Guide to CBD and the Pathways of Neuropathy
February 15, 2022
My uncle had chemo for stage 4 melanoma. The new immunotherapy treatments now have him in remission but a nasty side effect came about.
Neuropathy. Especially in the feet.
Research is slowly teasing out the mechanics of what drives neuropathy and there are definitely tools we can look at to support this process.
The powerful balance of GABA and glutamate in our nerves is front and center. We'll dive deep into that below.
It's the whole basis behind topical ketamine but there are ways to support without the tolerance that accompanies ketamine.
This ties into the real star behind the curtain…hyperactive immune response and inflammation!
We'll cover it all.
Let's get started…here are the topics we'll cover:
- A quick intro to neuropathy in the body
- The powerful GABA/glutamate balance
- Immune response and inflammation - the root trigger?
- Glutathione depletion and neuropathy
- Inflammation and neuropathy
- The nerve repair pathways and neuropathy
- CBD and neuropathy pathways
- Other key tools to support repair
- How much CBD to take for neuropath
- What's the best CBD for neuropathy
Let's get started!
A quick intro to neuropathy in the body
Many different issues cn cause neuropathy.
The most common are:
- Diabetes
- Traumatic injuries
- Infections
- Exposure to toxins (chemo)
- Genetic factors
Let's touch on the pathways affected by each so we can address them further as we drill down.
Diabetes and neuropathy
Metabolic imbalances create a cascade of chemical issues downstream.
One of them is called the polyol cycle which converts fructose (sugar we get from food) into glucose (sugar our body can use for fuel).
Essentially, too much sugar intake creates an excess of sorbitol (part of the conversion) which can build up in cells since it's not readily broken down.
As sorbitol does not easily dissolve across cell membranes this increases cellular osmolarity, ultimately leading to cell damage.
https://www.sciencedirect.com/topics/medicine-and-dentistry/polyol-pathway
Certain tissues are more prone to this damage including retinas and…nerves!
The key point is that we have a powerful detox system and its star player is glutathione.
Excess sorbitol exhausts our glutathione function!
These data suggest the hypothesis that the hyperglycemia-induced enhanced activity of the polyol pathway leads to GSH depletion
https://pubmed.ncbi.nlm.nih.gov/8622605/
Glutathione is critical for keeping oxidative stress under wraps. When it fails, damage occurs across the body and especially in the nervous system and brain since that system is very energy-intensive.
We'll look at how to support that below.
Traumatic injuries and neuropathy
Simply put…this is physical damage to the nerves themselves.
Be it compression, crushing, or even severing, it can lead to temporary or long-lasting pain and even decrease muscle function as a result.
It's a two-part process and we'll learn about both below but first:
- Immune response and inflammation for the injury
- Repair response (also part of the immune system)
Inflammation is a double-edged sword.
It's critical to address the initial site of injury but any lingering or overexpression can damage tissue.
The repair piece is more interesting and there are ways we can support that (the neurogenesis section below).
Speaking of the immune response.
Infections
A list of different infections can also cause neuropathy including Lime, hepatitis, Epstein-Barr, and more.
This can be caused by the infection itself but also by the immune response to it in the form of inflammation and even autoimmune where the body attacks itself.
The latter is something we can look at (see CBD and autoimmune) as the endocannabinoids system (where CBD works0 is tasked with balancing immune response.
There's an interesting pathway we need to understand from infection to nerve damage.
Glutamate! The primary immune sentinel of our nervous system is called microglia.
They coordinate the attack on infection and release a tremendous amount of glutamate (the nervous system's "gas pedal").
Here's the kicker:
a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143501/
So infection can cause too much glutamate to be released which is highly toxic to the nerves.
It's red-lining an engine. Too much and it breaks down.
Excessive glutamate is literally toxic to our cells and nerves.
Speaking of toxic.
Exposure to toxins (chemo, radiation, etc)
First, we need to understand that the immune system is in charge of the birth/death cycles of cells and nerves.
