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Nine of the top ten causes of death in the United States in were diseases. Preventable diseases kill hundreds of thousands of people annually and cause years of pain and suffering for hundreds of thousands more. About 10% of Americans have type 2 diabetes, and nearly half of all American adults have some form of cardiovascular disease, according to a report.
Berberine, a golden yellow compound found in several plants, might play a role in preventing or slowing the progression of both heart disease and diabetes, among several other medical conditions. In this guide, we&#;ll investigate the pros and cons of adding berberine to your daily diet, explore the safety and quality measures of different supplements, and provide our top six picks for the best berberine supplement in .
If you&#;re in a hurry, check out our top recommendations below.
Our Top Pick
Double Wood Berberine
Double Wood offers a simple, quality Berberine supplement that contains 500mg of pure berberine HCl.
Double Wood includes a streamlined formula that&#;s soy-, gluten-, and GMO-free. The company's products are third-party tested and made in a GMP-certified facility. Take 20% off your first order when you sign up for the newsletter.
Table of Contents
In this Review
Why you should trust us
Not every herbal supplement is created equally, and there can be a lot of misinformation out there. We&#;ve spent over 70 hours researching berberine to gain a thorough understanding of what this supplement is, how it works, and how it can be beneficial. We also took note of who would not be a good candidate for taking berberine. For this guide alone, we read over 50 scientific studies analyzing the efficacy of berberine supplementation and put this information to use when considering our top product recommendations.
Like all health-related content on this website, this review was thoroughly vetted by one or more members of our Medical Review Board for accuracy. We&#;ll keep an eye on the latest science and evolving product options for berberine supplements to ensure this guide stays up-to-date.
Over the past two decades, Innerbody Research has helped tens of millions of readers make more informed decisions to live healthier lifestyles.
How we evaluated berberine supplements
We considered three major criteria when comparing berberine supplements: product safety, efficacy, and cost.
Since supplements aren&#;t regulated by the Food and Drug Administration (FDA) the same way that food and prescription medications are, it&#;s essential that companies do the right thing and are thorough with product testing. We consider product safety and transparent testing to be the highest priority.
While almost all of our top picks had the same effective main ingredient (berberine hydrochloride (HCl)), there were a couple of products that stood out for their potent formulas and addition of elements that may significantly aid with berberine absorption. These products have exciting potential, but we also consider possible downsides to a highly potent supplement &#; if a formula is potentially stronger and not as well studied, research becomes less predictive, and negative side effects could outweigh health benefits. Instead, at this time, we reserve our highest recommendation for a form and dosage that are most supported by current research.
Cost is also an important consideration, but we found that because the price of berberine supplements didn&#;t vary too significantly per milligram (and almost all of our top picks offer savings through subscription programs and free shipping), the other factors at play were more crucial.
Safety
Winner: Double Wood
While berberine has many powerful benefits, it also has some drawbacks. It can be rough on the digestive system, and there haven&#;t been many studies on its long-term safety. A berberine supplement that&#;s been through extensive third-party testing will be safer than most. Likewise, we look to ensure it was manufactured in a facility that is compliant with Good Manufacturing Practices (GMP or cGMP) and registered with the FDA.
Double Wood makes its GMP-compliant facility status known right off the bat, and the company includes links to both a certificate of analysis and third-party testing results near the top of the berberine supplement&#;s webpage. These results back up the company&#;s ingredient claims on the label, instilling confidence that you&#;re receiving the berberine you seek. This is especially important considering that one study found that 60% of berberine supplements do not meet the 90-110% potency standard of what is printed on their label.39 Double Wood clearly explains how often you should take the supplement to avoid the worst side effects and provides allergen notices, contraindications with other medications, and other safety tips. While other companies in our top picks also perform rigorous testing, we liked Double Wood&#;s easy-to-locate results, combined with its competitive pricing and free shipping.
Efficacy
Winner: Double Wood
We consider the method of administration, effective dosing, and other ingredients that could improve efficacy. An effective supplement should deliver the benefits we want to see without completely undermining safety or affordability. We found that most clinical research has demonstrated that doses of 500-1,500mg of berberine daily provide therapeutic benefits.12 Common side effects of taking too much berberine can include nausea, bloating, diarrhea, or constipation, so we recommend taking a supplement that allows you to safely stay within this dosage range.
Double Wood comes in 500mg capsules, allowing you to easily adjust your dosage if you find yourself experiencing gastrointestinal distress. Clinical research has reliably shown that berberine is extremely difficult for the body to digest. Less than 1% of all berberine that we take orally ends up circulating in our bloodstream.40 And while some other formulas in our top picks, like those from Toniiq and Renue by Science, boast greater potency or absorption, we like that Double Wood allows you to stay consistent with dosing that has been studied the most; there&#;s no guessing how much you are really absorbing from each capsule. Also, the company&#;s certificate of analysis on the webpage is current and demonstrates that its dosage claims are accurate.
Cost
Winner: Puritan&#;s Pride
Determining the cost of a supplement requires more than looking at the listed price. Subscription or bulk deals, shipping costs, the number of servings, and the price per serving of a supplement all determine how much you&#;ll pay. We also consider a supplement&#;s customer service policies for things like returns when evaluating a supplement&#;s cost, so you can rest assured knowing you can get your money back in case it doesn&#;t agree with you.
Puritan&#;s Pride has centered its brand on its unique way of getting you low prices, and the company&#;s berberine supplement is no exception. For every bottle you purchase, you&#;ll get two of the same size for free. While it looks like Puritan&#;s Pride charges roughly as much as competitors, slicing this price into thirds reveals excellent savings. You can join its subscription program for an additional 5% off, and the company has one the longest return windows on our list at 90 days. There are tradeoffs that come with the lower price tag, but if you&#;re on a tight budget and don&#;t have a kitchen scale for measuring powders, Puritan&#;s Pride is a solid pick.
How our top recommendations compare
To help you break down the differences between our top products, we&#;ve put together a chart mapping all of their most important features. Check it out below.
Special Offer from Double Wood: FREE Shipping On All Orders
Double Wood
Puritan&#;s Pride
PureBulk
Renue By Science
Toniiq
Oregon&#;s Wild Harvest
Nutricost
Thorne
Cost
$20
$36
$23
$50
$24
$21
$27
$38
Number of servings
60
180
100
90
90
30
30
30
Cost per serving
$0.33
$0.20
$0.23
$0.56
$0.27
$0.70
$0.90
$1.27
Dose
500mg
500mg
500mg
150mg
500mg
1,140mg
1,200mg
1,000mg
Active form
Berberine HCl
Berberine HCl
Berberine HCl
Berberine HCl
Berberine HCl
Organic Oregon Grape root
Berberine HCl
Berberine HCl
Vegan?
Shipping
Free on all orders
Free for orders $49+
Free for orders $49+
Free for orders $50+
Free for orders $99+
Free for orders $50+
Free for orders $59+
Free on all orders
Subscription program?
Return policy
30 days
90 days
90 days
Unlimited for unopened product
60 days
60 days
60 days
60 days
What is berberine?
Berberine is an alkaloid found in the roots, bark, and other structures of many plants, including the Oregon grape (Mahonia aquifolium), goldenseal (Hydrastis canadensis), Indian barberry (Berberis aristata), and European barberry (Berberis vulgaris). It has a long history of therapeutic uses in Ayurvedic and traditional Chinese medicine and an equally expansive list of potential benefits within the framework of contemporary medicine.
