Updated Research on CBD and the Pathways of Rheumatoid Arthritis
We wrapped up our big review of CBD and autoimmune at its root.
It's a fascinating update that dives into new research on how the immune system starts to "misread" our cells as foreign.
The big advances are on the front of protein mimicry, where proteins from specific bacteria (usually escaping our gut, mouth, throat, etc) look like proteins that our own cells make.
Strep bacteria in the throat - skin cells and psoriasis as an example.
Since rheumatoid arthritis is one of the most common and the cells targeted are so specific, is there also a connection there?
More importantly, what does updated (last few years really) say about CBD and the pathways of RA?
All good questions and we're going to do a deep dive.
Here are the topics we'll cover:
- A quick look at the process of rheumatoid arthritis
- Protein mimicry and rheumatoid arthritis
- The gut barrier and rheumatoid arthritis
- Inflammatory response to rheumatoid arthritis
- Research on CBD and rheumatoid arthritis
- How much CBD for rheumatoid arthritis
- What's the best CBD for rheumatoid arthritis
Let's get started.
A quick look at the process of rheumatoid arthritis
Let's start with genes since there's a major clue there.
Of course like any disease, RA is a combination of genes and environment but the particular genes point us in the right direction.
Focus is now squarely on HLA genes (Human Leukocyte Angiten).
This complex of genes governs our immune system creation of antibodies and to which targets.
This is the crux of autoimmune diseases….the immune system reads our own cells as foreign and attacks.
RA is no different.
There is clearly a genetic inheritance here:
The heritability of rheumatoid arthritis is approximately 40% to 65% for seropositive rheumatoid arthritis and 20% for seronegative rheumatoid arthritis.
Smoking is a known risk factor but the newest kid on the block is the gut microbiome.
Here's where it gets interesting:
The researchers found that 75% of people with new-onset, untreated rheumatoid arthritis had the bacterium Prevotella copri in their intestinal microbiome.
The keyword there is "new-onset". The beginning of the disease.
More interesting, the researchers injected this particular gut bacteria into mice who had colitis (a gut inflammation disease) triggered and the ones with prevotella had more serious symptoms.
There's a known correlation between RA and gut inflammation.
That's just the tip of the iceberg and we'll get into it further below.
As for the process of rheumatoid arthritis, the disease is characterized by inflammation in the synovial membrane.
This is a special type of cell that lines joint tissue which acts as a lubricant for movement.
Inflammation is a response of the immune system generally to attack or damage.
Essentially, the immune system is attacking the synovial cells that line connective tissue in joints.
The net result is pain, swelling, rigidity, and worse. This makes sense if the lubricant of the joints is slowly being attacked.
There are some interesting caveats to look at.
RA hits women at 2.5 times that of men.
Look at this stat:
The demographic characteristics are those of a typical RA cohort with 79% females, more than 90% Caucasians, and a mean age of 57 years
Check out our review on progesterone (drops by 50% at age 40) and how it calms immune function.
The age of 57 speaks volumes there as well (loss of estrogen and progesterone - check out CBD and perimenopause pain).
As for caucasian??? Hello Vitamin D.
Vitamin D is so critical to immune function that we did a full review on it here.
It appears that vitamin D deficiency is highly prevalent in patients with RA and that vitamin D deficiency may be linked to disease severity in RA.
Mind you, their definition of deficiency is very outdated (especially if you have risk factors like RA) level of 20. Endocrinologists are now saying 75-80 is the goal.
Really read the review...it's probably the greatest epidemic going.
As for progesterone, what about times when it rises naturally such as pregnancy?
Most of the pregnant women with RA have low disease activity during pregnancy (60%) and may achieve remission by the third trimester as well.
Umm…levels of progesterone by trimester:
10 to 44 ng/mL during the first trimester of pregnancy. 19.5 to 82.5 ng/mL during the second trimester of pregnancy. 65 to 290 ng/mL during the third trimester of pregnancy.
So...progesterone and Vitamin D.
Keep in mind that these are critical pathways and if they've run low for some time, it will take time for them to re-establish.
