Siberian Rhubarb Guide for Perimenopause

It's been two years now.

Around age 47, perimenopause completely knocked me off my feet.

 

I'm not talking hot flashes (although those were definitely on board).

24/7 rolling anxiety and panic attacks.  Heart racing.  Stomach issues.  Sleepless nights.

That whole story is here but the medications my doctors (plural) prescribed just sent me further into a tailspin.

 

 

Eventually, I got off of all of them and found a doctor who worked with my hormones.

 

It was night and day.

First the bioidentical progesterone.  Next, the estradiol and estriol (bi-est 80/20).

It wasn't cheap but I could actually function again.

That being said, it wasn't quite right.  I didn't feel myself from the tinkering and testing of different levels.

 

It was so frustrating that we did our full review of estradiol for perimenopause; progesterone, or estrogen and mental health to answer nagging questions about how to best supplement it.

If you check out that page, you'll see that we go deep into any topic.

We wanted to get research on all the questions we had.

Safety.  Best way to apply.  When to take it.  Etc.

In that 20 hour process of researching, we came across a few interesting studies on Siberian Rhubarb.

 

It peaked our attention enough it check it out.

I had two residual issues aside from a general roller coaster effect on mood (we'll explain why this happens during perimenopause below).

 

• I would wake up in the middle of the night with a jolt.  Usually around 4am and then it was hard to really sleep well after.
• My heels had tremendous pain.  

 

Yes, I've been to many doctors for the feet, had MRI's, tried every product under the sun.

I also noticed that early evening, I would start to feel anxious as if something was "wearing" off.

Hormones no doubt since I take them in the morning.

So I tried Siberian Rhubarb.

Okay...this is going to require a full review!

 

It immediately changed how I felt.

In fact, I had almost a sedative or very relaxed feeling.

This is fascinating since it's just Siberian Rhubarb in the ingredients (I have to be very suspicious these days as I react to almost anything due to histamine from loss of progesterone).

My sleep changed immediately. 

I wish I would have found this a while back and saved a few years of torture.

Better yet, I wish I would have had this when my periods first started to go wonky (around age 45-46 actually).

No crying over spilled milk...unless estrogen is yo-yoing.  When that happens, I might cry over anything!

 

Let's get started.  We want to know EVERYTHING about Siberian Rhubarb.

We'll cover these topics: 

• A quick introduction to perimenopause
• Meet your estrogens (and their receptors)
• Siberian Rhubarb and the 11 symptoms of perimenopause
• Does Siberian Rhubarb boost estrogen?
• Is Siberian Rhubarb an alternative to hormone replacement?
• Can you take Siberian Rhubarb with hormone replacements?
• Are there long term studies on Siberian Rhubarb?
• How long does it take for Siberian Rhubarb to work?
• The connection between Siberian Rhubarb and Resveratrol
• Is Siberian Rhubarb safe and protective against estrogen?
• Siberian Rhubarb and breast cancer
• Siberian Rhubarb side effects
• When to take Siberian Rhubarb
• Where to buy Siberian Rhubarb

A quick introduction to perimenopause 

As if you need an introduction.

If you're reading this, perimenopause is likely an unwanted house guest.

Unlike the 3 days, this could take 3 years.  Or 10!

In fact, progesterone, the first to go, may start decreasing years prior.

 

It actually starts to go down late 30's and early 40's.  50% by age 40.

If you really think back, you may see signs of it...irregular periods.  Weird bouts of incontinence.

By the time that periods start to bunch up or miss, you may already be out of progesterone.

In fact, the last batch of periods usually don't create progesterone because they don't produce an egg.

That goes first and it's more or less a smoother transition albeit with huge impacts on health (see CBD and autoimmune).

Not so much for estradiol (our main estrogen out of three).

 

Some women (Hi, my name is Andrea) get wholloped.

It's a higher number than you might guess.

This site has a good review of how many women are affected by type of issue: 

https://www.amjmed.com/article/S0002-9343(05)00885-5/fulltext

Approximately 25% of women entering perimenopause have a debiitating one.

Learn about why women get hit so hard here.

More interestingly was this study of women who didn't have anxiety prior to perimenopause only to see it occur during this transition: 

Women with low anxiety at baseline were more likely to report high anxiety symptoms when early or late perimenopausal or postmenopausal compared to when they were premenopausal (odds ratios ranged from 1.56 to 1.61) 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641149/

Almost 60% risk for women with LOW anxiety profiles before perimenopause.

To understand why it's you, check out CBD and perimenopause anxiety.  

Estrogen and progesterone are powerful neurochemicals.

 

 

Essentially, estradiol also goes down but it does it over a shorter time span and there can be a painful roller coaster effect.

Basically, FSH (a master signalling hormone) and estrogen (we'll use interchangeably for estradiol) are locked in a cat-and-mouse battle to the end.

 

Upon lower levels of estradiol, FSH may signal to the ovaries to ramp up production.

You can actually see estradiol spike and drop due to this effect.

THAT'S perimenopause.  Or at least the troublesome part of it.

Think of your worst PMS writ large.

Until we get 12 months without a period, this can be the norm.

There's nothing normal about it.

So...outside of bandaids for symptoms, the primary way to address this was with hormone replacement.

A study in 2002 on synthetic or horse-derived hormones scared women to a point where many of them dropped their hormones.

 

That has changed course since as new studies showed the flaws of that study and more women turned to bio-identical (see Estradiol for perimenopause).

There are still conflicting studies on the safest course however which is what prompted us to do the full review.

More here:

• Oral bioidentical estradiol and progesterone safety review
• My estrogen journey 

 

After all, we focus on CBD (for perimenopause anxiety or perimenopause depression) but look...hormones are so critical to every system in your body and brain.

 

You might as well just rip out serotonin (target of SSRIs) or GABA (target of benzos)....in a way, you are...more on that later.

What led us to the Siberian Rhubarb was how it addressed the safety issue with estrogen.

The fact that it was so effective is a bonus!

We have to first introduce the players in this perimenopause game as it directly affects Siberian Rhubarb's effect.

Meet your Estrogens (and their receptors) 

In highsight, I wish I would have tried SIberian Rhubarb (for estrogen pathway) and pregnenolone (for progesterone and other steroidal hormones - see our full review on pregnenolone for perimenopause here) first.

Way back at age 45-46 really.

Let's first get a lay of the landscape which will help explain how Siberian Rhubarb works.

Estrogen is a powerful operator in your body and not just for reproduction.

 

You have estrogen receptors on almost every cell of your body and brain. 

• Muscle
• Neurons
• Bone
• Heart

 

You name it!

There are actually two receptors ERa and ERb (alpha and beta).