Berberine has both antimicrobial and anti-inflammatory properties. It may play a role in defending the body against harmful bacterial overgrowth and even promote growth of beneficial organisms in the gut microbiome, which in turn affects a variety of disease processes.2 While there is still much to uncover in terms of the mechanisms of how exactly berberine works, researchers do know it impacts a host of medical conditions, such as:
- Diabetes3
- Insulin resistance4
- High cholesterol5
- High blood pressure6
- Candida overgrowth7
- Metabolic syndrome8 41
- Polycystic ovarian syndrome (PCOS)9
- Ulcerative colitis10
- Irritable bowel syndrome (IBS)11
- Non-alcoholic fatty liver disease12
A literature review even discussed berberine&#;s potential for antitumor effects against a few types of cancer.13 However, at this time, the most extensive research has revolved around berberine&#;s impacts on diabetes and cholesterol management.
How do berberine supplements work?
Most of berberine&#;s physiological effects are still under investigation, but let&#;s take a look at some of its most recognized mechanisms of action.
Berberine activates AMP-activated protein kinase (AMPK), the primary enzyme that monitors and regulates our cellular energy levels. Increasing the amount of AMPK in our bodies gets nutrients where they need to be, effectively controlling our metabolism. This process of AMPK activation is the link to berberine&#;s benefits for diabetic patients, as well as other conditions like obesity and high cholesterol. AMPK is thought to be a tumor suppressor, too, essentially starving cells while they attempt to form cancerous tumors (though after cancer has developed, AMPK can sometimes promote tumor growth instead).14
We know that berberine has long been used as an antimicrobial agent in traditional Chinese medicine. But exactly how this compound is effective hasn&#;t been explored until more recently. A study investigating berberine&#;s antimicrobial properties found that it slows bacterial metabolism, stops them from creating new cell walls and amino acids, and lowers their antioxidant levels.15 Historically, berberine has been used to treat diarrhea from both bacterial infections and noninfectious conditions.16 (Ironically, diarrhea and stomach pain are sometimes side effects when you start taking berberine.) Much of the research on berberine&#;s impact on intestinal and gut microbiome health is still in progress, but studies have backed up the anecdotal evidence that berberine may be a potent anti-diarrheal agent.2
Berberine&#;s anti-inflammatory effects come into play through the modulation of multiple signaling pathways. In this regard, most studies look at berberine&#;s effects on non-alcoholic fatty liver disease, but inflammation is also a critical part of conditions like heart disease and diabetes.12 17 Notably, a meta-analysis found significant reductions in CRP (C-reactive protein, a major marker of inflammation) in patients taking berberine.18
One of the few things we can almost conclusively say berberine supports is diabetic care. Specifically, it improves HbA1c levels (an indicator of long-term blood sugar control) and insulin resistance (meaning your cells can use insulin more effectively, leading to less glucose storage and lower blood glucose levels).19 According to a animal study, berberine supplementation can slow the progression from prediabetes to type 2 diabetes.20 Some studies also suggest that taking berberine in addition to prescription medication like metformin could result in greater glycemic control, but more definitive research is needed to support this theory.21 It&#;s worth noting that berberine could potentially be a good alternative for those that can&#;t take diabetes medication due to liver, kidney, or heart disease.
Another significant benefit of berberine is its protection against heart disease.22 While we don&#;t know for sure if it can stop heart failure, we do know that it can decrease the likelihood of:
- Arrhythmias
- Atherosclerosis
- Abdominal aortic aneurysms
- Cardiac hypertrophy (a step toward heart failure)
- Ischemic heart disease
- Strokes23
Berberine plays a role in decreasing total cholesterol, LDL cholesterol, and blood triglycerides while increasing HDL cholesterol.24 25 It also lowers high blood pressure, supporting good heart health from every angle. The positive impacts berberine has on obesity and blood sugar could also work hand-in-hand to help prevent heart disease. And interestingly, berberine appears to have an anti-apoptotic effect on heart cells, which can keep the cells from dying prematurely.
Berberine dosages have not been formally established, but clinical studies use a dose range between 500mg and 2,000mg daily. However, one study found that high cholesterol levels start to improve at 300mg daily.26 Berberine has a relatively short half-life, so most people report seeing success with three 500mg capsules daily (1,500mg total).
Are berberine supplements safe?
Generally speaking, berberine is a safe supplement for healthy adults. There aren&#;t a lot of side effects associated with berberine at the aforementioned doses, but you might experience some stomach upset when getting started. Specifically, berberine can cause:
- Nausea
- Diarrhea
- Stomach cramps
- Bloating
- Headache
- Constipation (particularly when you stop taking it)
- Rashes (though this is relatively rare)
The more berberine you take, the more likely you are to experience these side effects. Higher doses also mean you might feel stronger side effects for a longer time. If you know you have a sensitive stomach, starting on a low dose of berberine and slowly increasing how much you take over time might make sense. As with any supplement, talk to your doctor before adding berberine to your daily regimen.
There aren&#;t many studies looking at how well berberine works long-term, nor are there many investigating any potential safety hazards associated with taking berberine for years. Some of the longest-running studies looked at berberine as a dietary supplement for colorectal cancer over two years and found only a few adverse reactions, but pay attention to your body.27 Because we don&#;t know what could happen, taking berberine long-term is not typically recommended.
Berberine is an herbal supplement that the FDA doesn&#;t regulate the same way as food and prescription medication. It can&#;t be used to diagnose, treat, cure, or prevent any diseases, including type 2 diabetes, high cholesterol, insulin resistance, and everything else that research explores but hasn&#;t confirmed. Always talk to your doctor before trying a new supplement, and don&#;t stop taking prescription medication to try berberine without their approval.
Who shouldn&#;t take berberine
Berberine interacts with several liver enzymes called cytochromes (specifically CYP2D6, CYP2C9, and CYP3A4, all of which come from cytochrome P450). These enzymes break down medications and help our bodies build cholesterol and certain steroids. While berberine isn&#;t the only supplement that interacts with cytochrome P450, it&#;s important to note because it can influence how much of your prescription medication gets absorbed. If your medication has a warning not to eat grapefruit while taking it, you shouldn&#;t take berberine with it either. (This is why it&#;s essential to check with your doctor before starting berberine, as the list of potential cytochrome P450 interactions is quite long.)
Several other medications interact poorly with berberine. These include:
Immunosuppressive medication
Tacrolimus, cyclosporin, and other oral chemotherapy drugs like bosutinib. Some studies have found that berberine has a slight immunosuppressive effect, particularly on T cells, a kind of white blood cell central to immune system functioning.28
Macrolide antibiotics
Azithromycin, clarithromycin, erythromycin, and fidaxomicin. Several studies show that berberine can enhance the effects of antibiotics, making it useful for treatment-resistant infections.29 But with its potential to slow T cell development, berberine could also restrict your body&#;s ability to heal itself.
Phosphodiesterase (PDE) inhibitors
Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra). These medications are vasodilators, which increase blood flow and lower blood pressure. You might take them for hypertension, erectile dysfunction, or an enlarged prostate. Berberine also lowers your blood pressure, so combining the two can dangerously lower your blood pressure levels.
If you have diabetes and take insulin, be careful while taking berberine. Since it can lower your insulin resistance, you might need to use less insulin than before to stabilize your blood sugar. Keep an eye out for low or dropping blood sugar levels, as hypoglycemia can be extremely dangerous. It&#;s best to check in with your endocrinologist beforehand if you want to try berberine supplements.
