CBD for Perimenopause Pain - Joints, Muscles, Neuropathy, and more

cbd for perimenopause pain with joints muscles and nerves


It's the last thing.

 

After finally getting hormone levels relatively dialed in and addressing every supplement and lifestyle pathway that I can, one...nagging...problem.

 

Intense pain in my heels!

 

It started right at the beginning of full perimenopause implosion (that story is here).

 

I injured my left foot and it just would not get better.

 

My first (of many) podiatrist put me in a boot for plantar fasciitis (the default diagnosis).

 

Now my other heel was hurting from the boot.

 

Okay...30 days of bedrest was the next recommendation.

 

Turns out that was a bad recommendation!

 

It felt like I was walking on glass.

 

At my lowest point, I was using knee pads to get out to the pool to try and exercise.

 

Scooting around on an office chair.

 

So depressing.  And painful.

 

Multiple doctors later with MRI's, X-rays, inserts, special shoes, PT, you name it.

 

It was 2 years of a very slow recovery.

 

I also had other weird pains out of nowhere when perimenopause came on: 

  • Joint pain in my hands
  • Back pain that felt like my old menstrual cramps
  • Pain around my ovary (first both and then just left side) which scared the crap out of me!

 

Turns out I'm in good (if you can call it that) company!

 

Pain is intimately tied to perimenopause process for many women and we'll dive deep into why below.

 

We'll also look at CBD for help here as well as every gadget, balm, and elixir I've tried.

 

We're talking cutting edge like nano-vibration devices and naltrexone (yes, the drug used to treat alcohol dependency) microdosing.

 

Fascinating stuff.

 

After researching the pain pathway in our CBD and the connection with Tylenol article, we want to turn our full attention perimenopause pains and aches.

 

When researchers blocked CB1 receptors (part of endocannabinoid system), Tylenol's pain effect went away!

 

Same for COX inhibitors (Celebrex, etc).

 

After all...pain is the final thing for me and mostly likely one of the first issues for millions of women.

 

It's the final symptom listed on the Menopause Rating Scale.

 

We'll cover these areas: 

  • Why does perimenopause cause pain
  • Estradiol and perimenopause pain
  • Progesterone and perimenopausal pain
  • Inflammation and perimenopausal pain
  • Perimenopause and joint or muscle pain
  • Perimenopause and nerve pain or neuropathy
  • Histamine and perimenopausal pain 

 

There are two important things to understand before we go deep into this area.

 

  • Perimenopause can be characterised by spikes and drops in estradiol and general drops in both estradiol and progesterone into menopause
  • Estradiol and progesterone are intimately tied into every aspect of our body including pain

 

It's not just about making babies!

 

For a good understanding of what's going on, check out perimenopause versus menopause.

 

For our full review on estradiol (our main estrogen called E2), go here.

 

Most women (and doctors) don't realize that estradiol can actually jump during perimenopause as it enters a cat and mouse game with FSH, another hormone.

 

It's these extreme rises and drops during this transition that cause many of the side effects including a variety of pains.

 

There are also different type of pains which are important: 

  • General pain threshold - old injuries, joints, tendons, muscles, fibromyalgia, etc
  • Inflammatory pain - including arthritic pain
  • Nerve pain or neuropathy - turns out my heels are in this category
  • Hormone specific pain - breast, nipples, ovaries, etc

 

Now...we want to separate out perimenopause pain from just getting older pain.

 

This gives us a clue here: 

In multivariable analyses, women with menopause symptoms had nearly two-fold odds of chronic pain (odds ratio 1.84, 95% confidence interval 1.79-1.90, P < 0.001) and multiple chronic pain diagnoses (odds ratio 1.79, 95% confidence interval 1.74-1.83, P < 0.001). 

https://www.ncbi.nlm.nih.gov/pubmed/30839364

 

Essentially, women who had other symptoms from menopause had much higher odds of chronic pain.

 

Not just getting old!

 

To isolate out the hormonal effects, we can look at people that undergo hormone treatment for gender reassignment.

