Hesperetin

Hesperetin is a flavanone, a compound in the flavonoid family. In citrus fruit it mostly sits in a sugar-bound form called hesperidin. French chemist Lebreton first isolated hesperidin in 1828 from the white inner layer of citrus peel. Its name comes from hesperidium, the botanical term for a citrus fruit.

It is thought to help defend the plant. In the USDA data, lemons hold 27.9 mg of hesperetin per 100 g and oranges 27.3 mg, about 18 times more than grapefruit (1.5 mg). Peppermint has 10.2 mg.

Almost all the research on this page used hesperidin, not hesperetin. Trials give hesperidin as a supplement or in orange juice. Bacteria in the gut turn it into hesperetin, the form that reaches the blood, and each study card says which one was given.

Most readers do not know how slow this is. In 16 volunteers, blood hesperetin peaked about 7 hours after ordinary orange juice. It peaked after 0.6 hours when an enzyme had first turned the juice’s hesperidin into hesperetin-7-glucoside.

The same molecule is also the raw material for a drug. A European assessment report explains that diosmin can be made by extracting hesperidin from citrus rind and converting it. One leg-vein medicine holds 90% diosmin and 10% flavonoids counted as hesperidin. We include that drug only where the combination is named.

Health benefits of hesperetin

• ★★★Diosmin and hesperidin medicine eased heavy, painful legsIn 7 trials in chronic venous disease, the medicine Daflon (diosmin with hesperidin) beat placebo for heaviness (0.35 times the risk) and leg pain (0.53). It is a drug, not hesperetin or food.
• ★★The same medicine eased hemorrhoid symptomsPooled trials of MPFF (mostly diosmin with some hesperidin) found the odds of bleeding were 0.082 times as high and of discharge 0.12 times. After hemorrhoid surgery, 22 trials found less pain, bleeding and swelling.
• ★★Mixed effects on cholesterolIn 12 trials of hesperidin extracts, LDL cholesterol fell by 0.22 mmol/L. An earlier pool of 10 trials found no change in cholesterol or blood pressure.
• ★★Mixed effects on blood sugarOne pool of trials found fasting blood sugar fell with hesperidin. A pool of 6 trials found no change in fasting glucose or HbA1c (long-term blood sugar).
• ★★No effect on weight, fat or waistIn 11 trials of orange juice, hesperidin or both, body weight changed by -0.31 kg and waist by 0.07 cm, both within chance.

Foods high in hesperetin

Citrus is the main source. In the USDA data, lemons (27.9 mg per 100 g) and oranges (27.3 mg) lead, followed by peppermint (10.2 mg). One orange (131 g) gives 35.7 mg and one lemon (58 g) 16.2 mg, and the ranking below shows the rest.

USDA reports hesperetin, the sugar-free part, while the fruit carries it mostly as hesperidin. Orange juice is the other big source: a 500 mL portion held 345 mg of hesperidin in one trial.

Trial doses are far above a normal serving. Hesperidin weighs about twice as much as hesperetin (molar masses 610.6 and 302.3). So by our arithmetic, 500 mg of hesperidin holds about 250 mg of hesperetin, roughly the amount in 7 oranges by the USDA figure. 1,000 mg holds about 14 oranges’ worth.

That is a rough guide, since fruit varies. The ranking below is from USDA data.

How hesperetin works

Most of what we know about how hesperetin works comes from test tubes, cells and animals, and from a few small absorption trials in people. Three ideas keep coming up.

It has to be freed by gut bacteria before it can work. It nudges blood vessel cells to make nitric oxide. And it switches on the cell’s own defenses. Here is each one, and what has been seen in people.

It needs gut bacteria to set it free

Hesperidin is hesperetin with a sugar, rutinose, attached. Reviews say bacteria in the gut, mainly in the upper colon, cut that sugar off and release hesperetin.

A trial fed each form directly into the small intestine of healthy volunteers. About 80% of the hesperidin form was recovered unabsorbed, and no hesperetin metabolites appeared in blood. The glucoside form was split by the gut wall and absorbed, with only about 3% recovered. EFSA, the EU’s food safety agency, adds that only conjugated forms, such as hesperetin glucuronide, enter the blood.

That is why timing and form matter. In the juice trial below, hesperetin-7-glucoside gave twice the total exposure of natural juice. Its peak was about 4 times higher and came in 0.6 hours instead of 7.0.

A micronized 2S-hesperidin extract was also better absorbed. 70% of the dose was recovered in urine as metabolites and breakdown products, against 55% for the micronized mix and 43% for the standard mix.