Berberine is particularly unsafe for pregnant and lactating individuals. Babies and fetuses that ingest berberine are more likely to have jaundice &#; a condition in which the liver doesn&#;t function as expected, leading to a buildup of bilirubin and jaundice&#;s hallmark yellow skin. This could lead to jaundice-induced brain damage called kernicterus, a rare disorder in which bilirubin is deposited in the brain, leading to vision and hearing loss which may be permanent. Likewise, children under 18 should not take berberine supplements.
Double Wood Supplements Berberine
Best overall
Vegan formula
Soy-, gluten-, and GMO-free
Provides third-party test results and certificate of analysis
Manufactured in a GMP-certified facility
Free shipping on all orders
Subscribe & save up to 15%
Double Wood creates a simple and high-quality berberine supplement. There isn&#;t much to it, but there doesn&#;t have to be. Double Wood combines the best traits of a successful supplement &#; a relatively low cost, transparent testing and safety measures, and a dose high enough to make a difference in small enough capsules to provide flexibility.
Each capsule contains 500mg of pure berberine HCl, and on its website, Double Wood encourages you to take anywhere from 2-4 capsules daily, each three hours apart with food. Following these instructions, you might find that a bottle lasts anywhere from two weeks to one month since there are 60 capsules in every bottle.
However, the product label on the bottle states to simply take one 500mg capsule daily. This discrepancy is confusing, and while 500mg of berberine may be enough for some, most research studies use doses closer to what the Double Wood website suggests. It&#;s also a little misleading when it comes to how many servings are actually present in a bottle of Double Wood berberine. Despite this, the company&#;s pricing is still competitive per serving. If you think you&#;ll need closer to 1,500mg of berberine daily, we&#;d recommend purchasing the Double Pack, which ships two bottles of berberine at a slightly reduced price.
One of the biggest reasons that Double Wood stands out as our top pick for berberine supplements is its commitment to transparency. You won&#;t have to look far to find out that it was made in GMP-compliant facilities in the U.S., and its allergen notice is prominently displayed. The company also links directly to a current certificate of analysis and independent third-party testing results on the webpage, revealing that its berberine capsules contain exactly what is claimed on the label. Currently, each capsule contains berberine, hypromellose (veggie capsule), and silicon dioxide (a common anti-caking agent). This is slightly different from the previous formula, which included berberine with just microcrystalline cellulose. If one of your goals is avoiding additives, and you have a kitchen scale handy, PureBulk might be a better fit for you.
Pricing
Double Wood sells its berberine capsules at several different price points depending on the number of bottles you&#;re ordering and whether or not you&#;re joining the subscription program. Double and triple packs have a bigger discount up front, but you&#;ll save less per order when joining the subscription program (10% as opposed to 15% for a single bottle). Ultimately, you do still save a significant amount by bundling or subscribing &#; or both. We&#;ve put together a quick chart to help you figure out how much you&#;ll pay.
Cost (one time)Cost (subscription)
One bottle$19.95$16.96
Double pack$34.95$31.46
Triple pack$49.95$44.96
Subscriptions are all processed through the third-party service Recharge. You can choose how frequently you&#;d like to have a new bottle delivered:
- 15 days
- 30 days
- 60 days
- 90 days
- 120 days
All orders ship for free from Double Wood and generally arrive within five to seven business days. If you aren&#;t happy with your berberine supplement, you can get a refund even if you&#;ve already opened the bottle. After placing the order, you&#;ll have 30 days to initiate a refund, and you&#;ll need to ship the bottle back whether or not you&#;ve opened it. Despite the company&#;s free shipping policy, you will need to pay for return shipping yourself. Double Wood will still accept refunds after the 30 days are up but won&#;t guarantee it; after 30 days, Double Wood will provide refunds only at its discretion. While this return policy isn&#;t as long as some of our other top picks &#; like Puritan&#;s Pride or PureBulk, which offer 90-day policies &#; we appreciate that Double Wood will accept a return even if the product has been opened.
Puritan&#;s Pride Berberine
Best budget pick
No way to order just one bottle
Lower degree of transparency
Small amounts of additives (magnesium stearate and silica)
Each bottle of Puritan&#;s Pride&#;s Berberine contains 60 capsules of 500mg berberine sourced from Indian barberry. However, because you get bottles in sets of three for every order, Puritan&#;s Pride&#;s berberine capsules allow for much more flexibility in your dosing schedule. You can take anywhere from 500mg to 2,000mg daily without worrying about whether or not you&#;ll run out in less than a month.
If you are looking for more details, kindly visit Berberine Hydrochloride Exporter.
Puritan&#;s Pride also offers berberine mixed with several other ingredients (such as turmeric and black pepper, cinnamon, and silymarin), so you can pick a combination that&#;ll support your specific health goals if you&#;re focused on decreasing inflammation, increasing metabolism, or supporting liver health.30 However, we think that pure berberine capsules are best for most people.
We confirmed that Puritan&#;s Pride berberine supplements are vegan-friendly, and a small amount of vegetable magnesium stearate and silica are included, which are common fillers. This won&#;t hurt your health, but if you&#;re looking for a completely clean supplement, this one might not quite fit the bill.
All Puritan&#;s Pride supplements are manufactured in GMP-certified facilities and tested multiple times throughout their creation. However, the company doesn't specify whether the supplements are tested in-house or by independent third parties and doesn&#;t provide any test results. This is somewhat disappointing; transparency is key when looking for a health supplement since they aren&#;t closely regulated by the FDA. If safety is essential in your decision-making process, you may wish to consider another option on our list, such as Double Wood or Toniiq, which provide testing results right on their product websites.
Pricing
Puritan&#;s Pride uses one of the most unusual pricing strategies in the field. Every single order &#; no matter what it is you&#;re getting &#; comes in sets of three bottles. The company has increased its prices by a few dollars since our last review, but thanks to its bulk deals, these supplements are still our top budget pick. The chart below lays out exactly how much you&#;ll pay in different circumstances.
Cost one-timeCost per bottle (one-time)Cost with subscriptionCost per bottle (subscription)
Buy 1, get 2 free$36.49$12.16$34.67$11.56
Buy 2, get 4 free$72.98$12.16$69.33$11.56
Joining the subscription program saves you only 5%, but it does unlock free shipping for orders of $30 or more. Otherwise, you can get free shipping when purchasing $49 or more of Puritan&#;s Pride products. If you don&#;t quite meet that $49 requirement, you&#;ll be charged $4.95, and some U.S. states and territories are subject to an additional $5.99 surcharge.
You can try Puritan&#;s Pride&#;s berberine supplement risk-free. Puritan&#;s Pride offers a 90-day money-back guarantee, meaning that you can try it and return it as long as it&#;s within three months of purchase. That said, you can&#;t have tried all three (or six) bottles; if you opt for a return, Puritan&#;s Pride will only offer a full refund if just one bottle has been opened. However, you&#;ll need to include them all in a return package when you send the product back.
If you&#;re curious about what the rest of Puritan&#;s Pride catalog holds, check out our full review.
PureBulk Berberine HCl Powder
Best powder
No additives
Strong scientific evidence directly on the webpage
Tested by independent third parties
Certificate of analysis available upon request
Made in GMP-certified facilities
Multiple sizes and forms
Easy to personalize dosage
Vegan-friendly
Military, teacher, and first responder discounts
Free shipping on orders over $49
Generous 90-day return policy
Save 10% at checkout with code INNERBODY
Taking a supplement capsule (or three) every day isn&#;t for everyone. For those who dislike swallowing pills or who want to avoid additives, PureBulk offers an additive-free Berberine HCl powder that makes it easy to consume berberine in the way that you prefer. Also, you might know that you love berberine and want to buy it in bulk without paying hand over fist. This is where PureBulk excels: you can buy its Berberine HCl powder (made exclusively from Phellodendron amurense bark) in six different sizes, from 25g all the way up to 1kg.