 

This is important for Siberian Rhubarb and the safety aspect.

There are also three different "flavors" of estrogen: 

• Estradiol - our most powerful estrogen - pro-growth and excitatory
• Estrone - weaker version that acts as a reserve for estradiol
• Estriol - perhaps more protective but generally only spikes when pregnant

Estradiol is really the workhorse.

Now, the two receptors have different functions and even favorite hangouts in the body and brain.

We can generally think of them this way: 

• ERa - pro-growth, pro-reproduction, and excitatory (revs up pathways)
• ERb - a counter force to ERa with anti-inflammatory and calming (inhibitory) effects

 

Now, these systems are incredibly complicated (ridiculously so...thanks Mother Nature) but that's a good, rough sketch for our discussion.

There are so-called "knock out" experiments where researchers will genetically remove receptors for either ERa or ERb receptors and watch the effects.

They can be very different!

For example, with metabolism and fat creation (a common complaint with perimenopause): 

αERKO mice are diabetic and insulin resistant. βERKO mice exhibited insulin responsibility and have not excessive fat in the body 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389841/

In general, when you take out all estrogen, health suffers across a range of issues: 

ERKO females display aggressive behavior and depression. Additionally, estrogen signaling contributes to brain integrity and exerts different effects on behavior

 

As for anxiety, I can definitely attest to this: 

ERα, which has a generally anxiogenic effect, ERβ, which has a generally anxiolytic effect,

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815294/

Anxiogenic means increases anxiety (ERa).  Anxiolytic means anti-anxiety (ERb).

This matches the pro-growth, excitatory nature of ERa.

Feels a lot like glutamate and GABA but on cellular growth as opposed to neurotransmission!

Why are we getting into all this for Siberian Rhubarb?

 

For this reason...the whole question of safety, estradiol versus estriol, etc revolves around these receptors. 

• Estradiol hits both ERa and ERb receptors equally and with maximum strength.
• Estrone hits ERa slightly higher than ERb but with less strength
• Estriol hits ERb with more strength at a lower amount

 

To be more exact: 

With estradiol as the standard, binding affinity for both estrogen receptor (ER)-α and -ß is equal at 100.[20] Estrone has a binding affinity for ER-α of 60 and for ER-ß of 37. Estriol binds to ER-α with an affinity of 14 and to ERß with an affinity of 21. Therefore, estradiol has the strongest binding affinity for both ER-α and -ß. 

https://www.medscape.com/viewarticle/571299_6

When I wanted to increase my estradiol levels (due to mood and sleep issues), my doctor pushed back based due to (perceived) safety concerns.

This is primarily due to estradiol's strong effect on ERa receptors which is pro-growth and in some circumstances (genetics, etc), may contribute to breast or endometrial cancer (see the estradiol review please...it was .0003 versus .0006 depending on delivery method and that was with synthetics!!).

 

Old information dies slowly.  SSRIs and benzos are much more lucrative!

The whole reason many doctors promote estriol (E3) is because of research showing it might be protective from E1 (estradiol) pro-growth activity.

 

You can see from the ERa and ERb spread above how this works.

Estriol has a stronger activity on ERb.

Can we get that in a different way?

Let's turn our attention to Siberian Rhubarb. 

How does Siberian Rhubarb work for perimenopause 

So...the question is this...can we find a substance that interacts more with the ERb receptors?

Essentially, that's why doctors are prescribing Estriol (E3)...as a protective measure against the pro-growth aspects of Estradiol (E1), our workhorse estrogen.

 

That's where Siberian Rhubarb comes in.

Technically, Siberian Rhubarb is a SERM (Selective Estrogen Receptor Modulator).

 

That's a technical description of a substance that mimics estrogen in some capacity.

Think of the receptors ERa and ERb as locks.

The different versions of estrogen have keys to these locks although they prefer certain locks over others (i.e. estriol prefers ERb).

 

A SERM can open the same locks!

For example, Tamoxifen, the anti-breast cancer drug is a SERM.

 

Granted, it's synthetic and has side effects but it also blocks pro-growth (pro-cancer in this case) estrogen activity.

Guess what receptor is uses for this action: 

Estrogen Receptor β Expression Is Associated with Tamoxifen Response in ERα-Negative Breast Carcinoma

https://clincancerres.aacrjournals.org/content/13/7/1987

ERb (beta)!

Siberian Rhubarb is another SERM which almost exclusively targets the ERb (beta) receptor.

 

This is true for most phytoestrogens (such as soy) which are derived from plants.

So essentially, Siberian Rhubarb fills in for estrogen but with a strong preference for the ERb receptor.

Siberian Rhubarb and MAO, FSH, and LH

 

That's a mouthful but these different pathways are key to estrogen and neurotransmitter processing.

Remember, perimenopause severity can be caused by a chaotic dance between FSH and estradiol (hence the spikes).

 

MAO is involved in metabolism of neurotransmitters like serotonin (see CBD and serotonin) which is critical for mood balance.

In fact, estradiol itself governs MAO activity which speaks to mood swings during this time:

Estradiol Modulation of Monoamine Metabolism One Possible Mechanism Underlying Sex Differences in Risk for Depression and Dementia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126841/

Don't worry, we're going to walk through Siberian Rhubarb and the 11 symptoms of peri/menopause (unless you want to tack a few more on) below.

 

The Quercetin connection and Siberian Rhubarb.

 

Siberian Rhubarb also has quercetin. 

Quercetin is the new wonder anti-oxidant. 

Quercetin has a higher reduction potential compared with curcumin at three different pH settings and is comparable to Trolox at pH 7-9.5; 2) its TAC is 3.5 fold higher than curcumin; 

https://www.ncbi.nlm.nih.gov/pubmed/21445799

We love curcumin (turmeric) but 3.5% higher abilities as an antioxidant??!

Think of perimenopause as a period of stress on the body.  Stress creates inflammation which creates oxidation.  (see CBD and oxidation or CBD and inflammation).

So, SIberian Rhubarb has the following known attributes:

• Strong preference for ERb activity (protective arm of estrogen)
• Helps to balance neurotransmitter metabolism and levels (MAO)
• Powerful antioxidant (quercetin)

 

These are all great but for perimenopause, it's really door 1 we want to focus on.

Check out our review on Estradiol for perimenopause to see just how powerful estrogen is to the body and brain.

Just today, I read an article by a doctor on how maybe it's the natural way to have hormones drop and that's okay.

Yes...it was a male doctor.

 

Otherwise, that shit wouldn't be in print!

Excuse our language but we've felt the effect of estradiol/progesterone leaving and and it was incapacitating.

So what's the net effect of these pathways on perimenopause?

