Dihydroberberine

• Improved glucose metabolism
• Enhanced insulin sensitivity
• AMPK activation
• Cellular energy regulation

• Weight management
• Lipid profile improvement
• Reduced cellular senescence
• Gut health support
• Cardiovascular health
• Reduced inflammation

Dihydroberberine (DHB) is a reduced form of berberine that serves as both a metabolite and precursor to berberine in the body. Its primary mechanism of action centers on enhanced bioavailability and improved cellular uptake compared to standard berberine. When ingested, DHB is rapidly converted to berberine in the intestinal wall, resulting in significantly higher plasma berberine levels than equivalent or even higher doses of berberine itself. This conversion process is facilitated by intestinal nitroreductases, allowing DHB to bypass many of the absorption limitations that affect standard berberine.

Once converted and absorbed, DHB/berberine activates AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis. This activation occurs through inhibition of mitochondrial respiratory complex I, which increases the AMP:ATP ratio in cells, triggering AMPK phosphorylation. Activated AMPK then orchestrates numerous metabolic processes, including enhanced glucose uptake in peripheral tissues through GLUT4 translocation, reduced hepatic glucose production, improved insulin sensitivity, and increased fatty acid oxidation. DHB also modulates the gut microbiome, potentially reducing the production of harmful metabolites like trimethylamine (TMA) that contribute to cardiovascular disease.

Additionally, DHB appears to inhibit mTOR (mammalian target of rapamycin) signaling, which may contribute to its anti-aging and anti-senescence effects by promoting autophagy and reducing cellular senescence. The compound also demonstrates anti-inflammatory properties through inhibition of NF-κB signaling and reduction of pro-inflammatory cytokines. Unlike standard berberine, DHB’s enhanced bioavailability allows for lower effective doses, reducing the gastrointestinal side effects commonly associated with berberine supplementation while maintaining or improving therapeutic efficacy.

Due to its enhanced bioavailability (approximately 5 times greater than standard berberine), dihydroberberine is typically effective at much lower doses than berberine. The standard recommended dosage range is 100-200 mg per day, which provides equivalent or superior effects to 500-1000 mg of standard berberine HCl.

Dihydroberberine is typically taken with meals to maximize its effects on postprandial glucose metabolism. Due to its improved half-life compared to berberine (approximately 8 hours vs. 4 hours), once or twice daily dosing is usually sufficient. For those taking 200 mg daily, splitting into two 100 mg doses (morning and evening with meals) may provide more consistent benefits throughout the day.

Dihydroberberine (DHB) demonstrates approximately 5 times greater bioavailability compared to standard berberine HCl. In human pharmacokinetic studies, 100-200 mg of DHB resulted in significantly higher plasma berberine concentrations than 500 mg of berberine HCl.

Already inherently more bioavailable than standard berberine, Taking with meals containing some fat may further enhance absorption, Liposomal formulations may provide additional bioavailability improvements, Combining with black pepper extract (piperine) may potentially enhance effects, though less necessary than with standard berberine

DHB is best taken with meals to maximize absorption and to directly impact postprandial glucose metabolism. Its effects last approximately twice as long as standard berberine (8 hours vs. 4 hours), allowing for less frequent dosing.

When ingested, DHB is rapidly converted to berberine in the intestinal wall by intestinal oxidoreductases. This conversion process occurs more efficiently than the absorption of standard berberine, resulting in higher plasma berberine levels.

Half Life: Approximately 8 hours, compared to 4 hours for standard berberine

Peak Plasma Time: Reaches peak plasma concentration in approximately 30-60 minutes

Duration Of Action: Maintains therapeutic effects for approximately 8 hours per dose

In a 2021 randomized, controlled, crossover pilot trial published in Nutrients, 100 mg and 200 mg doses of DHB resulted in significantly higher plasma berberine concentrations compared to 500 mg of berberine HCl. The area under the curve (AUC) for plasma berberine was approximately 5 times greater with DHB than with an equivalent dose of berberine.

The enhanced bioavailability of DHB allows for lower effective doses, which significantly reduces the gastrointestinal side effects commonly associated with berberine supplementation, such as diarrhea, constipation, and abdominal discomfort.