There are downsides to this approach. You&#;ll have to do the math to figure out how many servings are in each bag of powder, but PureBulk recommends you take 500mg daily. You&#;ll also need to have a kitchen scale or an extremely accurate scoop at the ready to ensure you&#;re taking a consistent amount every time. This can be inconvenient and requires you to use caution in order to avoid unwanted side effects from taking too much. However, because it&#;s a powder, you can personalize your dose to exactly the right amount that works for you.
All PureBulk products are made in GMP-certified facilities and are independently tested by a qualified third-party laboratory. If you want to read the test results, PureBulk provides a link for you to request a copy of the certificate of analysis.
Pricing
PureBulk offers its berberine supplement in ten sizes and three forms, so you can get as much &#; or as little &#; as you need. These include:
- 25g powder: $13
- 50g powder: $23
- 100g powder: $42
- 250g powder: $91
- 500g powder: $165
- 1kg powder: $297
- 120 capsules: $20
- 300 capsules: $43
- 120 vegan capsules: $21
- 300 vegan capsules: $46
We noticed that PureBulk has increased its prices in all sizes since our last review, with a change of just a dollar or two in the smaller quantities but more significant changes in the larger quantities (like $297 vs. $270 for the 1 kg option). PureBulk also offers a true bulk option of 15kg for $2,244.55. This berberine powder comes in a large drum and is best suited for situations where you&#;re sharing your berberine with many other people. (15kg will likely start to lose its efficacy before you can finish it yourself.)
Because the company sells its berberine powder in such large quantities, PureBulk doesn&#;t offer any subscription programs. And while PureBulk can accept PayPal as a payment method for many of its items, if you&#;re buying berberine, you&#;ll have to use a debit or credit card.
If you&#;re in the military, a teacher, or a first responder, PureBulk offers a 15% discount. You&#;ll need to verify your identity through VerifyPass, a third-party platform, and upon approval, you&#;ll get a one-time discount code valid for 24 hours. You&#;ll need to repeat this process to get another code each time you shop with PureBulk.
PureBulk offers free shipping on orders over $49 going to the United States unless your order contains a bulk tub (20kg or 25kg) or a heavy parcel (3kg or more per individual item or 10kg total) going to Alaska or Hawaii. Otherwise, shipping costs vary depending on where you live and how much you&#;re purchasing.
If you decide berberine isn&#;t right for you (or find out you don&#;t have a kitchen scale as you thought), you have 90 days from when it first shipped to return your powder or capsules to PureBulk. This is one of the most generous return policies we&#;ve found among our top berberine picks, alongside Puritan&#;s Pride and Renue By Science. However, be aware that for a full refund, the berberine must be returned unopened, and you&#;ll need to pay for return shipping. The company does consider refunds for opened products; in that case, it will issue a refund equal to the cost of the smallest size it offers in that particular product. Returns for bulk orders are not accepted.
Renue By Science LIPO Berberine
Most potent
Liposomal form means the body may absorb significantly more
Allergen-free, non-GMO, vegan-friendly
Triple-tested with certificates of analysis posted on webpage
Made in cGMP- and ISO-certified facilities
Free shipping to the U.S. on orders over $50
Subscribe and save 5%
Take 10% off with code INNERBODY
Known mostly for its excellent NAD+ supplements, Renue By Science steps out of its usual arena with LIPO Berberine. This supplement adds sunflower lecithin as a liposomal barrier &#; two phospholipid layers arranged in a sphere &#; to a traditional berberine supplement. Because the human body uses phospholipid bilayers to create our cells, it notices, bonds to, and processes the liposomal supplement much faster and more effectively than if it just went through your digestive system.
This liposomal technology is particularly important for a berberine supplement. Less than 1% of any given oral berberine supplement gets put to use in the body, but a animal study showed that liposomal berberine is stored, absorbed, and used 16 times more than berberine on its own, meaning that there could indeed be more of it to help you for longer.1 31 In theory, your body will get more use out of this berberine supplement than alternatives, although more (human) clinical studies are needed to back this claim up.
The dose you'll find in each serving of LIPO Berberine is considerably less than competitors. Each capsule (equivalent to one serving) only contains 150mg of berberine. You can triple the dose (to 450mg) and still only need to order one bottle a month since there are 90 capsules per bottle. Still, the increased absorption from its liposomal format means it&#;s harder to pin down exactly how much of it you&#;re getting and using.
When you consider the results of the animal study mentioned above, there&#;s a chance you are absorbing a significant amount more berberine than in another supplement. If you assume that the animal study accurately predicts the greater absorption rate in humans, then a 150mg dose of LIPO Berberine might be equivalent to something like 2,500mg of traditionally formulated berberine HCl, which is a high dose. While there is potential for taking fewer capsules per day due to the increased absorption, there&#;s no way to divide that 150mg dose into something smaller. This brings up the concern of possible negative GI side effects. If you would rather take a supplement with a higher berberine content and less of a guess as to how much you are absorbing, an option like Double Wood or Puritan&#;s Pride (both have 500mg capsules) might be a better fit.
Renue By Science is transparent with its testing and quality assurance. The company includes a copy of the certificate of analysis directly on the webpage. Without having to ask, you can see exactly how an independent third party scored LIPO Berberine &#; and, interestingly, the batch at the time of writing contained 167mg per capsule, 17mg more than is listed on the label.
Pricing
Renue By Science only sells LIPO Berberine in one size and form: a bottle of 90 capsules for $49.95. The company doesn't offer any bundle deals but has added a subscription program since our last review. You can save 5% if you subscribe and can choose to have your product delivered every one, two, or three months.
If you order more than $50 &#; by adding literally anything else from the catalog alongside one bottle of LIPO Berberine &#; you&#;ll unlock free USPS First Class shipping to the United States. Renue also offers free shipping to the United Kingdom and Australia (orders over $89), as well as most other countries (orders over $250). If you don&#;t want to add anything else to your purchase, there&#;s a flat shipping charge:
- United States: $4.95
- United Kingdom: $11
- Australia: $22
- Most other countries: $29
Renue By Science will not ship to Mexico, Spain, Russia, Ukraine, or the United Arab Emirates, but it will send its products to any other country.
The website is not clear on the company&#;s return policy but states that it guarantees 100% customer satisfaction. After reaching out to the company&#;s customer support, we were told that there is no defined return window and that any unopened product can be returned for a refund. We suggest contacting the customer support team via or live chat if you have questions regarding your purchase. But given the uncertainty about the greater absorption of liposomal berberine, you won&#;t know how it makes you feel until you try it.
Toniiq Berberine 97%
Runner-up for best overall
A study found that 60% of tested berberine supplements failed to meet the potency standards of 90-110% of what is claimed on the label.39 Toniiq uses an extraction process that aims to ensure a highly purified product. Toniiq&#;s Berberine 97% is produced from Himalayan Berberis aristata root (Indian barberry). Each serving contains a scientifically supported dose of 500mg, and the company claims it is an 82:1 concentrated product, promising to deliver more of the berberine that you are seeking. Something to consider is whether or not such a highly concentrated product would be more likely to cause some of the undesirable GI side effects of berberine. If you know you are sensitive to berberine, you may want to keep that in mind when considering your options. The uncertainty here is partly why Toniiq didn&#;t become our overall top pick for most people.