Siberian Rhubarb and the 11 symptoms of perimenopause 

This is a good place to introduce the MRS or Menopause Rating Scale.

Yes, Perimenopause is a totally different phase (with chaotic estradiol fluctuations) from menopause but they share the same symptoms: 

• Hot Flashes or periods of sweating
• Heart discomfort - racing, tightness, heightened sense of heart beat, etc
• Sleeping problems 
• Depressed mood
• Irritability
• Anxiety - restlessness, panicky
• Physical and mental exhaustion - brain fog, forgetfulness
• Sexual issues - changes in desire, activity, satisfaction
• Bladder issues
• Vaginal dryness
• Joint and muscular discomfort 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166422/

Any bells go off there?

I'm one of the lucky ones who can literally put a check by every one of those.

Apparently, I"m not alone: 

The most common symptom was mental and physical exhaustion which was reported by 88 (72%) women, followed by joint and muscular discomfort which was reported by 83 (68.59%). Hot flushes were reported by 54 (44.62%) respondents.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166422/

So...can Siberian Rhubarb help on this lovely scale?

Yes!

We're going to focus on a specific blend of Siberian Rhubarb extracts which has minimum levels of two key components: 

• > 54% rhaponticin, 
• > 27% desoxyrhaponticin

 

This is the German mix that has been studied and used for decades now called ERr 731.

It's readily available to purchase here.  Check out Menopause 731 as the dominant brand.

First, some studies in aggregate on the total MRS scale.  

After 6 months of treatment with ERr 731 in 252 women, there was a significant decrease of the MRS total score from 14.5 points at baseline to 6.5 points (P<.0001) 

https://www.ncbi.nlm.nih.gov/pubmed/19043936

The effect was more pronounced the worse the initial severity was.

Another study, same results: 

By 12 weeks, the MRS II total score and each MRS II symptom significantly decreased in the ERr 731 group compared to the placebo group 

https://www.ncbi.nlm.nih.gov/pubmed/16894335

Again, against placebo (very important for specific symptoms): 

after 12 weeks, the overall menopause-specific quality of life was significantly better in women treated with ERr 731 compared with placebo

 

And another well-controlled study: 

By 12 weeks, ERr 731 caused a highly significant reduction of the MRS total score from 27.0 +/- 4.7 points to 12.4 +/- 5.3 points when compared to the placebo-induced decrease from 27.0 +/- 5.3 points to 24.0 +/- 6.2 points 

https://www.ncbi.nlm.nih.gov/pubmed/19161045

Just to put that in context… 

• Placebo dropped the MRS levels from 27 to 24 on average.
• ERr 731 dropped the MRS levels from 27 to 12 on average!

 

More than half!

These studies look at perimenopausal and menopausal women which again, speaks to a loss of estrogen since the fluctuation of estradiol is gone by the time menopause is in full force.

 

To see just how critical estradiol/progesterone are, let's walk through Siberian Rhubarb's research on each one where it's specifically noted.

Since we know that Siberian Rhubarb (ERr 731) has a pronounced effect on ERb receptors, we'll drill down into that pathways effect when able.

Siberian Rhubarb and Hot Flashes or periods of sweating 

Siberian Rhubarb ERr 731 result:    -2.1 points (out of 4 total)
Placebo Result:  -0.2 points

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335 

This might be one of the most common symptoms of perimenopause.

It's also one of the biggest effects of Siberian Rhubarb!

ERr 731's effect: 

A significant reduction in each individual MRS item score, in hot flushes and the hot flush weekly weighted score, together with a marked improvement in treatment outcome were also observed 

https://www.ncbi.nlm.nih.gov/pubmed/19161045

The other studies all reflect this same effect.

Why does this happen?

Hormones!

This is consistent with the fact that estrogen therapy virtually eliminates HFs. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612529/

In fact, researchers have long known that ERb agonist (stimulators) reduce hot flashes.

Chalk that one up to ERb dominion.

Next up, one close to my heart (bad pun...apologies).

Siberian Rhubarb and Heart discomfort - racing, tightness, heightened sense of heart beat, etc

 

Siberian Rhubarb ERr 731 result:    -1.5 points (out of 4 total)
Placebo Result:  -0.1 points 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335

  

My blood pressure spiked, heart raced day and night.  I could feel and hear my heart beating. 

• EKG's.  
• 30 day heart monitoring.  
• Ultrasound.  
• Blood pressure meds.  Beta blockers.  

 

Nothing!

The doctors threw me on a slew of heart medications which made me feel terribly.

I had to drop all of those.

Hormones basically corrected the whole thing.

Why?

While cardiovascular disease (CVD) is the leading cause of death among women, epidemiologic studies indicate that females prior to menopause are somewhat protected against the development of CVD when compared to men.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655818/

And after perimenopause….

the incidence and severity of CVD (cardiovascular disease) increases postmenopause: 

The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2).

 

That article goes into ridiculous detail of all the effects estradiol has on our heart function.

To put a point to it: 

During perimenopause (the time period before menopause), there is a marked decrease in ovarian estrogen production. This is associated with an increase in heart rate (sinus tachycardia) and an increased frequency in palpitations and non-threatening arrhythmias, such as premature ventricular contractions or PVCs.

https://my.clevelandclinic.org/health/diseases/17644-women--abnormal-heart-beats

And finally:

Estrogen Linked To More Efficient Regulation Of A Woman's Heartbeat 

https://www.sciencedaily.com/releases/2002/11/021106074920.htm

This heart component is part of the MRS scale and the results: 

 At 12 weeks, the ERr 731 group demonstrated a significant decrease in total Menopause Rating Scale II (MRS II)† score (p < 0.0001), as well as significant decreases in all 11 individual symptom scores compared to placebo (p < 0.0001) 

https://pdfs.semanticscholar.org/a188/3e071695213724c1f9df258910481d6c2ae7.pdf

The words there are "all 11 individual symptoms scores".

Check out CBD and racing heart here.

Next up sleep.

Sleeping problems  

Siberian Rhubarb ERr 731 result:    -1.9 points (out of 4 total)
Placebo Result:  -0.1 points 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335 

We know from studies on hormone replacement that estrogen and progesterone are key to governing sleep: 

Estrogen replacement therapy improved sleep quality, facilitated falling asleep, and decreased nocturnal restlessness and awakenings (p < 0.001). 

https://www.ncbi.nlm.nih.gov/pubmed/9609575/

Some of this could be the result of other symptoms such as hot flashes (been there at 3 am!).

Estrogen-induced sleep improvement was associated with alleviation of vasomotor symptoms (r range 0.27 to 0.55), alleviation of somatic symptoms (palpitations and muscular pain, r range 0.26 to 0.36), and alleviation of mood symptoms (r range 0.28 to 0.37) on estrogen replacement therapy.

