August 14, 2013

Berberine Works But May Very Well Be Harmful

I have been getting a lot of email of late about the supplement Berberine, which appears to be the latest miracle cure being sold to those people with diabetes who believe that completely unregulated herbs imported from countries with long histories of food and drug adulteration are somehow safer and "more natural" than the tightly regulated pharamceuticals.

Berberine does appear to work to lower blood sugar. The problem is that we really know very little about how it does it or what its long term effects are on the body.  I see many mentions on sites promoting berberine supplements of the fact that berberine has a long history of use in Chinese medicine. However, quite a few of the traditional Chinese herbs have turned out to be highly toxic, and it's worth noting that the incidence of kidney and other urinary tract cancer among Chinese herbalists is far greater than that of the population at large. (Details HERE)

You can lower blood sugar by damaging your liver as happens with severe alcoholism.  You can lower blood sugar with drugs that raise the likelihood of heart attack, as is the case with most sulfonylurea drugs. (Details HERE) You can lower blood sugar with drugs that over time damage the pancreas as is the case with the incretin drugs.(Details HERE)  And you can lower blood sugar by taking drugs that turn bone precursor cells into fat cell, as happens with Avandia and Actos, which, over a decade of use of these drugs can lead to your developing bones so brittle that they are prone to breaking. (Details HERE)

Many of these severe, life-ruining side effects did not show up until people had taken these drugs for five to ten years. So the fact that a drug lowers blood sugar for three months in a small population without major harm tells you nothing about its actual safety.

To get a feel for the quality of the research supporting the claims about berberine, scroll down to the Reference section of this page: http://examine.com/supplements/Berberine/ .

Ignore the enthusiastic editorializing by the editors of the site who don't know very much about diabetes or the drugs that berberine is being compared to and pay attention to the quality of the journals publishing these studies. Most are very obscure. Some sound like they are one of the many  "pay to play" journals beloved by supplement sellers--journals that will publish anything as long as they are paid a hefty fee.

Those studies on berberine published in respected endocrinology journals involve small groups of people taking the drug for very short periods. The only one I could find with a large number of subjects is a meta analysis where data from 14 different very small studies was pooled. Meta analyses are only as good as the quality of the underlying studies, which in this case is not very good.

Some studies published in quality journals suggest that berberine's positive effects may stem from the fact that it activates AMP-Kinase, which is what metformin does. If this is the case, you have to ask yourself, why not just take metformin, a safe, very well understood drug that has been in use since the 1950s and which must meet rigorous manufacturing standards before it is sold.

Several mainstream studies claims to have found that berberine inhibits DPP-4 and raises the concentration of the incretin hormone GLP-1 which is the mechanism used by the incretin drugs Januvia,  Onglyza, and Trajenta. As discussed elsewhere, inhibiting DPP-4 can turn off a mechanism the immune system uses to kill cells that have become cancerous, which may make these a poor choice of drug. In addition, accumulating evidence is pointing to the possibility that artificially raising GLP-1 levels over a long period of time leads to the growth of abnormal cells in the pancreas which may grow into the ducts and cause pancreatitis or turn into precancerous tumors.  (Details HERE)

Mainstream research also finds that berberine has a significant impact on your liver. Repeated use downregulates several important enzymes (P450 cytochromes ) that the body uses to eliminate drugs. You can read about that here: http://www.ncbi.nlm.nih.gov/pubmed/21870106.

This means that if you are taking berberine, other drugs you take may not be eliminated properly if they use those enzymes and may build up to toxic levels, while others, which require those enzymes to be working so that the drug can be broken down into the active form of the chemical they contain may not work as expected.

In particular you should not combine repaglinide (Prandin) with berberine as that combination may produce hypos since repaglinide is eliminated from the body by an enzyme that berberine inhibits. Since metformin also inhibits one of these enzymes to some extent, combining berberine and metformin is probably a bad idea, too. (Note I have blogged about the combined effect of metformin and prandin HERE).

