Beyond CB1 and CB2: Exploring the body’s full cannabinoid receptor network

Understanding the relationship between cannabis and the CB1 and CB2 receptors matters, but they’re not the only places cannabinoids get busy. And, as always, we want Releaf patients to have access to the most up to date, accessible information regarding how their prescribed treatment options actually work, and also how they may not. 

So what else is going on beneath the surface?

• What is the full list of receptors that THC and CBD have been shown to interact with?

• Why is it that different patients sometimes experience such different results from the same product?

• What does this broader receptor network mean for dosing, side effects, and treatment planning?

• And how close are we to personalising cannabis treatment using this science?

Why CB1 and CB2 are just the beginning

The CB1 and CB2 receptors are the two main receptor types in the endocannabinoid system, making them really critical to understanding how cannabis offers both therapeutic and nontherapeutic effects. 

But as access and research into cannabis has increased, especially over the past two decades, we are finding that they're really just the tip of the iceberg. 

Now, we have covered how THC, CBD, and other minor cannabinoids interact with the endocannabinoid receptors many times on the Releaf blog. THC does bind quite heavily to CB1 receptors to produce some of its wide-reaching therapeutic potential (along with its psychoactive effects) - and CBD modulates the overall functioning of the ECS - and with this we aren't going to go any deeper here today. But, we are going to have a look at some other interactions cannabinoids can have in the body. 

Read more: What is the endocannabinoid system?

TRP channels: The body’s sensory switches

TRP channels make up one part of the membranes of sensory and immune cells. Each one has its own role related to a specific type of signal, such as heat, cold, pressure, or chemical stress. 

When something interacts with a TRP channel, the TRP channel ‘opens’ and allows calcium to flow into the cell, which then sets off a chain reaction. 

Cannabinoids interact with these channels in more than one way. Some activate them directly, but not all do, with some also changing how easily they open or close. Over time, repeated activation can lead to desensitisation, which helps explain why people using medical cannabis sometimes need to take what are referred to as ”tolerance breaks” - but, that desensitisation is actually what we are looking for at times…

Which TRP receptors respond to cannabinoids?

• TRPV1 - CBD, CBN, and our own endocannabinoid anandamide have all been shown to potentially activate the TRPV1 channel. This receptor helps regulate how we perceive pain, the impact, and even timing of seizures, and some of the physical responses to anxiety.
• TRPA1 - A key inflammatory sensor on pain-sensing neurons. It responds to environmental irritants and oxidative stress. Both CBD and CBC can modulate TRPA1, which acts as one of the key inflammatory sensor on pain-sensing neurons. The interaction with cannabinoids can reduce gut and joint inflammation.
• TRPV2 - Cannabinoids including both CBG and CBD activate TRPV2 receptors, which are mostly present in immune cells, muscle tissue, and certain tumour types. This binding effect can influence immune signalling and may even encourage cancer cell death (although further research is needed to confirm any cancer fighting effects). 
• TRPM8 - A cold-sensitive receptor that helps control nerve response and cell growth. CBG has been shown reduce pain signals associated with cold exposure, and has also become a potentially promising target in prostate cancer research as TRPM8 drives growth in some prostate cells.

Together, these TRP channels give us a clearer picture of how cannabinoids work beyond CB1 and CB2. Generally, many non-psychoactive cannabinoids collectively activate or sensitize TRP channels that regulate pain and inflammation.

GPRs: The emerging cannabinoid-like receptor family

Beyond CB1 and CB2, a group of G protein-coupled receptors (GPRs) are stepping into the spotlight. GPR55, which some refer to as a potential "CB3" receptor, is the most studied. It's blocked by CBD, a mechanism linked to seizure control and inflammation reduction.

The research is still lacking, but these GRPs are found in immune and digestive tissues, and their potential interaction with cannabinoids may help explain some of the wide-ranging effects seen with medical cannabis treatment.

In some studies, CBD’s ability to block the activation of GRP55 has been linked to reduced inflammation and anti-seizure potential. But debate still rages, as THC and THCV both bind GRP55, and in doing so, activates it. 

Researchers found that this causes a rise in calcium levels inside the cell. This changes how the neuron behaves and may affect how pain signals are processed. It also reduces the M-current, a small electrical flow that helps keep neurons calm. Turning that down makes the cell more reactive, which could either help or worsen pain, depending on the setting.

Along with GRP55, GPR18, and GPR119 also show promise as cannabinoid targets, but again, we await further clinical research results to determine this certainty. 

Neurotransmitter systems: Cannabinoids aren't just about receptors

One of the clinical targets researchers have really sunk their teeth into over the past 20 years is the brain's chemical messengers. Cannabinoids don’t just switch receptors on or off, they can also change how certain signalling chemicals are released, broken down, or recycled.

Serotonin, one of the brain's "feel-good" chemical (it’s linked to feelings of calmness, contentment, and stability), plays a regulatory role in far more than just mood. It impacts our sleep (as one of the building blocks of melatonin), digestion (specifically nausea), even wound healing. CBD has been shown to enhance serotonin activity, which may help explain its calming, antianxiety effects.

CBD also boosts levels of GABA, a neurotransmitter that plays a role in the activity of brain circuits (or overactivity, to be more precise). Up regulating GABA levels may have positive implications for conditions like epilepsy or anxiety, where too much neural activity causes problems.

Along with this, it reduces glutamate levels, another chemical that, when too high, can put stress on brain cells. By keeping both of these in check, CBD may help the brain stay balanced and avoid getting overstimulated.

When THC reaches the brains, it can cause a spike in the release of dopamine, which is another one of our “feel-good” chemicals. But, unlike serotonin, dopamine is integral to the relationship between reward, motivation, and pleasure. That's part of why cannabis can offer up feelings of euphoria, gratitude, and just general happiness.

It is important to point out that these effects don't follow a single route. Cannabinoids work on many neurotransmitter systems all at once, and it’s this layered, wide-reaching action that helps explain why the therapeutic effects of medical cannabis treatment are very much personalised. 

What does this all mean for UK medical cannabis patients?

Well, the biggest takeaway is that the while the endocannabinoid system, and its CB1 and CB2 receptors play a major role in how medical cannabis affects use, it simply isn't the whole story. 

We know now that the relationship between cannabinoids and the human body as a whole is far more complex than once believed, and that (in all honesty), we are still at least a few decades away from fully understanding the every single in-and-out of how these fascinating compounds actually work.

But what we do know is that cannabis-based treatments offer support for a huge range of health concerns and conditions. This is supported by an enormous body of research, and that research is only growing with each passing year. 

Can medical cannabis help with your health journey? 

Head to our fast, free medical cannabis eligibility checker to find out if you may be potentially eligible for medical cannabis treatment in the UK right now. It takes just 20 seconds to complete.

Releaf - Let’s rethink healthcare