Rutgers Cancer Institute of New Jersey
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Citrus fruits are well known for providing ample amounts of vitamin C. But they also supply bioflavonoids, substances that are not required for life but that may improve health. The major bioflavonoids found in citrus fruits are diosmin, hesperidin, rutin, naringin, tangeretin, diosmetin, narirutin, neohesperidin, nobiletin, and quercetin.
This article addresses the first five bioflavonoids listed above. Please see the article Quercetin for information on this supplement. A modified form of rutin, oxerutin, is also discussed in its own article.
Citrus bioflavonoids and related substances are widely used in Europe to treat diseases of the blood vessels and lymph system, including hemorrhoids, chronic venous insufficiency, leg ulcers, easy bruising, nosebleeds, and lymphedema following breast cancer surgery. These compounds are thought to work by strengthening the walls of blood vessels. Bioflavonoids are also often said to act as antioxidants; however, while they do have antioxidant activity in the test tube, growing evidence suggests that they do not act as antioxidants in people.45
Citrus fruits contain citrus bioflavonoids in varying proportions. Even different brands of citrus juice may vary widely in their bioflavonoid concentrations and composition.1 For use as a supplement, bioflavonoids are extracted either from citrus fruits or other plant sources, such as buckwheat.
A typical dosage of citrus bioflavonoids is 500 mg twice daily. The most studied citrus bioflavonoid treatment is a special micronized (finely ground) combination of diosmin (90%) and hesperidin (10%).
At least one good double-blind trial found diosmin and hesperidin also to be helpful for individuals who develop bruises or nosebleeds easily.13
Note : Do not use bioflavonoid combinations containing tangeretin if you are taking tamoxifen for breast cancer.
In addition, highly preliminary evidence suggests that citrus bioflavonoids may help reduce cholesterol levels,15,16 control inflammation,17,36 benefit people with diabetes,18 and reduce allergic reactions,19 and prevent cancer.
A 2-month, double-blind, placebo-controlled trial of 120 individuals with recurrent hemorrhoid flare-ups found that treatment with combined diosmin and hesperidin significantly reduced the frequency and severity of hemorrhoid attacks.21 Another double-blind, placebo-controlled trial of 100 individuals had positive results with the same bioflavonoids in relieving symptoms once a flare-up of hemorrhoid pain had begun.22 A 90-day, double-blind trial of 100 individuals with bleeding hemorrhoids also found significant benefits for both treatment of acute attacks and prevention of new ones.23 Finally, this bioflavonoid combination was found to compare favorably with surgical treatment of hemorrhoids.24 However, less impressive results were seen in a double-blind, placebo-controlled study in which all participants were given a fiber laxative with either combined diosmin and hesperidin or placebo.25
Two studies claimed to find that diosmin/hesperidin reduces pain after hemorrhoid surgery.38,39 In fact, these studies show little to nothing, as the researchers failed to use a placebo group, and simply compared treated participants to untreated participants. (For information on why this matters, see Why Does this Database Rely on Double-Blind Studies?)
Overall, the evidence remains incomplete, though promising.43
A 2-month, double-blind, placebo-controlled trial of 200 people with relatively severe chronic venous insufficiency found that treatment with diosmin/hesperidin significantly improved symptoms as compared to placebo.34
Another double-blind, placebo-controlled trial of diosmin/hesperidin enrolled 101 people with relatively mild chronic venous insufficiency.35 The results showed little difference between the two groups; the authors theorize that diosmin/hesperidin might be more effective in severe chronic venous insufficiency.
A 2-month, double-blind, placebo-controlled trial evaluated the effects of diosmin/hesperidin in 107 people with nonhealing leg ulcers (sores) caused by venous insufficiency or other conditions.26 The results indicated that treatment significantly improved the rate of healing.
Also, a 3-month, double-blind, placebo-controlled trial of 67 individuals evaluated buckwheat tea (a good source of rutin) for chronic venous insufficiency.27 The results showed less leg swelling in the treated group.
One study supposedly showed that the supplement oxyrutin is more effective than diosmin/hesperidin for chronic venous insufficiency, but the study was too poorly designed to provide meaningful results.40
Some people bruise particularly easily due to fragile capillaries. A 6-week, double-blind, placebo-controlled study of 96 people with this condition found that combined diosmin and hesperidin decreased symptoms of capillary fragility, such as bruising and nosebleeds.28
Two rather poorly designed studies from the 1960s found benefits with a combination of vitamin C and citrus bioflavonoids for decreasing bruising in collegiate athletes.29
Breast cancer surgery sometimes causes persistent swelling of the arm (lymphedema) caused by damage to lymph vessels. Citrus bioflavonoids as well as other natural supplements have shown promise for this condition. In a 3-month, double-blind study, 57 women with lymphedema received either placebo or combination therapy consisting of the modified citrus bioflavonoid trimethylhesperidin chalcone plus the bioflavonoid-rich herb butcher’s broom.37 The results indicated that use of the bioflavonoid combination resulted in significantly less swelling.