The way our body kills off wayward cells is to ramp up oxidative stress within the cell.
Chemo and radiation are essentially massive doses of oxidative stress to kill cells (hopefully more cancer than us!).
Our primary defense against damage from oxidative stress is glutathione so the impact there is expected:
Glutathione alleviated peripheral neuropathy in oxaliplatin-treated mice by removing aluminum from dorsal root ganglia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5375987/
Interestingly, glutathione keeps a check on excess glutamate (toxic when too high) as well since glutamate is one of the three ingredients for glutathione (with cysteine and glycine).
We'll cover NAC below which has fascinating effects on mental health, immune, and this balance above.
Let's turn to our internal code.
Genetic factors
Some of the genes tied to neuropathy risk are fascinating and should make perfect sense after everything you just read.
Gene variants for the glutathione pathway directly drive risk after chemo:
gene variations (GSTP1, glutathione-S-transferase genes P1; GSTM1, glutathione-S-transferase genes M1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471666/
Variants in IL10 (a key immune response pathway - actually anti-inflammatory) also appears:
Successfully replicated association with a neuropathic pain construct for 2 variants in IL10 underscores the importance of neuroimmune interactions
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828382/
A range of sodium management genes and even serotonin pathway genes also appear.
Sodium controls the cellular entry/exit process while serotonin is key to pain sensitivity thresholds and the repair side (via BDNF).
Keep in mind that the percentage of people who display neuropathy after chemo is very high so genes only carry so much weight in the face of such a powerful force.
Okay…let's go one level down before discussing how we can support these pathways.
We'll start with the brake and gas pedal.
The powerful GABA/glutamate balance
There's a delicate balance and interaction between GABA and glutamate when it comes to nerve function.
GABA is our brake pedal in the nervous system. It's the target of benzos (see CBD versus benzos) and key to anxiety, sleep, and yes…neuropathy.
GABA plays an indispensable role in control of neuronal excitability via control of homeostasis during neuropathic pain. Decreased GABAergic inhibition is an important component in neuropathic pain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509976/
See…GABA and glutamate control the balance of each nerve.
With neuropathy, GABA is outgunned or exhausted against glutamate:
Many neuropathic pain conditions are associated with reduced synaptic inhibition, such as occurs with a decreased GABA level, since GABA is a key inhibitory neurotransmitter in the GABAergic transmission.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509976/
Remember how hyperactive immune response (inflammation) releases excess glutamate?
Or how chemo eats up glutathione (which results in excess glutamate)?
Or how trauma causes inflammation (increased inflammation, more glutamate, you get the picture).
There are fascinating clues pointing to just how powerful this balance is.
Topical ketamine's primary action is to give the nerve's GABA pathway a pause from too much glutamate. Essentially, calming the nerve's excitability (glutamate).
Blockade of NMDA receptors disrupts normal excitatory glutamate signaling in the CNS and is associated with many anesthetic agents
https://www.frontiersin.org/articles/10.3389/fphar.2020.599721/full
NMDA is the receptor where glutamate does its work so essentially glutamate is taken offline so that GABA can recover and the nerve can catch its breath so to speak.
The problem with ketamine (even topical) is that it builds tolerance so we're actually going the wrong direction with longer-term use as the body ramps up glutamate to offset the pause!
After weeks of self-medication, the patient began to develop significant tolerance to ketamine and had to stepwise increase both dose and frequency of the ketamine.
https://www.frontiersin.org/articles/10.3389/fphar.2020.599721/full
This is true of most drugs that push a pathway in one direction or another.
Not good. This brings us to benzos.
Benzos boost GABA function which is why they're the primary medication for anxiety and insomnia.
This includes valium, Xanax, Ativan, Klonopin, and various sleep aids.
Aside from being very addictive, they also build a ruthless tolerance (in about 2 weeks generally).
