Hesperidin, found abundantly in orange peels and various citrus fruits, exhibits promising potential in reducing risk factors associated with cardiovascular disease, such as triglycerides and total cholesterol. Additionally, it appears to some have anti-inflammatory properties. While other potential benefits of hesperidin exist, further clinical studies are required to fully understand its range of effects.
Hesperidin is most often used for
Hesperidin is a flavanone glycoside (a type of flavonoid) that was isolated from the spongy inner peel of oranges, which is known as the mesocarp.
Hesperidin (Hsd) is prominently found in citrus fruits like oranges, lemons, clementines, mandarins, and grapefruits. The name hesperidin is derived from the word “hesperidium”, a word for a berry with a pulpy, segmented interior and a leathery rind containing aromatic oils. Its aglycone (i.e., missing a glycosyl group) form is called hesperetin (Hst).
Trials of the anti-inflammatory properties of hesperidin have yielded mixed results. One meta-analysis found that hesperidin, whether consumed through citrus juice or oral supplements, reduced the pro-inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-4 (IL-4) in a non-dose-dependent manner. However, a second meta-analysis did not replicate these findings for CRP and IL-6, although it did find a significant decreased in levels of the inflammatory marker vascular cell adhesion molecule-1 (VCAM-1). These conflicting outcomes could be attributed to variability in study quality, methodology, and participant characteristics, necessitating further research to validate the anti-inflammatory properties of hesperidin.
Additionally, one meta-analysis indicated that hesperidin supplementation led to significant reduction of several cardiovascular disease (CVD) risk factors. These benefits included decreased triglyceride (TG) levels, total cholesterol (TC), low-density lipoprotein (LDL) levels, tumor necrosis factor (TNF-α), and systolic blood pressure (SBP). Notably, these effects were predominantly observed with hesperidin doses exceeding 500 mg per day and were considerably influenced by factors such as the duration of hesperidin treatment (typically more effective when exceeding 6 weeks) and participants’ BMI, age, and overall health status.
Hesperidin also appears to promote blood flow, as demonstrated in one randomized controlled trial (RCT) involving participants with metabolic syndrome who took 500 mg of hesperidin daily for 3 weeks. Hesperidin improved blood flow by 2.5%, as assessed by flow-mediated dilation (FMD). Another study noted an improvement in microcirculation (blood flow in the small vessels) 6 hours after supplementation on a full stomach with either hesperidin capsules or standardized orange juice given for 4 weeks to healthy but overweight men. Despite these results being promising, it is still unclear whether these effects are long-lasting and whether they have an impact on blood pressure.
Furthermore, one RCT evaluated the impact of a synthetic form of hesperidin, hesperidin methyl chalcone (HMC), on muscle damage and pain associated with delayed onset muscle soreness (DOMS) induced by an intense anaerobic exercise protocol. HMC supplementation improved muscle recovery, performance, and postural balance. The group taking HMC also showed increased physical performance (measured by the number of repetitions to failure) and improved muscle soreness during passive quadriceps palpation, although not during activities like walking up and down the stairs.
Studies have not yet reported any side effects associated with hesperidin supplementation. However, it’s important to note that the absence of side effects in research does not definitively rule them out, and further investigation is warranted. One study found that a 500 mg dose of hesperidin methyl chalcone (HMC) did not affect renal and hepatic function markers.
One meta-analysis found that hesperidin supplementation was linked to an increase in body weight, which could potentially be concerning for people with obesity or overweight. However, this effect has not been consistently observed in other studies, and it may be influenced by many factors beyond hesperidin supplementation.
The precise mechanism of action of hesperidin is still unknown. However, a number of studies (mostly animal studies), have highlighted potential pathways through which hesperidin may exert its effects.
Hesperidin may improve lipid metabolism via several potential mechanisms: In rat models, a possible pathway involves inhibiting cholesterol synthesis by downregulating the expression of retinol-binding protein (RBP), heart fatty acid binding protein (H-FAB), and cutaneous fatty acid-binding protein (C-FAB). Animal studies suggest that hesperidin may also inhibit the enzymes 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and acyl coenzyme A: cholesterol acyltransferase (ACAT), which play a role in cholesterol biosynthesis.