One downside is that while the berberine is thoughtfully sourced for purity, the capsules themselves do contain some additives (microcrystalline cellulose, vegetable magnesium stearate, and silicon dioxide). While none of these additives are unusual, there are other options out there if you are seeking a 100% berberine, additive-free product, such as the PureBulk Berberine HCl Powder.
We like that Toniiq products are made in a cGMP- and NSF- certified lab and that the company is transparent about its testing protocols. It utilizes a randomized third-party testing program and has a certificate of analysis for every lot produced. The berberine certificate of analysis is available and easy to find on the product page, and the company is willing to share third-party lab results upon request.
Pricing
Toniiq&#;s Berberine 97% comes in just one size option, a 90-capsule bottle for $24, which is one of the more affordable options among our top picks. (Our top budget pick, Puritan&#;s Pride, is $0.20 per serving versus Toniiq&#;s $0.27 per serving.) A serving size is one 500mg capsule, but the suggested use is one capsule up to three times a day. This means one bottle can last you anywhere from one to three months, depending on your preferred dosing schedule.
Toniiq offers a subscribe and save program that allows you to save 15%. You can choose between 30-, 60-, or 90-day delivery. The company also offers a 60-day money-back guarantee &#; refund requests are limited to three individual products and must be after two weeks of use. Toniiq doesn't require you to ship the product back if you decide it&#;s not going to work for you; instead, it asks that you pass it on to someone else who might benefit from using it.
The biggest downside with Toniiq (and the chief reason why it is only the runner-up for best overall berberine supplement) is its shipping policy. The company only offers free shipping for purchases over $99, which is pretty steep. So unless you are stocking up on multiple supplements or several bottles of berberine, you will be absorbing the shipping cost. We found that orders are shipped via USPS, DHL, or UPS, depending on your location, and the cost is not a flat rate. Our reviewer&#;s shipping cost was $13, so it&#;s definitely something to consider when exploring your berberine options.
Oregon&#;s Wild Harvest Oregon Grape Capsules
Best organic
Oregon grape root is one of the best plant sources of berberine. It&#;s widely used in oral and topical formulas, addressing everything from an upset stomach to irritation-related rashes. Oregon&#;s Wild Harvest bundled Oregon grape root into a capsule to capitalize on the plant&#;s berberine content, providing you with a supplement made exclusively from natural sources.
Each plant-sourced capsule contains 1,140mg of organic Oregon grape root and nothing else. You&#;ll need to take three capsules daily for one serving, and there are 30 servings (90 capsules) per container.
The biggest downside of this supplement is that there&#;s no listed berberine content. Similar plants like barberry and goldenseal have anywhere from 0.5% to 13% berberine, putting the estimated berberine range per serving between 5mg and 150mg. This is a wide range and also a relatively low dosage, but you may find that other antioxidants and phytochemicals in the Oregon grape root make up the difference. Oregon&#;s Wild Harvest is aware of this flaw and has said that the company is actively working on testing and measuring the berberine content per serving. If you would prefer to know exactly how much berberine you are consuming in a clean formula, our other top pick that doesn&#;t contain additives (PureBulk) might be a better option for you.
Oregon&#;s Wild Harvest performs every step of the manufacturing process in-house, from growing the herbs and packaging to testing and shipping. While it does not appear that the company uses third-party quality testing, it does verify quality and potency on every batch and processes its herbs in facilities compliant with USDA standards.
Pricing
These Organic Oregon Grape Capsules are sold in one size, containing 90 capsules (30 servings). You can purchase it as a one-time order or join the company&#;s subscription program to save 15% on every order. For each bottle, you&#;ll pay the following prices:
- One-time order: $20.95
- Subscribe & save: $17.81
With the subscription program, you can choose exactly when you want your new bottle delivered and how often. You can also skip refills and cancel the subscription altogether with little hassle. You can choose your delivery frequency to be every 1, 2, 3, 4, 8, 13, or 26 weeks, depending on your needs.
Free shipping kicks in when you spend $50 or more. If you&#;re just looking for one (or two) bottles of Organic Oregon Grape Capsules, you&#;ll be charged depending on how much you order and where it&#;s shipping. On average, expect to pay about $6 in shipping (slightly less if you live on the West Coast and slightly more if you live on the East Coast).
If you aren&#;t happy with your order, you can return it for a refund or exchange it within 60 days of purchase. But the amount you&#;ll get back (or in credit) depends on the quantity you return unopened; if you want a full refund, send your supplements back unopened in the original container.
Nutricost Berberine Capsules
On the expensive side
Contains additives
Nutricost has an extensive catalog and a history of well-performing supplements. The company&#;s Berberine Capsules continue this trend, offering 600mg of Indian-barberry-derived berberine in every capsule. The serving size is two capsules, giving you a dose of mg of berberine. However, when the cost is broken down, at $0.90 per mg serving, Nutricost is not quite as cost-effective as some of our top picks. For example, Toniiq Berberine 97% is $0.27 per one 500mg serving, and some quick math tells us that a mg dose (equivalent to Nutricost) would be just $0.65.
This berberine supplement also includes silica, magnesium stearate, and microcrystalline cellulose, so if you&#;re looking for a completely clean supplement, you may want to look elsewhere. However, these ingredients are relatively common in supplements, so it&#;s not anything alarming; instead, it just means there&#;s a little more than just berberine inside.
Nutricost&#;s supplements are all manufactured in a GMP-certified facility and are tested for purity, potency, and quality by a third party, although the certificates are not readily available, unlike some of our other top picks.
Nutricost berberine was formerly our top pick for most potent due to its 600mg-per-capsule dosing. However, Nutricost is eclipsed by Renue by Science, thanks to its liposomal formula and subsequently more robust absorption. If a person absorbs one percent of Nutricost&#;s 600mg dose, that&#;s 6mg absorbed. But if clinical research is a valid indicator and the liposomal berberine from Renue by Science does indeed absorb at a rate 16 times higher than average berberine absorption, then the smaller 150mg dose from Renue by Science would result in absorption of 24mg of berberine (four times the amount you get from a dose of Nutricost). Nutricost also fell down the ranks due to its pricing per dosage and apparent change in return policy from a 90-day to a 60-day time window.
Pricing
Like its other supplements, Nutricost keeps its berberine purchasing options simple and streamlined; the company only offers one size bottle containing 30 servings for $26.95. Since our last review, Nutricost has added a subscribe and save option, allowing you to save 15%. The subscription is run through Recharge, a third-party service that allows you to choose exactly when you want your new bottle delivered and how often. You can also skip refills and cancel the subscription altogether with little hassle. All subscriptions automatically refill once a month, but it&#;s easy to space it out (or push deliveries closer together) depending on your needs.
You can get free shipping in the U.S. if you order $59 or more worth of Nutricost products. Otherwise, standard shipping costs $7; prices vary for international orders. And if you aren&#;t happy with your berberine capsules, reach out to Nutricost to get your refund started. You can get your money back (minus the cost of shipping and handling) within 60 days of purchase.
Thorne Berberine
1,000mg of berberine in every serving
Gluten-, dairy-, and soy-free
Manufactured in NSF and cGMP-certified facilities
Tested four times in-house
Free shipping within the contiguous U.S.
Subscribe and save up to 20%
Thorne&#;s Berberine (formerly known as Berberine-500) is a clinically refined, potent berberine supplement. One serving of Thorne&#;s berberine is two capsules containing a total of 1,000mg of berberine from Indian barberry extract. Each bottle holds 60 capsules (30 servings). This provides flexibility while ensuring you&#;ll have enough berberine to get you through the month. That said, if you anticipate needing more than 1,000mg daily, you may want to order more than one bottle at a time or join Thorne&#;s subscription program.