Other drugs affected by berberine include cyclosporin (Neoral, Sandimmune), lovastatin (Mevacor), clarithromycin (Biaxin), indinavir (Crixivan), sildenafil (Viagra), triazolam (Halcion), and many others.

As always, when you buy an unregulated supplement, you have no way of knowing what is actually in the pill. Herbs grown in third world countries often contain toxic herbicides which are prohibited in the U.S.. And supplements manufactured abroad may also contain lead and other toxic heavy metals, as well as other contaminants. As supplements are completely unregulated in the U.S. and receive no scrutiny unless they kill someone, the assurances of the supplement companies that their supplements are "pure" are worthless. When supplements are taken to the lab by consumer groups, they often turn out to contain different dosages thatn what the label claims and to be contaminated.

With all this in mind, it seems prudent if you are going to use a drug to lower your blood sugar, to stick to drugs that are regulated, provided in pills of known dosage, and which have long track records for safety. Currently, the only drugs that fit that description are: metformin, insulin, prandin, gliclazide (not available in the U.S.)  and acarbose.

23 comments:

Daria said...

Jenny,

Thank you so much, as always, for your very pertinent posts. Your recent post on phosphate additives made me look through all my supplements and discard rather pricey sustained release NAC and replace it with one that did not contain dicalcium phosphate. In the sea of semi useful, often derivative, information that's being put out there just to post frequently and thus stay on people's radar, your posts are true gems. Please keep posting, you are doing all of us a great service through your site, your blog and your books. Was meaning to ask you for a long time, what’s your position on some conflicting evidence about “slightly higher risk of developing Alzheimer’s in long-term users of metformin”?

Jenny said...

Daria,

A lot of data lately has been pointing to an association between any abnormally elevated blood sugar and Alzheimers. For example, people considered "normal" with prediabetic post meal blood sugars have a higher rate of Alzheimers than those who are completely normal.

So since most people with Type 2 Diabetes who are prescribed metformin still are told that it is "Good control" when maintain the damaging high blood sugars that produce the 7% A1c, it isn't surprising that metformin might correlate with more Alzheimer. It is the higher than normal blood sugars, not the metformin causing the problem. Metformin is just a marker for mediocre control.

Sol Orwell said...

Hiya Jenny,

I'm from Examine.com. I'd point out that it's a false connection to say "x can damage your body while lowering blood sugar" while completing ignoring the actual actions that cause the blood sugar to lower.

As for me not knowing about diabetes. I've had grandparents on both sides of the family die, one side from Type 1, and the other side from Type 2. I'm well aware of what it can do.

Your ability to strawman is A+

Jenny said...

Sol,

I did not in any way ignore the actions that cause blood sugar to lower. They were activating AMP-Kinase, inhibiting DDP-4 and raising GLP-1 levels (which is accomplished by inhibiting DPP-4, the protease that cuts up that enzyme.)

My web site documents in great detail why inhibiting DPP-4 and raising GLP-1 levels may be very dangerous.

Having relatives with diabetes does not in any way make you aware of what the last five year's research has found out about the side effects of the mechanisms used by newere pharmaceutical drugs. As it happens, inhibiting DPP-4 and raising GLP-1 is the mechanism used by almost all of the new drugs, and the long term use of these drugs is turning up some very disturbing side effects of those mechanisms.

Daria said...

Jenny, thank you for your answer!
Agree on danger of any abnormally elevated blood sugar, but have to disagree about metformin. It looks that metformin’s connection to Alzheimer’s is about AMPK overactivation.
http://www.scripps.edu/news/press/2013/20130410polleux.html
Also, it looks like “long-term use of sulfonylureas, thiazolidinediones, or insulin was not associated with an altered risk of developing AD”.
http://www.medscape.com/viewarticle/764413

Jenny said...

Daria,

I would not leap to conclusions about the effect of metformin on Alzheimers based mainly on mouse research in one strain of genetically modified mice.

