We've completed our review of Metformin and we immediately went on it!
Looking at its effects on everything from insulin sensitivity to cancer to remodeling the gut, it's hard to argue that it's not THE closest thing we have to a silver bullet (till CRPSR comes online).
Then, there are the longevity studies.
Simply put, this is probably the biggest thing we've seen since CRISPR.
We'll get into the actual studies below but as part of that research, we came across Berberine.
Berberine appears to influence the same powerful pathways that metformin affects.
Without the doctor's prescription and "potential for made in China" issues we see across the pharma space these days (Xanax latest to drop).
Here's the deal...most doctors will not prescribe metformin for you just to offset cancer and/or reverse epigenetic aging.
Forget weight-loss and pain!
They'll look at you like you're crazy.
Let's see if berberine might be a good substitute.
Maybe even better?
We'll find out.
We're going to cover these topics:
- What is Berberine
- How does Berberine work
- Berberine and the AMPK pathway
- Berberine and glucose and insulin
- Berberine and cancer
- Berberine and pain
- Berberine and the heart
- Berberine and hormones including PCOS and testosterone
- Berberine and oxidation and/or inflammation
- Berberine and anti-aging
- Berberine and gut bacteria
- Berberine and weight
- Berberine safety
- Side effect of berberine
- Berberine and Vitamin B12
- How to compare berberine and metformin
- Can you take metformin and berberine together?
- Where to buy quality berberine
- Can you get berberine on Amazon safely?
Let's get started. Lots to cover and years to roll back!
What is Berberine?
Berberine is primarily an extract from various plants such as Goldseal, Goldenrod, and Barberry among others.
The extract has been used for 1000's of years in Chinese medicine.
It really gained attention in the West around 1989 due to its ability to lower cholesterol.
Follow up studies showed that it had a pronounced effect on dropping cholesterol in the body around 2004.
After all, we have billions in Statin sales to protect even though they may degrade muscle tissue function.
As researchers put it:
Furthermore, the lipid-lowering effect of berberine is comparable to those conventional lipid drugs but with low toxicity.
From there, a range of effects has been discovered which mirror what metformin does.
- Reduces cholesterol
- Reduces sugar production
- Improves insulin sensitivity
- Anti-tumorigenic (anti-cancer)
- Helps to offset weight gain and obesity
- Helps with hormone-related issues such as PCOS
- Helps with mood
- Remodels gut bacteria in a positive way
- Helps with pain threshold
- Potentially reverses epigenetic aging
Did you catch the last one?
This is critical since almost any health issue is directly tied to aging.
This will make sense once we look at the pathways that berberine shares with metformin.
Let's go there now.
How does Berberine work
There appear to be two very crucial pathways that act as cascades across different systems in the body.
Berberine is showing similar effects to metformin on the following:
- Reduces Complex 1 mitochondrial production (we'll explain in a bit...we promise)
- Boosts the AMPK pathway
These two may be intertwined and there's some discussion as to which comes first.
As with everything in the body, it all comes down to reproductive success.
Basically, Berberine triggers a pathway designed as a sort of genetic hibernation.
Essentially, AMPK is triggered when things are tough.
- Lack of oxygen
Bad times! We have a massive review on AMPK and longevity.
Definitely not the right time to have babies.
Remember, ancient pathways like AMPK date back almost to the beginning of life.
We share it with all eukaryotes (has a nucleus in the cell) which puts its date back to about 2.7 billion years ago!
Nature holds onto tools that are successful and apparently, AMPK is critical.
Basically, when the environment is very poor for having offspring, this system is triggered as a sort of freeze ray.
As a cellular energy sensor, AMP-activated protein kinase (AMPK) is activated in response to a variety of conditions that deplete cellular energy levels, such as nutrient starvation (especially glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex.
Get our house in order and hope to live (and reproduce) for another day.
This happens at a cellular level.
The body becomes much more efficient and effective.
Cellular housekeeping gets ramped up as we're now in survival mode.
Part of this is the mitochondria effect.
In fact, it may be the first pin to drop according to research.
Mitochondria are literally the power plants of every cell in your body.
They're actually ancient bacteria that we kidnapped (negotiated with??) to make our energy in return for a safe place to be.
Power plants can be dirty as there's lots of waste product from making any type of energy.
Cellular energy is no different!
This waste is the oxidation (basically free oxygen in different forms) that can slice and dice DNA and healthy tissue.
It's what we're trying to eliminate with antioxidants!
Metformin and Berberine both slow down one of the most wasteful pieces of this energy production process.
Complex 1 as it's called.
Finally, berberine (like metformin) remodels the gut bacteria in your microbiome.
All-new research is pointing to the gut as a key component to almost every health issue.
Just yesterday, a drug was approved for dementia. One of the first ones yet.
What does it do? It remodels the gut which affects protein buildup in the brain!
We'll look at that further below but it's interesting.
For metformin and berberine to affect AMPK and mitochondria (which may have shared cause-effect relationships) is one thing.
For them, both to remodel the gut in a very specific way speaks to an inherent chemical similarity.
Here's the net takeaway before we dive deeper down…
The reason metformin and berberine appear to have such widespread and frankly, slightly fantastic effects is that they found a way to push on a very basic and ancient lever in the body.
Pull a block out from the bottom of the pyramid and the whole thing above comes down.
Let's dig deeper into these pathways to show just how powerful they are.
Berberine and the AMPK pathway
This really is the critical effect that drives so much else downstream.