In a review of 12 studies involving over 5,000 cases, researchers found that people who consumed the highest amounts of flavonoids in their diets had a lower risk of lung cancer than those who consumed less.46 The significance of these results is weakened by the fact that none of the studies were controlled trials, and the most favorable among them did not account for the quantity of fruits, vegetables, or vitamins in the participants' diets.
Extensive investigations of diosmin and hesperidin have found them to be essentially nontoxic and free of drug interactions.30 The combination has been given to 50 pregnant women in a research study, without apparent harm to mothers or babies.31
Some evidence suggests that the bioflavonoid naringen may interact with medications in the calcium channel blocker family, increasing blood levels of the drug.44 This may necessitate a reduction in drug dosage.
One highly preliminary study suggests that some citrus bioflavonoids in the diet of pregnant women might increase the risk of infant leukemia; hesperidin did not produce this effect, and diosmin was not tested.33
1. Ross SA, Ziska DS, Zhoa K, et al. Variance of common flavonoids by brand of grapefruit juice. Fitoterapia. 2000;71:154-161.
2. Godeberge P. Daflon 500 mg in the treatment of hemorrhoidal disease: a demonstrated efficacy in comparison with placebo. Angiology. 1994;45:574-578.
3. Cospite M. Double-blind, placebo-controlled evaluation of clinical activity and safety of Daflon 500 mg in the treatment of acute hemorrhoids. Angiology. 1994;45:566-573.
4. Thanapongsathorn W, Vajrabukka T. Clinical trial of oral diosmin (Daflon) in the treatment of hemorrhoids. Dis Colon Rectum. 1992;35:1085-1088.
5. Misra MC, Parshad R. Randomized clinical trial of micronized flavonoids in the early control of bleeding from acute internal haemorrhoids. Br J Surg. 2000;87:868-872.
6. Ho YH, Tan M, Seow-Choen F. Micronized purified flavonidic fraction compared favorably with rubber band ligation and fiber alone in the management of bleeding hemorrhoids: randomized controlled trial. Dis Colon Rectum. 2000;43:66-69.
7. Tsouderos Y. Venous tone: are the phlebotonic properties predictive of a therapeutic benefit? A comprehensive view of our experience with Daflon 500 mg. Z Kardiol. 1991;80(suppl 7):95-101.
8. Ihme N, Kiesewetter H, Jung F, et al. Leg oedema protection from a buckwheat herb tea in patients with chronic venous insufficiency: a single-centre, randomised, double-blind, placebo-controlled clinical trial. Eur J Clin Pharmacol. 1996;50:443-447.
9. Guilhou JJ, Dereure O, Marzin L, et al. Efficacy of Daflon 500 mg in venous leg ulcer healing: a double-blind, randomized, controlled versus placebo trial in 107 patients. Angiology. 1997;48:77-85.
10. Guilhou JJ, Fevrier F, Debure C, et al. Benefit of a 2-month treatment with a micronized, purified flavonoidic fraction on venous ulcer healing. A randomized, double-blind, controlled versus placebo trial. Int J Microcirc Clin Exp. 1997;17(suppl 1):21-26.
11. Guilhou JJ, Dereure O, Marzin L, et al. Efficacy of Daflon 500 mg in venous leg ulcer healing: a double-blind, randomized, controlled versus placebo trial in 107 patients. Angiology. 1997;48:77-85.
12. Guilhou JJ, Fevrier F, Debure C, et al. Benefit of a 2-month treatment with a micronized, purified flavonoidic fraction on venous ulcer healing. A randomized, double-blind, controlled versus placebo trial. Int J Microcirc Clin Exp. 1997;17(suppl 1):21-26.
13. Galley P, Thiollet M. A double-blind, placebo-controlled trial of a new veno-active flavonoid fraction (S 5682) in the treatment of symptomatic capillary fragility. Int Angiol. 1993;12:69-72.
14. Pecking AP, Fevrier B, Wargon C, et al. Efficacy of Daflon 500 mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer). Angiology. 1997;48:93-98.
15. Lee SH, Park YB, Bae KH, et al. Cholesterol-lowering activity of naringenin via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme A: cholesterol acyltransferase in rats. Ann Nutr Metab. 1999;43:173-180.
16. Shin YW, Bok SH, Jeong TS, et al. Hypocholesterolemic effect of naringin associated with hepatic cholesterol regulating enzyme changes in rats. Int J Vitam Nutr Res. 1999;69:341-347.
17. Emim JA, Oliveira AB, Lapa AJ. Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. J Pharm Pharmacol. 1994;46:118-122.
18. Manuel y Keenoy B, Vertommen J, De Leeuw I. The effect of flavonoid treatment on the glycation and antioxidant status in Type 1 diabetic patients. Diabetes Nutr Metab. 1999;12:256-263.
19. Middleton E Jr, Drzewiecki G, Tatum J. The effects of citrus flavonoids on human basophil and neutrophil function. Planta Med. 1987;53:325-328.
20. So FV, Guthrie N, Chambers AF, et al. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer. 1996;26:167-181.
21. Godeberge P. Daflon 500 mg in the treatment of hemorrhoidal disease: a demonstrated efficacy in comparison with placebo. Angiology. 1994;45:574-578.