The nervous system doesn't like its most basic pathway (GABA/glutamate)...literally the on-off switch for nerve activity to be hammered by benzos so it starts to push back the other way.
With use, natural GABA function actually goes down and glutamate goes up.
The DNA that makes the GABA receptors get turned off and it takes at least 30 days for them to come back on after stopping use. (see weaning off benzos here).
Here's the deal…stopping benzos cold turkey after longer use can actually cause seizures! A massive rush of glutamate.
Right below that is…neuropathy. They call it by its fancy name paraesthesia but we'll let you be the judge:
an abnormal sensation, typically tingling or pricking (“pins and needles”), caused chiefly by pressure on or damage to peripheral nerves.
So clearly, getting GABA and glutamate in balance is key with neuropathy.
We'll spend a great deal of time on the below.
Immune response and neuropathy - the root trigger?
The immune system really is front and center with neuropathy.
First, the GABA/glutamate balance is directly affected as immune sentinels called microglia release tremendous amounts of glutamate (the gas pedal that can burn out neurons) when hyperactive.
Secondly, inflammation in the form of cytokines can directly attack and damage nerves.
Numerous experimental studies have demonstrated that certain pro-inflammatory cytokines are elevated in neuropathic pain conditions, and administration of these cytokines can elicit pain hypersensitivity in the absence of injury or disease.
https://pubmed.ncbi.nlm.nih.gov/26437375/
Even in neuropathy caused by diabetes, cytokines are front and center:
This method detected the elevated levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, and interleukin (IL)-6, IL-1β as well as reduced anti-inflammatory IL-10 in lumbar dorsal root ganglia (LDRG) of HF mice.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192333
HF is short for high-fat diets fed to mice. What's interesting is that they found inflammation in the brain stem and spinal cord!
This is systemic nervous inflammation as a result of diabetes.
That's on the damaging side. It could result from injury, trauma, chemical interaction, and more.
The immune system is also in charge of the repair side which we'll touch on below.
First, let's stop the bleeding so to speak. Hello, glutathione!
Glutathione depletion and neuropathy
Glutathione is THE primary detox pathway in the body.
When Tylenol overdose causes liver failure (#1 cause in the US), it's because of a depletion of glutathione. (see CBD versus Tylenol here).
So…what's the connection with neuropathy?
Glutathione depletion is very relevant for neuropathy caused by chemo, radiation, chemicals, metabolic syndrome, and more.
For example, platinum-based chemo agents like Oxaliplatin can cause aluminum to build up in the dorsal ganglia (area of the spinal cord).
Look at glutathione's effect there:
The concentrations of aluminum in the DRG were decreased by the chelation action of GSH.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5375987/
And to the point…
This result also suggested that the aluminum chelation by GSH can provide an alleviatory remedy of neuropathic pain for cancer patients with oxaliplatin-induced neuropathic pain.
A study looked at nutrients that support glutathione directly (NAC, ALA, L-carnitine, Vitamin C, and selenium) supplementation and neuropathic pain.
The results:
Examining Table 1, it is apparent there were significant reductions in the primary endpoints of burning, numbness, and overall pain.
NAC is a fascinating supplement we've covered in depth here. Vitamin C directly supports the glutathione pathway. This is actionable guidance that's safe.
Let's turn to the repair side.
The nerve repair pathways and neuropathy
In many instances with neuropathy, we're ending up with damaged and/or destroyed neurons and pathways.
Again, the immune system is in charge of the repair, rebuild, and growth of all cellular types including nerves.
Two big players come to mind:
- NGF - Nerve growth factor
- BDNF - Brain-derived neurotrophic factor
These are powerful players in nerve growth/repair cycles but research is mixed.
On one hand, the release of these by microglia (immune system again) can be tied to heightened pain sensitivity.