 

Is there a difference from getting female hormones (primarily estradiol) versus male ones (testosterone)?: 

 Forty-seven MtF and 26 FtM completed the questionnaires. Fourteen of the 47 MtF (29.8%) reported painful conditions, which in 11 subjects were not present before the beginning of hormone treatment. 

https://www.ncbi.nlm.nih.gov/pubmed/17379410

 

What about the flux in hormones associated with perimenopause as opposed the general drop with menopause in general.

 

We can look at monthly cycle for this tidbit!

 

They gave electric shocks (one more burden we women have to bear) to women during their cycle in two groups: 

  • Women on birth control (a type of hormone replacement)
  • Women without birth control

 

The results: 

Nervous thresholds vary systematically across the phases of the menstrual cycle, with or without the use of oral contraceptives.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714915/

 

Phase 5 is the premenstrual period of the cycle when pain increases.

 

What happens then?

 

A severe drop in estradiol and progesterone together.

 

Hmmm…

 

During perimenopause, progesterone has already been dropping for about a decade and estradiol's going through swings of up and down craziness.

 

Must...get...one...more….eggggg.

 

Check out the chart here for a good bird's eye view: 

https://www.zrtlab.com/blog/archive/mood-menopause-perimenopause/

 

We'll get into the two hormone pathways with pain with more detail below.

 

We're also going to touch on how they affect everything from inflammation (key to arthritic pain) and neuropathy and more.

 

They're not JUST for making babies.

 

Good lord...this isn't Mad Men!

 

First up...our dominant actor on the stage.

Estradiol and perimenopause pain 

Estradiol is our primary estrogen (so we'll use them interchangeably) called E2.

 

It's a powerful pro-growth hormone with receptors in almost every part of the body and brain.

 

We'll look at estradiol's effect on perimenopausal pain in three acts: 

  • Estradiol and pain threshold
  • Estradiol and inflammation
  • Estradiol and neuropathy

 

Keep in mind that we have an entire pain response system called the opioid system.

 

Yes, it's name is tainted by the recent epidemic but it occurs naturally in our body.

 

We have a very complicated family of endorphins that move around this system as needed.

 

This gets to the "feeling" of pain or pain threshold.

 

Does estradiol affect that?

 

Researchers looked at levels of low and high estrogen within the same women (since we all have different pain thresholds) to see: 

During the low estrogen condition, however, significant reductions in endogenous opioid tone were observed at the level of thalamus, nucleus accumbens, and amygdala, which were associated with hyperalgesic responses. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808228/

 

Okay...the system doesn't work as well when estrogen leaves the building but does that translate into more pain by the person?

 

Yes!

 

Estrogen-associated variations in the activity of μ-opioid neurotransmission correlated with individual ratings of the sensory and affective perceptions of the pain and the subsequent recall of that experience. 

 

Did you catch that last part...subsequent recall???

 

So...locking the memory of pain into the system.  Fascinating (and we work on that below).

 

Keep in mind that some pain is driven by higher estradiol levels so what gives!

 

It may be the fluctuation of the hormone itself...the change: 

They also appear to be influenced by circulating gonadal steroids, with higher ratings of pain during low or rapidly changing levels of estradiol

 

Access to the pain response system being dependent on hormones may lie at the difference between male and female pain: 

More recent work has also shown that during sustained pain, women studied during a low-estradiol, low-progesterone state demonstrated a lower capacity to activate this neurotransmitter system than men, paralleled by higher ratings of pain and a greater negative affective state during the challenge  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808228/

 

There's a slew of different studies in that link which show how estradiol boost the MOR (mu opioid receptor) pathway which opioids use but we want to go another direction.

 

To Dynorphin (named after Greek word for "power").

 

It's another type of opioid that's intimately tied to perimenopause.

 

The original clue came from hot flashes (the most common symptom with perimenopause and menopause) which points to the hypothalamus.

 

In fact, you can find roots to all the perimenopause symptoms there.

 

Check our our review of perimenopause versus menopause for more detail.

 

Basically, this "family" of peptides including dynorphin are severely disrupted during perimenopause and beyond: 

The kisspeptin–neurokinin B (NKB)–dynorphin (KNDy) signalling system in the hypothalamus is the proximate and obligate stimulus of GnRH secretion, and is hypertrophied after the menopause 

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30886-3/fulltext


Why does this matter for perimenopausal pain?