Just a take a look at the knock-on effects from activating AMPK:
The net effect of AMPK activation is the stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, activation of adipocyte lipolysis, and modulation of insulin secretion by pancreatic beta-cells.
We'll decipher a bit.
First, it's the powerhouse behind the keto diet.
Again, the body sees that as a form of starvation (selectively anyway) and responds accordingly.
Then look at the reduction in making cholesterol, fat (lipogenesis), and burning up fat.
Again, getting ready for harsh times.
The most important piece there might be insulin modulation.
Forget diabetes and obesity (we'll touch on later since that's the actual basis for metformin prescriptions)...insulin is a master-signaler across the body and brain.
AMPK is essentially an energy sensor.
If it senses energy is low, it flips switches across our body to run as efficiently as possible.
It even targets systems to clear out bad (cancer, pre-cancer) and slacking (senescent) cells.
That's called mTOR and we'll look at it as well.
This may be key to its anti-aging effects as all those senescent cells bring down the whole neighborhood with inflammatory leakage.
Is there a shortcut besides starvation and lack of oxygen?
The beneficial effects of BBR are attributable to its effect as an AMPK activator.
The current research points to berberine and metformin's ability to downregulate energy production in that specific area of the mitochondria.
AMPK, being an energy sensor, sees this and responds as it would to any drop in energy (drought, famine, etc).
Look...some of the biggest supplements you'll find today owe their effects (at least partially) to this pathway:
Resveratrol, quercetin, epigallocatechin-3-gallate, and curcumin target and inhibit the mitochondrial F1F0–ATPase/ATP synthase,72, 73 whereas berberine is associated with the inhibition of respiratory chain complex I.
Resveratrol was all the rage for longevity. Quercetin is a powerful antioxidant you can find down at Safeway. Curcumin is literally at Costco.
They block a piece of the mitochondria machinery upstream while berberine downregulates it's completely (like metformin).
If you read the review of Metformin, you'll see why it's so powerful since it has been around longer and there's more research.
The key is this...the two appear to affect the same core pathway.
Let's look at a fascinating tie between the two in the gut.
Berberine and gut bacteria
This is fascinating.
Both metformin and berberine have very similar and positive effects on the gut bacteria make-up.
Specifically, …they boosted strains tied to health such as Akkermansia muciniphila
Yes, it's not dinner-table talk yet but this little guy is impressive and potentially devastating to the billion-dollar autoimmune pharma market.
So...it's effects at a summary level:
The presence of A. muciniphila has been associated with healthy intestine and its abundance has been inversely correlated to several disease states.
Okay...that sounds great and all but so what.
In conclusion, our results demonstrate that A. muciniphila adheres to the intestinal epithelium and strengthens enterocyte monolayer integrity in vitro, suggesting an ability to fortify an impaired gut barrier.
People, if you dig deep enough into any autoimmune disease (including dementia, arteriosclerosis, diabetes, etc, etc), you'll find the enemy comes through the intestinal or mouth barrier gate.
Supporting our gut barrier is job #1
In fact, berberine might even be better than metformin at this?
Sixty out of the 134 OTUs were decreased by both drugs, while those belonging to putative short-chain fatty acids (SCFA)-producing bacteria, including Allobaculum, Bacteroides, Blautia, Butyricoccus, and Phascolarctobacterium, were markedly increased by both berberine and, to a lesser extent, metformin.
If you read the laundry list of effects from akkermansia (reduce fat, better insulin, etc), we wouldn't be surprised if the tail is wagging the dog (gut bacteria drive mitochondria and AMPK pathways).
In fact, berberine and metformin are not absorbed that well through the gut leading researchers to postulate:
As berberine is poorly absorbed into the bloodstream from the gut, modulation of gut microbiota has been hypothesized as one of the mechanisms of its anti-diabetic effect.
There's some connection but the arrow of cause needs to be worked out but its effect on the gut barrier is clear:
AmEV treatment increased tight junction protein expression in Caco-2 cells and ultimately improved intestinal barrier integrity in a high-fat diet (HFD)-induced diabetic mice in an AMPK-dependent manner.
AmEV is the Akkermansia Municipalia. Tight junctions are the Holy Grail for gut health. AMPK...well...we know what that is now.
And back to berberine, besides having a bigger effect on the positive gut bacteria changes than metformin?
Look at the results in the gut bacteria comparing high-fat diet mice and healthy controls after berberine is administered:
As revealed by taxon-based analysis, significantly higher abundances of the phyla Actinobacteria and Verrucomicrobia were observed in the HFD group than in the NCD group (P<0.05), and these higher abundances were completely reverted by berberine co-administration.
Completely reverted. As if they hadn't been on a high-fat diet (in terms of gut bacteria).
All of this filters down into larger systems that govern health.
First up...sugar, insulin, and fat.
Berberine and glucose and insulin versus metformin
One of the primary effects of both AMPK activation and gut remodeling is on our entire energy complex.
This involves sugar, insulin, and fat of course.
First, how did berberine compare versus metformin?
It was found that the hypoglycemic effect of berberine is comparable to that of metformin. The level of hemoglobin A1c (HbA1c), fasting and postprandial glucose decreased by 7.5%, 6.9%, and 11.1% respectively at the end of the trial.
Okay...HA1C is the current dividing rod for cardiovascular health. It's a measure of sugar-damage blood by the way (see glucose review).
They referenced a study that compared metformin and berberine across a range of metabolic markers for newly diagnosed Diabetes II patients.