Suppression of peripheral NGF attenuates neuropathic pain induced by chronic constriction injury through the TAK1-MAPK/NF-κB signaling pathways
https://biosignaling.biomedcentral.com/articles/10.1186/s12964-020-00556-3
On the other hand, they're clearly tied to resolving nerve damage and repair:
Low BDNF was an independent, unfavorable prognostic factor associated with reduced overall survival (OS) (hazard ratio (HR) = 2·79, P = 0·0470).
CIPN (their target) was chemical-induced peripheral neuropathy.
So…what's going on here?
We've seen all the benefits of BDNF from exercise, mindful meditation, psilocybin, and yes…CBD.
Why is there a tie-in with pain?
It turns out that too much nerve growth can cause pain via a pathway called TRPV.
This is fascinating because TRPV is one heavily influenced by our endocannabinoid system…where CBD works!
The connection…
NGF modulates, by the PLC/PI3K/MAPK pathway, the TRPV1 channel (transient receptor potential, vanilloid subfamily type 1), a molecular integrator of painful stimuli.
https://cordis.europa.eu/project/id/603191/reporting
Painful stimuli. Burning. Pins and Needles. Sound familiar?
So…nerve damage elicits the growth brigade but there's associated pain which makes sense…a "Stay Out - Construction" sign if you will.
Interestingly, the endocannabinoid system is tasked with balancing these pathways in different parts of the body (say foot versus spinal cord).
The endocannabinoid system is the one to target! Let's go there now.
CBD and neuropathy pathways
CBD is a cannabinoid that's naturally found in the cannabis plant. It can interact with our own endocannabinoid system.
The key takeaway is that this system is tasked with balancing other powerful pathways such as:
- Nervous system - including neurotransmitters like serotonin and GABA
- Immune system - inflammation and birth/death cycles - cytokines and growth factors
- Endocrine system - hormones tied to all systems
Also, the opioid system, is our key pain management pathway.
We're going to break CBD's effect down into sections we covered above:
- CBD and inflammation for neuropathy
- CBD and GABA/glutamate balance for neuropathy
- CBD and glutathione depletion for neuropathy
- CBD and anandamide for neuropathy
- CBD and neuropathy research
Let's get started!
CBD and inflammation for neuropathy
Remember that injury, trauma, and the like are managed by the immune system.
The various cytokines are the soldiers of this system.
So what does CBD do?
CBD is a powerful immune response modulator. It can boost when low or calm when too high. See CBD and immune response.
Studies specific to neuropathy have born this out.
In one study, mice had osteoarthritis induced which generally triggers nerve damage.
CBD's results:
Acute, transient joint inflammation was reduced by local CBD treatment (P < 0.0001; n = 6). 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 (P < 0.05; n = 6-8).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690292/
CBD prevented the nerve damage that follows osteoarthritis.
Remember that microglia (the nervous system immune sentinels) can hyperactivate and cause more damage than good.
CBD's effect there:
In vivo, CBD has been shown to decrease microglial accumulation in the spinal cord in diabetic mice,81 which might contribute to attenuation of neuropathic pain, and CBD decreased haloperidol-induced activation of reactive microglial cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173676/
So…CBD calmed microglia response in the spinal cord (very important for neuropathy).
What about the elevated cytokines tied to neuropathy?
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.
https://www.hindawi.com/journals/mi/2015/538670/
What's the deal with IL10? Remember how it was decreased with people who had neuropathy?
IL10 is actually anti-inflammatory. CBD has been shown to increase it when systems are inflamed.
CBD has a long researched history of calming inflammation when excessive.
Check out CBD and neuroinflammation to learn more.
Let's turn to the nerve excitability balance.
CBD and GABA/glutamate balance for neuropathy
CBD is a positive allosteric modulator for GABA.
Simply put, this means that it boosts its function when running low. Benzos boost GABA but in one direction which leads to tolerance. Also, it hits dopamine which causes addiction.
CBD does not build tolerance and is non-addictive (unlike its cousin THC - more on the tolerance side).
We see the impact of CBD's effect on GABA (and glycine - another neural inhibitor) across many issues such as anxiety, sleep, and…pain!
