about the Endocannabinoid System (ECS), your body’s own “natural cannabinoid system.”

Crazy, right? Humans (and many animals) have a system that resembles the cannabis plant, in that in this system are endocannabinoids (Endo- means “within,” as in “within the body”) that are identical to phytocannabinoids (Phyto- means “related to plants”) found in the cannabis plant.

Now that you know we all have a cannabinoid system (including your pets), let’s dive into what exactly this system is, what it does, and why it’s so important.

Ready? Slap on your science hat, and let’s dig in!

Background: The Endocannabinoid System


You may or may not know, but the endocannabinoid system (ECS) is arguably the most important system in our body. It’s right up there with our nervous system, circulatory system, and digestive system.

Importantly, given the fact that the ECS is implicated in virtually every aspect of our physical and emotional health and is responsible for maintaining homeostasis (the self-regulating process that helps us maintain a balance between our interdependent physiological processes that ensures our survival), you can’t underestimate its importance.

Dr. Ethan Russo explains the endocannabinoid system thusly, as a “key mediator of physiological homeostasis” ensures that “various bodily systems function within tight parameters with neither a deficiency nor excess of activity.”

We’re talking about sleep, appetite, pain sensation, metabolic functions, the immune system, to name just a few elements the ECS powerfully influences or mediates. Or, as Prof. Vincenzo Di Marzo, an Italian professor and research director who studies the ECS concisely sums it up (in just five words): protect, relax, eat, forget and sleep. Here’s a mnemonic device to remember what the ECS does: PREFS.

Guess what? You now know more about the endocannabinoid system than probably 90 percent of the doctors in the world! Crazy, right? Medical schools are so behind the times that spend a scant amount of time covering this miraculous system. To be fair, it’s been less than a generation since we even discovered the ECS.

[To learn more about the endocannabinoid system, read Dr. Russo’s paper, Introduction to the Endocannabinoid System.]

The Role of Cannabinoid Receptors


Scientists have identified two receptors that are universally accepted as the primary cannabinoid receptors:

CB1 Receptor:


Like GPR55, CB1 is a G-protein coupled receptor. CB1 receptors can be found throughout the body, however, they’re most prominent in our brain and spinal cord. Not coincidentally, they’re highly concentrated in the brain regions where they have the most profound influence.

For example, CB1 receptors are densely expressed in the hypothalamus and the amygdala. The hypothalamus helps regulate your appetite, while the amygdala influences memory processing and emotional processing. Logically, given CB1’s role in pain sensation, CB1 receptors can also be found in our nerve endings.

CB1 is the brain’s receptor where THC most strongly affects pain, hunger, emotion, and short-term memory. It’s also the receptor responsible for getting you high! That sneaky little devil!


CB2 Receptor:


In a contrasting role (or rather, a complementary role), CB2 receptors are most prominently expressed in our peripheral nervous system, where, when activated play a significant role in our inflammatory and immune responses. (Note, that an abundance of research demonstrates how cannabis – or cannabinoids – reduce all types of inflammation, including neuroinflammation — which is highly significant given how important it is to minimize neuroinflammation to protect against neurodegenerative disorders.

Moreover, inflammation is broadly implicated in numerous conditions and diseases, hence why this receptor is so vital!

Leafly put together this handy graphic to contrast the benefits and effects of THC and CBD.

Source: Leafly

History of GPR55: What is the GPR55 Receptor and What Does It Do?


GPR55 was discovered fairly recently. In fact, the popular 90s sitcom, Friends, had already been on the air for five years and President Clinton was in his final year of office. Yup, the year was 1999.

When first discovered, there wasn’t a scientist in the world who fully understood its function. Or, even if or how it could be activated. Fast forward to 2007, and by then we had learned a hell of a lot more. Namely, that CBD could powerfully influence it (in a positive sense). Interestingly, CBD is an antagonist to GPR55, meaning it can block its ability to express itself.

But isn’t “blocking expression” bad? No. Not necessarily. In this case, it can be very positive. CBD, by blocking activation of GPR55 could save lives. How? Often, activation of GPR55 can dramatically increase the risk of osteoporosis and a number of cancers.

That CBD is able to block activation of GPR55’s has led many scientists to conclude GPR55 could be the next novel cannabinoid receptor, and likely the third most important receptor after CB1 and CB2. GPR55 could soon become CB3!

However, this conclusion is a ways away from achieving cannabinoid receptor Rockstar status, given the fact it only shares 14% of its identity to the CB1 and CB2 receptors. To put that in perspective, CB1 and CB2 are 64% similar. But one thing everyone agrees on: GPR55 plays a vital role in influencing the therapeutic benefits of cannabinoids, and CBD more than any other.

CBD Health Benefits via GPR55


Image Source: Shutterstock

CBD Benefits: Cannabinoids for the Treatment of Neuroinflammation

CBD’s blockage of GPR55 activity may also contribute to its ability to reduce inflammatory and neuropathic pain. Mice that are genetically unable to produce GPR55 receptors have lower levels of inflammation, inflammation-induced pain, and neuropathic pain after nerve constriction.

CBD Benefits: GPR55 and CBD in the Treatment of Epilepsy


CBD has emerged as a promising anti-epileptic treatment strategy in seizure disorders that don’t respond well to traditional medications. In cases like Dravet syndrome, mutations in DNA cause a reduction in the level of brain inhibition which manifests as epileptic seizures. (You may have heard of Charlotte Figi, the young girl with Dravet syndrome whose seizures were successfully treated with CBD-rich cannabis and is now the namesake of the popular Charlotte’s Web.) CBD restores brain inhibition and reduces seizures largely by blocking the activity of GPR55 in the hippocampus, a critical brain region for seizure activity.

CBD Benefits: GPR55 and CBD in the Treatment of Cancer


GPR55 has an increasingly appreciated role in cancer. Because of GPR55’s novelty, many of these studies are in their early stages and haven’t been translated to animals or humans yet.

However, in verified cell lines—which is often the first stage of cancer research—GPR55 activation is thought to have pro-tumor effects while blockade of GPR55 activity (i.e., the effects of CBD) has anti-tumor effects in colorectal cancer, breast cancer, pancreatic cancer, and brain cancer. CBD’s direct effect on these cancers remains an exciting yet untested future direction of cancer research.

CBD Benefits: GPR55 and CBD in the Treatment of Inflammatory Bowel Disease


Inflammatory bowel disease is the inflammation of the colon and intestines. Crohn’s disease and ulcerative colitis are the most common, and patients who suffer from these diseases have elevated GPR55 levels. This suggests that GPR55 may be having a pro-inflammatory role in the intestines. Indeed, blocking GPR55 activity in mice reduces gastrointestinal inflammation, perhaps underlying why CBD is becoming an increasingly popular treatment strategy for patients with inflammatory bowel disease.

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