 

Han and Xie found dynorphin to be 6-10 times more potent than morphine on a per mole basis 

https://en.wikipedia.org/wiki/Dynorphin

 

Is there a direct relationship between estradiol and dynorphin?

 

Estradiol and Progesterone positively moderate spinal cord dynorphin

 

This is part of the body's natural pain response to pregnancy.

 

Research is here.

 

And now you know why….the pain of pregnancy!!

 

But we have a multifaceted pain response system...why focus on dynorphin?

 

In males, spinal morphine antinociception results from the exclusive activation of spinal MOR whereas in females, spinal morphine antinociception requires the concomitant activation of spinal dynorphin (Dyn)/KOR as well as MOR 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778676/

 

Let's think of dynorphin as the female pain reliever system.

 

Again...it's a different pathway than what opioids use (which is the MOR system above).

 

Interesting, naltrexone, a drug used to treat alcohol dependence boosted the pain relieving effects of dynorphin at microdosing levels (5mg) with very few side effects (aside from less alcohol addiction!).

 

Like we said, our endorphin system is complicated so we won't get too lost in the weeds but estradiol has a handle on the pain threshold system.

 

What about inflammation and pain?

 

We'll look at the effect of estradiol on inflammatory pain below.

 

Next up...progesterone.

Progesterone and perimenopausal pain 

If you noticed above, progesterone was also listed as having an impact on that pain pathway above (dynorphin in the spine).

 

This isn't surprising considering progesterone's primary effect on the body.

 

In general, it has a calming effect across many pathways.

 

Research is pointing to this for pain as well: 

We demonstrate that physiologically high progesterone levels are associated with a reduction in the affective component of the pain experience and a dissociation between pain intensity and unpleasantness.  

https://www.frontiersin.org/articles/10.3389/fendo.2018.00413/full

 

Progesterone can have powerful anti-inflammatory effects in the body.

 

For example, when researchers looked at inflammatory markers for sepsis: 

progesterone ameliorates sepsis syndrome by reduction of the inflammatory cytokines IL-6 and TNF-α, and by restoration of antioxidant enzyme activities in some tissues. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264078/

 

Check out CBD and inflammation or CBD and oxidation to see why those are so important...especially for perimenopause.

 

Maybe more importantly is progesterone's effect on GABA.

 

GABA is our nervous system's "brake" which we covered in detail at our CBD and GABA for anxiety here.

 

What's the tie-in with pain?

 

It has been shown that GABA receptor agonists, as well as inhibitors of GABA uptake or metabolism, are clinically effective in treating this symptom. 

https://www.ncbi.nlm.nih.gov/pubmed/17175808

 

Basically, substances that boost GABA dull pain.

 

I felt this with my heels.

 

I had a glass of wine (alcohol boosts GABA) and my pain went away!

 

Obviously, that's a poor workaround but millions of women in perimenopause appears to be taking it.

 

The effects of progesterone on GABA?

progesterone and its neuroactive metabolites (allopregnanolone, pregnanolone) seem to facilitate GABAergic transmission through their action at GABAA receptors  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335177/

 

I actually take bioidentical progesterone before bed as it helps me sleep quickly and deeply.

 

Put a note next to GABA for below since we can affect that pathway.

 

Next, a source of many types of pain.  Inflammation.

Inflammation and perimenopausal pain 

A large segment of perimenopausal pain is a result of inflammation.

 

In general, inflammation is increasing as we get old but hormone shifts definitely come into play for women.

 

First up.

 

Estradiol and inflammation for pain

 

Estradiol has powerful anti-inflammatory effects.

 

For example: 

Estrogen seems to inhibit inflammation in female human colonic epithelial cell lines, through down-regulation of NF-κB and COX-2 expression and induction of anti-oxidant enzymes such as HO-1 and NQO-1. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707591/

 

That COX-2 reduction is important for pain.

 

It's just the basis of NSAID's like Ibuprofen and Advil (very popular with women for PMS, and perimenopause pain).

