Evidence Based
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10 Health Benefits of Hesperidin + Sources & Side Effects

Written by Carlos Tello, PhD (Molecular Biology) | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Carlos Tello, PhD (Molecular Biology) | Last updated:

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hesperidin

Hesperidin, a flavonoid found in orange peels, has many potential benefits. They include relieving the symptoms of vessel conditions such as chronic venous insufficiency and hemorrhoids, lowering blood pressure, and helping with diabetes and its complications. Read below to learn about these and other potential health benefits of this glycoside.

What Is Hesperidin?

Hesperidin is a flavonoid glycoside mainly found in citrus fruits such as oranges and tangerines. Upon consumption, hesperidin is degraded by gut bacteria in the colon [1, 2].

A similar flavonoid also found in citrus fruits is hesperetin. Some studies use hesperetin instead of hesperidin, often because the injection of synthetic hesperetin produces faster effects than consuming very high amounts of hesperidin [3].

Sources

Citrus Fruits [1, 4]:

  • Oranges
  • Tangerines
  • Lemons
  • Limes
  • Citrus fruit hybrids
  • Sun-dried tangerine peels

Various Herbs and Plants:

  • Ramie (Boehmeria nivea) [5]
  • Dangshen (Codonpsis pilosula) [6]
  • Japanese catnip (Schizonepeta tenuifolia) [7]
  • Indian valerian (Valeriana wallichii) [8]
  • Honeybush (Cyclopia subternata ) [9]
  • Nanche (Byrsonima crassifolia) [10]
  • Peppermint (Mentha × Piperita) [11]

Health Benefits of Hesperidin

Likely Effective for:

1) Chronic Venous Insufficiency

Chronic venous insufficiency, commonly known as varicose veins, is a condition in which the walls and valves in the veins fail to work. As a result, the blood cannot be returned to the heart and pools in the legs, increasing blood pressure until the smallest blood vessels (capillaries) burst. This can cause local inflammation and tissue damage, swelling, and even ulcer formation [12, 13].

Chronic venous insufficiency can generally be improved with non-invasive procedures such as wearing compression stockings, avoiding tight clothes, exercising more, losing weight, elevating the legs, and avoiding long periods of sitting or standing [14].

In more severe cases, the doctor may suggest procedures such as sclerotherapy, laser treatments, catheter-assisted procedures, vein stripping, phlebectomy, or endoscopic vein surgery [14].

Daflon is a purified citrus flavonoid mixture containing 10% hesperidin and 90% diosmin. Daflon administration inhibits the inflammatory response and free radical production in the vessels, reducing swelling and protecting their tissues [12, 15].

Six clinical trials on almost 500 people with chronic venous insufficiency found that Daflon improved capillary resistance, ulcer healing, vein elasticity, and blood flow [16, 17, 18, 19, 20, 21].

Another mixture with hesperidin, vitamin C, and butcher’s broom (Ruscus aculeatus) extract (Cyclo 3 Fort) also improved chronic venous insufficiency symptoms in a meta-analysis of 25 studies and over 10,000 people [22].

All in all, the existing evidence suggests that both Daflon and Cyclo 3 Fort improve chronic venous insufficiency symptoms. Note, however, that neither of them is approved by the FDA for this condition. Consult your doctor before taking hesperidin-containing supplements for chronic venous insufficiency.

2) Hemorrhoids

Hemorrhoids are swollen veins in the anus and rectum, similar to varicose veins. Hemorrhoids are often relieved by eating high-fiber foods, applying over-the-counter ointments or suppositories, regularly soaking them in warm water, and taking oral painkillers. Hemorrhoids with persistent pain or bleeding may be treated with minimally invasive procedures such as rubber band ligation, sclerotherapy, or coagulation techniques. Severe cases that don’t respond to these procedures may require surgical removal or stapling [23].

A flavonoid mixture with 10% hesperidin and 90% diosmin (Daflon) improved hemorrhoid symptoms such as pain, bleeding, heaviness, itching, and anal discharge in clinical trials on over 700 people. Daflon also reduced pain and bleeding after the surgical removal and stapling of hemorrhoids in 2 trials on almost 300 people [24, 25, 26, 27, 28, 29, 30, 31].

Similarly, the mixture of hesperidin with other flavonoids (such as diosmin, troxerutin, rutin, and quercetin) reduced pain, swelling, bleeding, and painkiller use in 2 clinical trials on over 200 people [32, 33].

As in the previous case, evidence suggests that Daflon and other hesperidin-containing flavonoid mixtures may improve hemorrhoid symptoms, but none of them is approved for this condition. You may discuss with your doctor if these supplements may help in your case.

Possibly Effective for:

1) Reducing Inflammation

Both orange juice and a drink with hesperidin reduced the production of pro-inflammatory proteins by white blood cells in a small trial on 10 people. In 4 clinical trials on over 200 people, supplementation with hesperidin reduced inflammation caused by conditions such as heart attack, non-alcoholic fatty liver disease, type 2 diabetes, and metabolic syndrome [34, 35, 36, 37, 38].

