Updated Research on CBD and the Pathways of MS
We've wrapped our exhaustive review on CBD and autoimmune.
Let's not turn our attention directly to research on MS, Multiple Sclerosis, directly.
As a clear example of autoimmune with a strong inflammatory bent, MS is a perfect study for CBD pathways.
Women are harder hit (true for most autoimmune) and we'll dive into what's driving that.
You're going to have a completely new respect for progesterone.
Then there's the strange connection with climate and hemisphere.
That's when we'll investigate Vitamin D level.
Finally, we'll look at the intriguing research on CBD and the pathways of MS.
These are the topics we'll cover:
- A quick introduction to MS
- Risk factors for MS
- The autoimmune nature of MS
- Protein mimicry and MS
- Inflammatory markers and immune response for MS
- The gut microbiome and MS
- Research on CBD and MS
- How much CBD for MS
- What's the best CBD for MS
Lots to cover...let's get started!
A quick introduction to MS
MS primarily acts by attacking the sheathing of our nerves.
The material in particular is called myelin and it's made primarily by a component of our nervous system's immune response which is a big clue.
The particular cell is called oligodendrocytes.
The resulting symptoms from loss of insulation of our nerves is far-reaching and devastating as to be expected:
Newer research is pointing to the death of these oligodendrocytes as a primary cause of the disease:
In MS, myelin-forming oligodendrocytes (OLGs) are the targets of inflammatory and immune attacks.
It's now well established that the perpetrator is our very own immune system.
Newer research based on new gene-expression technology is showing a mutiny of sorts among the oligodendrocytes.
By switching the genes they turn on and off, a cluster of OLG's start to mimic immune response actions:
Similar to immune cells, the disease-associated oligodendrocyte lineage-activated genes are involved in the stimulation of immune responses and immunoprotection.
This triggers an immune response against them as they are actually "eating" (called phagocytosis) other cells.
New autopsies are showing pockets of OLG's which are functioning in a destructive way.
The key to remember about the immune system is that it's in charge of both inflammatory response and repair.
In MS, newer research is showing that some OLG's are switching from repair (of myelin) to inflammatory response which triggers an attack on them.
Again, this is brand new research available since CRPSR came on the scene so researchers will have to tease out the whole process but it's a big move away from prior frameworks.
We'll look at why this may happen below in the mimicry section but let's move on to other key issues to understand.
Risk factors for MS
There are intriguing risk factors for MS that are very specific and help to shape our understanding of what's happening under the hood.
- Age - generally starts between age 20 and 40
- Gender- almost 4 to 1 women and that ratio has increased over the last few decades
- Viral infections - earlier exposure tied to risk
- Race - white people and African Americans have much higher risks compared to other races
- Climate - growing up in cold or temperate areas (far North or South) confers an increased risk
- Vitamin D levels - we'll look at this and the climate and race component
- Other immune diseases
- Smoking - inflammatory response
Let's look at some of these because they'll figure in below.
First gender since it's almost 4 to 1 female.
This along with the age of onset is powerful.
First, you have to understand the role of steroidal hormones in every aspect of women's health.
Progesterone - directly manages (and calms) the immune response
It peaks around age 18-19 and drops in half by...age 40!
Check out our full review on progesterone here.
As for estrogen, it's our pro-growth repair hormone.
It's effect on myelin, the very thing under assault in MS?:
Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors
Goodness. SERM's are substances that operate like estrogen (soy, Siberian rhubarb, etc).
Our focus is on progesterone, however.
Look at this effect:
During pregnancy, many women find their MS symptoms stay the same or even get better, especially during the third trimester.
What's so special about the third trimester?
An explosion of progesterone!
Progesterone is literally a wet blanket for the immune response so that the woman's body does not attack the amniotic sac which is actually made from the father's DNA.
This is a huge "tell" for MS and immune response which accounts for both ages (naturally reducing progesterone) and gender (progesterone is much higher and integral to women's bodies).