Other epidemiological studies have come up with results that are all over the place. Some show metformin reducing the incidence of Alzheimers. Some show a very small rise. None appear to look at the actual blood sugar levels of the subjects when taking the drugs or analyzes the medical and socio-economic reasons why some people with Type 2 are put on one drug as opposed to another.

Some epidemiological studies have suggested that AD is a much less important cause of dementia among people with diabetes than vascular dementia (tiny strokes) which makes sense given that high blood sugars promote strokes. (For example THIS study and THIS study.)

The link with blood sugar (where no drugs are taken) is far stronger than the signal coming out of studies of people taking drugs, as far as I can tell. (For example THIS study.)

So while this new finding is something that should motivate us to keep an eye on further research, it is no more conclusive than any of the other research done with mutant mice, most of which goes nowhere. And there is no strong signal emerging among the people, worldwide, taking metformin, that suggests that it is a potent threat for causing AD.

It certainly should NOT lead people to stop taking metformin.

Jenny said...

Looking into the issue of Metformin and AD further, I have found a mix of findings. Rodent studies suggest metformin does cross the blood brain barrier and that it can cause more deposit of amyloid. OTOH, taking metformin with insulin appears to reverse this process. Insulin fights the deposit of amyloid and when taken with metformin does a better job.

Meanwhile, on the epidemiological front we have conflicting results. There is clear data that the higher that A1c the more dementia we have. And a very recent large epidemiological study (Kaiser data) finds that people taking metformin have significantlyless dementia (of all types) than those taking TZDs or other diabetes drugs as the only drug they were taking. This contrasts with a UK study that found more AD in people taking only metformin. (It isn't clear if they were using the term AD to mean "dementia" since it is tough to distinguish the two without autopsy.)

I will be keeping an eye on this and will write about it in its own post (and on the Metformin page of the http://bloodsugar101.com site) in the future, as this is not an appropriate place to continue this discussion. Let's keep this post for the discussion of berberine.

So for now, it isn't

RLL said...

Jenny - this is off topic, but maybe of interest. My Ophth. discovered my retinopathy about eight years ago, and encouraged getting BGs to true normal. He did the required surgery and noted that there was some peripheral ongoing retinopathy which was not particularly threatening. I have kept my A1Cs at 4.8-5.1. He was amazed at a regular checkup last month to see that even that retinopathy is reversing. He was not exactly surprised. Truly close to normal BGs may reverse a lot of diabetic complications, even retinopathy!

Jenny said...

RLL,

That is wonderful news and should be very encouraging to others who are dealing with a retinopathy diagnosis!

Daria said...

Jenny,

Thank you for the additional research and info on metformin!

Anne said...

I considered taking berberine when I heard all the glowing reports. But finding out it is a DPP-4 inhibitor made me decide against it. Another reason I do not want to take it is that it is also an antimicrobial and I wonder what it does to gut flora.

Chen Jonathan said...

Hi, Janet
I would like to share a little newest information of Berberine.

/Berberine/DNA damaging/ protein synthesis initiation inhibition/ tumorgenicity/ Carcinogen
There are many reports on the subject of Berberine:
peer reviewed and pre-reviewed journals, online and not online.
The government FDA/NCTR (National Center for Toxicology Research) has had both the in vivo and in vitro evidences for this drug in their two+ year toxicology follow up. The summary is published in NCTR July-Sep publication.
http://www.fda.gov/aboutfda/centersoffices/oc/officeofscientificandmedicalprograms/nctr/whatwedo/nctrpublications/ucm363503.htm
1. Berberine, are potent inducers of DNA damage
2. Berberine-treated cells, DNA damage was shown to be directly associated with the inhibitory effect of topoisomerase II (an essential enzyme for DNA replication) and a key element for cell division and gene duplication fidelity.
Theoretically, this means any proliferating or newly dividing cells could subject to the cell division damaging inhibited by Berberine. Targeted delivery system for this compound may be preferred not to elucidate the long term damages of gene duplication.

The following describes the work done by NCTR.

