GPR55 — The Cancer-Promoting Endocannabinoid Receptor and How CBD Might Block It

If you’re using CBD or medical cannabis, you’ve probably read about the endocannabinoid system (ECS) — the vast network of receptors (CB1 and CB2) and cannabis-like chemicals found in our brains, central nervous system, immune system, and gut. Not only does the ECS regulate our biological activity, but it is directly affected by compounds from the cannabis plant, such as THC and CBD.

However, there is another receptor, the GPR55, which currently leaves scientists scratching their heads. Rather than creating internal balance like the more established ECS receptors, it appears to actually increase the spread of cancer cells and tumor growth.

Little wonder researchers are looking for ways to block GPR55 receptors in the body, and as luck would have it, CBD (Cannabidiol) is a prime contender.

What is the Endocannabinoid System?

The endocannabinoid system (ECS) was discovered in the 1990s when researchers were trying to figure out how THC, the psychoactive compound in cannabis, affects the body. They soon discovered a network of endocannabinoid receptors (CB1) throughout the brain and central nervous system, and not long after, the two natural cannabis-like chemicals, anandamide and 2-AG, that bind to them. Next came the discovery of another type of receptor (CB2) in the peripheral nervous system, immune system and gut, and with that the endocannabinoid system seemed complete.

Scientists realised that the ECS acts like a kind of ‘biological dimmer switch’, regulating cell activity through the release of endocannabinoids.

In cases of cancer, the CB1 receptor and its endocannabinoids were seen to elicit an antitumoral action; one of the reasons THC is thought to show such anti-cancer promise.

However, with the discovery of the GPR55 receptor came an endocannabinoid spanner in the works, as instead of working to maintain optimum health, this ‘orphan receptor’ seemed to cause some types of cancer.

The GPR55 Receptor

Identified in 1999, the G protein-coupled receptor 55, otherwise known as GPR55, is a receptor encoded in humans by the GPR55 gene. It is present in tissue throughout the body, in particular our bones, heart, lungs, gastrointestinal tract, liver, kidney, bladder, uterus, and nerve tissues.

Scientists originally termed it an orphan receptor, meaning it had a similar structure to other identified receptors, in this case endocannabinoid, but its endogenous ligand (binding molecule) had not yet been identified.

However, GPR55 receptors are now known to be activated by lysophosphatidyl-inositol (LPI), as well the endocannabinoid, anandamide and the phytocannabinoid THC. Crucially, the GPR55 receptor is blocked by Cannabidiol (CBD), which has particular significance when one considers the receptor’s sometimes errant behaviour.

So, while compared to the CB1 and CB2 receptors far less is known about GPR55’s role in the body, it is now considered an additional endocannabinoid receptor.

GPR55 and Cancer

Scientists have observed increased GPR55 receptor activity in certain types of cancer such as ovarian, breast, prostate, brain, skin, cervix, liver, blood, pancreas, and bile ducts. Research also suggests GPR55 signalling promotes the reproduction of cancer cells.

Spanish cannabinoid pioneer Cristina Sanchez, alongside her team of researchers, have found that “elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis.” They also suggest that not only could the receptor be a biomarker for this particular subtype of breast cancer, but also a therapeutic target if drugs are developed to block its expression.

A recent paper goes some way to explaining the GPR55’s pro-cancer role. Published in the International Journal of Cancer, scientists bred mice without GPR55 receptors, comparing their tumor burden (the number of cancer cells, the size of a tumor, or the amount of cancer in the body) with wild, GPR55 positive mice. The mice with GPR55 receptors had 50% more tumours, which researchers believe was due to the receptor’s role in creating a tumor-promoting environment by altering levels of white blood cells.

They concluded: “While CB1 appeared up‐regulated in inflamed nontumor tissue and down‐regulated in tumor lesions, GPR55 was found to be down‐regulated in nontumor tissue and up‐regulated in tumors when compared to healthy control colon. These findings corroborate the hypothesis that colonic tumor growth is facilitated by the absence of tumor‐suppressing CB1 and the presence of tumor‐promoting GPR55.”

CBD, GPR55, Cancer, and Epilepsy

It would seem that finding a drug to block GPR55 could be an exciting therapeutic target for certain types of cancer.

In a 2011 paper published Molecular Endocrinology, the authors state that “GPR55 antagonists may prove beneficial in slowing tumor proliferation, angiogenesis, and cancer pain.” By antagonist, they mean compounds that block signalling rather than binding with the receptor, and one of the most studied antagonists is CBD.

Scientists already know in preclinical studies that CBD has elicited various anticancer effects, such as selectively inhibiting the growth of different types of breast cancer cell, reducing their migration to other parts of the body, and encouraging cancer cell death (apoptosis) in thyroid cancer in rat cell cultures. However so far, no study has established that this antitumoral effect is due to CBD’s GPR55 blocking action.

A hint may lie in another health condition where CBD’s therapeutic effects are scientifically proven. In 2016, a GW Pharma funded paper was published examining whether CBD’s GPR55 inhibition could explain the cannabinoid’s anticonvulsant effect. Researchers observed that higher levels of the receptor’s main binding molecule, LPI, corresponded with excitatory synaptic transmission, commonly experienced during seizures. They found that administering CBD limited this neuronal excitation, which they thought may account for its much celebrated seizure-reducing effect.

While this doesn’t prove that CBD also reverses the pro-cancer conditions associated with high GPR55 expression, it certainly shows that by blocking the receptor biological changes do occur in the body.

GPR55 Shows Therapeutic Potential for Neurodegenerative Diseases

But that’s not where the GPR55 story ends. At the same university where Sanchez discovered the receptor’s cancer-promoting properties, another group of scientists have begun researching GPR55 as a potential therapeutic target for neurodegenerative diseases. But instead of looking for ways to block the receptor, they are examining its activity as neuroprotectant.

Javier Ruiz, Professor of Biochemistry and Molecular Biology at the Complutense University, explains how GPR55-deficient mice develop motor impairment, a common neurological deficit in experimental ALS (Motor Neuron Disease). Not only that, GPR55 activation was also found to ‘preserve neuronal integrity’, which in layman’s terms means it is neuroprotective.

Ruiz’s team have also found evidence of GPR55 changes in the central nervous system among subjects with ALS and other neurodegenerative diseases, which has led them to launch an initial study into this often-perplexing receptor.

Once again, the scientific narrative remains far from straight forward. On the one hand, the GPR55 has a neuroprotective effective, but so does CBD, the very same cannabinoid that inhibits its signalling.

It’s clear there’s still much to learn about GPR55’s role in the body, and with this knowledge will come a more refined use of cannabis strains for cancer, epilepsy, and neurological disorders. What remains to be seen is whether CBD will prove successful as a GPR55 blocking drug, further unlocking the secrets of this perplexing receptor.




Writer, medical cannabis advocate, British by birth but Andalusian by adoption. Follow me on twitter @Mary_Biles or

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Mary Biles

Mary Biles

Writer, medical cannabis advocate, British by birth but Andalusian by adoption. Follow me on twitter @Mary_Biles or

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