 

Interestingly, the more the severity of insomnia, the more the estrogen replacement helped!

Here, the key may also be progesterone!

I take it at night and it puts me right out.  Progesterone is a huge driver of GABA, the target for benzos.

 

 

That being said, Siberian Rhubarb  has almost a sedating effect on me...to the point where I take it about 2 hours before bed now.

 

This effect is mirrored on the boards and reviews of ERe 731 and depends on a person's body and metabolism.

Learn more at perimenopause sleep issues.  We did a huge review on the pathways of sleep.

Next up...let's look at mood.

Depressed mood 

Siberian Rhubarb ERr 731 result:    -.2.2 points (out of 4 total)
Placebo Result:  -0.2 points 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335 

Estrogen is all over neurotransmitters which are intimately tied to mood changes such as depression.

Just look at the pathway for the common antidepressants (see CBD versus SSRI).

Serotonin.

 

 

 

Guess what governs both the production and breakdown of serotonin?

Estradiol!!

 

Interestingly, there's longer term depression and there's the sudden swings of depression tied to perimenopause which can go away in minutes, hours, or longer.

What's causing that? 

We conclude that estradiol may have a fast, direct effect on brain membranes to modify serotonin receptor availability, while exerting a slow effect on the same receptors through an interaction with intracellular estrogen receptors in those brain regions that contain them. 

https://www.jneurosci.org/content/2/2/199.short

Check out CBD and perimenopause depression for a full walk-through of the pathways.

Maybe more importantly for Siberian Rhubarb (ERr 731) is the importance of the ER beta receptor for mood issues: 

Estrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons

https://www.ncbi.nlm.nih.gov/pubmed/19559077

 

 

That may sound like mumbo jumbo but it's literally how your brain makes serotonin and ERb receptors are at the heart of it.

See CBD, tryptophan, and serotonin for CBD and serotonin for more info.

It's why you feel really crappy when you have the flu!

Same effect with perimenopause.

The big German study: 

Subjects have reported symptom reduction that continues over 3, 6, 12, and 24 months to help improve quality of life through additional improvements in sleep quality and reduced anxiety and depression. 

https://pdfs.semanticscholar.org/a188/3e071695213724c1f9df258910481d6c2ae7.pdf

This same effect continues for the two main mood attributes of the MRS.

Learn all about perimenopause depression.

Siberian Rhubarb ERr 731 and Irritability 

Siberian Rhubarb ERr 731 result:    -.2.3 points (out of 4 total)
Placebo Result:  -0.3 points

 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335 

Somewhere between depression and anxiety is just being fed up.

I've been there.

There's discussion on whether this is an attribute of hormone fluctuate itself (neurotransmitters, etc) or a result of other so-called vasomotor symptoms: 

• Lack of sleep
• Anxiety or depression
• Hot flashes

 

The last one is reason enough to be irritable. 

We're not going to show our cards yet (the endocannabinoid system below) but just a peek!

 

There's a naturally occuring endocannabinoid in you right now called Anandamide.

It's called the "bliss" molecule (guess how it feels) and it's named after the Hindu goddess of bliss.

To see how powerful it is, check out the woman who can't feel pain, anxiety, or depression here...even during perimenopause!!

Let's just say she has anandamide in abundance due to a genetic variation in the chemical that breaks it down, FAAH.

Why does this matter?

This is mouthful but stick with us...there's a payoff: 

Despite these differences, FAAH inhibitors retain anxiolytic- and antidepressant-like effects in ovariectomized female rats [112]. Interestingly, however, anxiolytic- and antidepressant-like effects produced by estradiol administration are attenuated by CB1R blockade [112], whereas estradiol administration increases AEA levels [113] or AEA signaling [114], possibly via downregulation of FAAH driven by an estrogen response element on the FAAH gene that suppresses FAAH transcription when bound by estrogen 

https://pdfs.semanticscholar.org/a188/3e071695213724c1f9df258910481d6c2ae7.pdf

Goodness, let's decipher that.

Basically, estradiol exerts its antidepressant and anti-anxiety effects by boosting anandamide.

In fact, they were able to block estradiol's effect on depression and anxiety by blocking CB (endocannabinoid) receptors!

This means, the key to estradiol's control of mood is...the endocannabinoid system and anandamide in particular!

 

By the way, this was a sex dependent effect...only women used this pathway in other experiments: 

Remarkably, this effect of E2 is sex specific, occurring in females but not in males.  

https://www.sciencedirect.com/science/article/pii/S0896627312003753

Can we all agree that irritability is the opposite of bliss?

Learn how to boost anandamide and why endocannabinoid deficiency is so important (and miserable).

SSRI build tolerance which means your natural levels drop as a result.  

 

 

The anandamide connection is a great jumping off point for anxiety.

Siberian Rhubarb ERr and Anxiety - restlessness, panicky 

Siberian Rhubarb ERr 731 result:    -2.2 points (out of 4 total)
Placebo Result:  -0.3 points 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335 

This is really the reason I stumbled (tripped really) into studying all of this including CBD, Siberian Rhubarb, Pregnenolone, and everything else.

 

Rolling anxiety 24/7 and panic attacks that almost did me in.  My full story is here.

There were glimpses of it a few years before everything fell apart but no one told me to be on the lookout.

We've covered a great deal of what's going on at our CBD and perimenopause anxiety but what about Siberian Rhubarb ERr 731?

This may be the best result from Siberian Rhubarb.

The results on anxiety are well-documented and powerful.

Let's introduce the HAMA or Hamilton Anxiety Rating Scale.

It's a measure of anxiety essentially.

The effects were very fast (I felt them immediately) and by day 28, there was a marked drop in HAMA scores.

Check out the chart here: 

https://pdfs.semanticscholar.org/a188/3e071695213724c1f9df258910481d6c2ae7.pdf

The HAMA score dropped from 27 to 10 while placebo when from 25 to 22 (in line with the other MRS items).

How to score it: 

Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0–56, where <17 indicates mild severity, 18–24 mild to moderate severity and 25–30 moderate to severe. 

https://dcf.psychiatry.ufl.edu/files/2011/05/HAMILTON-ANXIETY.pdf

So the average dropped to 10!!

The trend continued over the course of the study: 

After 12 weeks, a reduction in the severity of anxiety from "moderate" or "severe" to "slight" was observed in 33 of 39 ERr 731 women completing the double-blind phase, which correlated well with the reduction in number and severity of hot flushes. 

https://www.ncbi.nlm.nih.gov/pubmed/17213754

Again, I felt the effect the first day and by far, it's the biggest impact (outside of sleep) from Siberian Rhubarb.