NCTR Study of Goldenseal, A Dietary Supplement
NCTR(FDA-National Center for Toxicology Research) scientists in collaboration with the Shanghai Institute for Food and Drug Control (China) have shown that goldenseal and one of its major alkaloid constituents, Berberine, are potent inducers of DNA damage in in vitro human cell cultures In cells treated with goldenseal, the extent of DNA damage was correlated to the Berberine content and was directly associated with the inhibition of topoisomerase II (an essential enzyme for DNA replication). Goldenseal is an herbal product used to remedy a wide variety of ailments including gastrointestinal disturbances, urinary tract disorders, and inflammation; and was shown to increase liver tumors in rodents in a National Toxicology Program two-year carcinogenicity study. Toxicology Letters (2013, 221: 64-72) .
For additional information, please contact Lei Guo, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.

Toxicology Letters (2013, 221: 64-72)

Abstract
Goldenseal has been used for the treatment of a wide variety of ailments including gastrointestinal disturbances, urinary tract disorders, and inflammation. The five major alkaloid constituents in goldenseal are Berberine, palmatine, hydrastine, hydrastinine, and canadine. When goldenseal was evaluated by the National Toxicology Program (NTP) in the standard 2-year bioassay, goldenseal induced an increase in liver tumors in rats and mice; however, the mechanism of goldenseal-associated liver carcinogenicity remains unknown. In this study, the toxicity of the five goldenseal alkaloid constituents was characterized, and their toxic potencies were compared. As measured by the Comet assay and the expression of γ-H2A.X, Berberine, followed by palmatine, appeared to be the most potent DNA damage inducer in human hepatoma HepG2 cells. Berberine and Palmatine suppressed the activities of both topoisomerase (Topo) I and II. In Berberine-treated cells, DNA damage was shown to be directly associated with the inhibitory effect of Topo II, but not Topo I by silencing gene of Topo I or Topo II. In addition, DNA damage was also observed when cells were treated with commercially available goldenseal extracts and the extent of DNA damage was positively correlated to the Berberine content. Our findings suggest that the Topo II inhibitory effect may contribute to Berberine- and goldenseal-induced nontoxicity and tumorgenicity..

Jenny said...

Jonathan,

Thanks for posting these illuminating toxicology reports!

Chen Jonathan said...

my fellow diabetes:
By now, my fellow diabetes! You must have heard this ancient Chinese over the counter herbal pills. If you browse over Google, amazon.com you will see thousands of endorsement from those Las Vegas witness stands. Those Chinese professors ‘xixo’ have pumped up publication in pre-peer-review Journals. They all claim Berberine is better than metformin. Berberine, this class I category toxic medicine (By China government) has become an US pass word to good health on all health links!

As a matter of fact metformin is effective for early or moderate diabetes. It is the long term use (approximately 6-10 years) that causes issues. Mostly because receptor desensitize – drug resistance. Now, after three/four pills a day. The sugar still remains high. And then, doctor would prescribe insulin quick/slow released format. You may answer that Las Vegas witness stand and start to use Berberine. It may work wonders, but whether it can sustain a long term usage that is a needed parameter for us diabetes. But, Berberine as a drug, probably its receptors will become desensitized for a long term usages. Then, it will share the same drug resistant situation as metformin.

So, my fellow diabetes, be alert!

Chen Jonathan said...


Another interesting non-peer-reviewed paper
MicroRNA-21-3p, a Berberine-Induced miRNA, Directly Down-Regulates Human Methionine Adenosyltransferases 2A and 2B and Inhibits Hepatoma Cell Growth http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0075628 from Taipei, Taiwan. A splendid work. But the results can point to either way Because the main claim of the authors are The overexpression of miR-21-3p suppresses growth and induces apoptosis in HepG2 cells. Overall, our results demonstrate that miR-21-3p functions as a tumor suppressor by directly targeting both MAT2A and MAT2B, indicating its therapeutic potential in HCC.. Because Muscle is also a fast growing dividing cells same as red blood cells. These proliferating cells may also face the challenge of Berberine induced miR-21-3p expression. This might already explained the increase of Atrogin-1 expression of muscle cells So without more study the authors can only conclude that Berberine smothers HepG2 cells in culture. You cannot use Berberine as a target drug to eliminate neoplastic cells.