22. Cospite M. Double-blind, placebo-controlled evaluation of clinical activity and safety of Daflon 500 mg in the treatment of acute hemorrhoids. Angiology. 1994;45:566-573.
23. Misra MC, Parshad R. Randomized clinical trial of micronized flavonoids in the early control of bleeding from acute internal haemorrhoids. Br J Surg. 2000;87:868-872.
24. Ho YH, Tan M, Seow-Choen F. Micronized purified flavonidic fraction compared favorably with rubber band ligation and fiber alone in the management of bleeding hemorrhoids: randomized controlled trial. Dis Colon Rectum. 2000;43:66-69.
25. Thanapongsathorn W, Vajrabukka T. Clinical trial of oral diosmin (DaflonŴ) in the treatment of hemorrhoids. Dis Colon Rectum. 1992;35:1085-1088.
26. Guilhou JJ, Dereure O, Marzin L, et al. Efficacy of Daflon 500 mg in venous leg ulcer healing: a double-blind, randomized, controlled versus placebo trial in 107 patients. Angiology. 1997;48:77-85.
27. Ihme N, Kiesewetter H, Jung F, et al. Leg oedema protection from a buckwheat herb tea in patients with chronic venous insufficiency: a single-centre, randomised, double-blind, placebo-controlled clinical trial. Eur J Clin Pharmacol. 1996;50:443-447.
28. Galley P, Thiollet M. A double-blind, placebo-controlled trial of a new veno-active flavonoid fraction (S 5682) in the treatment of symptomatic capillary fragility. Int Angiol. 1993;12:69-72.
29. Miller MJ. Injuries to athletes. Evaluation of ascorbic acid and water soluble citrus bioflavonoids in the prophylaxis of injuries in athletes. Med Times. 1960;88:313-316.
30. Meyer OC. Safety and security of Daflon 500 mg in venous insufficiency and in hemorrhoidal disease. Angiology. 1994;45:579-584.
31. Buckshee K, Takkar D, Aggarwal N. Micronized flavonoid therapy in internal hemorrhoids of pregnancy. Int J Gynaecol Obstet. 1997;57:145-151.
32. Bracke ME, Depypere HT, Boterberg T, et al. Influence of tangeretin on tamoxifen's therapeutic benefit in mammary cancer. J Natl Cancer Inst. 1999;91:354-359.
33. Strick R, Strissel PL, Borgers S, et al. Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. Proc Natl Acad Sci. 2000;97:4790-4795.
34. Laurent R, Gilly R, Frileux C. Clinical evaluation of a venotropic drug in man. Example of Daflon 500 mg. Int Angiol. 1988;7:39-43.
35. Danielsson G, Jungbeck C, Peterson K, et al. A randomised controlled trial of micronised purified flavonoid fraction vs placebo in patients with chronic venous disease. Eur J Vasc Endovasc Surg. 2002;23:73-76.
36. Manthey JA, Grohmann K, Guthrie N. Biological properties of citrus flavonoids pertaining to cancer and inflammation. Curr Med Chem. 2001;8:135-153.
37. Cluzan RV, Alliot F, Ghabboun S, et al. Treatment of secondary lymphedema of the upper limb with CYCLO 3 FORT. Lymphology. 1996;29:29-35.
38. La Torre F, Nicolai AP. Clinical use of micronized purified flavonoid fraction for treatment of symptoms after hemorrhoidectomy: results of a randomized, controlled, clinical trial. Dis Colon Rectum. 2004 Mar 25. [Epub ahead of print]
39. Colak T, Akca T, Dirlik M, et al. Micronized flavonoids in pain control after hemorrhoidectomy: a prospective randomized controlled study. Surg Today. 2003;33:828-832.
40. Cesarone MR, Belcaro G, Pellegrini L, et al. HR, 0-(beta-hydroxyethyl)-rutosides, in comparison with diosmin+hesperidin in chronic venous insufficiency and venous microangiopathy: an independent, prospective, comparative registry study. Angiology. 2005;56:1-8.
41. Liu B, Edgerton S, Yang X, et al. Low-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumor prevention. Cancer Res. 2005;65:879-886.
42. Reshef N, Hayari Y, Goren C, et al. Antihypertensive effect of sweetie fruit in patients with stage I hypertension. Am J Hypertens. 2005;18:1360-1363.
43. Alonso-Coello P, Zhou Q, Martinez-Zapata MJ, et al. Meta-analysis of flavonoids for the treatment of haemorrhoids. Br J Surg. 2006 May 31 [Epub ahead of print].
44. Yeum CH, Choi JS. Effect of naringin pretreatment on bioavailability of verapamil in rabbits. Arch Pharm Res. 2006;29:102-107.
45. Lotito SB, Frei B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Radic Biol Med. 2006;41:1727-1746.
46. Tang NP, Zhou B, Wang B, Yu RB, Ma J. Flavonoids intake and risk of lung cancer: a meta-analysis. Jpn J Clin Oncol. 2009;39:352-359.
Last reviewed December 2015 by EBSCO CAM Review Board Last Updated: 12/15/2015