 

Don't take our word for it: 

Selective COX-2 inhibitors are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly targets cyclooxygenase-2, COX-2, an enzyme responsible for inflammation and pain. 

https://en.wikipedia.org/wiki/COX-2_inhibitor

 

You know the pain you get during menstrual cramps and even perimenopause (a PMS cycle stretched out)?

 

They're caused by chemicals called prostaglandins.

 

COX activity is needed to increase these levels so blocking COX has a direct effect of reducing pain due to inflammation.

 

There's a reason Motrin directly targets women.

 

Estradiol reduces COX which reduces prostaglandin (inflammation) and brings down pain.

 

It's a lengthy chain but one worth noting if you're in pain.

 

We'll look at how we can affect it later.

 

Check out CBD versus Tylenol for a full deep dive on this process.

 

No wonder we feel premenstrual cramps when estradiol drops!

 

Again...prostaglandins are an inflammatory process.

 

Here's where it gets interesting: 

Prostaglandins and leukotrienes do not cause pain directly but both cause hyperalgesia. Hyperalgesia is a pain response to stimuli that are not normally painful, induced by the lowering of the nociceptor threshold level.  

https://www.sciencedirect.com/topics/neuroscience/prostaglandins

 

General all around pain.  Lowered threshold.  Everything just hurts MORE!

 

When do most women get fibromyalgia (which affects women almost exclusively)?: 

Most women with fibromyalgia are also between the ages of 40 to 55 years old. 

https://www.healthline.com/health/fibromyalgia/symptoms-women#periods

 

Are you kidding me????

 

That's the exact window for perimenopause.

 

It requires a whole separate article but….fascinating for estradiol's effect on pain.

 

What about progesterone?

 

Progesterone and Inflammatory Pain

 

An interesting study looked at various inflammatory pathways especially in the nervous system for progesterone.

 

Across the pathways, progesterone was anti-inflammatory especially for key reactions: 

Significant sTNF-α decrease (approximately 20%) occurred with 10−7 and 10−6 M progesterone 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117574/

 

Remember COX2 pain signals from above (the ones that Motrin reduce for PMS pain)?

 

Progesterone pretreatment decreased LPS-induced iNOS and COX-2 expression in a dose-dependent fashion,

 

That's a big deal for pain threshold and general body pain that women see as a result of perimenopause.

 

We'll look at CBD's effects on inflammation and neuroinflammation below.

 

Let's look at specific complaints that come up with perimenopausal pain.

Perimenopause and joint or muscle pain 

We saw how estradiol is tied to pain threshold and inflammation.

 

Those lie at the intersection of joint pain!

 

The big study in 2002 actually looked at this question specifically and they were using horse derived estrogen (not nearly as good as bioidentical estradiol): 

After one year, joint pain frequency was significantly lower in the estrogen alone compared to the placebo group (76.3% vs 79.2%, P=0.001) as was joint pain severity and the difference in pain between randomization groups persisted through year 3. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855295/

 

Then there's the lovely osteoarthritis...arthritis of the joints!

 

It's not just the joints though affected by estrogen drops: 

Although much of the attention has focused on the effects of estrogen on articular cartilage, estrogen deficiency also affects other joint tissues during the course of OA, such as the periarticular bone, synovial lining, muscles, ligaments and the capsule 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787275/

 

To see just how critical estradiol is for general bone health, look at studies on hormone replacement and rheumatoid arthritis specifically which is a combination of inflammation and joint atrophy: 

HRT for 2 years resulted in an increase of the bone anabolic factor, insulin-like growth factor 1 (IGF-1) (P < 0.05) and a decrease of serum levels of soluble IL-6 receptor (sIL-6R) (P < 0.05), which is known to enhance the biological activity of IL-6, an osteoclast-stimulating and proinflammatory cytokine. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC165058/

 

IL-6 is a powerful inflammatory agent (see CBD and neuroinflammation) tied to rheumatoid arthritis.

 

As for muscles, there are estrogen receptors directly on muscle cells.

 

This makes sense if you think about the sheer power needed for muscle contractions during birth.