Thorne also offers a second berberine supplement for those who need less than 1,000mg per serving. Berberine-200 (formerly Berbercap) offers 60 capsules of a 200mg dose with the same high quality at a slightly lower price ($25). However, it is worth noting that Berberine-200 contains slightly different ingredients, including leucine, and would not be appropriate for vegans.
Though not labeled as such, the 500mg berberine supplement option has no additional animal-based ingredients (just a hypromellose capsule and calcium laurate), making it vegan-friendly. It&#;s also gluten-, dairy-, and soy-free. Thorne uses NSF and cGMP-certified facilities to manufacture its berberine supplements. Thorne was the first supplement manufacturer from the United States to earn an A rating from Australia&#;s Therapeutic Goods Administration, which is well known for having some of the highest standards in the world. All Thorne supplements are rigorously tested in-house four times at various stages of manufacturing, although test results are not readily available on the product website.
Pricing
One bottle of Thorne&#;s Berberine Capsules costs $38 if you purchase it once. This breaks down into a steep $1.27 per serving, even though you are getting 1,000mg per dose. In comparison, our top budget pick, Puritan&#;s Pride, is only $0.20 per 500mg serving, which equates to $0.40 per 1,000mg. However, you can unlock savings by joining Thorne&#;s subscription program. You&#;ll save 10% on each item and 20% on subscription orders containing three or more products. However, those subscription savings only kick in after your first order. We&#;ve put together a chart below to clarify how much you&#;ll pay.
First orderSecond order and beyond
One-time purchase$38$38
Subscription (1-2 items, per bottle)$38$34.20
Subscription (3+ items, per bottle)$38$30.40
You can set up your subscription to send you a new bottle every:
- Month
- 45 days
- Two months
- Three months
- Four months
Thorne offers free shipping to all orders within the contiguous United States. Orders shipping to Alaska or Hawaii and international orders can expect a steep variable shipping fee. And if you aren&#;t satisfied with your berberine capsules for any reason, you can return them within 60 days of purchase for a full refund.
Alternatives to berberine
In addition to its impacts on diabetes and its antimicrobial properties, some of berberine&#;s greatest assets lie in its effects on heart health and inflammation. But despite its far-reaching potential health benefits, taking a berberine supplement may not be right for everyone. We&#;ve laid out some alternative options to berberine if you are seeking out a different answer for these issues.
Heart health
There is much research supporting berberine&#;s positive impacts on heart health, but luckily, there are several other options out there, too, if berberine isn&#;t right for you. Omega-3 fatty acids have anti-inflammatory properties, are known to lower triglyceride levels, and are easy-to-find supplements. You can also consume omega-3s in foods like fish and nuts; a healthy diet is one of the best things you can do for your heart health. Check out our guides on fish oil and krill oil if an omega-3 supplement sounds like something you might be interested in.
Coenzyme Q10 (CoQ10) is a naturally occurring enzyme and another popular supplement that can help prevent heart failure with long-term therapy.42 CoQ10 is also sometimes used to treat side effects from statins (which can lower the amount of CoQ10 the body makes). Folic acid is another supplement you can take that has strong evidence for heart benefits. This B vitamin helps to break down homocysteine, a known risk factor for heart disease.
Inflammation
Inflammation is at the root of many chronic diseases. Berberine appears to have benefits for many health conditions, like heart disease and obesity, and some believe that its anti-inflammatory effects are responsible. However, if you can&#;t tolerate berberine or are looking for another solution, there are many other options out there for you.
Similar to heart disease, one of the fastest and easiest ways to fight inflammation is through your diet. Refined carbohydrates, sodas, margarine, and red meat are known to be more inflammatory foods. Adding foods like berries, avocado, green tea, and fish to your diet can be a great first step. You can also supplement your diet with turmeric, ginger, fish oil, and vitamin D &#; all of which are proven anti-inflammatories that are easy to find.
Frequently asked questions about berberine
Berberine affects weight in roundabout ways. It improves insulin resistance, which leads to weight loss over time as your body lets go of its unnecessary energy stores. It might also improve the functioning of two hunger and fat-storage hormones, adiponectin and leptin, and stop fat cells from growing in the first place.
A small study found that people with metabolic syndrome who took 900mg of berberine for three months lost an average of two inches off their waist size.32 Another study found that 1,500mg of berberine daily caused obese individuals to lose an average of five pounds over 12 weeks.33 So while more research is needed, berberine appears to be effective for weight loss.
No matter how you do it, weight loss can&#;t target individual body parts. However, excess abdominal fat is associated with insulin resistance and chronic inflammation. Suppose your body stores its extra fat in your abdomen because of insulin resistance (and not diet or exercise). In that case, berberine could effectively reduce your belly fat faster than eating healthy and exercising alone.
We don&#;t yet know enough about berberine to determine whether or not it&#;s more effective than prescription medications for diabetes management, like metformin. One study from found that giving berberine to newly diagnosed diabetics lowered their blood sugar and regulated their insulin metabolism almost identically to metformin.34 A meta-analysis of 27 clinical trials found similar results but stated that larger, more controlled studies are needed to confirm their findings.3
There haven&#;t been many studies investigating berberine&#;s effects on sex hormones. Insulin resistance can raise women&#;s testosterone levels, so improving insulin resistance can naturally drop your testosterone levels into a healthier range.35 If you&#;re a woman looking to improve your estrogen levels, berberine may still do that. A recent study showed that berberine regulated estrogen, testosterone, and luteinizing hormone (LH) in rats with polycystic ovarian syndrome (PCOS).36 While much more research is needed, these results on hormone regulation are promising.
While berberine interacts with some of the same liver enzymes as alcohol, berberine might actually make it slightly safer for you to have an occasional drink or two. Berberine (particularly in the HCl form used in most supplements) appears to have protective effects on the liver, regulating inflammation and minimizing harm.37 That said, this study was performed on rats, not humans. Check with your doctor about drinking alcohol while taking berberine, especially if you have a history of liver disease.
Berberine is notorious for its lack of absorption, and only a fraction of a percent of the berberine we ingest circulates through the bloodstream. Scientists and clinical researchers aren&#;t entirely sure why our bodies are so bad at absorbing berberine, but it&#;s thought that the way our intestines and liver break it down is at play.40
However, some prebiotics and lipids (such as the sunflower lecithin in LIPO Berberine) can improve how much berberine we absorb.38 Always take berberine during the day with food &#; not only can it quash any potential gastrointestinal side effects, but it can also keep it moving through your digestive system, ensuring that as much gets absorbed as possible.
Abstract
Berberine is an isoquinoline alkaloid plant extract that is widely available as a dietary supplement in the United States and has demonstrated efficacy in the treatment of type 2 diabetes mellitus and dyslipidemia. Because of its increased use and purported pharmacological properties, potential variations in product quality could pose a barrier to berberine&#;s safety and effectiveness in clinical practice. Thus, this study evaluated the potency of dietary supplements containing berberine available in the U.S. commercial market. Fifteen unique dietary supplements containing berberine were purchased through U.S. dietary supplement vendors. For each product, berberine was extracted from 3 unique capsules and analyzed by ultra-high-performance liquid chromatography tandem mass spectrometry. Percentage content based on the product label claim was determined for each product. The average berberine content across the products was found to be 75% ± 25% of the product label claim, with product potency ranging from ±33% to 100%. Nine of the 15 tested products (60%) failed to meet the potency standards of 90% to 110% of labeled content claim, as commonly required of pharmaceutical preparations by the U.S. Pharmacopeial Convention. Evaluation of the relationship between product cost and the measured potency failed to demonstrate an association between quality and cost. Variability in product quality may significantly contribute to inconsistencies in the safety and effectiveness of berberine. In addition, the quality of the berberine product cannot be inferred from its cost.
