What Is Hesperidin?

Hesperidin belongs to the flavanones subclass of flavonoids and is found primarily in citrus fruits, such as oranges, grapefruits, lemons, and tangerines. Research has found that citrus flavanone hesperidin has antioxidant and anti-inflammatory effects. Because inflammation plays a major role in chronic diseases, such as heart disease, the effect of hesperidin supplementation on inflammatory markers has become an area of research interest. 

This article discusses the potential uses of hesperidin. It also covers the possible side effects, precautions, dosage, and interactions of taking hesperidin supplements.

Uses of Hesperidin

Hesperidin has been studied for the following conditions:

• Cardiovascular disease (i.e., high blood pressure, stroke, and heart attack)
• Blood vessel disorders (venous ulcers and hemorrhoids)
• Metabolic disorders (type 2 diabetes and nonalcoholic fatty liver disease)
• Neurodegenerative diseases

While supplements are not to be used as a cure or treatment, read on to see what the science says.

Cardiovascular Health

Researchers in one clinical trial looked at 159 participants between 18 to 65 years with either prehypertension (a warning sign of high blood pressure) or stage 1 hypertension. Consumption of orange juice containing hesperidin and hesperidin-enriched orange juice for 12 weeks reduced systolic blood pressure (the top number indicating the maximum pressure the heart exerts when beating) and pulse pressure (an indicator of arterial stiffness) in a dose-dependent manner.

This means the more hesperidin, the lower the blood pressure. However, the study was limited in that it was conducted in participants with pre hypertension and stage 1 hypertension and thus may not be extrapolated to the general population. Another limitation was that the study was only 12 weeks long.

Recombinant tissue plasminogen activator (rt-PA) is used to treat ischemic stroke. However, it is associated with adverse effects such as symptomatic intracerebral hemorrhage (SIH), also known as bleeding in the brain. One study assessed the impact of the addition of hesperidin to rt-PA therapy on the occurrence of SIH in 341 people with ischemic stroke (blood clot blocks an artery to the brain). The study showed that treating with hesperidin decreased SIH after rt-PA treatment and improved the recovery of participants with acute brain ischemic stroke within one day of rt-PA.

Researchers conducted another clinical trial with 75 participants between 40 to 65 years who had experienced a heart attack. Daily hesperidin supplementation for four weeks decreased inflammatory markers. It also increased adiponectin (a signaling molecule regulating sugar and fat metabolism) and high-density lipoprotein cholesterol.

Researchers concluded that certain flavonoids in the diet are associated with heart health benefits. Most participants were people assigned male at birth, so the findings may not be applied to the general population.

Blood Vessel Health

In a 2015 study, researchers conducted a clinical trial of 134 individuals aged between 18 and 75 with acute hemorrhoidal disease. A mixture of flavonoids consisting of diosmin, troxerutin, and hesperidin for 12 days reduced anal pain and bleeding compared to a placebo (a treatment without any medicinal value).

Additionally, the group treated with the mixture of flavonoids experienced a more rapid, steady improvement in swelling and blood clots compared to the placebo group. After six days, the amount of oral pain medication needed by those taking the bioflavonoids was also lower. As hesperidin was combined with diosmin and troxerutin, the effect of hesperidin alone on acute hemorrhoidal disease remains unclear. 

A clinical trial in 30 adult participants with venous ulcers (open sores on the skin of the leg) showed using pycnogenol (a herbal medicine) and the diosmin/hesperidin treatments for 90 days significantly decreased the circumference of the affected limbs. Because hesperidin was combined with diosmin to manage venous ulcers, it is unclear if hesperidin alone positively affects venous ulcers. 

Metabolic Health

In a study published in 2016, researchers conducted a clinical trial in 64 individuals aged between 30 and 65 years with a history of diabetes for at least three years. Hesperidin use for six weeks improved antioxidant capacity and blood sugar control and reduced oxidative DNA damage and lipid peroxidation in people with type 2 diabetes. Further study with larger sample size is warranted to confirm the results.