 

Studies are showing that the "change" or flux in hormones can affect our threshold and sensitivity in muscles: 

Mechanical sensitivity of masticatory muscles increases with ovarian hormone fluctuations 

https://www.practicalpainmanagement.com/resources/women-chronic-pain

 

Check out the non-reproductive effects of estradiol and progesterone for joint and muscle function here: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589942/table/table1-204946370800200206/

 

So when your doctor tells you your numbers are just fine for someone your age….remember this chart!

 

We'll get into CBD's effect on inflammation below.  Stay tuned.

 

Next up...nerve pain. 

Perimenopause and nerve pain or neuropathy 

On that same chart above, you'll see effects of the hormones on nerves specifically:

 

Let's look at a study where the administered estradiol following injury: 

Administration of 17β-estradiol is able to significantly attenuate this difference, reducing allodynia and inducing a complete recovery also in female mice.  

https://www.nature.com/articles/srep18980

 

Allodynia is a system-wide pain affect.  Think of it as reduced pain threshold.

 

You know...the aches and pains that come with aging and perimenopause!

 

Put a checkmark next to that for CBD later on.

 

Probably the most fascinating work on nerve pain deals with mast cells and histamines.

 

This is a topic close to our heart (see CBD and histamines here).

 

This is definitely a "woman's" issue as you'll see next.

Histamine and perimenopausal pain

Histamine response which occurs in our mast cells is best known for its role in allergic responses.

 

They are powerful inflammatory agents in men and women.

 

But they're not the same in both genders.

 

First, there's the influence of both estradiol and progesterone: 

Estrogens, including environmental estrogenic pollutants, can induce mast cell degranulation in vitro (109, 110), whereas progesterone appears to inhibit histamine secretion 

https://www.jimmunol.org/content/179/5/2673

 

Notice the "environmental estrogenic" there.  That's all the plastic and other sources of estrogen-like chemicals that we're swimming in.

 

Cell degranulation just means release of histamine and other inflammatory agents.

 

Keep in mind that progesterone starts to drop around age 40 and continues to very low levels by perimenopause.

 

Allergies and histamine issues start to rise for women around the same time!

 

Here's where it gets interesting.

 

Women have an estrogen receptor on their mast cells.  Men do not!

 

For example: 

E2, P4, T4, and DHT at physiological concentrations caused histamine release (12 to 13.6%) in PMCs from female rats, significantly different () from the basal release (5 to 6%). In contrast, histamine release from PMCs from male rats was not significantly affected by any of the concentrations of the four hormones and remained similar to the basal release 

https://www.hindawi.com/journals/jir/2015/351829/ 


E2 is estradiol. P4 is progesterone.  T4 is testosterone.

 

This is a huge deal.

 

It causes women's histamine response to be stronger and more wide-spread....over their whole life!

 

Why does this matter for pain (besides just being really uncomfortable and subject to autoimmune diseases?).

 

One of the substances released by the mast cell is NGF (nerve growth factor)21 which stimulates production of substance P and VIP (vasoactive intestinal polypeptide)3 — the main messenger molecules (neurotransmitters) of the pain system 

https://www.practicalpainmanagement.com/resources/women-chronic-pain

 

The female body is priming the pain system more regularly because of this difference.

 

That link has fascinating looks at sex hormones and pain plus the long term effect of this constant bombardment of inflammatory agents.

 

What we do know is that on the Menopause Rating Scale, Siberian Rhubarb (which stimulates estrogen receptor beta pretty exclusively) reduced the aches and pains of perimenopause.

See our full review on Siberian Rhubarb.

 

Clearly, it's a complicated interaction with histamines now thrown in the mix.

 

One last stop before we start to look at what we can do about it.

Perimenopause and ovary, breast, or nipple pain 

As we saw above, flux in estradiol and progesterone can have different effects on pain.

 

Some pains are the direct result of spikes in estradiol which should be familiar from pregnancy and even our monthly cycle.

 

In this category, you'll find breast and nipple pain.

 

Again, it's the flux of change in hormones at play here: 

Estrogen causes the breast ducts to enlarge. Progesterone production causes the milk glands to swell. Both of these events can cause your breasts to feel sore. 

https://www.healthline.com/health/breast-premenstrual-tenderness-and-swelling#causes

 

The ovaries are a different deal altogether.

 

First, your ovaries generally don't check out at the same time.