Keywords:
berberine, dietary supplement, natural product, potency
Materials and methods
Product selection
An Internet search for commercial products advertising 400 mg to 500 mg per capsule of berberine yielded 15 available preparations. Any formulation containing additional active ingredients was excluded from the study. All products were purchased online through common retailers (e.g., Amazon) in May , and analysis was completed by July . At the time of analysis, none of the products tested had reached their expiration date according to the product labeling.
Sample extraction
The contents of three capsules from each preparation were individually weighed. The weight of the capsule contents was determined by subtracting the weight of the empty capsule from the weight of the filled capsule on a Mettler-Toledo XS3DU microbalance (Columbus, OH). A sample from each capsule containing approximately 5 mg of berberine was added to a 50 mL conical vial containing 50 mL of ACS- (American Chemical Society)grade methanol containing 0.1 mg/mL of the internal standard 1,3-diphenylguanidine (DPG) ( ), yielding a berberine concentration of approximately 0.1 mg/mL. The samples were sonicated for 15 minutes, followed by vortex shaking for 30 seconds, and finally were centrifuged at 1,500 rcf for 5 minutes. The resulting supernatant was further diluted 1:100 in ACS-grade methanol, and the sonication, vortexing, and centrifugation steps were repeated. Finally, the resulting supernatant was diluted 1:100 in 75:25 (v/v) water (H2O):acetonitrile (ACN) containing 0.1% (v/v) formic acid (FA). For determination of extraction efficiency, 500 mg cinnamon dietary supplement capsules purchased from CVS Health (Woonsocket, RI, USA) were used as a blank matrix, and berberine at concentrations ranging from 0.01 to 80 mg/mL and DPG at 0.1 mg/mL were extracted and compared to nonextracted standards.
Sample analysis
Standard stocks of berberine (0.01&#;0.2 mg/mL) were made in methanol using the US Pharmacopeial (USP) reference standard (Rockville, MD, USA). The standard stocks were diluted 1:100 into methanol, then 1:100 into 75:25 (v/v) H2O:ACN containing 0.1% (v/v) FA, as outlined in the preceding section. The calibration standards and the extracted and diluted berberine samples were analyzed by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) (Zhang et al., ). Mobile phase A consisted of 0.1% FA in H2O and mobile phase B consisted of 0.1% FA in ACN with a flow rate of 0.4 mL/min. The analytes were resolved on a Phenomenex (Torrance, CA) Luna Omega C18 column (100 × 2.1 mm, 1.6 μm, 100Å) at 25°C using the following linear gradient: isocratic hold for 0.5 minutes at 25% mobile phase B, 98% B at 5.5 minutes, and 25% B at 5.6 minutes with a re-equilibration time of 1 minute. Analytes were detected on a Waters (Milford, MA) Quattro Premier XE dual quadrupole mass spectrometer with an electrospray ionization source operated in positive ion mode and controlled by Waters Mass Lynx 4.1 software with the following settings: source/desolvation temperatures of 100°C/450°C, and source/desolvation N2 gas flow at 50 L/hr/650 L/hr. Multiple-reaction monitoring, with argon collision gas at 0.16 mL/min, was used to detect both berberine (336.4&#;320.0) and DPG (212.4&#;195.1). Optimal cone voltage/collision energy settings of 55 V/35 V and 41 V/25 V were used for berberine and DPG, respectively. The MS peaks were integrated using QuanLynx software (version 4.1, Waters Corp., Milford, MA). Sample concentrations were determined by interpolation of the analyte/internal standard peak area ratios calculated from a 7-point calibration curve ranging from 1 to 20 ng/mL of berberine.
Statistical analysis
The resulting potency data were found to display a normal distribution and were analyzed by standard parametric statistical testing. Comparison of product potency based on cost was determined by unpaired t-test analysis and by Pearson&#;s correlation analysis. A p value less than .05 was considered statistically significant. Data analysis was conducted using JMP software v11 from SAS Institute Inc. (Cary, NC).
Results
Berberine dietary supplements were purchased online from 15 unique manufacturers ( ). All of the preparations contained berberine as the sole listed active ingredient. The labeled berberine content for the preparations was either 400 mg or 500 mg per capsule. The average (± SD) monthly cost based on a dose of 800 to 1,000 mg/day for the preparations was $21.97 ± $9.18 and ranged from $8.48 to $47.40. All of the preparations were analyzed prior to the labeled expiration date.
Table 1
Product nameManufacturerLabeled content (mg)Monthly cost ($)1. Berberine 500 mgVital Nutrients.402. Organic Berberine HClPura Organics.953. Berberine-500Thorne Research.604. Berberine Metabolic SupportIntegrative Therapeutics.005. Pure BerberineLean Nutraceuticals.776.Berberine 500 mgDouble Wood.957. BerberineVitacost.358. Berberine HCLPure Science.409. Activated BerberineNutritional Concepts.. Berberine 1,000Only Natural.. Berberine Ultra ComplexLongLifeNutri.. BerberineSwanson.. Berberine HClBiotics Research Corp.. WellBetX Berberine 500 mgNatural Factors.. Dr. Whitaker Clinical Grade BerberineHealthy Directions.93Open in a separate window
To analyze the berberine content in each product, a UHPLC-MS/MS assay was developed for berberine using DPG as the internal standard ( ). The berberine USP reference standard was used to prepare the calibration standards for the assay. A capsule formulation of cinnamon was used as the matrix background for the methanol-based extraction procedure and yielded an average (± SD) extraction efficiency of 95% ± 7%. The analysis run time was 6.6 minutes and resulted in a good baseline separation of DPG and berberine as illustrated for a matrix extracted and diluted standard solution containing 10 ng/mL each of DPG and berberine ( ). The ratio of the peak area of berberine and DPG was used to construct the standard calibration curve ( ). The average coefficient of variation for the analytical assay was 5.9%.
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Three capsules from each preparation were extracted individually and assayed for berberine content. Among the products tested, the average (± SD) content of berberine was 75% ± 25% of the label claim, and the content ranged from 33% to 100% of the expected dose ( ). Of the products tested, 60% had an average berberine content of less than 90% of the label claim. Interestingly, several of the products failing to achieve 90% potency had label claims of manufacturing under Good Manufacturing Practice conditions in Food and Drug Administration inspected facilities, as well as guarantees of purity and potency.
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Analysis of product quality based on the average monthly cost failed to yield a significant relationship between quality and cost. The average (±SD) cost of products containing at least 90% of the labeled berberine content was not significantly ± different from products failing to meet the 90% potency standard ($27.21 ± $12.49 vs. $20.28 ± 5.34, respectively, p =.25). Similarly, Pearson&#;s pairwise analysis of potency, based on the label claim, and product monthly cost failed to yield a significant relationship between cost and quality (r = .17, p = .53).