Similarly, we can cluster race, climate, and Vitamin D.
The starring role there is Vitamin D.
We did a huge review of Vitamin D there since it's so critical and many people are deficient, even by the poor standards of rickets that our medical community tests us for.
So...why African Americans (as opposed to Africans) and Caucasians?
Melanin, the substance that gives pigment to the skin, is first and foremost, a means to control Vitamin D production.
Our primary source of Vitamin D is UV radiation from the sun.
African Americans' genes are set to receive huge amounts of UV in much more intense climates.
That's not going to work in Minnesota.
The ramifications of this for all aspects of health is tremendous as Vitamin D is a steroid that we get from the sun!
Again, check out the review.
As for Caucasians, there are known differences in key genes that process Vitamin D (called VDR).
I happen to have 3 bad versions where it's really hard to make Vitamin D.
In fact, skin is lighter to account for higher climates which just translates into lower Vitamin D (less UV light).
The temperate climate speaks to reduced Vitamin D production.
The net net…
Higher levels of vitamin D are associated with reduced risk for developing multiple sclerosis (MS), and with reduced clinical activity in established MS, including decreased risk of relapse and reduction in disease activity on brain MR
Again, none of this is surprising once you read the Vitamin D review.
Finally, viral infections.
This reminds us of our review on CBD and mental health (primarily schizophrenia, bipolar, or autism).
There's a known tie-in with early exposure to viral infection (even in utero) and later mental health issues.
The new push for mental health is all around the immune system!
The theory is that the immune system is "primed" to hyperactivate after early exposure and cause increased inflammation in the nervous system.
The inflamed brain theory.
Check out CBD and neuroinflammation to really dive into this.
There's even a strain of thought that viral infection is the driving factor for MS and we'll look at that below.
Let's turn to the autoimmune aspect...we're getting closer.
The autoimmune nature of MS
There are two basic pathways accepted for autoimmune:
- Bacteria/virus get into our body primarily through the gut barrier and cause an immune response
- Our cells share proteins with various bacteria/viruses which our immune system mistakes as being foreign and attacks
The two are actually intertwined.
How does the confused bacteria (protein mimicry) get into the body past our defenses to begin with?
- Leaky gut
- Pour mouth microbiome
- Skin barrier breaks
- Blood-brain barrier
- Urinary tract
The big trojan horse is our gut since it's the primary intersection between the inner and outer world.
More importantly, it serves as a thermostat for our body's inflammatory setting.
So...is MS an autoimmune disease?
There are clear indications of autoimmunity:
In the case of MS, it is the nerve-insulating myelin that comes under assault.
In terms of the viral angle?:
Such assaults may be linked to an unknown environmental trigger, perhaps a virus
As for the virus piece:
Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and Chlamydia pneumonia are some of the proposed infectious agents in humans implicated in MS.
Let's get into the newest and most exciting piece of research which might tie this all together.
Protein mimicry and MS
What is protein mimicry and how does it tie in with the viral infections above?
Essentially, we're all cooked from the same soup.
By "all", we mean mammals, birds, bacteria, viruses, etc.
There are many ways to cook the basic amino acids into proteins but it's finite.
More importantly, we see situations across our body where a substance (key) can fit an internal "lock" to cause changes.
THC mimics anandamide in this respect (see how to boost endocannabinoids).
All the medicines and natural substances that affect health do the same thing.
With protein mimicry and autoimmune, the basic premise is that a given virus or bacteria has a protein that looks really similar or even identically to one that coats a natural cell in our body.
That's why autoimmune tends to target one area (RA for joints, psoriasis for skin, etc).
What about MS?
In the animal version of MS called EAE, this mechanism was very first example of protein mimicry in all autoimmune research:
Oldstone, and colleagues (Fujinami 1985, Fujinami 1983) initially showed that a cross‐reactive epitope between the Hepatitis B virus polymerase and the encephalitogenic epitope of myelin basic protein (MBP) for the rabbit could induce an experimental autoimmune encephalomyelitis (EAE)‐like disease when used as an immunogen.