Hesperidin also reduced the levels of inflammatory cytokines and messengers in rats and cells [39].

Although the results are promising, further clinical research is needed to establish how to use hesperidin in inflammatory conditions. You may discuss with your doctor if it may help in your case.

2) Reducing Oxidative Damage

Both hesperidin and hesperetin function as antioxidants. They both have radical scavenging activity, meaning they stop free radicals from damaging cells [39].

In a clinical trial on 16 healthy people, a mixture of citrus flavonoids increased antioxidant activity after meals, which may help prevent chronic disease development [40].

In another trial on 25 men with high blood cholesterol, orange juice increased antioxidant activity and blood hesperetin levels. This may help prevent heart disease by preserving blood vessel function [41].

In 2 clinical trials on 28 people with type 1 diabetes and 64 with type 2 diabetes, oral hesperidin increased total antioxidant capacity while reducing DNA and fatty molecule damage by free radicals [42, 43].

Hesperidin had significant radical scavenging activity in red blood cells and stopped hydrogen peroxide from damaging their membranes. It also protected several tissues from DNA damage, possibly helping prevent diabetic complications [39].

All in all, limited evidence suggests that hesperidin may help prevent oxidative damage by scavenging free radicals.

3) Lowering Blood Pressure

Oral hesperidin lowered blood pressure and improved blood vessel function in 2 clinical trials on almost 100 overweight but otherwise healthy men [41, 44].

Similarly, hesperidin lowered blood pressure and reduced inflammation in one trial on 64 people with type 2 diabetes and improved blood vessel function in one on 24 people with metabolic syndrome [37, 38].

The similar flavonoid hesperetin promoted blood vessel widening in a small trial on 10 women and a cell-based study [45].

Although promising, the evidence to support the role of hesperidin in blood pressure lowering is still limited. Further research is needed to determine how to effectively use it for this purpose. Do not take hesperidin or citrus fruits instead of the blood pressure-lowering medication prescribed by your doctor.

4) Diabetes

Daily consumption of orange juice lowered blood sugar in a small trial on 10 apparently healthy women. Similarly, a supplement with hesperidin and other citrus flavonoids (Eriomin) reduced blood sugar, insulin resistance, systemic inflammation, and oxidative stress in a trial on over 100 pre-diabetic people, helping reverse this condition [46, 47].

In diabetic rats, oral hesperidin mildly decreased blood glucose levels and helped prevent eye damage (retinal vasculopathy) [48].

Hesperidin may also help prevent diabetic complications by reducing oxidative damage, as seen in 2 clinical trials on 28 people with type 1 diabetes and 64 people with type 2 diabetes [42, 43].

To sum up, limited evidence suggests that hesperidin and other citrus flavonoids may help with diabetes and its complications. You may discuss with your doctor if this compound may help in your case. Never use it to replace what your doctor recommends or prescribes.

Insufficient Evidence for:

1) Weight Loss

Hesperidin and p-synephrine (part of bitter orange extract) increased the rate at which the body burns calories (metabolic rate) in a clinical trial on 50 volunteers [49].

A combination of a water-soluble form of hesperidin (glucosyl-hesperidin) and caffeine reduced stomach fat, body weight, and BMI in another trial on 75 moderately overweight people [50].

Hesperidin increased adiponectin, a protein hormone that helps control glucose and fat energy production, in diabetic rats. Increasing adiponectin may help prevent fat buildup and ultimately obesity [51].

Because only 2 clinical trials and a study in animals have been conducted, there is insufficient evidence to support the use of hesperidin to promote weight loss.

2) Lowering Blood Cholesterol

Eating citrus fruits or drinking their juice lowered blood cholesterol levels in 10 trials on over 500 people [52, 53, 54, 55, 56, 57, 58, 59, 60, 61].

However, the actual contribution of hesperidin to this effect is less clear and probably needs to act synergistically with other citrus flavonoids. A clinical trial on 65 people found that hesperidin reduced LDL oxidation, which helps prevent cholesterol buildup in the arteries. Conversely, both hesperidin and another citrus flavonoid (naringin) failed to lower cholesterol in a trial on over 200 people with high blood cholesterol [62, 63].

In rats fed a high-cholesterol diet, hesperidin supplementation reduced total cholesterol levels by preventing both its production and uptake [64].

To sum up, while the cholesterol-lowering effects of citrus fruits are proven, the contribution of hesperidin is less clear until further clinical research is conducted.

3) Protecting the Brain

Hesperidin’s antioxidant properties may protect the brain from oxidative damage [39].

In a clinical trial on 37 healthy elderly people, consuming orange juice enriched in hesperidin and other flavanones for 8 weeks significantly improved cognitive function [65].