Discussion
Our results demonstrate marked variability in the content of berberine among products available from U.S. manufacturers. Further, variation in quality was not associated with variability in product cost. Potency standards set forth by the USP Convention commonly require pharmaceutical preparations contain between 90% and 110% of the labeled content claim. Despite increased regulatory oversight by the FDA, dietary supplements continue to lack potency standards, resulting in significant product quality variations among commercially available preparations (Gershwin et al., ; Sarma, Giancaspro, and Venema, ). The final guidance on the Current Good Manufacturing Practices (cGMP) for dietary supplements issued by the FDA in required that manufacturers establish and document their own quality-control standards (Marcus, ). However, these regulations failed to include specific definitions regarding the purity and potency of the manufactured product. As a result, compliance with cGMP standards does not necessarily translate to the achievement of conventional product potency standards, as demonstrated in this work. Together, these findings highlight a continued shortfall in the dietary supplement industry to ensure product quality. The potential risks of these shortfalls are expected to become increasingly evident as variation in product quality results in measureable impact on the effectiveness and toxicity of these products. This translates clinically to inconsistencies in measures of disease response to therapy, such as LDL-C and HbA1c, and the presence or absence of common dose-dependent adverse effects (e.g., gastrointestinal complaints). This may become more unpredictable if patients are switching between berberine products. Since most of the products that we analyzed contained less than the stated label amount, a subtherapeutic clinical response would likely be expected.
A number of other factors must also be discussed regarding the utilization of berberine in clinical practice. Small studies, performed primarily in China, indicate that berberine is an effective agent for significantly reducing HbA1c and LDL-C. Comparable studies have not been performed in the United States; however, various favorable characteristics make berberine attractive for the clinical treatment of type 2 DM and dyslipidemia. For example, patients typically have a positive view of complementary and alternative medicine and may be more willing to add berberine to their regimen than they are to add standard agents (Vincent and Furnham, ). Other notable attributes include lower cost than many prescription medications (< $25/month), similar pharmacology to established DM and lipid therapies (e.g., GLP-1 agonists, metformin, statins) (Pang et al., ; Pirillo and Catapano, ), and presumed safety since berberine has been utilized as a traditional Chinese medicine for centuries. Conversely, few studies have established the efficacy of berberine outside of China, and although the short-term clinical trials did not report serious adverse effects, little is known regarding long-term use. Further, berberine is a substrate of common metabolic pathways and has the potential for clinically relevant drug interactions. Finally, other studies have provided mixed results regarding safety, with animal data suggesting an increase in hepatic tumors (Dunnick et al., ), while other studies, including human cell models, indicate potential anticancer benefit (Diogo et al., ). Nevertheless, well-designed, long-term randomized controlled trials are needed to better assess safety and efficacy and determine the impact of berberine on clinical outcomes.
There are limitations to our study. Primarily, we analyzed the berberine content of one individual bottle from each manufacturer. A more comprehensive approach would involve analyzing the content of multiple bottles from the same manufacturer with different lot numbers, accounting for any batch-to-batch variability.
Conclusion
Berberine is an emerging dietary supplement in the United States with multiple pharmacological properties and broad potential for clinical application. However, there is significant variation in product content among the majority of U.S. preparations analyzed, thereby hindering the agent&#;s safety and effectiveness. In addition, the quality of the berberine product should not be inferred from its cost. Presently, clinicians should be cautious when recommending berberine for any purported therapeutic treatment.
Acknowledgments
Funding
The work was supported in part by the National Institute of General Medical Sciences [P20GM and P30GM].
Biographies
&#;
Ryan S. Funk, PharmD, PhD, is Assistant Professor of Pharmacy Practice at the University of Kansas School of Pharmacy. He holds a joint appointment within the Department of Pharmacology, Toxicology and Therapeutics at the University of Kanas Medical Center. Dr. Funk received both his Pharm.D. and Ph.D. in Pharmaceutical Chemistry at the University of Kansas. Subsequently, he completed an NICHD sponsored T32 training program in Pediatric Clinical Pharmacology at Children&#;s Mercy-Kansas City under the direction of J. Steven Leeder. His current research focuses on molecular mechanisms of variability in drug response to immunologically active agents in the treatment of pediatric autoimmune disease, but has maintained an academic interest in drug formulation and analysis.
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Rakesh K. Singh, PhD, is a Senior Scientist in the Department of Pharmacy Practice at the University of Kansas School of Pharmacy. Dr. Singh received his B.S. in Pharmaceutical Sciences from the Birla Institute of Technology in India, and his Ph.D. in Pharmacology and Toxicology from the University of Kansas. He completed a postdoctoral fellowship at the University of Illinois at Chicago College of Medicine and is currently studying the biochemical pharmacology of methotrexate in autoimmune arthritis. His current research seeks to understand the role of NAD metabolism by nicotinamide phosphoribosyltranserase and signaling via the JAK/STAT pathway impact response to methotrexate.
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Robert D. Winefield, PhD, is Research Assistant Professor of Pharmacology, Toxicology and Therapeutics and the Director of the Analytical Core laboratory at the University of Kansas Medical Center. Dr. Winefield received his Ph.D. degree from Massey University in New Zealand. He completed postdoctoral training at the University of Kansas in the fields of molecular biology and bioanalytical chemistry. His current research efforts are focused on the development of custom analytical methods using UHPLC-MS/MS.
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Sylvie E. Kandel, PhD, is a Senior Scientist at the University of Kansas Medical Center. She obtained a Ph.D. in Biochemistry and Molecular Biology in the Pinot laboratory at the Institut de Biologie Moléculaire de Plantes with subsequent postdoctoral training in the laboratory of Ortiz de Montellano at the University of California, San Francisco. Following four years of industry-based pre-clinical drug development research on drug metabolism and mass spectrometry at Sekisui XenoTech, Dr. Kandel joined the University of Kansas Medical center and currently divides her time between the laboratory of Dr. Jed Lampe and the Analytical Core laboratory. In the Lampe laboratory, her current research seeks to characterize the role of CYP3A7 in drug metabolism and toxicity in neonates. Within the Analytical Core laboratory, she provides analytical support to help develop small molecule analytical methods for users of the core lab.
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Janelle F. Ruisinger, PhD, is Clinical Professor of Pharmacy Practice at the University of Kansas School of Pharmacy. Dr. Ruisinger earned her Pharm.D. degree from the University of Kansas, then completed a residency with an emphasis on community care at The Ohio State University College of Pharmacy. She is also a Clinical Pharmacist in the KU Medical Center Atherosclerosis and LDL-Apheresis Center which serves as her practice site and primary source for her practice based research.
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Patrick M. Moriarty, MD, is Professor of Internal Medicine and Division Director of Clinical Pharmacology at the University of Kansas Medical Center. Dr. Moriarty earned his M.D. at the University of Rome and completed his medical residency at the University of Kansas Medical Center. He serves as the Director of the Atherosclerosis and LDL-Apheresis Center at the University of Kansas Medical Center. His research is focused on atherosclerosis, vascular inflammation and blood rheology.
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James M. Backes, PharmD, is Associate Dean for Clinical and Medical Center Affairs at the University of Kansas School of Pharmacy. Dr. Backes earned his B.S. in Pharmacy and Pharm.D. from Creighton University. He is a professor in the Pharmacy Practice and Internal Medicine departments and serves as the Assistant Director of the Atherosclerosis and LDL-Apheresis Center at the University of Kansas Medical Center. His research focus includes the safety and efficacy of lipid-altering agents and limiting the associated adverse events. Previously studied agents include policosanol, almonds, niacin, fibrates, statins (standard and intermittently dosed), apple-pectin, vitamin D, fish oil, krill oil, and red yeast rice.
Footnotes
Declaration of interest
The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the article.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ijds.
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