A reduction in:
- Hemoglobin A1C
- Fasting blood glucose
- Insulin resistance index
- Total cholesterol
In fact, in another study with 1000's of participants, berberine was as effective as other lipid-lowering drugs such as statins:
In the comparative study between berberine and oral lipid-lowering drugs, there was no statistical significance in reducing the level of TC and LDL-C, but berberine shows better effect in lowering the level of TG and raising the level of HDL-C.
The same was found for blood pressure which we'll cover in the heart section.
Let's not forget the gut effect we talked about above:
Several reports indicate that Akkermansia muciniphila affects glucose metabolism, lipid metabolism, and intestinal immunity and that certain food ingredients such as polyphenols may increase the abundance of Akkermansia muciniphila in the gut.
- Sugar use. Check!
- Fat (lipid) creation. Check!
Again, this also comes down to AMPK activation.
To be noteworthy, via activation of AMPK, berberine can stimulate glucose uptake in muscle, liver, and adipose, and inhibit gluconeogenesis in the liver by downregulation of gluconeogenic enzymes (phosphoenolpyruvate carboxyl kinase and glucose-6-phosphatase).
As for fat creation and usage?
Berberine has been shown to be a potential tool to treat obesity by downregulation of adipogenesis and lipogenesis.
Lipogenesis is the technical word for making more fat!
When AMPK is activated (times are tough), you don't make fat. Times are tough!! You use fat since it's a store of energy!
As we mentioned before, your energy system balance is critical to many different systems.
For example, the human growth hormone has an inverse relationship with insulin.
More insulin means less growth hormone.
This is bad as we age.
Speaking of bad as we age….
Berberine and cancer
AMPK is all about cellular housekeeping and efficiency.
Part of this is to get rid of the dead weight.
Bad cells or cells that have the potential to go bad.
Keep in mind that our bodies get "pre-cancer" all the time.
We have entire systems (immune system) design to detect faulty cells and destroy them.
It's generally called autophagy...basically cell suicide.
When there's too much damage (such as oxidation from power-production) or too much energy going elsewhere, cancer can make its escape into being.
There are extensive studies on metformin and preventing (even slowing down) cancer.
It was a "side effect" of people taking metformin for diabetes.
A 30% reduction in all types of tumors!
Those patients who had cancer also did better with metformin.
This really points to mTOR as a critical player.
mTOR is a pro-growth, pro-cellular creation.
Metformin actually downregulates mTOR activity which has anti-tumor properties.
And berberine's effect?
Berberine has been shown to exert antitumor effects through multiple routes, for example, suppressing cell proliferation, metastasis, and angiogenesis in numerous tumor types, including breast cancer, gastric cancer, melanoma, and hepatoma.
So...like metformin, does berberine affect mTOR pathways in the same way?
Berberine decelerates glucose metabolism via suppression of mTOR‑dependent HIF‑1α protein synthesis in colon cancer cells.
This is part of how berberine is toxic to cancer cells as they went on to say.
This isn't surprising considering AMPK's powerful effect on cancer:
The current evidence suggests that AMPK can act as a tumor suppressor by modulating inflammation, opposing metabolic changes that occur during tumorigenesis and directly inducing cell-cycle arrest.
Newer research is even pointing to other pathways outside of AMPK for metformin and berberine alike.
One interesting candidate is P53.
Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells.
The beauty of these effects is that they're not specific to one type of cancer.
For example, even the triple-negative breast cancers which don't respond well to any intervention show promise.
There's a range of different pathways all in play but here's one example:
Berberine inhibits NLRP3 Inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cells.
We're talking about a baseline level master system with AMPK.
Very exciting stuff.
Let's move on to pain.
Berberine and pain
This seems like a strange topic for a chemical usually tied to metabolism and GI tract issues.
It mirrors metformin's impressive results on this front.
Especially for chronic or neuropathic pain.
The studies are coming in on this front and of course, they start in the gut:
Results: In mouse models, berberine prolonged GI transit and time to diarrhea in a dose-dependent manner, and significantly reduced visceral pain.
Research is here.
Interestingly, they found this pain effect was via the mu and delta-opioid receptors.
That's an obvious channel for pain but it's not the only one.
TRPV is a well-known pathway for pain, especially neuropathic pain or pain that gets "stuck" in our nervous system.
In one study where berberine reduced this type of pain, researchers pinpointed a specific effect in this channel:
Moreover, berberine administration reversed the mRNA and protein expression of TRPV1 in dorsal root ganglion neurons after peripheral nerve injury.
This is important as it brought down pain response both in the nervous system (dorsal root) and at the specific location.
New research is pointing to this "peripheral" pain as a powerful effect on chronic pain.
Also, check out our review of low dose naltrexone for this entire system.
Speaking of Tylenol (and the whole litany of NSIAD's), berberine's effect on the COX2 pathway is equally compelling:
Histopathological changes were reduced and the expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) were markedly attenuated by berberine 10 mg/mg.
In danger of going too deep into the weeds, let's just explain that all those are members of an elite team of inflammatory damage and pain in our bodies when chronically elevated.
The bad and ugly of inflammation all reduced by berberine.
As expected, berberine is showing the same effects on pain pathways as metformin.
Next up...a sorta important system. The cardiovascular system.
Berberine and the heart
If you consider the effects on all the cardio-related markers affected above (cholesterol, blood pressure, insulin, etc), you would expect to see overall positive effects for both metformin and berberine.
Let's go there.
Check out the metformin review for its effect on cardiovascular health.
