Berberine is a supplement that I’ve written about as a ‘Lifehack’ in a number of different articles. It is a natural compound with some amazing research on it in animal and cell studies, and it seems to be almost unbelievable. The drawback is poor absorption in the intestines, which can decrease its effectiveness.
Berberine has some fascinating research on it, so I’m going in-depth on:
Berberine is a natural compound found in plants such as Oregon grape, barberry, and goldenseal. The plants that contain berberine have been traditionally used for gastrointestinal infections. It has been used for thousands of years as part of Traditional Chinese Medicine, and different plants that contain berberine have been used by various cultures around the world.
When berberine is isolated as a supplement, it is a yellow powder that is very bitter.
There are literally thousands of studies on berberine that address a bunch of different aspects of health. I’m just going to hit the highlights here…
One way that berberine improves blood glucose levels is through activating AMPK (adenosine monophosphate-activated protein kinase), which is an enzyme involved in regulating energy production in the body. When energy is low, AMPK causes glucose or fatty acids to be brought into the cell and used for energy. Activating AMPK also decreases the production of cholesterol and triglycerides. AMPK activation also modulates insulin release from the pancreas and causes lipolysis (using fat for energy).
Berberine activates AMPK in a dose-dependent manner (meaning that more berberine causes more AMPK). [ref] In addition to moderating the release of insulin, berberine also up-regulates the expression of the insulin receptors. This should increase insulin sensitivity.[ref]
A clinical trial found that berberine lowered fasting blood glucose levels, postprandial blood glucose levels, and decreased insulin resistance after a month. There was also a decrease in IL-6 and TNF-alpha (inflammatory cytokines). This trial included a comparison group that was using standard drug therapy (blood pressure medicine and diabetes drugs). Both groups were told to exercise for a half-hour a day. Both groups had about the same reduction in treatment parameters – in other words, berberine was as effective as diabetes drugs plus blood pressure meds.[ref]
A meta-analysis that combined the data from 14 trials of berberine found that berberine was about as effective as prescription diabetes medications (metformin, glipizide, or rosiglitazone). No serious adverse effects reported. [ref]
Berberine has been shown in studies to reduce both LDL and triglyceride levels. Average LDL reductions ranged from 20 to 50 mg/dL. [ref] One study found that berberine upregulates the LDL receptor, which causes a decrease in serum LDL levels. For the 32 patients in the study who had high cholesterol, three months of berberine reduced LDL by 25% and also reduced triglycerides by 35%. [ref]
Combining berberine with a statin, simvastatin, was shown to be much more effective than either berberine or the statin alone.[ref]
Berberine may be most effective, though, for people who have high cholesterol due to a PCSK9 genetic variant. (Go check your genes :-)
A clinical trial showed that berberine reduced non-alcoholic fatty liver disease. Berberine was shown to be more effective even than the diabetes medication pioglitazone (Actos) for weight loss and improving lipids. The study participants took 500 mg of berberine 30 minutes before each meal (3x per day). Participants were also told to reduce calorie intake and exercise in the control, berberine, and Actos groups. So the good results were due to a combo of exercise, decreased calories, and berberine. [ref]
Animal studies show that berberine is working to reduce fatty liver disease at least partly through increasing SIRT1. SIRT1 is a gene associated with longevity and a healthy lifespan. A deficiency of SIRT1 causes fatty liver. On the other hand, increasing SIRT1 slowed insulin resistance in mice bred to be fat and diabetic. [ref]
One clinical trial of 500 mg of berberine, 3X daily, found that there was an average weight loss of 5 lbs after 12 weeks. [ref]
The intestines are lined with an intestinal barrier to keep out microbes. The epithelial cells that make up the intestinal cell wall are adhered together in what is known as a tight junction — basically, a way that the cells prevent anything from slipping in between them. Inflammatory cytokines such as TNF-alpha and interferon-gamma can damage the tight junctions, leading to ‘leaky gut’. Berberine has been shown in cell studies to prevent the inflammatory cytokines from causing leaky gut. [ref] In a mouse model of inflammatory bowel diseases, berberine reduces the damage and prevents the decrease of the tight junction protein (zonulin).[ref]
While it is generally a good idea to prevent the ‘leaky gut’, some medications actually include substances that decrease tight junctions so that the medication is better absorbed. So you may want to be careful of stacking berberine with certain prescription drugs.
Studies show that one cause of the DNA mutations that cause cancer is chronic inflammation. Researchers estimate that about 20% of cancers are related to inflammation – either through infection (e.g. HPV for cervical cancer), exposure to toxins and irritants (e.g. lung cancers), or inflammation due to autoimmune diseases. Inflammatory cytokines are a double-edged sword, though, with cancer. On the one hand, they can exacerbate or promote cancerous growth; on the other hand, they can also attack and destroy cancerous cells.[ref]
Berberine has been shown to promote the apoptosis (cell death) of cancer cells and also suppress metastasis. In humans, the effects of berberine on cancerous cells are most likely to be seen in the intestinal cells – because it isn’t very well absorbed. Within the intestines, it acts as an anti-inflammatory and helps to protect the intestinal wall. It does this by activating AMPK and inhibiting NF-κB. [ref]
In mouse models of colon cancer, berberine cuts the number of tumors in half. It does this through activating AMPK, inhibiting mTOR, and inhibiting NF-κB. [ref]
Traditionally, plants containing berberine have been used to combat viral and bacterial pathogens.