A lot has to learn before we say Berberine is better than metformin HCl. By the way I am not associated with any pharmaceutical and the same. I

Chen Jonathan said...


Hi,

You can hardly find any negative report on Berberine. I manged to find one in WebMed.

This case almost clearly stated that people with heart problems can be induced by Berberine to have arrhythmias attack. It is a interesting case indeed.. Berberine has an unique effect on heart functions.

[ Reviewer: 25-34 Female on Treatment for less than 1 month (Consumer)

[Comment:
A pharmacist in Vietnam advised me to take Antesik, a local Berberine-based medication, for indigestion. I took less than the recommended dosage over two days and woke up both nights with an extremely rapid heart rate which took several hours to slow down. This has never happened to me before and it was frightening. I see that this medication is used to treat heart disease but it seemed to cause heart problems for me! My stomach does feel better though. I would like to know if this is a recognized side effect of Berberine.]]

This phenomenon can be explained by the following study and Berberine effect on myostatin: MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice: Thomas E. Callis, Kumar Pandya, [...], and Da-Zhi Wang http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735902/ [ Transgenic over expression of miR-208a in the heart was sufficient to induce hypertrophic growth in mice, which resulted in pronounced repression of the miR-208 regulatory targets thyroid hormone–associated protein and myostatin, negative regulators of muscle growth and hypertrophy. Studies of the miR-208a Tg mice indicated that miR-208a expression was sufficient to induce arrhythmias.] This is almost like the overexpression MicroRNA-21-3p, a Berberine-Induced miRNA, Directly Down-Regulates Human Methionine Adenosyltransferases 2A and 2B and Inhibits Hepatoma Cell Growth that I just described above. Berberine is to diversified a chemical that need to be careful with.

Chen Jonathan said...

Atrogin-1 affects muscle protein synthesis and degradation when energy metabolism is impaired by the antidiabetes drug berberine.
Wang H, Liu D, Cao P, Lecker S, Hu Z.
http://www.ncbi.nlm.nih.gov/pubmed/20522589#

Jenny said...

Jonathan,

The body does not become resistant to metformin. The only reason metformin appears to become ineffective is that people who take it are told by their doctors to keep their blood sugars at levels high enough to slowly kill their remaining beta cells. If you keep your blood sugar under 140 mg/dl (7.7 mmol/L) at all times, metformin will continue to be effective for decades.

OTOH, the sulfonylurea drugs like glimipiride, glipizide etc DO will run into the problem of the receptors burning out after they are taken for a while. This can be reversed by stopping those drugs.

Chen Jonathan said...

Jenny,

Thanks for the info. I had to give up Metformin HCl due to Pain on my back and shoulder when I had to take 4x500 mg a day.

Berberine probably will cause more long term ill effects, as the literature start to illustrate.

This is a good site. Good job.

conchchowder said...

I'll take my chances with berberine.

conchchowder said...

I'll take my chances with berberine.

Michl said...

>To get a feel for the quality of the research supporting >the claims about berberine, scroll down to the >Reference section of this page: http://examine.com>/supplements/Berberine/ .

You make several very relevant points but there are two weaknesses that worry me. One is, that you don't do an apples to apples comparison of the dangers of metformin and berberine except discussion of quality control and manufacturing standards. The other is that it;s unclear what someone is supposed to conclude by scrolling through the references except that there are a lot of authors with non-anglo names. Is that what you had in mind?

alpha beta circuloid said...

Whether you take berberine or a pharma drug you will enventually die at some point in time from something. All the studies in the world are just that. The problem with pharma and herbalists is they are both after whats in your wallet. Ive taken berberine with good results however it isnt a cure all. It doesnt always work well if i continue to eat alot of sugar. Arnica 6x with protein and excercise works well at various times also.

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