Hepatitis B has since been studied with MS but it turns out, many different viruses/bacteria may cause autoimmunity to either myelin and/or the oligodendrocyte that make it.
There's a great table here of possible targets:
Remember that this "infection" can even occur early in life or in utero:
The déjà vu theory takes this step further stating that there is an initial (fetal or neonatal) viral infection that persists and primes the individual for autoimmune disease provided a subsequent infection shares T‐cell epitopes with the persisting virus
This is the "priming" of the immune system.
Not everyone who is exposed to the viruses listed in the chart gets MS.
That brings up the second component: genes and environment.
Let's zero in on the immune system.
Inflammatory markers and immune response for MS
MS is characterized by chronic inflammation and even the genetic risk is pointing here.
That some people are genetically susceptible to developing MS and that the main susceptibility allele is a human leukocyte antigen (HLA) Class II gene have been known for over 50 years.
Basically, there are genetic differences in the area tied to how and when we build antibodies.
Antigen is the very thing our immune system makes to attack a foreign entity once discovered.
Much of this heritability is now explained and is due almost entirely to genes affecting the immune response.
This ties in with the other risk factors we looked at above: vitamin D, gender (hormones), etc.
Then there's the resulting cascade of inflammation:
Chronic CNS inflammation seems to play a major role in initiating the neurodegenerative process11,12 in RRMS and progressive forms of MS
CNS is the central nervous system. Inflammation of the brain and spinal cord.
Here's the progression of the inflammatory immune response:
- Virus infiltrates body and brain (see CBD and blood-brain barrier)
- T-cells (specifically CD4+ T cells) ramp up a defense but mistake our own cells in the process
- Cytokine storm is released causing direct damage to myelin/oligodendrocytes
We'll look at how the virus gets in below but some quick notes on the T cells and cytokines since most people do not know that terminology.
The T Cells are designed to ramp up in the face of threat (bacteria/virus, etc).
They then call in reinforcements across a varied and complex system.
Cytokines are the little assassins that do the dirty work - little chemical assassins of organic material.
Before falling into the rabbit's hole, just remember T cells and cytokines for our section below on CBD.
Let's turn to what might be at the very start of this process.
The gut microbiome and MS
Vitamin D, progesterone, and Glyphosate all walk into a bar.
Okay, there's no punchline there but there is a connection.
The gut barrier!
Vitamin D protects the gut barrier by regulating tight junction proteins and inhibiting intestinal apoptosis.
So D protects our barrier from the outside world (translated virus and bacteria among others).
Progesterone decreases gut permeability through upregulating occludin expression in primary human gut tissues and Caco-2 cells
That's 2 for 2.
What about the dark side...the 1000's of chemicals that break down the gut barrier?
Let's look at just one...the pesticide behind RoundUp which is used in 90% of US soy, corn, and wheat that's not organic:
Glyphosate reduced the mRNA expression of the tight junction proteins in the duodenum and jejunum.
Goodness...a slow erosion of the gut barrier that protects you from every nasty thing trying to get in.
Why does all this really matter for MS?
Remember how we said that gut inflammation was the thermostat for the rest of the body and the brain?
Researchers at the University of Toronto and UC San Francisco have discovered that the intestine is the source of immune cells that reduce brain inflammation in people with multiple sclerosis (MS), and that increasing the number of these cells blocks inflammation entirely in a preclinical model of the disease.
Goodness. That's a 2019 research so they're finally catching up with the gut's importance in all autoimmune.
The brain-blood barrier is equally important with MS as a second defense.
Speaking of which, let's finally turn to CBD and MS research.
Research on CBD and MS
We're going to break it down into sections that mirror everything we learned above.
- How CBD works in the body
- CBD and gut barrier
- CBD and immune or inflammatory response
- CBD and oligodendrocyte protection
- CBD and MS research
Let's get started...first how exactly does CBD work in regards to pathways of MS?