In fact, CBD's original claim to fame was for its anti-seizure effect…the epitome of GABA/glutamate imbalance.
First, the calming effect on glutamate:
The G protein-coupled receptor GPR55 acts as a “gate” regulating glutamate release with a calcium-dependent mechanism. CBD seems to antagonize the GPR55 activation, thus reducing glutamate release and neuro-excitability in the CNS
A study looked at traumatic brain injury (see CBD and TBI) and its effect on neurotransmitter imbalance (GABA, glutamate, serotonin, etc).
CBD's effect there:
CBD oral treatment restored the behavioral alterations and partially normalized the cortical biochemical changes.
https://www.frontiersin.org/articles/10.3389/fphar.2019.00352/full
Learn more about CBD and GABA or CBD and glutamate.
The glycine piece is interesting with neuropathy. New research is really focusing on that direction.
Glycine Inhibitory Dysfunction Turns Touch into Pain through PKCgamma Interneurons
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2043493/
We did a big review of glycine since it's so critical to sleep and keeping glutamate under check.
CBD is also an allosteric positive modulator (feedback mechanism) for glycine.
Let's look at the other big check on glutamate.
CBD and glutathione depletion for neuropathy
We know that chemo agents can deplete or main detox pathway called glutathione.
You can't take glutathione orally as it doesn't make it past the gut so we need to support in other ways.
NAC is a key player there. So is CBD!
The primary function of glutathione is to reduce oxidative stress. Oxidative stress is a signal to the immune system that a nerve needs to kill (hence the inflammation above).
First, how does CBD compare to the primary anti-oxidants, Vitamin C and E which support glutathione?
CBD exhibits much more antioxidant activity (30–50%) than α-tocopherol or vitamin C [4].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023045/
And for glutathione itself??
Repeated doses of CBD in inflammatory conditions were found to increase the activity of glutathione peroxidase and reductase, resulting in a decrease in malonaldehyde (MDA) levels, which were six times higher in untreated controls
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023045/
Peroxidase and reductase break down glutathione so with CBD, more glutathione is available.
The key there is "in inflammatory conditions".
This is the beauty of CBD and really the endocannabinoid system. Its response depends on the state of the system.
Check out CBD and oxidative stress or CBD and glutathione.
Let's turn to anandamide, our "bliss" molecule.
CBD and anandamide for neuropathy
We have a whole review on people who don't make FAAH here.
FAAH breaks down anandamide in the body and people who can't make FAAH, can't feel pain. At all.
Or anxiety or depression.
That's a big wake-up call right there.
We know that THC imitates anandamide at the CB1 receptor but that's the wrong approach as the body will push back with tolerance and reduce natural CB1 receptor activity and numbers.
CBD, on the other hand, does not build tolerance.
It slows FAAH activity so anandamide can remain longer.
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)
https://www.nature.com/articles/tp201215
That's from a powerful study on CBD and schizophrenia (details here).
Anandamide is a key stress response buffer that gets exhausted with neuropathy…especially peripherally (feet, etc).
Okay…let's dive into direct research.
CBD and neuropathy research
We're finally getting actual studies now on CBD and neuropathy. Two massive trials are currently underway now.
Let's get started!
First, placebo, double-blind study on topical CBD for neuropathy:
There was a statistically significant reduction in intense pain, sharp pain, cold and itchy sensations in the CBD group when compared to the placebo group. No adverse events were reported in this study.
https://pubmed.ncbi.nlm.nih.gov/31793418/
Another study:
These findings demonstrate that, in a meaningful proportion of otherwise treatment-resistant patients, clinically important improvements in pain, sleep quality, and SGIC of the severity of their condition are obtained with THC/CBD spray.
https://pubmed.ncbi.nlm.nih.gov/24420962/
Remember…THC boosts anandamide but long term, it builds tolerance. CBD also supports anandamide but without tolerance.