In rats, pre-treatment with hesperidin and curcumin protected the brain against a sugar that causes oxidative damage in the brain (D-galactose). It reduced cognitive impairment by preventing nerve cell death [66].

In mice with Alzheimer’s disease, hesperidin administration reduced symptoms such as learning and memory problems or reduced physical activity [67].

Pre-treatment with hesperidin and L-arginine slightly protected against memory loss in rats recovering from a stroke [68].

All in all, a small clinical trial and some animal studies are insufficient to claim that hesperidin protects brain function. Larger, more robust clinical research is needed to confirm these preliminary findings.

4) Preventing Bone Loss

Estrogen deficiency during menopause causes bone loss and osteoporosis. In a clinical trial on 12 healthy postmenopausal women, a hesperidin supplement combined with calcium prevented bone loss. However, hesperidin alone was only effective in mice. In these animals, it reduced the amount of the cells that break down bone tissues to release minerals (osteoclasts) [69, 70].

Androgen deficiency can also cause bone loss. Male androgen-deficient mice fed a diet with hesperidin had less bone loss compared to mice fed a normal diet [71].

In the body, the gut microbiota transforms hesperidin into hesperetin-7-glucuronide. Its administration in rats helped increased bone cell formation [72].

Again, a small clinical trial and a few animal studies cannot be considered sufficient evidence that hesperidin prevents bone loss. Further clinical research is required.

Animal and Cell Research (Lack of Evidence):

No clinical evidence supports the use of hesperidin for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed should not be interpreted as supportive of any health benefit.

Depression

In rats with stress-induced depression, oral hesperidin reduced depressive symptoms. This may be due to the control of the HPA axis, which is a stress response system [73].

The opioid system is also a contributing factor to major depression. Hesperidin reduced depressive symptoms, possibly by interacting with this system, in mice [74].

Hesperidin also lowered glucose and inflammation levels in diabetic rats, which enhanced brain function and reduced depressive symptoms [75].

Stress and Anxiety

Stress increases oxidative damage in the body and activates the HPA axis. Hesperidin’s antioxidant activity helped reduce stress in mice [76].

Pain

Hesperidin helped reduce pain in mice with pain due to prolonged inflammation. It stopped cytokine production by blocking NF-κB activity [77].

A combination of hesperidin and diosmin relieved pain caused by nerve cell damage in rats [78].

Skin Health

Topical hesperidin balanced the skin barrier function and stimulated skin cell production in healthy mice [79].

A topical formulation with a hesperidin-derived compound (hesperidin methyl chalcone) reduced inflammation and oxidative damage caused by UV radiation in mice and cells [80].

Sedative

A study found that valerian plants produce hesperidin and another flavonoid (6-methylapigenin). Both compounds had sedative effects in rats [81].

Further animal studies found that hesperidin enhances the sedative and pain-relieving effects of diazepam, possibly by interacting with opioid receptors [82, 83].

Allergies

Oral ingestion of hesperidin in mice helped stop allergic reactions in asthmatic mice [84].

Cancer

Below, we will discuss some preliminary research on hesperidine’s potential anticancer activity. Remember that many substances have anticancer effects in cells, including downright toxic chemicals like bleach. This doesn’t mean that they have any medical value. On the contrary, most substances (natural or synthetic) that are researched in cancer cells fail to pass further clinical trials due to a lack of safety or efficacy.

Both hesperidin and hesperetin may neutralize reactive oxygen species, possibly preventing oncogenes from turning healthy cells into cancerous cells. For instance, hesperidin injection protected rats from the oxidative damage caused by gamma-radiation [39, 85].

In rats, orange and satsuma mandarin juice enriched in hesperidin significantly reduced the incidence of colon and lung cancer [4].

In male rats with colon cancer, hesperidin administration stopped tumor growth and promoted cancer cell death [86].

Additionally, hesperidin stopped the growth and spreading of lung cancer cells. It blocked blood vessel formation, which contributes to tumor growth [86].

Side Effects of Hesperidin

In clinical trials, hesperidin and juices or fruits containing this flavonoid were generally safe and only occasionally caused mild digestive effects such as diarrhea, stomach pain, and upset digestion.

Similarly, its combination with diosmin (Daflon) caused no major side effects in clinical trials [25, 87].

Hesperidin can slow blood clotting and increase blood flow, which may help prevent heart disease but also worsen bleeding disorders or increase the risk of bleeding in people undergoing surgical procedures [88].

Because it may lower blood pressure, people with diagnosed low blood pressure may want to avoid hesperidin to prevent their pressure from dropping to too low values [41, 44].

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About the Author

Carlos Tello

Carlos Tello

PhD (Molecular Biology)
Carlos received his PhD and MS from the Universidad de Sevilla.
Carlos spent 9 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and non-academic audiences. He strongly believes that scientific literacy is crucial to maintain a healthy lifestyle and avoid falling for scams.

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