Furthermore, clinical studies on G-hesperidin (see FAQ “What are the other forms of hesperidin?”) suggest that it enhances very low density lipoprotein (VLDL) catabolism, leading to reduced TG and LDL levels. G-hesperidin also appeared to work by activating the lipoprotein lipase (LPL), an enzyme responsible for hydrolyzing TG. In vitro studies further suggested that G-hesperidin may suppress excessive liver LDL secretion by decreasing the release of apolipoprotein B (a key LDL component).
Regarding its anti-inflammatory effect, both in vitro and in vivo studies suggest that hesperidin may reduce inflammation by suppressing the expression of inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), along with inflammatory markers (e.g., TNF-α, IL-6), thereby reducing prostaglandin levels.
Additionally, one hypothesis explaining hesperidin’s blood pressure-lowering effect is that it increases nitric oxide (NO) production, which induces vasodilation by relaxing blood vessels smooth muscles, leading to a reduction in blood pressure. Another potential mechanism involves hesperidin reducing levels of the vasoconstrictor angiotensin-2 through inhibition of the angiotensin-converting enzyme. It’s worth noting that these mechanisms remain hypothetical, and require clinical confirmation.
Hesperidin and hesperetin also appear to moderately increase blood flow either by stimulating the production of intracellular hydrogen peroxide, which activates the Src family kinase, a group of enzymes that regulate the production of nitric oxide in blood vessels, or through estrogen signaling, which is also involved in the production of nitric oxide.
- Hesperitin glycoside
- glucosyl hesperidin
- Vitamin P
- 3' 5 7-trihydroxy-4'-methoxyflavanone
- Hesperitin (its aglycone)
- Eriodictyol (another flavonoid known as Vitamin P)
Most studies tend to use 500 mg or more of supplemental hesperidin, and use the standard form of hesperidin if taking it as a daily preventative.
For the prevention of muscle soreness associated with delayed onset muscle soreness (DOMS), a daily dosage of 500 mg of hesperidin methyl chalcone (HMC) for 3 days prior to intensive anaerobic exercise has shown positive outcomes. HMC concentration typically peaks 1–2 hours after oral administration.
When it comes to food products, the amount of hesperidin contained in orange juice or other citrus peels (e.g., tangerine peel) may vary depending on multiple factors. As a result, establishing a recommended quantity of specific foods containing hesperidin to achieve effects similar to those obtained with oral supplements is challenging. For instance, one study analyzing the composition of citrus juices found hesperidin concentrations ranging from 20–60 mg/100 ml in orange juice, 8–46 mg/100 ml in tangerine juice, 4–41 mg/100 ml in lemon juice, and 2–17 mg/100 ml in grapefruit juice. Sun-dried tangerine peels, used in traditional Chinese medicine, appear to confer such a substantial dose of hesperidin that additional supplementation may not be required. These peels may be made more palatable by blending them into a shake.
- ^Lorzadeh E, Ramezani-Jolfaie N, Mohammadi M, Khoshbakht Y, Salehi-Abargouei AThe effect of hesperidin supplementation on inflammatory markers in human adults: A systematic review and meta-analysis of randomized controlled clinical trials.Chem Biol Interact.(2019-Jul-01)
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- ^Buzdağlı Y, Eyipınar CD, Kacı FN, Tekin AEffects of hesperidin on anti-inflammatory and antioxidant response in healthy people: a meta-analysis and meta-regression.Int J Environ Health Res.(2022-Jun-28)
- ^Khorasanian AS, Fateh ST, Gholami F, Rasaei N, Gerami H, Khayyatzadeh SS, Shiraseb F, Asbaghi OThe effects of hesperidin supplementation on cardiovascular risk factors in adults: a systematic review and dose-response meta-analysis.Front Nutr.(2023)
- ^Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, Pullikotil P, Senese N, Tesauro M, Lauro D, Cardillo C, Quon MJCitrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndromeJ Clin Endocrinol Metab.(2011 May)