Another clinical trial was conducted with 50 participants between 18 and 70 years old with nonalcoholic fatty liver disease (NAFLD). One gram of hesperidin for 12 weeks, accompanied by diet and physical activity, improved NAFLD compared to a placebo. It lowered inflammatory markers and improved lipid profiles. Further studies with a longer duration are needed to determine the long‐term outcomes of hesperidin supplementation in people with NAFLD.

Similarly, another clinical trial performed on 100 participants with NAFLD found that hesperidin and flaxseed supplementation, alone or in combination, for 12 weeks improved sugar and fat metabolism and reduced inflammatory markers. The study was limited due to its design and potential for bias.

Hesperidin alleviated diabetic neuropathy and oxidative stress, according to a rat study cited in a systematic review. More clinical trials in humans are needed to clarify the efficacy of hesperidin in alleviating diabetic neuropathy.

In a test tube (in vitro) model of retinal ganglial cells (bridging eye nerve cells), hesperidin protected against high glucose-induced cell death. Furthermore, a study in rat models found that hesperidin decreased blood sugar levels and pro-inflammatory cytokines (inflammatory markers). Nevertheless, human clinical trials are needed to verify the efficacy of citrus flavonoids, such as hesperidin, in humans. 

Cognitive Health

A clinical study in 44 healthy young adults between age 18 and 30 showed increased blood flow to the brain two hours after drinking 500 mL of citrus juice containing a little over 42 mg of hesperidin. More human clinical studies with larger sample sizes are needed to understand how hesperidin enhances cognitive function.

In a clinical trial of 37 healthy older adults between 60 and 81 years old, daily flavanone-rich orange juice containing hesperidin and narirutin showed beneficial effects on cognitive function. Furthermore, the group that consumed orange juice with higher hesperidin content had better cognitive, executive, and memory function than those with a lower amount of hesperidin.

Since this study was in healthy older adults, further research could investigate the potential for hesperidin to reduce cognitive decline in older adults or those with neurodegenerative disease. 

Animal studies indicated hesperidin improved symptoms of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, depression, and other neurodegenerative diseases. However, human clinical studies are needed to clarify hesperidin's effects in protecting and enhancing brain function for these particular conditions.

Other Uses

In addition to the potential health benefits listed above, animal and/or test tube studies suggest the following potential properties of hesperidin:

• Anti-inflammatory properties
• Antioxidant properties
• Anticancer properties
• Antimicrobial properties
• Anti-glaucoma (group of eye diseases) properties

What Are the Side Effects of Hesperidin?

Your healthcare provider may recommend you take hesperidin for specific reasons. However, consuming a supplement like hesperidin may have potential side effects. These side effects may be common or severe. 

Common Side Effects

Some hesperidin products list the following as some of the potential side effects:

• Abdominal pain
• Contact dermatitis (itchy rash caused by direct contact with a substance)
• Diarrhea
  
• Nausea

No side effects were reported in clinical studies assessing the efficacy of hesperidin supplementation on high blood pressure, hemorrhoidal disease, type 2 diabetes, and NAFLD.

In ischemic stroke, hesperidin has been shown to improve the adverse effects of rt-PA therapy.

In an animal study of male and female rats with high blood pressure, hesperidin increased urinary volume and sodium elimination but did not cause any change in potassium excretion. In short, hesperidin acted somewhat like a diuretic, or water pill. However, these same effects may not occur in humans.

High-quality studies using hesperidin would need to be done with human subjects before conclusions can be made on fluid- and sodium-excretion effects of hesperidin. 

Severe Side Effects

No serious adverse effects were reported in a study evaluating the effect of hesperidin supplementation for heart attack.

Precautions

In general, hesperidin is well-tolerated and safe. However, the following conditions were excluded in clinical trials looking into the therapeutic effect of hesperidin:

• Pregnancy or breastfeeding
• Anemia (lack of healthy red blood cells)
• History of bleeding in the brain
• Bleeding in the urinary tract or gastrointestinal tract within three weeks
• Major surgeries within two weeks
• Use of anticoagulants (blood thinners)
• Low platelet count
• Coagulation (blood-clotting) disorders

Avoid using hesperidin if you have a known allergy or intolerance to flavonoids or citrus products.