Berberine is actually better researched here since it's been in use in China and studied more extensively.
Intravenous infusion of berberine in 12 patients with heart failure refractory to digitalis and diuretics led to an acute decrease in peripheral resistance and an increase in cardiac index.
Goodness. The standard medicines were not working and berberine improved heart function in people with heart failure.
If you look at the effects, it's across the board in heart dynamics.
That set up off researcher's interest.
Then you have the balancing of fat creation, use, and removal.
For example, with triglycerides:
The majority of the studies have shown a reduction of blood TAG ranging from 17% to 22%, while high reductions (28%–42%) are seen in a few studies in patients who are diabetic and have dyslipidemia or metabolic syndrome.
Do you see how the more out of balance, the higher the result?
We love seeing that as it speaks to CBD's strength which is to support balancing (such as with serotonin).
The beauty is that it does this without the toxicity of the statins and other lipid-lowering medications.
Via complicated mechanisms (the body's ridiculous), berberine exerts positive effects on blood pressure directly:
Results of the study suggest that chronic administration of 100 mg/kg/day berberine not only lowered blood glucose but also reduced blood pressure and improved vasodilation in diabetic rats.
Let's just finish this section with the following catch-bag of heart-related issues:
Recent researches showed that BBR had the effect of anti-heart failure, anti-hypertension, anti-hyperlipidemia, anti-insulin resistance, anti-arrhythmias, and anti-platelet aggregation.
There's plenty of studies there to keep you busy to your heart's delight (we're so clever).
Now, to a totally separate system.
Berberine and hormones
Here's where we geek out a bit.
Look, we spend about 3-4 hours a day buried in research.
95% of that research is on CBD since that's our first love but when we come across a substance with truly amazing abilities to reduce suffering safely, we have to take a detour.
There's no real benefit to us other than...we want to use it ourselves!
Why bring this up now?
We dreaded studying hormones with CBD.
They're so ridiculously complicated...maybe second only to our immune system.
For a substance like berberine to have positive effects on this intractable system is simply...fascinating.
Unfortunately, the whole purpose of every system in our body is successful reproduction.
Don't kid yourself...the genes are indeed selfish.
The hormone system has to work well as the star player in this goal.
What does berberine have to say in this story (similar to metformin, we may add)?
We'll touch on just a few (albeit powerful) examples of its effect:
- Berberine and PCOS (polycystic ovarian syndrome)
- Berberine and testosterone
There...one for each gender.
First, for the ladies.
Berberine and PCOS
PCOS is essentially an issue of hormone imbalance.
It may stem however as a result of insulin resistance (remember, we said insulin is a powerful signaller across the body).
The correlation is significant:
Overall, insulin resistance and the compensatory hyperinsulinemia affects some 65–70% of women with PCOS (3,4), with 70–80% of obese (BMI >30) and 20–25% of lean (BMI<25) women exhibiting these characteristics.
Further studies have linked the interplay of insulin, hormone imbalance, and PCOS.
The benefits of metformin for PCOS have been known for some time now:
Importantly in PCOS metformin for up to 6 months reduced hirsutism and in most studies significantly reduced androgen levels, with reductions in testosterone being between 25–50%.
Again, you can check out the metformin review for PCOS here.
What about berberine versus metformin for PCOS markers?
No significant difference was found between berberine (BBR) and metformin (MET) on alleviating insulin resistance, improving glycolipid metabolism, or reproductive endocrine condition.
So...they work the same across these contributors.
The big one is the last one…" endocrine condition". Translated: hormone balance and levels.
Remember how we said reproductive success is our gene's goal and it's a very complicated system?
Results of berberine on this highly choreographed danced for women with PCOS:
Zhang A.P.  found in a single-arm study that the ovulation rate of PCOS patients increased from 24.44% to 65.56% (P<0.05) after BBR treatment (300 mg, tid, 3 months).
More than double the success rate!
Mother Nature would approve.
Brand new research is pointing to gut barrier issues and bacterial infection driving PCOS. That's right in berberine's wheelhouse!
Berberine and testosterone
Now, there's a known effect in the women that have PCOS where they have increased testosterone levels.
Berberine has been shown to normalize this and offset the effects such as hair growth that accompany PCOS:
Importantly in PCOS metformin for up to 6 months reduced hirsutism and in most studies significantly reduced androgen levels, with reductions in testosterone being between 25–50%.
Too much testosterone (androgen) is a bad thing but not enough is equally bad...especially for men.
On one hand, berberine has been shown to downregulate testosterone but that's usually via studies on prostate cancer where excess testosterone is a bad thing.
There are also studies on how berberine brings down inflammation and damage in the testes to actually support hormone levels:
This is critical for male fertility:
BF (protected and treated groups) significantly improved the semen quality, oxidative stress, and inflammation associated with male infertility.
This is the balance thing we spoke of.
- Reduce when too high.
- Boost when too low.
And what about normal levels?
The administration of BF to healthy rats showed no significant change in the levels of GSH, testosterone, or albumin compared to the normal control group.
In fact, when they used a chemical to disrupt testosterone production, berberine rescued the system from this effect.
Como se dice...Goldilocks?
We look forward to more information and research.
Next, the root of all (physical) evil.
Berberine and oxidation and/or inflammation
Roughly 12,000 words investigating the powerful effects there.
Metformin and Berberine are no slouch in that area as well.
This isn't surprising since the AMPK pathway is their favorite tool.