Diabetic neuropathy of the feet:
Subjects taking the CBD tablet reported statistically and clinically significant pain reduction from baseline as compared with placebo. They also had significantly more favorable Patient Global Impression of Change (PGIC) scores than the placebo group.
That was 20 mg sublingual which is a very low dose (more on that later).
One note…sleep and anxiety were also significantly improved.
A list of various studies can be found here:
https://www.health.state.mn.us/people/cannabis/docs/rulemaking/neuropathybrief.pdf
Again, remember…we want to support all these systems without causing tolerance.
Let's look at other tools to use with CBD.
Other key tools to support neuropathy issues
We're going to focus on these key supplements that don't build tolerance and have high safety:
- Magnesium glycinate and neuropathy
- Vitamin D (get levels tested) and neuropathy
- Vitamin B6 and neuropathy
- NAC and neuropathy
- L-Carnitine and neuropathy
- Curcumin and neuropathy
- Berberine and neuropathy
A quick intro, please!
Magnesium glycinate and neuropathy
Mag supports GABA, acts as a stress response buffer, and many people are deficient.
The beneficial effects of magnesium treatment have also been demonstrated in patients suffering from neuropathic pain, such as in those with malignancy-related neurologic symptoms, postherpetic neuralgia, diabetic neuropathy, and chemotherapy-induced peripheral neuropathy.
https://www.ncbi.nlm.nih.gov/books/NBK507245/
I take 3 100mg mag glycinates daily with meals and as needed for sleep or migraines (another issue with GABA/glutamate imbalance).
Full review here.
Vitamin D (get levels tested) and neuropathy
Vitamin D is actually a steroid we get from the sun. The problem is that roughly half of us are deficient and that's based on the ridiculous RDA levels for bendy knees and rickets (under 30 ng/ml).
It manages the immune system and if you've taken in anything from above, the immune system is front and center with neuropathy!
One example:
Oral supplementation of vitamin D 3 (50,000 IU) once weekly for 12 weeks was associated with improvement in the serum level of vitamin D and significant decrease in the symptoms and sign of diabetic neuropathy.
https://pubmed.ncbi.nlm.nih.gov/30641826/
For diabetic patients with neuropathy.
More detail here on Vitamin D in general. It's a monster!
Vitamin B6 and neuropathy
All B vitamins are essential to nerve function but B6 stands out for neuropathy.
Corticosteroids and anti-TB drugs isoniazid (among others) can deplete B6.
The tie with neuropathy:
Deficiency of B6 can cause nerve damage called peripheral neuropathy. Symptoms may include burning, shooting and tingling pain in your arms, legs, hands and feet. Some describe it as a “pins and needles” feeling.
https://www.healthline.com/nutrition/vitamin-b6-deficiency-symptoms#TOC_TITLE_HDR_8
Get tested….too much B6 can also cause issues.
There's a big tie between B6 and rheumatoid arthritis. (see CBD and rheumatoid arthritis).
B1 and 12 also have important roles with nerve function so a B complex may be ideal.
NAC and neuropathy
We mentioned NAC quite a bit already. It's a key rate-limiting factor for glutathione.
As for neuropathy:
The pattern of results suggests that compared to placebo and over a time period of 8 weeks, adjuvant NAC is more efficacious in improving neuropathic pain associated with diabetic neuropathy than placebo.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875491/
Big review on NAC here.
L-Carnitine and neuropathy
Carnitine is another powerful anti-oxidant with additional effects on nerve function.
Four randomized controlled trials tested ALC in patients with neuropathy secondary to diabetes and to antiretroviral therapy for HIV. Compared to placebo, ALC produced a significant pain reduction equal to 20.2% (95% CI: 8.3%-32.1%, P<0.0001) with respect to baseline.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498091/
The studies also showed positive effects on nerve function and repair.
Don't use with Coumadin (warfarin). Always check with your doctors for any supplements.
NAC is a safer bet there.