• Mild gastrointestinal discomfort (much less common than with standard berberine)
• Potential hypoglycemia when combined with anti-diabetic medications
• Occasional headache
• Rare allergic reactions

• Pregnancy and breastfeeding (insufficient safety data)
• Children and adolescents (insufficient safety data)
• Hypoglycemia or history of severe hypoglycemic episodes
• Severe liver or kidney disease
• Scheduled surgery (discontinue 2 weeks before due to potential hypoglycemic effects)

• Anti-diabetic medications (may enhance hypoglycemic effects)
• Oral hypoglycemic agents (may require dose adjustment)
• Insulin (may enhance effects, requiring dose adjustment)
• Medications metabolized by CYP3A4 (potential interaction, though less pronounced than with standard berberine)
• Blood pressure medications (potential additive effects)
• Statins (potential for enhanced effects, monitor closely)
• Immunosuppressants (theoretical interaction, monitor closely)

No established upper limit, but doses above 200 mg daily have not been extensively studied. Most research has focused on 100-200 mg daily doses, which appear to be well-tolerated in healthy adults.

Long-term safety data specifically for dihydroberberine is limited, as it is a relatively newer form of berberine. However, berberine itself has been used in traditional medicine for centuries with a good safety profile. The reduced dosage needed with dihydroberberine may further improve long-term safety by reducing potential cumulative side effects.

Elderly: Generally considered safe, but start with lower doses (100 mg daily) and monitor for hypoglycemia or drug interactions, as elderly individuals often take multiple medications.

Hepatic Impairment: Use with caution in mild to moderate liver impairment; not recommended in severe liver disease.

Renal Impairment: Use with caution in mild to moderate kidney impairment; not recommended in severe kidney disease.

Diabetics: May be beneficial but requires careful monitoring of blood glucose levels and potential adjustment of anti-diabetic medications.

Dihydroberberine offers a significantly improved safety profile compared to standard berberine, primarily due to the lower effective dose needed. This results in fewer gastrointestinal side effects, which are the most common complaints with standard berberine supplementation. Studies indicate that the incidence of digestive discomfort is substantially lower with dihydroberberine compared to equivalent effective doses of berberine HCl.

Dihydroberberine is regulated as a dietary supplement in the United States. Like other dietary supplements, it is not FDA-approved for the treatment, prevention, or cure of any disease. Manufacturers must ensure safety and accurate labeling but are not required to prove efficacy before marketing. The FDA can take action against unsafe products or those making unapproved disease claims.

Eu: In the European Union, dihydroberberine falls under food supplement regulations. It is not approved as a medicinal product. Regulatory status may vary between individual EU member states, with some potentially having more restrictive policies.

Canada: Health Canada regulates dihydroberberine as a Natural Health Product (NHP). Products containing dihydroberberine require a Natural Product Number (NPN) to be legally sold in Canada, which involves some evaluation of safety and quality.

Australia: The Therapeutic Goods Administration (TGA) regulates dihydroberberine as a complementary medicine. Products containing dihydroberberine must be listed or registered on the Australian Register of Therapeutic Goods (ARTG).

Japan: In Japan, dihydroberberine may be regulated as a ‘Foods with Functional Claims’ depending on the specific product formulation and claims.

China: As a derivative of berberine, which has a long history in Traditional Chinese Medicine, dihydroberberine may have a unique regulatory status in China that bridges traditional medicine and modern supplement categories.

Us: Must be labeled as a dietary supplement, include a Supplement Facts panel, list all ingredients, and cannot make disease treatment or prevention claims.

Eu: Must comply with the Food Supplements Directive and include mandatory nutrition information, warning statements, and recommended daily dose.

Canada: Must display an NPN, medicinal and non-medicinal ingredients, recommended use, cautions, and warnings.

Across most jurisdictions, marketing of dihydroberberine supplements is restricted from making specific disease treatment or prevention claims. In the US, structure/function claims (e.g., ‘supports healthy blood sugar levels’) are permitted with appropriate disclaimer statements, but claims about treating diabetes or other specific diseases are prohibited.