In a randomized control trial from the ’80s, patients with ‘acute diarrhea’ due to E. coli were given either 400 mg of berberine or nothing (I think…). Twice as many in the berberine group stopped having diarrhea compared to the control group with E. coli (42% vs 20%). The study also looked at cholera and found that berberine reduced stool volume (measured in liters – ugh!) when stacked with tetracycline.[ref] My take away — don’t get cholera.
In mice, berberine prevents the recurrence of C. difficile infections. (Note that the C. diff was initially treated with vancomycin – this was just looking at the recurrence rate)[ref]
Cell studies show that berberine has some efficacy against Candida. [ref][ref] A lot of studies show that berberine can augment specific antibiotics. This may not be a stand-alone treatment option, but rather something to consider alongside other antibiotics.
A placebo-controlled clinical trial found that berberine was better than placebo for reducing the symptoms of IBS-D. The patients receiving berberine had decreased diarrhea frequency and less abdominal pain. [ref]
Berberine can act as an inhibitor of acetylcholinesterase. Acetylcholine is the main neurotransmitter in the peripheral and central nervous system, and acetylcholinesterase is basically the off switch for stopping the neuron after firing. Inhibiting acetylcholinesterase turns off the ‘off switch’. This potentially would be good for Alzheimer’s patients. [ref][ref] (I’m not sure at what doses, though, you would need to take to really impact acetylcholinesterase. .. It seems like if normal doses acted as an acetylcholinesterase inhibitor it would be noticeable in healthy people.)
An interesting study came out recently that showed that berberine interacts with BMAL1, a core circadian clock gene. The study found that berberine increased FGF21 (important for weight loss) through modulating BMAL1 in brown fat. The study concludes that berberine may be good for people with obesity that is related to circadian rhythm dysfunction.[ref] (Read more about circadian dysfunction and weight gain.)
PCOS (polycystic ovarian syndrome) is a condition that can involve altered hormone levels, insulin resistance, and ovarian cysts.
A study in China found that 400 mg of berberine, 3 times per day, improved menstruation and ovulation in women with PCOS. [ref] Trials show that berberine is more effective than metformin (diabetes medication) in some parameters for women with PCOS. [ref]
An animal study showed that berberine decreased neuropathy by suppressing TRPV1, a receptor associated with feeling pain, such as from hot peppers. Berberine also reduced TNF-alpha, an inflammatory cytokine. [ref]
Animal studies show that berberine may be an effective antidepressant. It upregulates BDNF.[ref] In mice, berberine increases norepinephrine, serotonin, and dopamine. [ref] Animal studies also show that berberine decreases anxiety.[ref][ref]
While the mechanism of how berberine could decrease depression and anxiety is pretty solid, I can’t find any clinical trials in humans to validate this. YYMV.
Safety is really important, especially in a supplement that many people take on a long term basis.
Berberine has been repeatedly shown to lower blood glucose levels. Thus, combining it with other medicines that lower blood glucose levels could drop your levels too low.
In both animal and human studies, berberine lowers blood pressure in diabetics.[ref] If you are already taking blood pressure lowering medication or supplement, berberine may drop your blood pressure a little more.
Berberine is metabolized using the CYP3A4 and CYP2D6 enzymes. So it may interact with medications that also use those enzymes. If you are on prescription medications, talk with your doctor before adding in a bunch of berberine.
There have been a number of clinical trials show that berberine is a safe compound when it comes to the major adverse effects (e.g. liver toxicity, bone fractures, heart problems). Most studies use 400 to 500 mg, three times per day. Some people get transient side effects such as an upset stomach, and diarrhea or constipation at higher doses. [ref][ref][ref]
The studies on using berberine for IBS with diarrhea point to slowing down transit time in the intestines. Indeed, a study from 1994 showed that 1.2g of berberine slowed down intestinal transit time.[ref] While a benefit for people with IBS-D, slowed transit may be something to keep in mind if you are often constipated.
Looking at toxicity studies in rats shows that there was an increase in liver tumors with high doses of goldenseal after two years. Note that the study used goldenseal powder, which contains berberine as one component. The rat dosage at which tumors increased was 2,370mg/kg which should equal a dose of over 24g of goldenseal for a 130lb person.[ref]
My take away (I’m not a medical expert!) is that berberine is fairly safe for healthy people up to the doses that are going to give you intestinal issues anyway.