Think of a river bed that's dry. The first rain doesn't fill it up!
We'll zero in on the inflammatory markers with RA specifically.
T Cells are important players as they are called in to respond to an intruder (or synovial cell).
Along with them, you have a host of little assassins called cytokines.
Two key pro-inflammatory cytokines in RA are IL-1 and TNFα. Regulation of these cytokines is of crucial importance in the RA disease.
IL17 and IL18
Let's look at some of the most exciting (and new) research.
Protein mimicry and rheumatoid arthritis
- Why the joints with rheumatoid arthritis?
- Why the skin with psoriasis?
- Why the brain with dementia?
The autoimmune diseases all have paths in common but clearly, there's something different.
This is where the new research centers and will likely continue.
It turns out that there are similarities between the chemical signatures of proteins in our various cellular machinery and that of bacteria and other substances.
There are three interesting paths:
- Strep bacteria (throat)
- Proteus bacteria
The original clues came about when arthritis and rheumatic disease would follow infections.
They found that murine antibodies to measles virus and herpes simplex virus (HSV) were found to react against human cells.
Researchers went on to show that a hepatitis B protein resembled a key protein of myelin (our nerve sheath) production and when given to rats, they developed encephalomyelitis (the animal equivalent of MS).
Think about that.
A protein from hep c mimics one in our nerve protection pathway.
When given to an animal, the immune system starts attacking our nerve sheaths!
The molecular machinery of life is highly conserved and there are only so many ways you pattern amino acids. A larger number but finite.
That's why there are multiple pathogens that are tied to RA:
Clinical and experimental studies have reflected a role for microorganisms in the development of RA and among the most important ones are Porphyromonas gingivalis (P. gingivalis), Proteus mirabilis (P. mirabilis), Escherichia coli (E. coli), and EBV
That's a shortlist!
Interesting though...gingivitis...mouth bacteria.
E coli - gut. Proteus - gut.
As for gingivitis:
Several studies have described up to a two-fold increase in RA in patients who also have periodontal disease compared with controls
Before we fall down the rabbit hole, let's zero in on just this one example.
Why would gingivitis increase the risk for RA?
Several studies have documented a similarity (up to 82%) between P. gingivalis enolase and human α-enolase within the 17-amino acid immunodominant region
So...the immune system misreads a key protein (enolase) of our body as being a bad bacteria from our mouth.
As for proteus mirabella:
In fact, chronic infection by P. mirabilis could induce, through molecular mimicry, chronic inflammation of joints
A different set of proteins are being misidentified there.
Then there are the traveling pathogens…
The results indicate that bacterial DNA and bacterial cell wall constituents are retained in the joints of some patients with arthritis, where they might enhance synovial inflammation.
DNA of bacteria was found in the joints of people with RA.
This all begs the question…
How are bacteria getting into our bodies and joints, to begin with?
The first sin, if you will.
The gut, mouth barrier and rheumatoid arthritis
We covered this quite a bit at our CBD and autoimmune review.
Our bodies are surrounded by trillions of potential attackers. By the second.
Certain barriers protect us from the harsh reality of microscopic enemies.
- Urinary and reproductive tracts
By far, the gut is our greatest vulnerability.
A virtual Trojan Horse for bacteria, viruses, and more.
The system nature developed to form a barrier between the outside world and our inner workings is a beautifully intricate system.
The basic layers are:
- Microbiome - the trillions of bacteria, fungi, and more that occupies our gut
- Microbiome film - the thick layer that coats our gut barrier
- The tight junction cells that make up our actual barrier
- The immune system players which guard against intruders
The gut is sometimes referred to as our second brain and with good reason.
It's the largest collection of neurons outside of the brain!
If bacteria or viruses are getting into our body and triggering an immune response in our joints, the gut is probably the break in the damn.
The clues abound for RA:
Human studies revealed that patients with RA display significant differences of the intestinal microbiota and a decreased gut microbial diversity in comparison to healthy controls (3), both related with disease duration and autoantibody levels
Remember the prevotella bacteria from above (protein mimicry)??:
microbial composition in subjects with early rheumatoid arthritis differs to controls, with a reduction of certain bacteria belonging to the family Bifidobacterium and Bacteroides [15, 16], and a marked increase of species belonging to the genus Prevotella
More important, rats raised without gut bacteria can develop arthritis when certain strained are injected.