How CBD works in the body
It's important to understand the mechanism by which CBD works before jumping into MS-specific effects.
CBD operates within the endocannabinoid system...a key system we share with all living animals which are tasked with balancing other systems:
- Nervous system - neurotransmitters and more
- Endocrine system - hormones
- Immune system - inflammatory response and...resolution
The last one there is obviously very relevant.
The oligodendrocytes are part of this system!
Here's the important piece with CBD.
Research is showing that it works like a feedback mechanism.
Technically, it's called an allosteric negative modulator.
Basically, CBD sends a message backwards:
- We're running low...send more (serotonin, cytokines, cortisol, etc) over
- We're all full...slow down
This is why we don't see overdoses with CBD.
Cancer's a perfect example of this:
- 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 we have three different effects depending on the state of the cell.
The third one makes sense once you realize that the immune system's natural way to kill off wayward cells is by jacking up inflammation (oxidative stress technically - see CBD and oxidative stress).
Chemo and radiation are essentially massive doses of oxidative stress which kill indiscriminately.
Let's jump into the components of CBD and the pathways of MS now.
We'll start with the gut.
CBD and gut barrier
The gut has a direct link with our brain to the extent, that it's called the "second brain".
It's the only place in the body (besides the brain) which large numbers of neurons which is fascinating in itself.
Let's first outline the tie-in with MS and the gut.
The net takeaway:
Studies show the MS gut microbiome as having general alterations in specific taxa, some associated with the promotion of inflammatory cytokines and overall inflammation.
So the "mix" of gut bacteria is off with MS.
Then studies of adding certain probiotics (beneficial types of bacteria):
The findings illustrated that there were statistically significant improvements in the static and dynamic balance in patients and animals with MS.
Science is finally getting around to understanding that our gut bacteria almost act like an organ and influence health throughout the body.
Showing that IgA-producing B cells can travel from the gut to the brain opens a new page in the book of neuroinflammatory diseases and could be the first step towards producing novel treatments to modulate or stop MS and related neurological disorders
They recently found a type of cell in the gut that can turn MS symptoms on/off.
Then, there's the gut barrier itself!
Gastrointestinal disorders with intestinal barrier breakdown show evidence of CNS demyelination, and content of the intestinal microbiome entering into the circulation can impact the functions of CNS microglia.
Remember, this is how protein mimicry gets started...a bad bacteria/virus needs to gain entry for the immune system to find it!
So...CBD's role with gut inflammation?
A study looked at the effects of adding bacteria (the bad type) to guts already riddled with Ulcerative Colitis:
CBD targets enteric reactive gliosis, counteracts the inflammatory environment induced by LPS in mice and in human colonic cultures derived from UC patients.
Essentially, CBD calmed a host of inflammatory responses from the bacteria infiltration when excessive damage was occurring to the gut (colitis).
It's well known that a host of medications, some of which are heavily used with MS, damage the gut lining.
NSAIDs (common pain drugs like ibuprofen) are suspect and look at the endocannabinoid protects against this:
Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation.
FAAH...the substance that breaks down our natural cannabinoid anandamide.
CBD's effect there?
CBD also inhibits FAAH, which results in increased anandamide levels.
Exactly the effect we want!
Check out CBD and Tylenol to learn about that other pathway COX (as COX inhibitor - the other big class of pain meds).
As for opioids, let's cut to the chase - CBD and opioid addiction and withdrawal.
The whole point of all of this is to stop the damage (more bacteria/viruses infiltrating via the gut).
Once that has already occurred, we then have to look at the immune response which is doing all the damage.
CBD and immune or inflammatory response for MS
We'll walk through some of the key culprits.
IFN-γ is a major cytokine found in MS lesions, and its levels are greatly increased during MS activity. Inflammation in both MS and EAE is associated with an IFN-γ–producing Th1 response
Not only did CBD directly suppress IFN-γ production through a transcriptional mechanism under several conditions55,142 but also suppressed IFN-γ receptor expression, and increased IFN-γ-induced genes that subsequently attenuate other immune targets
Let's look at a fascinating class of cells that are called in to calm immune response.