Resveratrol, found in grapes and red wine, is also a SIRT1 (sirtuin 1) activator. [ref] The combo of berberine and resveratrol decreased fat accumulation more than either one alone (in mice). [ref] Resveratrol is also not very well absorbed in humans…
Astaxanthin is a red-orange carotenoid found in a specific type of algae that turns red when stressed out. Fish that eat the algae then are high in astaxanthin – red salmon, red trout, lobster, shrimp, krill, and crabs. It is also why flamingos are red. As a supplement, astaxanthin has been shown to decrease cholesterol and help with fatty liver disease.
In people diabetes, a combo of metformin and fenofibrate has been used for lowering blood glucose levels and improving lipid levels. A recent publication theorizes that berberine plus astaxanthin may act in a similar manner to metformin plus fenofibrate.[ref]
There is a neutraceutical called Armolipid Plus that has berberine, astaxanthin, folic acid, CoQ10, red yeast rice, and policosanol in it. This has been shown to reduce total cholesterol and LDL c. The conclusion of a meta-analysis of the trials claims it to be a good alternative to statins for people with mild to moderately high cholesterol. [ref] Another study points to it being more effective in people with PCSK9 or LDLR genetic variants. [ref]
Berberine is very poorly absorbed in the intestines. By ‘very poorly absorbed’, I mean that studies show that less than 1% is absorbed and makes it into the bloodstream. Plus, the part that is absorbed gets metabolized pretty quickly.[ref] [ref] I take this to mean that only a tiny amount of the 500 mg doses in the human trials are actually driving the blood glucose lowering effects.
If you are taking berberine for its effects on the gut – stopping diarrhea or as an antimicrobial – then the poor absorption could be a benefit.
If you are taking berberine for any other reason, then read on to learn more about why the absorption of berberine is poor and some possible workarounds.
P-glycoprotein mediated efflux comes into play here with the poor absorption of berberine. P-glycoprotein – also known as multidrug resistance protein 1 or ABCB1 – is expressed on the surface of intestinal cells, and its role is to pump toxins (and drugs) back out of the cells. It’s a nice system to keep out ‘xenobiotics’ or foreign stuff the cell doesn’t like. Bad stuff comes in, and the cell pumps it back out using p-glycoprotein.
Genetic variants in the ABCB1 increase this protein for some people, making absorption of berberine varied.
There are pharmacological ways to get around the p-glycoprotein problem, and drug manufacturers use them to increase the absorption of medications. [ref]
Natural p-glycoprotein inhibitors include silymarin (milk thistle) and curcumin.[ref] A combination of berberine and milk thistle has proven efficacious for diabetic patients. [ref] Both milk thistle and curcumin are available online and at your local health food store.
Gut microbiome interaction:
Certain microbes that could be present in the gut microbiome convert berberine into dihydroberberine, which is absorbed 5-times more easily. Once dihydroberberine is absorbed in the intestinal cells, it is transformed back into berberine. [ref] You may be thinking – why not just take dihydroberberine, but it looks like when you take it in that form, it will get converted back into berberine in the stomach anyway.
Unfortunately, all of the microbiome studies that I can find on berberine are done in rats. I don’t know how applicable the studies are to human gut microbiomes. [ref][ref][ref] There is a trial proposed for testing berberine with bifidobacteria, so perhaps there will be answers soon. [ref]
Once berberine been absorbed and taken to the liver, it is metabolized using mainly the CYP3A4 enzyme. Grapefruit juice inhibits CYP3A4. I honestly don’t know how much of a benefit it would give to consume berberine with grapefruit juice, but it seems like an easy experiment to do.
There are a few animal studies looking at transdermal formulations of berberine. The transdermal applications did increase the berberine concentration more than oral administration. The drawback here is that the berberine has to be combined with something to cross the skin barrier, and some of those compounds aren’t all that great. Berberine is hydrophilic and won’t easily combine with a lipid. [ref] [ref]
Smaller doses (500mg or less) taken 3 to 4 times per day are used in clinical trials. This effectively spreads out the absorption of berberine throughout the day and mitigates the possible intestinal discomfort from higher doses.
Which supplement to take?
There are lots of options when you go to Amazon to buy berberine. I’ve tried a couple of different brands, and the higher quality brands seem (unsurprisingly) more effective than the cheap stuff. Read the reviews and go with the brand with which you are most comfortable. Currently, I’m creating my own capsules using pure berberine powder along with quercetin. It is a bit of a pain to have to cap my own supplements, but it eliminates the excipients that I don’t want. Berberine is terribly bitter, so there is no hiding the taste in a smoothie or juice.
I mentioned at the beginning that several articles here on Genetic Lifehacks include berberine as a possible ‘Lifehack’.
PCSK9 and High Cholesterol – berberine acts as a natural PCSK9 inhibitor to lower cholesterol
Advanced Glycation End Products – berberine reduces the formation of AGEs; genetic variants can increase the formation of AGEs.
Longevity and Genetics – berberine increases FOXO3A
Genetic Variants Associated with PCOS – berberine has been shown in clinical trials to help with PCOS
Leptin Receptor Genes – berberine acts favorably on leptin levels
Psoriasis Genes – topical berberine has been shown to help psoriasis