 

One may go first and the other keeps trying to make an egg.

 

I would experience pretty intense pain which would subside generally within the day.

 

These are spasms of activity as the ovary is closing shop.

 

Spikes and drops of hormones.  They can also be ovarian cysts that rupture.

 

Of course, check with your doctor but they're generally benign and occur with fluctuations in hormones (literally, the theme of this entire article).

 

These cysts often develop due to normal hormonal changes in puberty or during menopause.  

https://www.ncbi.nlm.nih.gov/books/NBK539572/

 

You can learn all about them above. 


Now, let's get into the arena that CBD operates in.

 

The endocannabinoid system and perimenopause.

The endocannabinoid system and perimenopause pain 

This is the system that is generally tasked with balancing other key systems:  

  • Nervous system - neurotransmitters such as GABA, serotonin, and others
  • Immune system - inflammatory agents such as microglia, cytokines, and more
  • Endocrine system - hormones!   

 

The three lie at the intersection of perimenopause pain.

 

There are some very interesting effects here to look at.

 

First, we'll start with the woman who is unable to feel pain (lucky her).

 

She has a mutation in the FAAH gene which keeps her from ever feeling pain, anxiety, or depression.

 

Sounds interesting!

 

Basically, FAAH is a naturally occuring endocannabinoid you have in you right now.

 

It eats up another endocannabinoid, Anandamide.

 

Anandamide is the so-called "bliss" molecule named after Anand, the Hindu goddess of bliss.

 

That woman doesn't make FAAH (or very little) which means her system's Anandamide is at full peak!

 

This is important since we can actually affect this pathway (more below) without the hammer effect of THC (which mimics Anandamide but has issues - see why CBD is a must if you use THC here).

 

The full review of the woman who can't feel pain is here.

 

What about that whole COX2 angle above which is the target for Motrin, Celebrex, and the NSAID's of the world?

 

Researchers blocked CB1 receptors (the primary receptor of the endocannabinoid system in the nervous system) and the effects on Tylenol was significant: 

Acetaminophen’s analgesic properties are blocked by the administration of CB1 receptor antagonists at doses that inhibit known CB1 receptor agonists (104, 112). 

https://www.jneurosci.org/content/38/2/322

 

Essentially, when the endocannabinoid receptors were knocked out genetically, no more pain relief!

 

This applies for COX2 inhibitors like Celebrex as well.

 

All the NSAIDs that inhibit COX2 can influence the cannabinoid system 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056416/

 


As for inflammation, the endocannabinoid system may be THE system to balance our response to outsides stress and intruders (histamine and immune response).

 

To put a dot on it: 

Endocannabinoids, a group of less well-known endogenous bioactive lipids, have such manifold immunomodulatory effects able to influence both inflammation and pain. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685274/

 

We'll leave the heavy lifting to that link which goes through multiple pathways of inflammatory pain and this system.

 

Let's get to the question that started all this discovery.

Can CBD help with perimenopause pain 

We've outlined some of the core pathways of perimenopausal pain: 

  • Pain threshold changes due to hormone flux
  • COX2 and prostaglandins
  • Inflammatory pain due to hormone fluctuations
  • Anandamide and FAAH levels

 

Let's look at CBD's effect since it can influence the endocannabinoid system from above.

 

First, pain threshold.

 

THC appears to have a direct effect on the "feeling" of pain where CBD exerts more effect on the inflammatory and nerve transmission of pain.

 

There is one specific pathways affected directly by CBD for pain threshold.

 

Serotonin!

 

In fact, one study showed that CBD directly affected the serotonin pathway and consequently, system-wide pain (called allodynia):

Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain.

https://www.ncbi.nlm.nih.gov/pubmed/30157131

 

This is incredibly important for perimenopause anxiety.

 

Why??

 

Estradiol directly controls serotonin at both the production and breaking down ends!

 

In case you've missed it, estradiol is asleep at the wheel which is why depression and anxiety are so prevalent during perimenopause.

 

Remember Estradiol's effect on Allodynia from above?: 

Administration of 17β-estradiol is able to significantly attenuate this difference, reducing allodynia and inducing a complete recovery also in female mice. 

https://www.nature.com/articles/srep18980

 

This cross-reaction between estradiol and CBD could very well be via the serotonin pathway.