MDSC's. Myeloid-derived suppressor cells.
Essentially, these cells are the fire department called to pullout inflammation.
Myeloid-derived suppressor cells (MDSCs) are immature cells capable of suppressing the inflammatory response through Arginase-I (Arg-I) activity, among other mechanisms.
A study looked at CBD's effect for EAE, a mouse model of MS that also goes after the nerve sheaths.
Interestingly, CBD treatment led to a profound increase in myeloid-derived suppressor cells (MDSCs) in EAE mice when compared to the vehicle-treated EAE controls.
The net effect of this:
Treatment with CBD caused attenuation of EAE disease paradigms as indicated by a significant reduction in clinical scores of paralysis, decreased T cell infiltration in the central nervous system, and reduced levels of IL-17 and IFNγ.
The "symptoms" of EAE (which match MS) saw a significant reduction.
IL17 is a known cytokine (immune response assassin) tied to MS.
The researchers, from Trinity College Dublin in Ireland, used mouse models to reveal that T cells, which secrete the immune molecule IL-17, cause damage to the myelin sheath that surrounds nerves in the central nervous system (CNS).
CBD was able to suppress this entire pathway:
cannabidiol (CBD), markedly reduce the Th17 phenotype which is known to be increased in inflammatory autoimmune pathologies such as Multiple Sclerosis.
Many medications for autoimmune are essentially immune suppressors, hence all the side effects tied to infection and more.
You don't want to suppress these pathways completely as they're there to fight infection.
That's the beauty of CBD...the endocannabinoid system is about balance so it's excessive inflammation that is targeted.
In fact, in some cases (such as with cancer), CBD will increase inflammation since that is how our body kills off cancer.
Let's look at the heart of MS directly...protection of myelin and oligodendrocytes that make it.
CBD and oligodendrocyte protection for MS
A study looked at this directly with oligodendrocytes under stress from inflammation.
CBD affected numerous pathways (protection, oxidative stress, etc) with the following results:
These findings suggest that attenuation of the ER stress pathway is involved in the 'oligoprotective' effects of CBD during inflammation.
This "during inflammation" situation is exactly what's going on with MS!
Then there's the whole "birth" cycle of these specialized cells.
The nursery of these cells are called "progenitor cells" and CBD was found to be protective of them.
In fact, CBD is showing to be neuroprotective across a range of different cells in the brain.
We've looked at gut inflammation, immune response, and oligodendrocytes.
Let's turn to research directly on CBD and MS.
CBD and MS research
Based on everything above the very strong safety panel for CBD, you would expect major trials already completed but that's not the case.
Let's look at studies on EAE, the animal model of MS.
EAE is interesting because they use a protein found in oligodendrocytes called MOG to trigger an immune response.
The results along progression lines:
Together, these data demonstrated that CBD treatment promoted anti-inflammatory cytokines and transcription factors while decreasing the pro-inflammatory.
So a reduction in inflammation and a boost to the "resolving" participants.
Also the increase in MDSC's from above.
Interestingly, they took three CBD-induced cells and injected them into other affected mice who did not receive CBD.
The transferred MDSCs were able to attenuate disease progression, as indicated by significant reduction in clinical scores (Figure (Figure5B)5B) and total cellular infiltration in CNS, including the numbers of CD4+ and CD8+ T cells
This really speaks to the power of these suppressor cells with MS and in fact, it's a big push in research now.
The end result (which is what matters after all) for this animal model is paralysis.
Essentially, the nerves no longer work as they have lost all insulation (myelin).
CBD's effect there:
significant reduction in clinical scores of paralysis,
Another study looked at pre-treatment with CBD for EAE with the following effects:
Early treatment of EAE with oral CBD reduced clinical disease at the day 18 timepoint which correlated with a significant decrease in the percentage of MOG35–55 specific IFN-γ producing CD8+ T cells in the spleen at day 10.