We now know that inflammation in the gut sets the thermostat for immune response in the rest of the body.
In this respect, the microbiome makeup works as a general setting for how our immune will over or under respond to threats.
Then, there's the big one. Gut permeability. Leaky gut.
When this complex system breaks down, bacteria can escape into our bodies.
We did a full review on CBD and leaky gut since it's at the heart of autoimmune.
High levels of Prevotella copri and similar species are correlated with low levels of microbiota previously associated with immune regulating properties.
So...as prevotella gains ground in our gut's real estate, other beneficial bacteria that govern our inflammation response suffers.
The gut barrier is so important for RA:
Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis.
Think about that...when the system is calling in backup for keeping the barrier up, it's literally a signal that we're entering the diseased part of RA.
A cry for help or a canary in the coal mine if you will.
So...why are women hit so hard by RA (and autoimmune in general)?
Clearly, it's a hormone aspect but what?
We thought you would never ask…
Progesterone decreases gut permeability through upregulating occludin expression in primary human gut tissues and Caco-2 cells
As we said, progesterone drops naturally to 50% by age 40.
When does RA start to rear up? Exactly.
Before moving forward, let's end with the tantalizing piece:
Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis.
That's a 2020 paper from nature.
"Cannabinoid type 1 receptor agonist". Hmmm. We'll get into that below.
By the way, they were able to prevent/reverse the disease by restoring the gut barrier.
Clearly, the gut's in play.
You can't address the flooding till you fix the hole first.
Let's quickly look at the inflammatory markers since they will be important for CBD's research.
Inflammatory response to rheumatoid arthritis
We already mentioned some key players but just a recap before we dive into CBD.
T cells are the instigators of our inflammatory cascade that occurs when pathogens (bad bacteria, etc) are found.
Similarly, they get called up when the immune system mistakenly views our own proteins as bad actors.
What then follows?
IL1 and TNFα. are both implicated as inflammatory markers.
More recent research has since narrowed it down to IL17 and IL18.
As we mentioned, IL4 and 10 are calming agents used to resolve inflammation. More of that, please!
Remember, the inflammatory cytokines are actual instruments of destruction to the joints and connective tissue in RA.
There's master control above in our immune system with a pro-inflammatory setting.
Okay...let's finally jump into CBD.
Remember the "endocannabinoid receptor agonist" from above?
What's the connection there?
Research on CBD and rheumatoid arthritis
First, CBD works as a feedback mechanism in our endocannabinoid system.
That system is tasked with balancing other key systems:
- Nervous system - neurotransmitters and more
- Endocrine system - hormones
- Immune system - inflammatory response!
Goodness...right in our wheelhouse.
We're going to focus on these topics with CBD for RA:
- CBD and gut barrier for rheumatoid arthritis
- CBD and immune setting for rheumatoid arthritis
- CBD and inflammatory cytokines rheumatoid arthritis
- CBD and Rheumatoid arthritis research
Notice that we went in the sequence that the disease follows: gut - the immune response - inflammation - disease.
Let's get started!
CBD and gut barrier for rheumatoid arthritis
Let's start at the beginning.
We have to reinstate our gut barrier to stop the influx of bacteria, viruses, and more into our body where the immune system panics.
What does research show there?
Researchers introduced a particular vicious pathogenic bacteria called C diff to gut cells.
This immediately led to what you might expect...inflammation, cell death, breakdown of the gut barrier.
C diff is the nasty infection that's becoming resistant in hospitals.
Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.
- Blocked the cell death in of gut cells caused by C diff
- Restored gut barrier integrity
- Operated via CB1 receptor
Do you remember how the 2020 research looked at CB1 receptors as a key to blocking the progression of RA?
What about occludin, the "glue" of our gut?
CBD, markedly reversed the TcdA-induced decrease of both occludin and ZO-1 co-expression in cultured cells, thus restoring the epithelial barrier architecture
ZO just happens to be zonulin, which was the canary in the coalmine that our gut was under attack with RA.