Dosage: How Much Hesperidin Should I Take?

The following doses of hesperidin were used in clinical trials for various conditions:

• Prehypertension or stage 1 hypertension: 500 mL per day of orange juice containing 345 mg per day of hesperidin (the natural hesperidin content) or enriched orange juice containing 600 mg per day of hesperidin for 12 weeks
• Improving the treatment outcomes of ischemic stroke and improving adverse effects of rt-PA therapy: Four mg per kilogram (kg) (4 mg/kg) body weight (400 mg maximum) hesperidin taken by mouth during rt-PA treatment
• Heart attack: One capsule of 600 mg of pure hesperidin taken by mouth in the morning with breakfast every day for four weeks
• Venous ulcers: One tablet of diosmin/hesperidin (450/50 mg) taken by mouth twice daily for 90 days
• Hemorrhoidal disease: One sachet (containing 300 mg each of the flavonoids diosmin, troxerutin, and hesperidin, plus 12 mg of vitamin C and inactive ingredients) of the powder diluted in half glass of water three times daily by mouth for three days; then one sachet twice daily for two days and one sachet once a day for another seven days; starting from day 13th, one tablet (which contains diosmin 300 mg, troxerutin 300 mg, hesperidin 100 mg plus inactive ingredients) by mouth daily for a month 
• Type 2 diabetes: One capsule of hesperidin 500 mg taken by mouth once per day for six weeks
• Nonalcoholic fatty liver disease: Two capsules of hesperidin 500 mg taken by mouth daily for 12 weeks, for a total daily hesperidin dose of 1 g
• Cognitive function: 500 mL of citrus juice containing 42.15 mg of hesperidin for blood flow to the brain; another study assessing hesperidin and cognitive function gave participants 250 mL of orange juice twice daily for eight weeks; the high hesperidin drink contained a daily dose of about 275 mg; the low hesperidin drink contained 32 mg daily

What Happens If I Take Too Much Hesperidin?

Based on clinical trials, no more than 600 mg of hesperidin daily was safe for humans.

However, a daily hesperidin dose of 1 gram (equivalent to 1,000 mg) has been used in NAFLD. Even though this dose is more than the daily hesperidin dose of 600 mg from other clinical trials, no side effects were reported. 

The safety of long-term use of any of these amounts remains unclear.

Interactions

Hesperidin may interact with the following medications:

• Anticoagulants/antiplatelet medications (blood thinners): Citrus sinensis (sweet orange) extracts containing hesperidin have shown anticoagulant (blood thinning) activity based on a laboratory study.
• Blood pressure medications: Hesperidin and hesperetin (a product of hesperidin) showed blood pressure–lowering effects. Therefore, taking hesperidin with blood pressure-lowering medications may cause an additive effect. 
• Calcium channel blockers: In a rat study, hesperetin reduced calcium concentration, producing a relaxant effect in blood vessels. Due to the overlapping mode of action and potential additive effect, calcium channel blockers should not be taken with hesperidin. 
• Vincristine (anticancer drug): Hesperetin, but not hesperidin, increased vincristine uptake. If you undergo chemotherapy, please consult your oncologist before starting a hesperidin or other supplements. 
• Daunomycin (also called daunorubicin): Hesperidin also interacts with daunomycin (anticancer drug) by increasing drug uptake. If you undergo chemotherapy, please consult your oncologist before starting a hesperidin or other supplements. 

It is essential to carefully read a supplement's ingredients list and nutrition facts panel to learn which ingredients and how much of each ingredient is included. Please review this supplement label with your healthcare provider to discuss potential interactions with foods, other supplements, and medications.

How to Store Hesperidin

Store hesperidin in a cool, dry place. Keep hesperidin away from direct sunlight. Discard as indicated on the packaging. Keep it out of the reach of children and pets.