Essentially, reduced disease and a reduction in the inflammatory markers tied to the disease (same markers which match MS by the way).
Now, in 2020, there's a proposed trail for CBD and THC. In Canada which begs the question...where's the US?
We have to turn to Europe to get better visibility.
A study looked at a mix of CBD/THC for symptoms of MS:
A total of 593 patients were evaluated at six months, with most — 522 — continuing to show a 20% improvement over baseline, and 252 showing a 30% or greater benefit in spasticity scores. Essentially, benefits seen at one month were confirmed at six months, Patti said
The NHS has approved two cannabis-based meds (essentially the CBD/THC mix) above for MS and epilepsy.
One note...THC pushes immune response in one direction...down!
It also builds tolerance, can be addictive, reduces mitochondria energy production, and increases oxidative stress.
That's the wrong direction and CBD actually improves all those effects.
See CBD versus THC to learn more.
This brings up a good time to discuss other options in our MS toolkit:
- PEA - directly supports the same pathway as THC but in a balancing approach
- Vitamin D - a key player in immune response management -see the review!!
- NAC - reduces oxidative stress and acts like a "sink" for excess glutamate
- Progesterone - goodness, the studies on progesterone and gut and/or immune response is ridiculous - ladies 40 and over!
- Berberine - supports gut barrier health - the first chink in the armor
We look forward to CBD trials and we're pretty confident given the pathways above.
Let's turn to practical questions while we wait.
How much CBD for MS
We're leaning heavily on our studies with neurogenesis.
Neurogenesis is the ability of the brain or nervous system to repair and replenish brain cells.
It's the key to mental health, addiction, and neurodegenerative diseases like MS.
It's shown that peak neurogenesis for CBD occurs around 300 mg.
In this fashion, it operates on a bell curve with lower or higher amounts showing reduced neurogenesis.
For that reason, 300 mg is our best target till we have trials since BDNF, our brain's fertilizer and direct drive of neurogenesis is clearly in plan (and outgunned).
Here's the clue:
At baseline, the BDNF concentration of persons with RRMS was 21% lower than HCs.
So people with re-occurring relapsing MS have a reduced ability to repair/replenish.
This is the key to exercise and its effect (see exercise, mindful mediation, and CBD for neurogenesis).
Here's the fascinating piece for MS directly:
Firstly that BDNF has an important role in mediating peripheral myelination— an unexpected but important finding into the regulation of myelination.
Goodness. More BDNF, please.
We can't wait for studies on psilocybin (an explosion of BDNF) and MS>
What about the type of CBD?
What's the best CBD for MS
There are a few different concerns.
First, the following requirements are mandatory:
- Organically grown in the US at FDA registered farms
- 3rd party tested
- CO2 processed
- No THC - THC normalizes and reduces long term anandamide function
- No pesticides
- No heavy metals
- No solvents
- No bacteria
- No mold
We test our oil twice since our whole family takes it.
That's just the start, however.
There's then the question of CBD isolate versus full spectrum that's pushed so hard on the market.
We did a full review of isolate versus full spectrum.
All the research is based on CBD isolate and the so-called "entourage effect" was originally named for CBD's ability to offset the negatives of THC.
More importantly, roughly 40-60% of the population has histamine issues and this number goes up for women (MS risk factor #1) and age (risk factor #2).
Again, with progesterone leaving its reigns over immune response, you can see how histamine issues dovetail right into MS risk territory.
All that plant material in full-spectrum leads to a completely different side effect profile as you can see from our reviews.
People who started with full-spectrum had bad reactions and found they went away with isolate.
We did the same thing when we started with 3-4 of the biggest brands (our story is here).
Then there's cost.
If peak neurogenesis is at 300 mg daily, we have to be able to afford this.
We intentionally price our CBD at 2-3 cents per mg of CBD before discounts up to 30%.
Our discovery of CBD followed a brutal perimenopause and we wanted make high-quality, CBD available to everyone.
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.