AMPK is all about cellular efficiency and conservation.
Lean times require a tidy ship.
Let's look at a few of many (probably almost all) inflammatory pathways.
NF-κB and Berberine
That's not a droid in Star Wars. It's an inflammatory marker reflecting that we came in contact with bad stuff.
A laundry list of everything you're supposed to stay away from:
NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.
Too much of this result and there are implications to almost every class of disease you want to look at.
Look, we need NF-kB but our current environment is crying wolf.
Pesticides, chemicals, pollution, etc.
Remember how berberine tightens up our intestinal walls so that bacteria can't get through and escape into the body (the basis for auto-immune).
That's the "bacteria or viral antigens" in the last description.
When the gut barrier is not working correctly, NF-kB is the kind of responder that's unleashed...with lots of collateral damage.
That's plugging the hole at the beginning but berberine (and metformin) even have effects once inflammation gets started.
To cut to the chase:
We found that berberine suppressed NF-κB activation induced by various inflammatory agents and carcinogens.
Also, excess fat sets up a situation of low-grade, chronic inflammation.
By positively affecting fat creation (we'll look at berberine and weight below), we're bringing down the total "load" of inflammation across the body.
Berberine via activation of AMPK can exert an anti-inflammatory effect in adipose tissue induced by a high-fat diet.
As for oxidative stress, it's the same effect.
One example is a study where researchers induced high levels of oxidative stress and looked at berberine's effect on it:
In conclusion, the present study demonstrated that the treatment with berberine resulted in an obvious reduction of oxidative stress and GFAP-immunoreactive astrocytes in the hippocampus of STZ-induced diabetic rats.
Chronic, systemic inflammation is a hallmark of aging and aging disease.
Berberine and anti-aging
Just to show how powerful AMPK really is.
It can turn back the clock!
That sounds like salesly BS...we get it but new studies on metformin pointed the way.
This is brand new research that confirmed hunches from before.
The big study basically found that metformin used for 1 year time-reversed epigenetic aging by 2.5 years.
What is epigenetic aging?
Your genes haven't changed much since you were 18, 1, or even in utero.
Other than mutations along the way, the blueprint is the same.
The construction guys are just not as good.
The layer that sits on top of your genes and turns them on and off.
The difference between a 50-year-old body and a 25-year-old body is primarily in epigenetics.
That's why this study (reference below) is the biggest thing we've seen since CRISPR.
A review of the study is here:
DHEA, a steroidal hormone was also included.
In fact, another study looked at Metformin and DHEA with similar results.
We covered this in-depth with our metformin review but what about berberine?
First, most of the pathways of aging have something in common:
Most of these mechanisms converge on AMPK regulation on mitochondrial oxidative stress.
Hopefully, that sounds familiar by now!
There's also the integrity of DNA which is under constant assault...primarily from oxidation damage in the mitochondria energy-making process.
Berberine also shows an effect here:
Furthermore, RC can directly recognize and bind nucleic acids and various proteins, including telomerase, DNA topoisomerase, p53, NF-κB, MMPs and estrogen receptors, thereby can potentially alter aging-associated cellular processes.
We recognize a few of those.
- P53 was the pathway for cancer risk we discussed above.
- NF-XB is the inflammatory agent at play
Estrogen receptors? Very cool since perimenopause (crazy flux in estrogen) is what brought us to this line of study, to begin with (check out that story here).
The researchers then turn to the Drosophila, the fly used in so many longevity experiments.
Berberine was found to extend life span and energy:
Life span Berberine (1 mM) increased mean (by 27%), median (by 57%) and maximum (by 78%) life span of flies.
The study showed this effect was due to a pathway that involved tryptophan to kynurenine which is known to associate with aging.
We have multiple longevity deep dives:
- Yamanaka Factors
- CBD and longevity
- Tools for Longevity
- Pterostilbene and longevity
- Steroidal hormones and longevity
As for berberine, a quick teaser.
There's a chemical called IDO which results from the tryptophan to kynurenine process.
It's been directly tied to aging and cancer (as well as AMPK).
Berberine's effect here?
The ability of berberine to inhibit human preparation of IDO is stronger than that of a most powerful IDO inhibitor, 1-methyl-TRP.
We expect studies like that for metformin to show the same effect for berberine if not better.
This may speak to the wide array of effects across the body. All those issues are directly tied to aging!
Let's go North for a bit. To the brain.
Berberine and mental health including anxiety, depression, and schizophrenia.
Descartes really screwed us.
Separating the mind from the body was a critical failure that we're STILL trying to remedy.
The brain IS the body. All these pathways operate in our nervous system as well.
In fact, the brain is the largest user of energy (mitochondria activity) and the biggest producer of waste material (oxidation) by body weight.
Rogue oxidative agents (ROS) are extremely dangerous in the brain.
Let's look at just a few examples of berberine's effect on mental health:
- Berberine and anxiety
- Berberine and depression
- Berberine and schizophrenia
Two common. One very complicated and devastating.
We'll start where we started...with anxiety. Check out CBD and anxiety mechanisms here.
Berberine for anxiety
First, the poor animal experiments.
Their results on mice:
These results suggested that berberine at 100 mg/kg had a significant anxiolytic-like effect, which was similar to that observed with 1 mg/kg diazepam and 2 mg/kg buspirone.
What's diazepam? Just Valium...the pandora's box of benzo addiction (see CBD versus benzos here).
Wait a minute...a herbal extract had the same effect on anxiety-like behavior in mice as one of the most abused drugs ever marketed??