People differ too. A review suggests that gut bacteria that make the enzyme alpha-rhamnosidase explain part of why trial results disagree. In 8 men, a hesperetin-7-glucoside and cyclodextrin compound gave over 100 times the blood exposure of a hesperidin and dextrin mix. That was a small non-randomized study by authors at the maker, Taiyo Kagaku.

It nudges blood vessel cells to make nitric oxide

Nitric oxide relaxes blood vessels. In cultured artery cells, hesperetin switched on the kinases Src, Akt and AMPK, which switched on eNOS, the enzyme that makes nitric oxide. It also lowered the sticking of immune cells to the vessel lining.

In a separate study on human vein cells, hesperetin raised the amount of eNOS through estrogen receptor alpha. Naringenin did not raise nitric oxide at all.

Not every test points the same way. In 16 men, a single dose of orange juice raised blood flavanone metabolites to 15.20 µmol/L in total. Vessel function still did not change. The dish studies do not show whether the amounts reached after a glass of juice are enough, and blood levels vary between people.

It switches on the cell’s own defenses

In liver cells loaded with fat, and in rats on a high-fat diet, hesperetin switched on Nrf2. Nrf2 is a control protein that tells cells to make their own protective enzymes, such as SOD and GPx. Hesperetin also held back NF-κB, a switch that turns on inflammation.

When Nrf2 was silenced, or those enzymes were blocked, the anti-inflammatory effect disappeared, so the two seem linked. A 2015 review adds that the antioxidant effect of hesperidin and hesperetin is not only direct radical scavenging. It also strengthens the cell’s own defenses, partly through an ERK and Nrf2 route. These are lab models, and they do not show that food amounts do the same in people.

What has been seen in people

The effects in people are smaller and less steady than those in dishes. In 24 people with metabolic syndrome, 500 mg of hesperidin a day raised flow-mediated dilation from 7.78% to 10.26%, which fits the nitric oxide findings. But 450 mg a day for 6 weeks in 68 overweight adults changed nothing in vessel function. Nor did 210 mg a day for 6 weeks in 37 men.

Some meta-analyses find small drops in CRP of about 0.4 to 0.6 mg/L, while others find none. Varying absorption may explain part of the mixed picture, according to one review. All of these are among the study cards above.

Is hesperetin safe? Supplements, dose and interactions

Hesperidin from citrus is a normal part of diets. EFSA notes that hesperidin has a history of use in the EU from foods and supplements. Before 1997, supplements usually gave no more than 600 mg a day. We found no upper level for plain hesperidin or hesperetin from EFSA, the FDA or NIH (US National Institutes of Health).

Glucosyl hesperidin is hesperidin with an extra glucose. In 2024 EFSA found that up to 364 mg a day was safe for adults. It based this on a no-effect level of about 1,000 mg per kg of body weight in a 90-day rodent study. Human trials up to 3 g a day for 12 weeks showed no clinically relevant blood changes. The FDA had no questions about the same ingredient (GRN 901, 2019), as EFSA reports.

• Trial doses and side effects. Trials gave 210 to 1,000 mg of hesperidin a day for 2 to 12 weeks. The trial abstracts did not highlight side effects. One meta-analysis checked, in 22 trials of the diosmin and hesperidin fraction after hemorrhoid surgery, and saw no substantial effect on adverse reactions.
• The diosmin and hesperidin drug. A Hungarian assessment report describes a 450 mg diosmin and 50 mg hesperidin tablet, authorized in EU states under well-established use. It is a prescription-only medicine for chronic venous insufficiency and acute hemorrhoidal crisis. A review of its trials found the most common adverse events were digestive and autonomic. It is a drug, so use it under medical advice.
• Drug interactions. We found no controlled human study of hesperidin supplements with prescription drugs. The risk is unknown rather than shown to be absent, so ask a pharmacist if you take regular medicines.
• Pregnancy, breastfeeding and children. We found no safety trials of hesperidin supplements in pregnancy or breastfeeding. EFSA’s glucosyl hesperidin opinion covered children from age 1, but that is a different ingredient, so ask a doctor.

How to get more hesperetin

• Best food. Oranges and lemons, at 27.3 and 27.9 mg per 100 g, hold about 18 times more than grapefruit (1.5 mg). One orange gives 35.7 mg.
• Juice or fruit. Juice worked as a carrier. In 16 men, a juice raised flavanone metabolites to 15.20 µmol/L, while a hesperidin supplement matching its dose did not differ from control. In a newer trial of 37 men, juice and a 210 mg hesperidin drink gave comparable blood exposure.
• Food versus supplement. A form with the sugar changed gives faster, higher absorption. Micronized 2S-hesperidin gave 70% urinary excretion against 43% for a standard mix. Trial doses of 450 to 1,000 mg of hesperidin are many oranges’ worth, and results were mixed.

