Berberine: Research, Benefits, Absorption, and Genetics

Berberine is a natural supplement with some amazing research on it for reducing high blood glucose levels and reducing high cholesterol. The drawback, though, is poor absorption in the intestines, decreasing its effectiveness.

In this article, I’ll go in-depth on research studies on berberine, including:

• how berberine works
• who might benefit from it
• how it is metabolized
• ways to increase absorption

What is Berberine?

Berberine, a natural compound, is found in plants such as Oregon grape, barberry, and goldenseal.

Plants containing berberine have traditionally been used for gastrointestinal infections. For thousands of years it has been used as part of Traditional Chinese Medicine, and different plants containing berberine have been used by various cultures around the world.

When isolated as a supplement, berberine is a very bitter, yellow powder.

What do research studies show about berberine?

There are thousands of studies on berberine, covering various impacts on health and disease prevention.

I’m just going to hit the highlights here…

Benefits: Decreased blood glucose and increased insulin sensitivity

One way that berberine improves blood glucose levels is through activating AMPK (adenosine monophosphate-activated protein kinase). AMPK 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 berberine to lower fasting blood glucose levels, postprandial blood glucose levels, and decrease insulin resistance after a month. There was also a decrease in IL-6 and TNF-alpha (inflammatory cytokines). This trial included a comparison group 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 combining the data from 14 trials of berberine found that berberine to be about as effective as prescription diabetes medications (metformin, glipizide, or rosiglitazone). No serious adverse effects were reported.[ref]

Check your genetic variants related to high blood glucose levels.

Clinical studies on improving cholesterol levels with berberine supplement:

Berberine has been shown in studies to reduce total cholesterol, which includes both LDL and triglyceride levels. Average LDL reductions ranged from 20 to 50 mg/dL.[ref]

Why does berberine help to modulate high cholesterol levels? 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, like simvastatin, might be much more effective than either berberine or statins alone.[ref] Talk with your doctor about this if you have any questions on whether it is right for you.

Berberine may be most effective, though, for people who have high cholesterol due to a PCSK9 genetic variant (check your genes).

Effectiveness of berberine for fatty liver disease (NAFLD)

A clinical trial showed that berberine reduced non-alcoholic fatty liver disease. Berberine has been 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, in mice bred to be fat and diabetic, increasing SIRT1 slowed insulin resistance.[ref]

Check your genetic variants related to NAFLD.

Improves intestinal barrier function

An intestinal barrier lines the intestines to keep gut microbes out of the rest of the body. The epithelial cells making up the intestinal cell wall adhere together in tight junctions. Essentially, tight junctions are the adhesion complexes that prevent anything from slipping in between the cells.

Inflammatory cytokines such as TNF-alpha and interferon-gamma can damage or loosen the tight junctions, leading to a ‘leaky gut’.

Cell studies show that berberine prevents 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, allowing for better medication absorption. So, you may want to be careful of stacking berberine with certain prescription drugs. Check with your doctor or pharmacist.

Berberine supplementation for PCOS: beneficial effects

PCOS (polycystic ovarian syndrome) is a condition that can involve altered hormone levels, insulin resistance, and ovarian cysts. The insulin resistance component of PCOS is important, and berberine may help to mitigate it.

• A study in China found 400 mg of berberine, 3 times per day, improved menstruation and ovulation in women with PCOS.[ref]
• Trials show berberine to be more effective than metformin (a diabetes medication) in some parameters for women with PCOS.[ref]

Check your genetic variants for PCOS.

Cancer studies involving berberine

Studies show one cause of DNA mutations 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]

Research studies show that berberine promotes apoptosis (cell death) in cancer cells and suppresses metastasis.

Due to poor absorption, the effects of berberine on cancerous cells are more likely to be seen in intestinal cells. Within the intestines, berberine 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]

Antimicrobial properties of berberine

Traditionally, plants containing berberine have been used to combat viral and bacterial pathogens.

In a randomized control trial, patients with acute diarrhea due to E. coli were given 400 mg of berberine. Twice as many patients 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]

In animal studies, 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 berberine to have some efficacy against Candida.[ref][ref]  Many studies also show that berberine can augment specific antibiotics. Berberine may not be a stand-alone treatment option, but rather something to consider alongside other antibiotics.

Antiviral properties of berberine links to insulin resistance:

Animal research clarifies that berberine protects against insulin resistance.

What is interesting, though, is that the animals in the trial with induced insulin resistance also had a decrease in the levels of interferon-gamma.

Interferon is our main initial protection against viral infections, so the link between insulin resistance and low interferon-gamma levels is important.  Reversing insulin resistance with berberine subsequently increased interferon-gamma levels.[ref]

Berberine for Irritable Bowel Syndrome:

A placebo-controlled clinical trial found that berberine was better than a placebo for reducing the symptoms of IBS-D. Patients receiving berberine had decreased diarrhea frequency and less abdominal pain.[ref]

Acetylcholinesterase inhibition by berberine

Berberine can act as an inhibitor of acetylcholinesterase.

Acetylcholine is the main neurotransmitter in the peripheral and central nervous system, and acetylcholinesterase is the enzyme that stops acetylcholine. It acts as 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] This is more theoretical, though, and I don’t think that normal doses of supplemental berberine have a bit

Circadian rhythm, berberine, and weight loss:

An interesting study came out recently that showed that berberine interacts with BMAL1, a core circadian clock gene. The study found 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 if related to circadian rhythm dysfunction.[ref]

Related article: Circadian dysfunction and weight gain.

Weight loss due to berberine – maybe?

Since berberine activates AMPK, it should cause either reduced fat accumulation or weight loss.[ref] But a lot of things that cause weight loss in theory or in animal studies don’t pan out in clinical trials.[ref]

One clinical trial of 500 mg of berberine, 3X daily, found an average weight loss of 5 lbs occurred after 12 weeks.[ref]

Diabetic neuropathy may be helped by berberine

An animal study showed 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]

Depression and anxiety: berberine studies

Animal studies show berberine may act as an effective antidepressant. Berberine upregulates BDNF (brain-derived neurotrophic factor).[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.

Safety of Berberine and Interactions:

Safety is essential, especially in a supplement that many people take on a long-term basis. So let’s take a look at the research studies on berberine.

How does berberine interact with medications?

Berberine has repeatedly been shown to lower blood glucose levels. Thus, combining it with other medicines that lower blood glucose levels could drop your levels too low (hypoglycemia).

In both animal and human studies, berberine lowers blood pressure in people with diabetes.[ref] If you are already taking blood pressure-lowering medication or supplements, berberine may drop your blood pressure a little more.

Berberine uses CYP3A4 and CYP2D6 enzymes for metabolism. Thus, 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.

Related articles: Check your CYP2D6 genetic variants and check your CYP3A4 variants here.

Safety of berberine supplements

There have been a number of clinical trials showing berberine as a safe compound when it comes to 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.

Toxicity studies in rats showed an increase in liver tumors with high doses of goldenseal after two years. Note 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]

Other toxicology studies mention caution with berberine use during pregnancy. Researchers also caution about interaction with G6PD deficiency.[ref] (Check your genes for G6PD deficiency)

My takeaway (I’m not a medical expert!) is that berberine is fairly safe for healthy people up to the doses that are going to cause you intestinal issues.

Related Articles and Genes:

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

Genetics and Type 2 Diabetes  – berberine decreases blood glucose levels for some people

Psoriasis Genes – topical berberine has been shown to help psoriasis