Compare that with SSRIs or benzos which both build tolerance and the latter has brutal addiction risks.

 

 

The anandamide and estradiol connection above figures directly into this as well.

We're not surprised: 

ERα, which has a generally anxiogenic effect, ERβ, which has a generally anxiolytic effect, 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815294/

Anxiogenic means to cause anxiety.  Anxiolytic means anti-anxiety.

Remember..ERa is pro-growth (excitatory) and ERb is calming and anti-inflammatory.

Let's look at the cognitive effects now.

Siberian Rhubarb and Physical and mental exhaustion - brain fog, forgetfulness 

Siberian Rhubarb ERr 731 result:    -1.6 points (out of 4 total)
Placebo Result:  -0.1 points 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335 

Just check out our review on Estradiol for perimenopause to see how integral E2 is for the brain's function.

Little things like memory.  Cognition.  That's a fancy way to say "thinking".

To the extreme are effects of estrogen in women with dementia: 

Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). 

https://n.neurology.org/content/57/4/605.short

When you look at the interaction between estradiol and BDNF (our brain's fertilizer) and serotonin (our brain's builder), it's no wonder.

Check out CBD and BDNF or CBD and Serotonin to see how powerful these pathways are.

How dare that doctor say that estradiol isn't needed!

 

So what about Siberian Rhubarb?

We know that it has a preference for Estrogen Beta receptors.

These just happen to be the most prevalent estrogen receptors in the brain: 

Activation of estrogen receptor-b regulates hippocampal synaptic plasticity and improves memory 

https://www.researchgate.net/profile/Ronald_Mervis/publication/5555290_Activation_of_estrogen_receptor-_regulates_hippocampal_synaptic_plasticity_and_improves_memory/links/02e7e52a2049b1fa64000000.pdf

Let's put this in context.

The hippocampus is the seat of memory and mood control.

It's very "plastic" which means that it can change all the time.  Very dynamic

This also makes it vulnerable to stress, infection, trauma, and...loss of hormones.

 

Check out CBD and hippocampus neurogenesis to learn all about it.

Also, CBD, exercise, and meditation for neurogenesis.

 

 

Very fascinating that ERb receptors are at the heart of remodeling this very important brain area.

In the study, they used "knock out" mice who genetically had their ERbeta receptors blocked.

This consequently blocked the ability of the hippocampus to restructure.

Remember that Siberian Rhubarb showed marked improvements across all MRS items including memory, brain fog, and cognitive function.

Also check out DHEA and progesterone for brain fog.  

The unbalanced relationship between DHEA and cortisol can make some patients experience low androgen symptoms – fatigue, foggy thinking, decreased stamina, and low libido 

https://www.zrtlab.com/blog/archive/low-libido-perimenopausal-patients/

Look...research is showing the timing is critical.

There's a critical window right around perimenopause where hormone replacement (or substitution with SIberian Rhubarb) is critical: 

Women who had originally been randomized to hormone therapy—HT; (estrogen [E] + progesterone [P])—for 2 to 3 years and then stopped treatment (past-users) had a 64% decreased risk of cognitive impairment 5–15 years later, as compared with those who had originally been randomized to placebo and never took HT  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838456/ 

That being said, we found research on how CBD might "reopen" this window in case you're starting hormone support late.  

One note...estradiol also drives acetycholine, your "calm and focused" powerhouse which is key to ADHD and dementia risks!  

Big review on brain fog here.  

On to another part of the body!

Siberian Rhubarb and Sexual issues - changes in desire, activity, satisfaction 

Siberian Rhubarb ERr 731 result:    -.9 points (out of 4 total)
Placebo Result:  -0.0 points 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335

Interestingly, this one of the three categories where placebo had no effect at all.

We've spent the better part of this article looking at heart, brain, and the like.

Let's look at the slew of issues related to sexual health and perimenopause.

You can check out our CBD and Orgasm here.

Needless to say, estradiol is all over this process for women.

Simply put: 

Both estradiol and testosterone have been implicated as the steroid that critically modulates sexual desire in women; although, estradiol seems at first glance to be the more likely candidate for this role. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720522/

In fact, when ovaries are surgically removed, sex drive drops as a result.

Read through that article on testosterone which is frequently prescribed for female libido.

That may result for age-old dogma which resulted from levels of testosterone not natural to the female body.

And yet...it's still popularly prescribed!

Estradiol, however IS directly tied to female sexual desire and satisfaction.

This isn't all that confusing considering that estradiol naturally peaks right before ovulation.

These studies demonstrated that women’s sexual desire consistently exhibited a well defined midcycle peak, irrespective of the measure used to estimate ovulation. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720522/

Nature makes sure that the will is there in advance!

To separate out testosterone, later studies were able to split out estradiol from testosterone and the results: 

Thus, Roney and Simmons (2013) provided correlational evidence indicating that circulating estradiol, but not testosterone, was associated with the midcycle peak in women’s sexual desire.

 

Remember how SIberian Rhubarb focuses on the ERbeta receptor?

Researchers have found genetic differences for this receptor tied to both female libido and lubrication: 

https://www.ncbi.nlm.nih.gov/pubmed/25385158/

Check out CBD and Orgasm to really understand what's going on!

Siberian Rhubarb ERr 731 and bladder issues 

Siberian Rhubarb ERr 731 result:    -1.4 points (out of 4 total)
Placebo Result:  -0.0 points 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335

In hindsight, bladder and incontinence issues were the first sign of approaching perimenopause.

Years in advance...if I had only listened.

That's a telltale sign of progesterone lessening since it goes first (can start in late 30's and early 40's).

The urinary tract is under the control of female hormones which makes sense since they both (reproductive tract) start from the same tissue in the embryo.

As for estradiol: 

In addition estrogen deficiency occurring following the menopause is known to cause atrophic change and may be associated with lower urinary tract symptoms such as frequency, urgency, nocturia, urgency incontinence and recurrent infection

 

As for perimenopause (kicks off in full pace with final period)

Epidemiological studies have implicated estrogen deficiency in the aetiology of lower urinary tract symptoms with 70% of women relating the onset of urinary incontinence to their final menstrual period. 

https://www.ncbi.nlm.nih.gov/pubmed/24336244

The key word above is atrophy or "to wither".

To lose vitality!

We've discussed quite a bit how estradiol is pro-growth and this is no exception.

There's a downside to losing this pro-growth aspect of estradiol and we see it in MRS categories like this.

 

It's also interesting that there's less effect on "growth symptoms" relative to the mood changes and hot flashes (by default, a mood issue with serotonin control) from Siberian Rhubarb.