History of hesperetin

The story starts with hesperidin. French chemist Lebreton first isolated it in 1828 from the white inner layer of citrus peel. The name comes from hesperidium, the term for fruit of citrus trees, and hesperetin is what is left when the sugar is removed.

EFSA notes that hesperidin is still isolated from citrus peels, juice or seeds. A 2001 review called it an abundant, inexpensive by-product of citrus growing.

A drug grew out of it. A Hungarian assessment report says diosmin was first isolated in 1925 and has been used in medicine since the 1960s. It was first marketed in Europe in 1971 and reformulated in micronized form in 1986.

Diosmin differs from hesperidin by one double bond and can be made from it. That drug is the only hesperidin-related product with strong evidence on this page.

Supplements and cohort science came later. EFSA reports hesperidin supplements in the EU before May 1997, usually not above 600 mg a day. Glucosyl hesperidin has been sold in Japan since 1998, about 20 tons a year.

In 2007, a US study of 34,489 women used USDA flavonoid databases to link flavanone intake to fewer deaths from coronary heart disease. In 2024 EFSA concluded glucosyl hesperidin was safe up to 364 mg a day.

Frequently asked questions about hesperetin

What does hesperetin do for the body?

Most of the evidence is on hesperidin, the form in oranges, and it is mixed. One analysis of 12 trials found LDL cholesterol down 0.22 mmol/L and CRP down 0.56 mg/L. Another, of 10 trials, found no change in cholesterol or blood pressure. Only a drug, diosmin with hesperidin, reached strong evidence, for leg vein disease, and almost all results come from supplements, not food.

Is hesperetin the same as hesperidin?

No. Hesperidin is hesperetin with a sugar attached, and the sugar must be cut off by gut bacteria before hesperetin is absorbed. In 16 volunteers, blood hesperetin peaked after 7.0 hours with natural orange juice and 0.6 hours when the juice held hesperetin-7-glucoside. Nearly every trial on this page gave hesperidin.

Which foods are high in hesperetin?

Lemons (27.9 mg per 100 g) and oranges (27.3 mg) lead the USDA data, and peppermint has 10.2 mg. The ranking above shows the rest. Per serving, one orange gives 35.7 mg and one lemon 16.2 mg. Orange juice is a source too, with 345 mg of hesperidin in 500 mL in one trial.

How much hesperidin should you take a day?

No dose is proven best. Trials used 210 to 1,000 mg a day, and one analysis found about 1,000 mg the most effective for blood fats and pressure. We found no upper level from EFSA, the FDA or NIH for plain hesperidin. EFSA reports that supplements before 1997 usually stayed under 600 mg. Talk to a clinician before going higher, especially if you take medicines.

Does hesperidin lower blood pressure?

Results disagree. A meta-analysis of 10 trials found systolic pressure only 0.85 mm Hg lower, within chance. Two newer analyses found a clear drop in systolic pressure. In 24 men, 500 mL of orange juice a day for 4 weeks lowered diastolic pressure. In a 64-person diabetes trial, 500 mg a day lowered systolic pressure from 122.7 to 119.0.

Does hesperidin or hesperetin have side effects?

Few have been reported, but the trials are short. EFSA saw no clinically relevant blood changes in trials of glucosyl hesperidin up to 3 g a day for 12 weeks. For the diosmin and hesperidin drug, the most common events were digestive. We found no studies in pregnancy or of interactions with medicines, so ask a doctor or pharmacist.

What is diosmin, and how does it relate to hesperetin?

Diosmin is a flavone that can be made from hesperidin. The purified fraction sold as Daflon is 90% diosmin and 10% flavonoids counted as hesperidin. In 7 placebo-controlled trials with 1,692 patients it eased leg heaviness, swelling and pain, and in a hemorrhoid analysis it cut bleeding. These results are for the drug combination, not for hesperetin.

Is orange juice or a hesperidin supplement better?

Neither is proven. In 16 men, juice raised blood flavanone metabolites and a supplement matching its dose did not. In 37 men, juice and a 210 mg hesperidin drink gave comparable levels, and neither improved vessel function. No trial tested time of day, but one found blood hesperetin peaking about 7 hours after natural orange juice.