Buspirone is an SSRI, another class commonly used with its own issue (See CBD versus SSRI's).
How does berberine do this?
Anxiety usually is a question of GABA dysregulation.
That's why the benzos are so effective (temporarily)...they directly juice up GABA levels.
What does berberine do there?
Berberine alkaloids bind with the high‐affinity benzodiazepine site on the GABAA receptor.
Even more complicated is the role of dopamine.
Another study looked at rats exposed to a traumatic situation (analog for PTSD):
However, rats in the PTSD+BER30 group showed significant restoration of the time spent in the open arms of the maze compared with that of the PTSD group.
They actually showed that berberine normalized the dopamine levels (critical to brain function) caused by trauma!
And compared to the popular SSRI fluoxetine (Prozac):
After BER treatment, the levels of DA in the striatum also increased significantly to 256.80% of that in the PTSD group (p<0.05). The DA concentrations in the brain regions of rats receiving 10 mg/kg FLX were similar to those in rats receiving 30 mg/kg BER.
Goodness. So...equivalent measured responses to popular benzos and SSRI's.
People...this is incredibly exciting for a range of issues...especially addiction which warps dopamine function.
We can (and will) write an entire article on berberine and anxiety.
You really have to look at the new research regarding neuroinflammation and anxiety here.
Berberine and depression
We'll start with the current medical treatment of depression.
Primarily revolving around serotonin. We went through how SSRI's really work here (hint hint...BDNF via the endocannabinoid system) but for now, serotonin pathways.
A study tried to get to the bottom of the anti-depressant effects of berberine.
They found the following:
Chronic administration of berberine (5 mg/kg, i.p.) for 15 days significantly increased the levels of norepinephrine (29%), serotonin (19%) as well as dopamine (52%) but at higher dose (10 mg/kg, i.p.), there were no change in the norepinephrine (12%) levels but a significant increase in the serotonin (53%) and dopamine (31%) levels was found.
This is a big deal. You're talking about the key neurotransmitters tied to depression.
What's going on here?
Let's introduce MAO, the famous (infamous??) Chinese leader.
Just joking...MAO is a powerful chemical with ties to almost all mental health issues.
It's tasked with breaking down neurotransmitters like those above.
Too much activity and the system runs low in critical substances for your brain to work well.
What is berberine doing here?
Berberine showed significant inhibition of MAO-A and -B with IC50 values of 43.7 ± 1.1 and 7.4 ± 1.0µM respectively.
As for depression...even major depression's connection to MAO:
The MAO-A DVS was highly significantly elevated in every brain region assessed (t-test; P=.001 to 3x10(-7)). The MAO-A DVS was elevated on average by 34% (2 SDs) throughout the brain during major depression.
So that's the serotonin angle for depression. It's literally the basis behind SSRI's, the most popular class of medications for depression.
I was put on Lexapro and it almost killed me. That story on how I used CBD to wean off of Lexapro here.
Your doctor probably won't know this but the real star with serotonin is BDNF, our brain's fertilizer.
What does berberine do there?
Berberine up-regulates the BDNF expression in the hippocampus and attenuates corticosterone-induced depressive-like behavior in mice.
Goodness. Check out CBD and BDNF to understand why.
Now, all the new research is pointing to inflammation and depression (which BDNF works to counter).
Berberine has powerful neuroprotective qualities.
We're about to throw the kitchen sink of neuroinflammation at you but don't fret (or get depressed)...we'll interpret after:
Our findings also demonstrate that berberine significantly down‐regulates LPS‐ or interferon (IFN)‐γ‐induced nitric oxide synthase (iNOS) and cyclo‐oxygenase‐2 (COX‐2) expression in BV‐2 microglia cells. Berberine also inhibited LPS‐ or IFN‐γ‐induced nitric oxide production. In addition, berberine effectively inhibited proinflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 expression.
Basically, that study is showing how berberine calms the immune watchdogs in our brain from releasing a litany of inflammatory and nasty chemical agents that are directly tied to depression, Alzheimer's and just about every mental health issue out there.
Check out CBD and microglia to understand how this is THE new direction in mental health research.
Finally, let's pick the most difficult, intractable, and seemingly impossible mental health issue.
Berberine and Schizophrenia
These are early days...but exciting ones.
New research is pointing to an excessive immune response state with schizophrenia (overactive microglia pruning synapses) and to an inflammatory angle with too much oxidative stress in the brain.
First, the microglia:
Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.
Synapses are literally the branches in our brain that make connections with neighbors.
This is thought to be the tie-in with infection while pregnant and schizophrenia risk.
We have a massive review of how the immune system is the future of mental health.
The immune system is primed to run hot!
And remember all the cytokines (chemical assassins) above that berberine downregulates?
Levels of pro-inflammatory markers, such as cytokines, have been found to be increased in the blood and cerebrospinal fluid of patients with schizophrenia.
This again points to an overactive immune response.
We've looked at both of those above in terms of berberine's positive effects.
There are clinical trials going right now which we look forward to.
Let's look at some avenues.
First, researchers induced schizophrenia-like effects in mice with a specific chemical (used to simulate the disease).
MK-801 injection led to motor perturbations in both the open field and accelerating rotarod tests, which were restored by BBR.
So...berberine blocked the negative effects of this chemical.
Check out CBD and schizophrenia here. Its effect are downright fascinating and it has powerful anti-psychotic effects (also see why you MUST take CBD if smoke cannabis with high THC).