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- ^Watanabe M, Matsumoto N, Takeba Y, Kumai T, Tanaka M, Tatsunami S, Takenoshita-Nakaya S, Harimoto Y, Kinoshita Y, Kobayashi SOrange juice and its component, hesperidin, decrease the expression of multidrug resistance-associated protein 2 in rat small intestine and liver.J Biomed Biotechnol.(2011)
- ^Mas-Capdevila A, Teichenne J, Domenech-Coca C, Caimari A, Del Bas JM, Escoté X, Crescenti AEffect of Hesperidin on Cardiovascular Disease Risk Factors: The Role of Intestinal Microbiota on Hesperidin Bioavailability.Nutrients.(2020-May-20)
- Blood Flow - Hiroko Takumi, Hiroyasu Nakamura, Terumi Simizu, Ryoko Harada, Takashi Kometani, Tomonori Nadamoto, Rie Mukai, Kaeko Murota, Yoshichika Kawai, Junji TeraoBioavailability of orally administered water-dispersible hesperetin and its effect on peripheral vasodilatation in human subjects: implication of endothelial functions of plasma conjugated metabolitesFood Funct.(2012 Apr)
- Blood glucose - Morand C, Dubray C, Milenkovic D, Lioger D, Martin JF, Scalbert A, Mazur AHesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteersAm J Clin Nutr.(2011 Jan)
- Total cholesterol - Khorasanian AS, Fateh ST, Gholami F, Rasaei N, Gerami H, Khayyatzadeh SS, Shiraseb F, Asbaghi OThe effects of hesperidin supplementation on cardiovascular risk factors in adults: a systematic review and dose-response meta-analysis.Front Nutr.(2023)
- Low-density lipoprotein (LDL) - Miwa Y, Mitsuzumi H, Sunayama T, Yamada M, Okada K, Kubota M, Chaen H, Mishima Y, Kibata MGlucosyl hesperidin lowers serum triglyceride level in hypertriglyceridemic subjects through the improvement of very low-density lipoprotein metabolic abnormalityJ Nutr Sci Vitaminol (Tokyo).(2005 Dec)
- Low-density lipoprotein (LDL) - Miwa Y, Yamada M, Sunayama T, Mitsuzumi H, Tsuzaki Y, Chaen H, Mishima Y, Kibata MEffects of glucosyl hesperidin on serum lipids in hyperlipidemic subjects: preferential reduction in elevated serum triglyceride levelJ Nutr Sci Vitaminol (Tokyo).(2004 Jun)
- Low-density lipoprotein (LDL) - Demonty I, Lin Y, Zebregs YE, Vermeer MA, van der Knaap HC, Jäkel M, Trautwein EAThe citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately hypercholesterolemic men and womenJ Nutr.(2010 Sep)
- C-Reactive Protein (CRP) - Lorzadeh E, Ramezani-Jolfaie N, Mohammadi M, Khoshbakht Y, Salehi-Abargouei AThe effect of hesperidin supplementation on inflammatory markers in human adults: A systematic review and meta-analysis of randomized controlled clinical trials.Chem Biol Interact.(2019-Jul-01)
- C-Reactive Protein (CRP) - Buzdağlı Y, Eyipınar CD, Kacı FN, Tekin AEffects of hesperidin on anti-inflammatory and antioxidant response in healthy people: a meta-analysis and meta-regression.Int J Environ Health Res.(2022-Jun-28)
- Fasting Glucose - Shams-Rad S, Mohammadi M, Ramezani-Jolfaie N, Zarei S, Mohsenpour M, Salehi-Abargouei AHesperidin supplementation has no effect on blood glucose control: A systematic review and meta-analysis of randomized controlled clinical trials.Br J Clin Pharmacol.(2020-Jan)
- Total cholesterol - Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, Pullikotil P, Senese N, Tesauro M, Lauro D, Cardillo C, Quon MJCitrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndromeJ Clin Endocrinol Metab.(2011 May)
- Total cholesterol - Mohammadi M, Ramezani-Jolfaie N, Lorzadeh E, Khoshbakht Y, Salehi-Abargouei AHesperidin, a major flavonoid in orange juice, might not affect lipid profile and blood pressure: A systematic review and meta-analysis of randomized controlled clinical trialsPhytother Res.(2019 Mar)
- Rheumatoid Arthritis Symptoms - Kometani T, Fukuda T, Kakuma T, Kawaguchi K, Tamura W, Kumazawa Y, Nagata KEffects of alpha-glucosylhesperidin, a bioactive food material, on collagen-induced arthritis in mice and rheumatoid arthritis in humansImmunopharmacol Immunotoxicol.(2008)
- Neutrophil Count - Perche O, Vergnaud-Gauduchon J, Morand C, Dubray C, Mazur A, Vasson MPOrange juice and its major polyphenol hesperidin consumption do not induce immunomodulation in healthy well-nourished humansClin Nutr.(2013 Mar 26)