ERalpha activity is more pro-growth.

We'll discuss maybe a "middle way" to get the best of both worlds.

A related issue (with similar effects)...vaginal health!

Siberian Rhubarb - ERr 731 and Vaginal dryness 

Siberian Rhubarb ERr 731 result:    -.8 points (out of 4 total)
Placebo Result:  -0.0 points 

Scale 1-4 on MRS scale - https://www.ncbi.nlm.nih.gov/pubmed/16894335

This is also a function of atrophy or loss of replenishment (growth in the estradiol parlance).

It had the lowest improvement scores of any of the MRS categories at .8 (almost one point out of 4).

Placebo had zero!

You can't be tricked into building tissue!

We saw above in the libido section how ERbeta activity does have an effect on lubrication so 1 out of 4 is still a big deal.

 

Needless to say, this has a direct effect on libido for women and any benefit here will drive that score.

Finally, a topic close to my heart (feet, actually).

Joint and muscular discomfort 

Siberian Rhubarb ERr 731 result:    -.1.4 points (out of 4 total)
Placebo Result:  -0.1 points

 

1.4 points out of 4 improvement.

That's more like it!

We discussed out estrogen has its hands everywhere in the body.

There are estrogen receptors on your ligaments, tendons, cartilage, etc.

 

Just pay attention to the next time you see a woman walking around in a boot.

Let me guess...she's in her 50's or 60's.  Start to notice it.

Anyway...don't take our word for it: 

Beyond the known relationship between estrogen and bone, it directly affects the structure and function of other musculoskeletal tissues such as muscle, tendon, and ligament. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341375/

A primary complaint with menopause is loss of skin and hair "vitality".

This is primarily due to estrogen's pro-growth replenishment of collagen.

That same collagen (just lots more of it) is key to bone, joints, tendons, and the like.

In these other musculoskeletal tissues, estrogen improves muscle mass and strength, and increases the collagen content of connective tissues. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341375/

As for joint issues, the signs are equally present: 

Consistent with a role for estrogen in regulating musculoskeletal function, menstruating women suffer more ACL ruptures than men (Shultz et al., 2005, 2011), and menopause is characterized by increased risk of musculoskeletal injury

 

Read that article...it's an exhaustive list of how estrogen works with the mechanics of your body.

Then there's autoimmune and arthritic pain.

 

One study looked at women who used hormone replacement versus those that didn't for osteoarthritis: 

Ever hormonal replacement therapy users were at decreased risk of OA, the OR being for ever users in comparison with never 0.73 (95%CI 0.69-0.78).

 https://www.ncbi.nlm.nih.gov/pubmed/14585523

.73 or a 27% reduction in risk.

There's a fascinating and very complete analysis of ERa and ERb effects on autoimmune progression.

Keep in mind that most of our modern diseases are autoimmune in nature.

Interestingly, women are hit with 80% of diagnosis....usually in their 40's or 50's.  Sure it's just a coincidence.

The net net is this: 

• The anti-inflammatory effect of estradiol appears to be ERalpha-based
• The neuroprotective effect appears to be ER beta based (where Siberian Rhubarb) operates.

 

This is important for pain associated with the nervous system (Fibromyalgia, Regional Pain Complex, etc).

As researchers found while looking at ERb knockout mice: 

Protection from Neuropathology Is Mediated by ERβ 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976208/

Both are very important to the physical and nerve side of pain for women in perimenopause.

Check out CBD versus Tylenol for pain to understand the pain pathway.

Also, CBD and neuroprotection here.

Okay...we covered a lot.  We'll break these out eventually to entire articles on each.

Let's look at some common questions asked about Siberian Rhubarb.

Does Siberian Rhubarb boost estrogen? 

The next three questions all revolve around this key concept.

What's the effect of ERr 731 on estrogen levels?

There isn't one.

It doesn't boost estrogen in any of its forms (E1 - Estrone, E2 - Estradiol, E3 - Estriol).

 

It's technically called a SERM or Selective Estrogen Receptor Modulator.

It can open the door (to genes) that estrogen opens...primarily the ER beta door.

There are no reports of elevate estrogen levels from Siberian Rhubarb.

It's a substitute teacher when the real teacher (estrogen) is out but only in a few subjects (the ER beta ones above).

 

As studies confirmed: 

A lack of observed increases in progesterone and 17β-estradiol also suggest safety for breast and endometrial tissue 

https://pdfs.semanticscholar.org/a188/3e071695213724c1f9df258910481d6c2ae7.pdf

Which brings up a good question...can we just take Siberian Rhubarb?

Is Siberian Rhubarb an alternative to hormone replacement? 

Yes.  Partially.  But based on the new research, HRT bioidentical and oral is the way to go.  Work with your naturopathy (doctors are pretty oblivious about the importance of hormones from our experience). 

Remember that there are two receptors with very different effects in the body: 

• ER alpha is pro-growth, anti-inflammatory
• ER beta is  pro-maintenance and neuroprotective

 

They can oppose each other or work the same depending on the tissue.

It's complicated after all!

So...we can see from above that Siberian Rhubarb address many of the MRS symptoms above.

That being said, there are powerful effects of progesterone and ER alpha for health and wellness.

One option might be to look at pregnenolone for the progesterone side.  Check out pregnenolone review to understand why.

As for ER alpha, the purported downside has been the pro-growth effects on cancer (for people with genetic disposition and for synthetic) and blood clots.

 

Check out the full review on estradiol to parse out what the real risk it.  

Newer research is really turning this on its head such as the FDA trials for Bijuva (bioidentical oral estradiol and progesterone).  

Big review on that above that most doctors don't know about!

We need some pro-growth as the opposite is atrophy.

According to most of the medical world, it's perfectly fine that we wither away but not to us!

My ideal situation?? 

• Bioidentical estradiol at a lower level (Estrace is an example)
• Siberian Rhubarb for ERb effects and protection against estradiol effects (the reason doctors prescribe estriol (E3) to begin with)
• Pregnenolone for the roughly 50 other steroidal hormones (DHEA's a big deal!)
• Bio-identical progesterone (Prometrium as an example)

 

Technically, we should be able to get the progesterone (and even some estradiol) from the preg but you need to run hormone panels to see how you progress.

Worst case, Siberian Rhubarb is an insurance plan against estradiol's progrowth ways AND it helps with symptoms.  Bonus.

 

Next up.

Can you take Siberian Rhubarb with hormone replacements? 

We should expect that the two will be additive.

Meaning...if Siberian Rhubarb is opening ER beta doors, that leaves more estradiol available.

We really need research on this front.

It may be that Siberian Rhubarb just blocks ER beta activity (since it's locked in).