We could write a full article on each of these and we plan to.
We have to move on but other mental health issues are equally in play.
Speaking of inflammation, a great deal of it comes from our fat tissue.
Berberine and Weight
Berberine shares many of metformin's qualities in terms of obesity, metabolism, and fat creation.
A great deal of this is due to the gut remodeling of bacteria:
The present findings indicated that berberine, through modulating gut microbiota, restored the gut barrier, reduced metabolic endotoxemia, and systemic inflammation, and improved gut peptide levels in high-fat diet-fed rats.
That "gut peptide levels" is a bigger deal than you may realize.
For example, berberine helped to balance peptide YY.
What exactly is that?
Simply put...it regulates appetite:
In humans, peripheral infusion of PYY(3-36), at a dose that produced normal postprandial concentrations, significantly decreased appetite and reduced food intake by 33% over 24 h.
That's just one player in a complicated dance of appetite.
Then there's the effect on brown fat.
Brown fat actually burns more calories than white fat.
Animal experiments showed that berberine (5 mg/kg body weight) administration increased whole-body energy expenditure by 20% without changes in physical activity.
Let's really take that in.
Basically, the body would use 20% more energy without any change in food or activity!
You know who has lots of brown fat and energy...babies and children!
Again, we need a full article but metabolism is completely in berberine's wheelhouse due to its effect on AMPK and gut interaction.
SO…..is berberine safe?
Berberine safety and side effects
We wouldn't spend hours researching and writing about berberine if it wasn't safe.
In the end, we partially do this for ourselves.
We want to take things that work (research) and are safe.
After 2000 plus years of use, the general consensus is:
The body of evidence derived from animal and human studies support the notion that BBR is generally well tolerated and safe at the doses used for lipid-lowering.
For treatment of 1000's of patients for hypertension:
This study indicates that berberine has comparable therapeutic effect on type 2 DM, hyperlipidemia and hypertension with no serious side effect.
The known side effects for metformin deal with GI issues initially. This usually goes away after 1-2 weeks.
This is actually a good thing in our book. Remember, bad bacteria balance in the gut drives a lot of issues and any big change to this is going to be a uncomfortable short term. But good longer term!
Interestingly, berberine had a better profile there:
A Y.  reported that the incidence of nausea, vomiting, diarrhea, abdominal pain and other adverse reactions in the BBR group was lower than that in the MET group. Zuo F.  found that the gastrointestinal adverse reaction in the BBR group was less severe than that in the MET group.
This is interesting since they're hitting very similar levers in the body and especially the gut.
It just speaks to the body responding to chemicals crafted by a few billion years of evolution.
We see this with the safety profile between CBD and the synthetic equivalent used for seizures called Epeliodex.
Night and day on the safety and side effect profile.
At normal doses found on the market, the risk profile is very strong:
Standard doses of BBR are usually well-tolerated and adverse reactions are rare.
There are two key interactions to take note of:
BBR is involved in different pharmacological interactions: the drug displaces bilirubin from albumin about tenfold more than phenylbutazone and also warfarin, thiopental, and tolbutamide from their protein binding sites, increasing their plasma levels.
This means that jaundiced babies and pregnant women should avoid berberine.
Also, people who take warfarin or similar blood thinners as it will increase their levels.
In fact, berberine has anti-platelet effects of its own!
Another study showed that it might reduce the effect of a chemo agent called Paclitaxel.
Make sure to work with your doctor for berberine or any supplement.
Our goal is to use berberine to avoid ever needing chemo to begin with!
Side effect of berberine
Look...when we first started metformin, we had about 1-2 weeks of gas and GI issues.
It was stark!
This eventually goes away and then it's smooth sailing.
That's the common complaint with both metformin and berberine although berberine appears to be much better tolerated on this front.
Try to get through this period and understand what's happening.
It's literally remodeling your gut bacteria.
When certain lines die-off or other lines explode in numbers, gas and GI discomfort is the result.
Remember the Akkermensia Municipalia above?
We WANT more of that.
Our theory is that the more discomfort you have, the greater the need in your gut for a change.
Here's the side effect breakdown which mirrors what we had with Metformin:
The incidence of gastrointestinal adverse events was 34.5% during the 13 weeks of berberine treatment including monotherapy and combination therapy. These events included diarrhea (n: 6; percentage: 10.3%), constipation (4; 6.9%), flatulence (11; 19.0%) and abdominal pain (2; 3.4%).
Now...those studies were combining berberine with metformin and insulin.
When they looked at just berberine alone…
None of the patients suffered from severe gastrointestinal adverse events when berberine was used alone.
Remember how we said this eventually goes away (as the gut biome finds balance)?
In combination-therapy, the adverse events disappeared in one week after the reduction in berberine dosage.
As for liver and kidney function:
Liver and kidney functions were monitored in this study. No significant changes in plasma ALT, γ-GT and creatinine were observed during the 13 weeks of berberine treatment.
This hopefully dispels some of the scare-mongering we've seen online.
Berberine will use the popular P450 liver pathways which most drugs use so that has to be taken into account.
It may make the other medications stay longer and at higher levels.
Tests reflected for losartan, midazolam, omeprazole, and dextromethorphan.
The fact that the prior study looked at a liver function after 13 weeks helps to allay fears here.
What about the B12 issue?
Berberine and Vitamin B12
This is interesting.
Metformin is known to reduce B12 levels.
This requires B12 supplementation since B12 is so critical.
If you know someone on metformin, make sure they check into testing and supplementing B12.