Check out CBD and gut barrier for more information.
Once bacteria are freely entering our bloodstream, what about the immune response that occurs and leads to RA?
CBD and immune setting for rheumatoid arthritis
CBD has a known anti-inflammatory effect in cases where the immune response is hyperactive.
This is very important and speaks to the beauty of CBD (the endocannabinoid system really).
For example with cancer or virally infected cells:
- Healthy cell with low inflammation - CBD has no effect
- Healthy cell with high inflammation - CBD reduces inflammation
- Cancerous or virally infected cell - CBD INCREASES inflammation
Read that back over because it's pretty impressive.
It makes sense once you understand that our body's natural way to kill off wayward cells is to boost inflammation (oxidative stress) in a process called apoptosis.
Chemo and radiation are essentially giant doses of oxidative stress.
See CBD and oxidative stress for more.
What about the T cells that become activated with rheumatoid arthritis?
A study on mice with the animal version of MS showed a fascinating effect:
Moreover, CBD inhibited MOG-induced T-cell proliferation in vitro at both low and high concentrations of the myelin antigen.
MOG was the injection or trigger that set off the immune response.
So...in the body, CBD calmed the T cell response that leads to a version of MS (also, autoimmune).
Let's look at RA specifically.
Here's a big one:
In this study, we show that CBD increases intracellular calcium levels, reduces cell viability, and IL-6/IL-8/MMP-3 production of rheumatoid arthritis synovial fibroblasts (RASF).
Let's translate...this is really important.
Remember that RA operates in the synovial tissue...the connective tissue that forms a sort of lubricant for joints.
As RA progresses, more and more "diseased" tissue is created which eventually crowds out good synovial cells.
This leads to the loss of function, pain, and other symptoms.
Fibroblasts are the nurseries of this new tissue.
Essentially, CBD is specifically targeting the diseased nurseries of diseased synovial cells.
It does not affect the neighboring healthy tissue.
This may sound like magic since most modern medicines pushed in one direction (kill all tissue or suppress all immune function) but it's really the endocannabinoid system.
Don't take our word for it…
This effect was enhanced by pre-treatment with TNF suggesting that CBD preferentially targets activated, pro-inflammatory RASF.
It's tasked with balancing cell birth/death and death applies to cells that are damaged.
Let's turn our attention to the cytokines, little chemical assassins that are doing the damage with RA.
CBD and inflammatory cytokines rheumatoid arthritis
CBD has a known anti-inflammatory response on cytokines:
The levels of IL-4, IL-5, IL-13, IL-6, IL-10, and TNF-α were determinate in the serum. CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels.
Remember that IL10 is a calming cytokine sent in to "resolve" inflammation. Very important!
Let's recount some of the main players with RA:
Let's start there.
CBD-treated mice had less proliferation in ex vivo-activated draining lymph node cells, decreased levels of IFN-γ secreted by the activated lymph node cells and diminished TNF-α production by knee synovial cells.
As for IL17…
Interestingly, “IL-17 signaling” was also identified as a critical pathway suppressed by CBD (5 μM) in T cells in vitro
Interestingly, CBD suppresses this immune response when hyperactive….not when normal.
In fact, when T cells were impaired, CBD would boost their levels!
This is critical as most of the RA and autoimmune medications suppress the immune response in one direction.
This is why there's a nasty list of side effects from their use which are missing from CBD.
The immune system does so much more than just fight infection! Mental health. Cancer. Everything is now pointing to this system.
Let's look at research on CBD and RA specifically including symptoms.
CBD and Rheumatoid arthritis research
There are trials currently underway for CBD and RA directly.
Let's look at other research we have till then.
Let's focus on pain first (see CBD versus Tylenol to learn more).
A study looked at Sativex which is a combination of CBD and THC:
In the first-ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment.
Another study looked at transdermal CBD directly:
Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner.
Maybe more importantly (the thing that causes the pain), were the results on inflammatory markers:
Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNFα) revealed dose-dependent reductions of pro-inflammatory biomarkers.