 

Check out: 

 

What about prostaglandins, the chemicals literally behind PMS cramps and pain: 

Hormonelike substances (prostaglandins) involved in pain and inflammation trigger the uterine muscle contractions. Higher levels of prostaglandins are associated with more-severe menstrual cramps. 

https://www.mayoclinic.org/diseases-conditions/menstrual-cramps/symptoms-causes/syc-20374938

 

CBD was shown to directly decrease prostaglandin production here: 

https://www.jstage.jst.go.jp/article/bpb/34/5/34_5_774/_pdf/-char/en

 


Also, a novel effect of CBD on prostaglandin and the COX pathway led to it's effect in diabetic mice: 

Cannabidiol (CBD) decreases insulitis, inflammation, neuropathic pain, and myocardial dysfunction in preclinical models of diabetes. 

http://jpet.aspetjournals.org/content/351/2/457

 

Remember that estradiol down-regulateds COX2 so it needs some help: 

E2 down-regulates a component of an inflammatory response, cyclooxygenase– 2 (COX-2) expression.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010190/

 

These are complicated and interwoven systems so we clearly need more research to tease out the mechanism.

 

Until then, we have to "black box" it and look at the actual results.

 

What about joint and muscle pain...a common complaint with perimenopausal pain?

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.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851925/

 

Another study found that CBD could actually prevent later-developing pain for osteoarthritis: 

Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690292/

 

This leads us to the powerful anti-inflammatory effect of CBD.

 

Other studies are digging into the effect of CBD on inflammatory agents and the effects are varied across dozens of pain pathways such as with arthritis: 

In this study, the authors showed that daily oral (5 mg/kg) or intra-peritoneal (25 mg/kg) administration of CBD inhibited disease progression. Furthermore, the study demonstrated that 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. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

 

Interestingly, there's one place that CBD actually INCREASES inflammation.

 

Cancer cells!

 

Check out the following: 

 

As we mentioned above, the entire pain complex whether driven by hormone flux during perimenopause or a sharp stick is governed by the endocannabinoid system.

 

For example, the woman who is unable to feel pain due to a mutation in her FAAH gene.

 

Can CBD affect that pathway?

 

We're going to end with a litany of pain pathways affected by CBD including the FAAH and Anandamide one: 

CBD also regulates the perception of pain by affecting the activity of a significant number of other targets, including non-cannabinoid GPCRs (e.g., 5-HT1A), ion channels (TRPV1, TRPA1 and TPRM8, GlyR), PPARs, while also inhibiting uptake of AEA and weakly inhibiting its hydrolysis by the enzyme fatty acid amide hydrolase (FAAH)  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277878/

 

Let's decipher this please. 

  • 5HT is serotonin which we discussed
  • TRPV are specific channels for pain which CBD affects
  • PPAR is another specific pathway for pain positively influenced by CBD
  • Finally...AEA is anandamide and there's FAAH.

 

CBD's effects were shown on those two in a powerful way for its effects on schizophrenia:

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.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/

 

CBD boosts anandamide levels by blocking FAAH.

 

Perimenopause can be an intense period of change.

 

This is stress to the body as our hormones have powerful anti-inflammatory and neuroprotective effects.

 

Some pain may reside in the nervous system itself as it's under duress.

 

At a top-down level, CBD has the following effects there: 

CBD decreases the production of inflammatory cytokines, influences microglial cells to return to a ramified state, preserves cerebral circulation during ischemic events, and reduces vascular changes and neuroinflammation

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

 

You can get into the details via that link there.

 

Finally, remember the GABA pathway...calming nerves such as when I had a glass of wine and my pain just went away?

 

What about CBD and GABA?

Across regions, CBD increased GABA+ in controls 

https://www.ncbi.nlm.nih.gov/pubmed/30758329

 

Check out CBD and GABA for more detail.

 


This all started with chronic pain, eventually only in my heels.

 

Let's look at other things we've found along the way (among sea of things that did not work).

Other tools for perimenopause pain 

Obviously, we have to address hormone swings.