As a relatively new derivative of berberine, dihydroberberine faces regulatory challenges in some markets where regulatory frameworks may not have specific provisions for novel compounds derived from traditional ingredients. Some regulatory bodies may require additional safety data due to its status as a modified form of a natural compound rather than a whole herb extract.

As research on dihydroberberine expands, regulatory status may evolve. Increased clinical evidence could potentially lead to consideration as a medical food or even a pharmaceutical ingredient in some jurisdictions, though this would require substantial additional research and regulatory submissions.

International shipping of dihydroberberine supplements may be subject to varying import regulations. Consumers and businesses should verify the legal status in destination countries before importing, as some countries may have restrictions on novel supplement ingredients.

Medium to high

Dihydroberberine typically costs $0.50-$2.00 per effective daily dose (100-200 mg), depending on brand and formulation. While this is higher than many basic supplements, it must be considered in context of its enhanced bioavailability.

Despite its higher per-unit cost compared to standard berberine, dihydroberberine often represents better overall value due to several factors:

1. Enhanced bioavailability means effective doses are approximately 1/5 of standard berberine (100-200 mg vs. 500-1000 mg).

2. Reduced side effects may improve compliance and consistent use, enhancing long-term benefits.

3. The longer half-life (approximately 8 hours vs. 4 hours for berberine) allows for less frequent dosing, potentially reducing the total daily amount needed.

4. For individuals who experience digestive discomfort with standard berberine, dihydroberberine may be the only viable option, making its value proposition stronger despite higher cost.

Vs Berberine: While dihydroberberine typically costs 2-3 times more per capsule than standard berberine, the 5x greater bioavailability means that the cost per bioavailable unit is actually lower. For example, 100 mg of dihydroberberine provides similar or greater effects than 500 mg of berberine, making it approximately 40-60% more cost-effective on a bioavailability-adjusted basis.

Vs Prescription Medications: For individuals using dihydroberberine to support metabolic health, the cost is generally significantly lower than prescription medications for similar concerns, particularly for those without insurance coverage. However, it should never be used as a replacement for prescribed medications without medical supervision.

The cost of dihydroberberine has been gradually decreasing as manufacturing scales up and more companies enter the market. Early products (circa 2019-2020) were significantly more expensive than current options. This trend is expected to continue as production efficiency improves and competition increases.

Purchasing larger quantities can often reduce the per-dose cost, Some manufacturers offer subscription programs with discounted pricing, Combination products that include dihydroberberine with synergistic ingredients may provide better overall value than taking multiple separate supplements, Due to its longer half-life, some individuals may achieve desired results with once-daily dosing rather than twice-daily, potentially reducing costs

Like most dietary supplements, dihydroberberine is typically not covered by health insurance plans. However, some Health Savings Accounts (HSAs) or Flexible Spending Accounts (FSAs) may allow reimbursement if prescribed by a healthcare provider for a specific medical condition.

When evaluating the long-term economic value of dihydroberberine supplementation, potential indirect cost savings should be considered, such as reduced healthcare expenses related to metabolic health management and fewer missed workdays due to health issues. However, these potential savings are speculative and would vary significantly between individuals.

Properly stored dihydroberberine typically has a shelf life of 2-3 years from the date of manufacture, though this can vary based on specific formulation and storage conditions.

Store in a cool, dry place away from direct sunlight. Optimal storage temperature is between 59-77°F (15-25°C). Refrigeration is not necessary but may extend shelf life. Keep container tightly closed to protect from moisture and air exposure.

Exposure to heat: Temperatures above 86°F (30°C) may accelerate degradation, Moisture: Humidity can cause hydrolysis of dihydroberberine, Light exposure: Direct sunlight or strong artificial light can cause photodegradation, Oxidation: Prolonged exposure to air can lead to oxidative degradation, pH extremes: Highly acidic or alkaline environments can affect stability

Dihydroberberine is generally less stable than berberine in its pure form, which is why it’s typically formulated with stabilizers in commercial supplements. The reduced form of the molecule is more susceptible to oxidation back to berberine when exposed to air or other oxidizing conditions.