Remember that pain travels in the spinal cord for processing.
Dose-dependent is important because it shows cause-effect.
Let's dig a little deeper but try to keep our head above water.
We need to introduce key endocannabinoids as this is the system at play.
Anandamide (named after the Hindu goddess of bliss) is our primary endocannabinoid.
OEA and PEA are supporting players.
Here's why they matter:
IL-6, IL-8 and MMP-3 (determined only in synovial fibroblasts (SFs)) were downregulated in primary synoviocytes and SFs of RA and OA after AEA, PEA and OEA treatment.
Goodness...they drop the inflammatory markers that drive RA specifically in the cells that matter (synoviocytes).
Why bring this up?
Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH)
CBD boosts anandamide levels by blocking FAAH.
This is so important across many health issues that we did a full article on how to boost endocannabinoids and endocannabinoid deficiency.
Anandamide is a heavy hitter with RA:
Anandamide attenuates the inflammatory phenotype of rheumatoid arthritis synovial fibroblasts by activating multiple receptor pathways
To translate, anandamide directly calmed the inflammation "setting" of the nurseries that create RA synovial cells.
Check out our review on PEA which is also a big supporter of anandamide.
Looking at CBD and RA pain, we're starting to get more information.
Researchers injected a known irritant to joints and found the following:
Acute, transient joint inflammation was reduced by local CBD treatment
And the resulting pain:
Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (P < 0.0001; n = 8), and was also found to be neuroprotective
We look forward to the trials underway for CBD and RA directly.
Also of interest:
- PEA - critical supporter of anandamide
- Vitamin D - after reading all the research, we're wondering if RA and autoimmune isn't a Vitamin D deficiency issue
- Berberine - supports gut barrier
- Progesterone - again, the research is fascinating considering the typical patient (women, over 50)
Let's turn to some practical questions.
How much CBD for rheumatoid arthritis
In the research above, studies made reference to a range of CBD for effectiveness in their given pathways.
It was generally between 300-800 mg of CBD daily.
The 300 mg matches what we see for peak neurogenesis. See the review of CBD and brain repair here.
Higher levels of between 600-800 mg daily are found in research for more serious issues like schizophrenia, opioid withdrawal, and public speaking with social anxiety.
The higher amount might then be spot-used when there are pain flareups.
CBD should be taken at least 4 hours away from medications and always work with your naturopath or doctor.
We really like the 300 mg long term since it's tied with peak neurogenesis which is the process of repair and rebuilding of nerves.
Then there's the type of CBD.
What's the best CBD for rheumatoid arthritis
It's a must that the following is part of any CBD:
- Organically grown in the US at FDA registered farms
- 3rd party tested
- CO2 processed
- THC free - THC is one-way immunosuppressive and more importantly, it builds tolerance
- No pesticides
- No heavy metals
- No solvents
- No bacteria
- No mold
We test our oils twice to be sure - the whole family uses it!
Then there's the full spectrum versus CBD isolate question.
The dozens of studies referenced on this site all have one thing in common - CBD isolate. CBD by itself.
We did a full review of CBD isolate versus full spectrum to dispel some of the main misconceptions.
First, 40-60% of the population has histamine (allergy) issues.
This goes up for women and as we get older. Sound similar to the RA risk segment?
As we mentioned, progesterone is a powerful player in our immune system control and we see many side effects of full-spectrum go away with CBD isolate.
CBD by itself has actually been shown to calm histamine response (see CBD and mast cells).
All the plant material in full-spectrum however can have a totally different side effect profile as you can see from our reviews.
We don't need more inflammation (histamine is a powerful inflammatory player in our immune system).
Then there's the price.
The key is the cost per mg of CBD.
We intentionally price our 6000 mg bottles at 2-3 cents per mg of CBD before discounts up to 30%.
It's consistently the lowest we can find on the market and for a reason.
We found CBD (after trial and error with full-spectrum) due to a brutal perimenopause (speaking of losing progesterone).
That story is here. If we can help others avoid similar suffering, then it's worth it.
Be well. Take care of each other. Take care of yourself.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.