Similar Supplements

Other flavonoids with antioxidant and/or anti-inflammatory properties similar to hesperidin include the following:

• Naringenin
• Eriodictyol
• Naringin
• Narirutin
• Poncirin
• Didymin
• Prunin
• Apigenin
• Diosmetin
• Luteolin
• Rhoifolin
• Diosmin
• Nobiletin
• Tangeretin
• Quercetin
• Kaempferol
• Rutin

The flavonoids listed above are similar to hesperidin in that they are citrus-derived. Hesperidin, naringenin, eriodictyol, naringin, narirutin, poncirin, didymin, and prunin belong to the flavanone subclass of flavonoids. 

Apigenin, diosmetin, luteolin, rhoifolin, and diosmin belong to the flavone subclass, while nobiletin and tangeretin belong to the polymethoxyflavone subclass. Quercetin, kaempferol, and rutin belong to the flavonol subclass. 

Depending on the uses, hesperidin can be combined with other flavonoids. For example, diosmin and hesperidin are used together to manage chronic venous disease.

Sources of Hesperidin & What to Look For

Hesperidin can be obtained via food or supplements. However, the poor absorption of hesperidin has led to an interest in developing hesperidin supplement formulations with enhanced absorption.

Food Sources of Hesperidin

Citrus fruits that are a source of hesperidin include the following:

• Lemons
• Limes
• Mandarins
• Oranges
• Grapefruits

Like other bioflavonoids, hesperidin works best when given with vitamin C.

Hesperidin from orange juice has greater availability compared to hesperidin from whole oranges. Moreover, hesperidin levels have been shown to be 3 times greater in commercially squeezed orange juice than in home-squeezed orange juice.

Citrus fruits, especially grapefruit juice, interact with certain medications. Please consult with your healthcare provider before adding them to your diet. 

Additionally, reading the nutrition fact label is essential as some juices may contain high amounts of sugar.

Hesperidin Supplements

Hesperidin is available as capsules and powders. It is also used in tablet form with other flavonoids, such as diosmin.

The absorption of hesperidin relies on the conversion of hesperidin to hesperetin (the more readily absorbed form) by bacteria in the colon. As hesperidin is composed of hesperetin (the non-sugar part) and rutinose (the sugar part), removing hesperidin's sugar to form hesperetin improves absorption.

The dependence of intestinal microbiota to convert hesperidin (the food-bound form) to hesperetin (the active form of hesperidin) suggests that the difference in gut microbiota between individuals contributes to variability in the absorption and metabolism of hesperidin.

The micronized 2S hesperidin form, found naturally in orange juice, has the highest rate and extent of absorption.

Few strategies have been developed to improve the bioavailability (how well something is absorbed) of hesperidin and hesperetin. One of the strategies involved loading hesperidin onto agents known as metallic nanoparticles and assessing it in breast cancer lab models. It was found that this formulation delivered hesperidin to tumor cells more effectively.

Another strategy involved offering hesperetin and other flavonoids, such as quercetin, to improve hesperetin absorption in breast cancer patients.

Mixing hesperidin with chitoolIgosaccharide (the degraded product of chitin, a major part of crab, lobster, and shrimp shells) enhanced hesperidin's water solubility (for greater absorption) and antioxidant effects. Furthermore, the methylated form of hesperidin, also known as hesperidin methyl chalcone, is highly water soluble.

Summary

Hesperidin, a flavonoid within the flavanone subclass, is derived from citrus fruits and has antioxidant and anti-inflammatory properties. Human and lab studies have demonstrated the therapeutic potential of hesperidin in heart disease, blood vessel disorders, metabolic disorders, and neurodegenerative diseases. 

No significant side effects have been reported in clinical studies. However, caution should be taken if you have a history of bleeding or blood-clotting disorders and if you take certain medications, such as blood thinners, blood pressure-lowering drugs, including calcium channel blockers, and certain anticancer drugs.

It is also important to note that while citrus fruits are a source of hesperidin, they can interact with certain medications. Speak with your healthcare provider to discuss whether citrus fruits are appropriate for you.