Quality dihydroberberine supplements are typically packaged in opaque, airtight containers, often with oxygen absorbers or desiccants included. Some premium products may use blister packs to protect individual doses from environmental factors until use.

High-performance liquid chromatography (HPLC) to measure active compound content over time, Accelerated stability testing under various temperature and humidity conditions, Real-time stability testing to confirm shelf life estimates, Photostability testing to assess degradation under various light conditions

For powdered forms, once reconstituted in liquid, dihydroberberine should be used within 24 hours and kept refrigerated to minimize degradation.

When traveling, keep dihydroberberine in its original container, avoid exposure to high temperatures (such as in a car on a hot day), and consider using travel pill containers with good seals if original packaging is too bulky.

Synthesis Methods

Natural Sources

Quality Considerations

Commercial Forms

Sustainability Considerations

Unlike its parent compound berberine, which has a rich history of use in traditional Chinese, Ayurvedic, and Native American medicine dating back thousands of years, dihydroberberine (DHB) is a relatively recent development in the field of nutritional supplements. DHB is not directly found in significant quantities in medicinal plants and does not have a traditional history of use as a distinct compound.

Dihydroberberine was first identified as a metabolite of berberine, produced in small amounts by gut bacteria during the digestion of berberine-containing herbs. The scientific understanding of DHB began to develop in the early 2000s, with significant research emerging around 2008 when a landmark study published in the journal Diabetes identified DHB as a more bioavailable derivative of berberine with potential therapeutic applications for metabolic health.

The deliberate production and use of DHB as a supplement is even more recent, primarily developing in the 2010s and gaining significant commercial attention in the late 2010s and early 2020s. The first branded form of DHB, GlucoVantage®, was introduced to the market around 2018-2019, marking the beginning of its commercial availability as a distinct supplement.

The development of DHB as a supplement represents a modern scientific approach to improving upon traditional herbal medicines. By identifying a more bioavailable metabolite of a traditional compound and developing methods to produce it directly, researchers and supplement manufacturers have created a more efficient version of berberine that maintains its beneficial properties while reducing side effects and required dosages.

While DHB itself doesn’t have centuries of traditional use to reference, its development is firmly rooted in the long history of berberine-containing plants in traditional medicine systems. These plants, such as goldenseal, barberry, and goldthread, were traditionally used for various conditions including digestive issues, infections, and inflammatory conditions. Modern research has validated many of these traditional uses and expanded our understanding of berberine’s mechanisms of action, particularly in metabolic health, which has directly informed the development and applications of DHB.

As a relatively new supplement, the history of DHB is still being written, with ongoing research continuing to explore its potential benefits and applications. Its development represents an interesting bridge between traditional herbal medicine and modern nutritional science, taking the wisdom of traditional plant use and enhancing it through scientific understanding of metabolism and bioavailability.

No comprehensive meta-analyses specifically on dihydroberberine exist yet, as it is a relatively newer form of berberine with fewer clinical studies compared to standard berberine.

Several clinical trials are currently investigating dihydroberberine’s effects on metabolic health, insulin sensitivity, and weight management., Research into dihydroberberine’s potential anti-aging and senolytic properties is emerging, with preliminary studies showing promise.

Long Term Studies: Longer-term human studies (>6 months) are needed to establish long-term safety and efficacy.

Diverse Populations: Studies in more diverse populations, including women, elderly, and different ethnic groups are needed.

Comparative Studies: More direct comparison studies between dihydroberberine and standard berberine at various doses would help establish optimal dosing guidelines.

Mechanism Elucidation: Further research into the precise mechanisms of dihydroberberine’s enhanced bioavailability and potential unique effects compared to berberine is warranted.

Many metabolic health experts consider dihydroberberine a significant advancement over standard berberine due to its enhanced bioavailability, reduced side effect profile, and comparable or superior efficacy at lower doses. The scientific community generally views the existing evidence as promising, though acknowledges the need for more extensive human clinical trials to fully establish its place in therapeutic applications.