Curcumin and neuropathy
Curcumin is fascinating. We haven't done a deep dive yet but it appears to have multiple effects and work like an adaptogenic.
This means it helps the body's pathways respond when pushed up or down by stress.
For neuropathy:
Treatment with 40 and 60 mg/kg body weight curcumin for 7 consecutive days significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946321/
Hyperalgesia is general heightened pain. Systemic pain (think spinal cord, brain, etc).
It also was shown to calm inflammation (immune response) in the spinal cord for neuropathy.
Having such wide-running effects across very different areas of the body is very similar to CBD which works in the endocannabinoid system.
Dig a little deeper and you find it operates on the CB1 receptors of the endocannabinoid system!
A tale for another review.
Berberine and neuropathy
Berberine is a powerful house for metabolic function and a big operator in the AMPK space.
AMPK is the closest thing we have to longevity science for now. See AMPK and longevity or Dr. Sinclair's Yamanaka Factor research (the next big thing).
If you want to see how powerful AMPK is across all pathways, just look at the berberines effect:
In conclusion, berberine exerts its neuroprotective effect against n-STZ-induced diabetic peripheral neuropathy via modulation of pro-inflammatory cytokines (TNF α, IL-1β, and IL-6), oxido-nitrosative stress, BDNF, IGF-1, PPAR-γ, and AMPK expression to ameliorate impaired allodynia, hyperalgesia, and nerve conduction velocity during T2DM.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636227/
It's the kitchen-sink approach.
- Inflammation (cytokines)
- Oxidative stress
- Growth factors (BDNF, IGF-1)
- Pain pathways (PPAR)
Reduced local pain, systemic pain, and better nerve function.
Big review on berberine here.
Let's get into practical questions on CBD for neuropathy.
How much CBD to take for neuropathy
There is still room for improvement on the dosing side.
Usually, we can point to 300mg as peak neurogenesis which is important here but not as much since BDNF may actually trigger downstream pain pathways.
The study above on neuropathy used 25 mg twice daily. That's a good place to start.
Between 50mg and 150mg daily is a safe range and test to see where you get the best result.
More serious issues (opioid withdrawal, social anxiety public speaking) were studied at
Hold the CBD under the tongue for up to 60 seconds and take preferably after meals so the liver is busy and more can get through.
Before sleep is also advantageous since CBD also helps with sleep (see CBD and sleep).
The 1000mg bottle is about 33 mg per dropper. You can do 3 droppers daily at that level or half a dropper of the 2000mg bottle.
CBD (oil or balm) can be applied topically as well (feet, etc).
Let's look at the type of CBD.
What's the best CBD for neuropathy
First, do no harm.
CBD must have the following:
- From organically grown hemp in the US at FDA registered farms
- CO2 cold-processed
- Third-party tested (ours is available at top of each page)
- Zero THC (builds tolerance and makes things worse long term)
- No pesticides
- No solvents
- No heavy metals
- No bacteria
- No mold
We test for all of this (available at the top).
Next up, we want CBD to isolate (CBD by itself).
First, all the research is based on CBD by itself.
More importantly, 40-60% of the population has histamine issues.
This number goes up as we get older and for women (when progesterone leaves).
We see many people have bad reactions to full-spectrum CBD which go away with isolate.
This is a big deal for neuropathy:
In neuropathic pain, histamine released in the periphery by mast cells has been shown to play an important role in the development of hypersensitivity following nerve injury.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012972/
Histamine is part of the immune system's inflammatory response after all!
CBD by itself calms histamine release (see CBD and mast cells).
As for THC…
We don't want THC since it builds tolerance and full spectrum can (and does) trigger histamine response which is just more inflammation (and pain and glutamate).
Then there's the question of cost.
The key there is the cost per mg of CBD. We price our 6000 mg bottles at 2-3 cents per mg before discounts up to 50% for a reason.
We found CBD as the result of a brutal perimenopause (that story is here) and if we can help reduce suffering, 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.