 

Check out the following: 

 

There are many other systems besides pain that are affected by these hormones.

 

Next up, some more radical approaches if you're stuck in pain.

 

Low Dose Naltrexone for perimenopausal pain

 

This may be the most fascinating option and one, most doctors don't even know about.

 

It's an old drug for alcohol abuse but at very low dosages (around 5mg), it can have a powerful effect on pain.

 

Especially, chronic pain such as fibromyalgia and regional pain complex syndromes.

 

 

By the way, those are "female" diseases with 80%+ of diagnosis being for women.

 

We'll do a full review because the safety profile is amazing and it's so powerful.

 

Why on earth a doctor would prescribe opioids before this route is beyond us!

 

Topical Ketamine for perimenopausal pain

 

This is another option which gets to the heart of nerve pain.

 

Essentially pain stuck in your nervous system.

 

It's usually given with a anti-inflammatory and gabapentin (remember..to slow down activity in the nerves locally).

 

Red light therapy

 

Some people swear by this.

 

It appears to increase blood flow when I use it but I can actually get more inflammation afterwards.

 

Nanowave technology.

 

Our colleague just went to the RAAD fest and is bringing back a device she swears immediately brought down pain (she's 70).

 

God knows we have plenty of painful sites to try it on so we'll do a full review if it lives up to its hype.

 

Other powerful players: 

  • Curcumin - system wide anti-inflammatory
  • Vitamin D
  • Methylated B vitamins for nerves 
  • Pregnenolone - precursor to all your steroidal hormones including allopregnenolone.  Full review here.

On to some practical questions.

How much CBD for perimenopausal pain 

There are three things to look at here.

 

First, the actual feeling of pain.

 

Some of the studies looked at lower levels around 50 mg above.

 

It usually makes sense to try around 25-30 to test your body's response.

 

Our study on anxiety showed that 300 mg was the maximum level for neurogenesis (making new nerve pathways).

 

This is the same theory behind ketamine above where we rebuild around damaged or hyperactive pain nervous pathways.

 

Obviously, everyone is different and pain pathways are different.

 

Test what works for you in terms of inflammation and pain relief.

 

Keep in mind that longer term issues such as inflammation and nerve pathways will change more slowly.

 

That's why SSRI's can take weeks to affect depression and pain.

 

They use the endocannabinoid system by the way!

 

Based on above there are some clear indications on the type of CBD to take.

What's the best CBD for perimenopause pain 

First, it has to meet the baseline requirements: 

  • Organically grown in the US at an FDA registered farm
  • CO2 processed
  • 3rd Party tested for:
  • NO THC (see CBD versus THC)
  • No heavy metals
  • No pesticides
  • No mold
  • No bacteria

 

We actually test IndigoNaturals twice since our whole families use it.

 

Then, the big one.

 

CBD Isolate versus Full Spectrum.

 

Everyone out there is pushing full spectrum (it's much cheaper to make).

 

The problem is histamines.

 

We discussed above how women have estrogen receptors on mast cells...where histamine is released from along with a host of inflammatory agents.

 

Estradiol is going full tasmanian devil during perimenopause and there's a clear connection with allergies and autoimmune.

 

We don't want to introduce anything the body will see as plant material (many of which are natural repellents to keep bugs away).

 

CBD Isolate is definitely the smarter approach here for women in perimenopause.

 

Check out CBD Isolate versus Full spectrum for more reason why.

 

I actually tried 3-4 of the biggest CBD brands (all full spectrum because that's better, right???) early in this process and the effects? 

  • Click in the back of my throat
  • Fever
  • Sinus blew up
  • GI problems

 

Literally the opposite direction of what I was trying for (especially for sleep and anxiety).

 

Histamine is excitatory and it eats up GABA!

 

That's why we do CBD Isolate.  All those side effects went away with Isolate (CBD by itself).

 

One note...for site specific issues (joint pain in thumbs, etc), the balm works well there.

 

For systemic issues (nervous system, gut inflammation, etc) tied to pain, the CBD oil is best.

 

Hold it under your tongue up to 60 seconds to increase bioavailability by 4 times!

 

Be well and I'll review both the naltrexone and nano-wave device soon if they're effective.

 

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