The doctors don't bring this us and there's even talk about it contributing to mental decline in the elderly.
What about berberine?
Berberine doesn't appear to have this effect on B12 and folate absorption.
We also don't see the excessive drop in glucose that can accompany metformin.
So...the two things I test for in myself with metformin:
- Drop-in b12 levels (although I supplement)
- Too much of a drop in glucose
These do not appear to be an issue with berberine.
So….which is better...metformin or berberine?
How to compare berberine and metformin
We originally found metformin via the longevity study which is quite frankly...revolutionary.
We went through the 1-2 weeks of GI issues and came out on the other side.
After researching berberine, we added it immediately.
We may even go to just berberine with time.
Here are the key considerations for comparing metformin and berberine for us:
- Effectiveness with metabolism, AMPK, and gut remodeling
- Safety - B12, Glucose effect, quality of substance
In terms of effectiveness, they are very comparable and berberine may have the leg up there.
The fact that they both boost very beneficial types of gut bacteria is downright fascinating.
Let's look at some actual research.
One study compared metformin and berberine for women with PCOS.
Here's a measure of weight and obesity:
Waist circumference and waist-to-hip ratio also decreased in all 3 groups; however, the berberine group showed a significantly greater reduction in these measures than the metformin or placebo groups.
Insulin levels were improved for both metformin and berberine at the same clip (unchanged in the placebo group).
There was one very intriguing difference.
However, sex hormone-binding globulin increased significantly in the berberine group compared with both metformin and placebo.
SHBG usually goes down as insulin and obesity goes up. This is intriguing and requires much more research.
As for the lipid provide:
The berberine group had a significantly greater decrease in triglycerides, total cholesterol, and LDL, and a significantly greater increase in HDL when compared to metformin.
These are very interesting findings and they definitely shift in favor of berberine since the entire metabolic profile is a key to why we're taking either of these.
In terms of comparing berberine and metformin's safety…
- They're very comparable with berberine having a leg up.
- Secondly, the B12 depleting effect of metformin is a concern.
You have to supplement and millions of people on metformin don't know this (Thanks Doctors!).
More importantly, it speaks to an underlying effect. The body is complicated (ridiculously so) and to knock B12 might point to other unknown pathways that could be affected.
If Berberine doesn't share this effect, it speaks to a better "acceptance" by our body.
Also, the fact that the GI issues are less pronounced with berberine mirrors this.
If we've learned anything from hydrogenated oil, fake sugar, the body seems to know better how to handle substances it's been around for 1000's of years.
Just our 2 cents.
For now, we'll take berberine and metformin together for longevity but I wouldn't be surprised if we don't move to berberine solely in the future as more studies come out.
Can you take metformin and berberine together?
This is a common question.
Research is showing that berberine increases both the level and time of metformin's blood levels:
Co-administration of berberine increased the initial plasma concentration and AUC of metformin and decreased systemic clearance and volume of distribution of metformin in rats.
They may work on slightly different pathways although the end result (AMPK, Mitochondria function, etc) is the same.
The question then is...why?
Based on the comparison above (albeit limited), we would need an "added" benefit beyond just a higher dose for either since they have similar results.
Some studies use berberine to offset the GI side effects of metformin but this just speaks to using berberine instead.
We'll do a full review of this question separately.
To some practical questions.
Where to buy quality berberine
Metformin is a pharmaceutical drug. You need a prescription for this.
It's also very standardized and regulated which is good.
That being said, this "oversight" doesn't seem to be helping with all our medications manufactured in China (see recent spate of contaminants in blood pressure meds, Xanax, etc).
We used to be able to trust our pharma supply. That's in question...bring the production back to the US, please!
Berberine is an extract from a plant. It's essentially a supplement...not very regulated.
For this reason, we really need superior brands.
Certain brands have long track records of actually testing their product for quality and contaminants.
It's very similar to what see in the CBD market.
Lots of crap product out there...some of it even unsafe.
We have test our CBD twice for this reason.
The same thing goes for berberine.
Of the brand's we researched (and hopefully it's obvious after all this that we don't mess around with research), our choice is:
Thorne Berberine 500 mg.
You can buy it here online.
Thorne is a well-established and tested supplement brand that has high marks when 3rd parties (like Consumer Labs) runs tests.
This brings up a related question.
Can you get berberine on Amazon safely?
We purchase almost daily from Amazon.
Chairs. Office supplies. Weird stickers. You name it.
We will NOT buy anything from Amazon that goes into our body.
There are too many bad actors on there and supplements are definitely suspect.
It's very easy for a company in China to knock-off brands down to the label and the look.
CBD is a perfect example.
Amazon doesn't allow CBD sales on its platform as of this writing.
Never-the-less, you'll find tons of it on there.
Good luck with that one.
It's either bogus...or even dangerous.
We only deal with large, well-established online sources like iHerb here.
Berberine review wrap
SO...we focus on CBD at Indigo Naturals.
Why on earth did we just write almost 9000 words on berberine?
Because it's needed. The more we dove into its properties, the more we realized it could help not just us...but almost everyone!
There's so much suffering out there and our whole start with CBD was a result of intense suffering (that perimenopause nightmare is here).
Berberine is a fascinating option for:
- Metabolic issues
- Mental health issues
- Cardiovascular issues
- And more!
We'll bring it back to where we started.
AMPK is a powerful and ancient pathway we can trigger with Berberine.
The fact that it reverses epigenetic aging borders on miraculous.
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.