It might mean you can get away with less bioidentical estradiol! (synthetic is a no-go).

Your doctor should love that since they've been told how dangerous it is since 2001.

Again, check out the research here.

Ultimately, watch your labs and find the right balance (which will likely change as perimenopause progresses into menopause).

 

Work with your doctors and know your labs!

Speaking of studies?

Are there long term studies on Siberian Rhubarb? 

Thank goodness for the Germans.

Unlike the US where a product can be brought to market first and safety tested after (the guinea pig method), Germany requires strict testing prior to market entry.

 

Extensive studies.

In fact, the reason we focus on ERr 731 formula is that this ingredient make-up and ratio is what underwent extensive testing.

We're all about the research (in case that wasn't obvious).

We want to focus on two criteria with Siberian Rhubarb ERr 731: 

• Long term safety
• Long term effectiveness

 

Let's look at both.

First, there was a study at 1 and 2 year markers for ERr 731 Siberian Rhubarb.

Good news on both fronts.

First, in the first 48 week results: 

Women who received placebo during the RCT and started taking ERr 731 in OS I reported a significant decrease in menopausal symptoms. 

https://www.ncbi.nlm.nih.gov/pubmed/18978638

This trend continued in the second 48 weeks: 

The symptom scores further decreased slightly in all women during OS II. 

 

As to the safety concern: 

There was no clinically relevant change in safety parameters, and no adverse events were observed with relation to the long-term use of ERr 731.

 

Thank you Germany!  (Ummm….FDA, maybe take a page from that playbook??)

A graph shows these results here: 

https://pdfs.semanticscholar.org/a188/3e071695213724c1f9df258910481d6c2ae7.pdf

Interestingly, when you look at the graph, there's a fast and significant drop in MRS symptoms by the 12th week. 

• Start - MRS rating of 34
• Month 1 - MRS rating of 27
• Month 2 - MRS rating of 20
• Month 3 - MRS rating of 12

 

It then starts to level out and end around 6-7.

Most importantly for our discussion is that it stays level over the course of the 2 year window.

This is important since the body/brain can normalize or adjust to outside inputs across a range of different drug classes.

 

See CBD versus SSRI or CBD versus Benzos for an example.

The brain does the same thing for THC which is why there's a risk for addiction (partially).  See CBD to protect against THC here.

The fact that long term studies of Siberian Rhubarb do not show this rebound effect is intriguing.

We're familiar with this balancing result from CBD and cannabinoids which makes us even more excited.

We'll look at that below.

This is one long term study but Germany has approved use since 1993 officially.

They have data on 140 million daily doses which we'll look at below in the safety section.

 

That's the long of it...how about the short of it?

How long does it take for Siberian Rhubarb to work? 

The study above is handy on this question.

I felt an almost immediate effect...with 1-2 days.

Anxiety was better.  Sleep was deeper.  Mood improved considerably.

Keep in mind I had already been on bioidentical progesterone for about 2 years now (really helped in the beginning), Bi-est (estradiol/estriol) for about 12 months, pregnenolone for about 2 months.

 

To see such a marked effect above and beyond what I was already doing is the reason we're even writing this.

I would so much love to turn back time and start with Siberian Rhubarb and Progesterone (pregnenolone first) when this all started.

I can't tell you the amount of suffering I could have avoided over a 2 year period (see my story here).

If we can help a few million women avoid this death trap, this is all worth it.

I digress...back to how fast it works.

You can see from the study above that in month 1, the total (all 11 categories) MRS score dropped from about 34 to 27.

 

That's 6 points or almost 20%

That drop accelerated in the 2nd month to a roughly 7 point drop.

That's a further 26% from month 1.

In month 3, the scale drops even faster from 20 to 12 roughly.

8 points!

It continues from there but the first 3 months shows a sizeable drop from 34 to 12 in 3 months.

This obviously depends on where you are in perimenopause and how your system reacts.

Again, I felt differently almost right away.

 

Let's look at an interesting side note.

The connection between Siberian Rhubarb , Resveratrol, and the endocannabinoid system 

We don't whant to go too deep here (in fear of falling down the rabbit's hole) but it's worth bringing up.

Technically, the primary class of chemicals that drive Siberian Rhubarb's effect on the estrogen pathway is called a stilbenoid.

It's a type of chemical made by plants.

Structurally, rhapontin is very similar to another stilbenoid, resveratrol.

Resveratrol is the chemical that made all the buzz a while back for anti-aging and anti-cancer.

For example, they both had liver-protecting effects after exposure to alcohol: 

Trans-resveratrol alone and hydroxystilbenes of rhubarb (Rheum rhaponticum L.) root reduce liver damage induced by chronic ethanol administration

https://www.ncbi.nlm.nih.gov/pubmed/19067386

 
CBD has equally powerful effects to protect the liver from alcohol.  (hmmmm)

Look, after all our research, certain chemicals have an ability to push the balance in a system but not overrun it.

CBD falls in this category (no reports of overdose even tested at ridiculously high levels)

Curcumin is another one that seems to balance without pushing in one direction

Then there's Siberian Rhubarb.

The Germans tested it at ridiculously high levels and with no adverse reactions.

You can die from drinking too much water!  This is interesting to us.

 

In implies feedback mechanisms to contain effects within certain bounds.

That's the entire role of the endocannabinoid system.

In fact, newer studies are looking at SERM's like those found in Siberian Rhubarb and interaction with CB (endocannabinoid) system receptors as the anti-cancer driver: 

Indicative of a potential ER-independent target, reports demonstrate that tamoxifen binds to cannabinoid receptors (CBRs)  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177629/

We did a huge review of CBD and turkey tail for cancer.

The connection has already been found for resveratrol (same family as rhapontin) and curcumin: 

The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid 

https://www.ncbi.nlm.nih.gov/pubmed/19359525

Let's just say we won't be surprised when researchers find the connection between Siberian Rhubarb and endocannabinoids.

For example, there's a curious situation where women who wait till later to start hormone replacement have poorer outcomes later on.

 

This was a big part of the flaw in the original 2002 WHI study that scared millions of women from hormone replacement.

When researchers went back in and looked at the study by age of start of hormone replacement, they found a much better effect when women started earlier in the perimenopause/menopause transition.

Now...look at that in relationship to a study with endocannabinoids: 

The present study demonstrates that an HT time window in mice can be prolonged by cotreatment with a CB1 agonist, implying a potential strategy for HT in long-term menopausal women. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546454/

To translate (Please!!), when they stimulated the endocannabinoid receptor (Anandamide will do nicely), it extended the window during which hormone replacement would be successful!

What boosts anandamide levels?

Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/

That's CBD! 

 

 

This is important if you're starting Siberian Rhubarb or hormone replacement later in the menopause transition.

After all, the estradiol and endocannabinoids are intimately intertwined!

On the main question of the day that brought most women to Siberian Rhubarb...safety. 

Is Siberian Rhubarb safe and protective against estrogen and cancer? 

The whole reason we started researching Siberian Rhubarb ERr 731 was for this reason.

There's a long and tumultuous battle for the hearts and souls (not to mention brains) of perimenopausal women.

Some doctors are saying HRT is protective against the ravishes of hormone drops while others are saying it causes…

Cancer.

  

Here's the quick take away. 

ERa activity is pro-growth and that growth in some women (based primarily on genetics) may influence estrogen-related cancers (usually breast and endometrium).

 

Estriol (E3) is usually recommended as a protective layer to offset this "proliferation" driven by estradiol via the ER-alpha activity.

We just learned how Siberian Rhubarb - ERr 731 also focuses primarily on the ER-beta receptor.

What are the effects of estrogen-related cancers?

First the animal studies.

They actually looked at genes being turned on and off relating to the estrogen cancer pathway: 

In this study design, neither an uterotrophic response nor a modulation of proliferation marker genes on mRNA level has been observed as a response to the long-term application of the rhapontic extract. 

https://www.ncbi.nlm.nih.gov/pubmed/21946530

Uterotrophic just means to cause the growth of tissue in the uterus.

You would expect to see the actual genes get turned on immediately if there was an effect there.

 

Remember, the latest review didn't show this result or thrombosis with bio-identical oral estradiol and progesterone!

The testing is getting pretty sophisticated now.

They can drill down to genes, metabolites, and really minute signs of bad effects. 

Additional genotoxicity studies for mutagenic potential—including the Ames test, cell mutation assay at thymidine kinase locus of L5178Y cells, micronucleus test for bone marrow cytotoxicity, and immunotoxicity analysis of leukocytes—also showed no relevant variations with ERr 731.  

https://pdfs.semanticscholar.org/a188/3e071695213724c1f9df258910481d6c2ae7.pdf

Multiple and minute pathways showing no ill effects.

In bigger studies, they're finding similar results across a range of different pathways: 

There were no differences in gynecological findings including endometrial biopsies, bleeding, weight, blood pressure, pulse, and laboratory safety parameters between the treatment groups. 

https://www.ncbi.nlm.nih.gov/pubmed/16894335

Interestingly, the other risk we always get warned about with estradiol is blood clots or thrombosis.

Siberian Rhubarb is actually antithrombotic and anti-allergenic: 

These results suggest that rhaponticin, in the rhizome of Rhei Rhizoma, is a prodrug that has extensive antiallergic and antithrombotic properties. 

https://www.ncbi.nlm.nih.gov/pubmed/12214867

The net net for Siberian Rhubarb and cancer is this: 

ERa has been shown to be implicated in uterine hyperproliferation and the maintenance of breast cancer, whereas in tissues where both ER subtypes are expressed, the ERb subtype acts as a negative regulator of ERa, offering protection against hyperproliferation and carcinogenesis. 

http://europepmc.org/abstract/MED/16894335

Again, I intend to use Siberian Rhubarb alongside reduced estradiol (bioidentical of course) for both symptom reduction AND as insurance for the small risks with estradiol (not synthetic and with progesterone).

Let's look at side effects.

Siberian Rhubarb side effects

This may be the best part of the whole review.

We could make it short and sweet but we'll look at the research of course.

First, big studies...

 

12-week randomized study: 

No adverse events were classified as being related to the investigational medication. 

https://www.ncbi.nlm.nih.gov/pubmed/16894335

The 6-month study: 

One adverse event was reported that was assessed as having no relation to ERr 731 intake. 

https://www.ncbi.nlm.nih.gov/pubmed/19043936

Two animal studies looked at ridiculous levels of Siberian Rhubarb (again, Thank YOU Germany!).

Based on these results, the no-observed-adverse-effect-level is 1000 mg/kg BW/day. No pathological findings were detected following ERr 731 treatment demonstrating that the toxicological risk for women taking ERr 731 regularly is extremely low. 

http://europepmc.org/abstract/med/18267351

That's over 14,000 times the standard dose of 4mg for a woman.

It's fascinating that these high doses don't have immediate side effects.

There's a great study based on German required reporting since 1993 through 2004 covering 140 million doses.

Out of 140 million doses, 124 adverse effect reports were made: 

The most common of those AEs were hypersensitivity, with 74 reactions, and gastrointestinal symptoms, with 47 reactions. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982646/.

In North America, 14 million prescriptions were made with the following results: 

The main complaints were gastrointestinal symptoms, with 23 cases, and failure to work as suggested, with 22 cases. 

 

So...upset stomach from taking it.

I personally had slight stomach issues when I took it with food of all things but the system is really sensitive (thank you histamines) to almost everything since perimenopause.

That went away after a week or so.

Online, there's some advice that the enteric coating requires a certain PH balance in the stomach so without food is best.

Others say with food.  You just need to test it for yourself.

When I take it on an empty stomach, no issues.

Which brings up a good question.

When to take Siberian Rhubarb

We saw above how anxiety was one of the top responders (MRS point movement):

A reduction of 2.2 points out of 4!

 

Now...we know that anxiety is intimately tied to GABA (as is the estrogen pathway).

GABA can make you calm, and then drowsy, and then sedated as amounts go up.

I definitely felt very calm and bordering on drowsy.

For that reason, I started to take it in the evening.

This can replace that dinner 1-2 glasses of wine many women are self-medicating with.

Oh...and alcohol...specifically wine...increases GABA!!

 

As do benzos...check out CBD and GABA for lots of info.

Test your system to see what works best. 

• With or without food
• Morning, afternoon, or night.

 

Watch your sleep response and adjust accordingly.

Where to buy Siberian Rhubarb 

This is the easy part.

You don't need a prescription and it's relatively inexpensive.

I purchase mine through Iherb here since they will give you back the money with purchases.

 

I wouldn't buy any supplement on Amazon.

There are just too many stories of Chinese companies repackaging all kinds of products with bogus ingredients.

Flawed socks are one thing.  Flawed supplements or vitamins that go in your body??

Look...they can't even get the prescriptions untainted these days (see blood pressure meds contaminated from China or the new one on gas relief tabs).

LifeExtension has a good brand called Menopause 731 available here and that's the one I tested.

 

 

 

 

Related Research:

Progesterone review

Why some women get hit so hard by perimenopause

Perimenopause versus Menopause

Vitamin D and perimenopause

 

Let us know how it works.  Take care of yourself.  Let's help each other through this.

 

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.