# Diosmin (derived from Citrus species, Rutaceae family)

**Canonical URL:** https://ingredients.hermeticasuperfoods.com/ingredients/diosmin-derived-from-citrus-species-rutaceae-family
**Data Source:** Hermetica Superfoods Ingredient Encyclopedia
**Updated:** 2026-04-05
**Evidence Score:** 1 / 10
**Category:** Compound
**Also Known As:** Diosmin C₂₈H₃₂O₁₅, 3',5,7-trihydroxy-4'-methoxyflavone-7-rutinoside, Diosminum, MPFF (micronized purified flavonoid fraction), Daflon (brand name), Venosmine, Diosmine (French/USAN)

## Overview

Diosmin (C₂₈H₃₂O₁₅) is a flavone glycoside that exerts venotonic, [anti-inflammatory](/ingredients/condition/inflammation), and [antioxidant](/ingredients/condition/antioxidant) effects by inhibiting phosphodiesterase to elevate cAMP, suppressing NF-κB-driven inflammation, activating the NRF2/Keap-1 cytoprotective pathway, and increasing venous smooth muscle tone through norepinephrine potentiation. In clinical practice, micronized purified flavonoid fraction (MPFF) containing 90% diosmin and 10% hesperidin at 1000 mg/day has demonstrated significant improvement in chronic venous insufficiency symptoms including edema, pain, and heaviness, and reduces hemorrhoidal bleeding episodes in randomized trials with documented safety over treatment periods of one to six months.

## Health Benefits

- **Chronic Venous Insufficiency (CVI)**: Diosmin, particularly in MPFF formulations, increases venous tone by potentiating norepinephrine-induced vasoconstriction and reducing venous distensibility, alleviating symptoms of edema, leg heaviness, pain, and varicose veins in patients with CVI stages C2–C5.
- **Hemorrhoid Treatment**: MPFF (diosmin 900 mg + hesperidin 100 mg/day) reduces the frequency, duration, and severity of acute hemorrhoidal episodes by decreasing capillary permeability, improving lymphatic drainage, and inhibiting prostaglandin-mediated inflammation in anorectal microcirculation.
- **[Anti-Inflammatory](/ingredients/condition/inflammation) Action**: Diosmin inhibits phosphodiesterase to elevate intracellular cAMP, reducing synthesis of pro-inflammatory prostaglandins (PGE2, PGF2α) and thromboxanes (TXA2, TXB2), while simultaneously downregulating NF-κB to suppress cytokine production and limit pathological angiogenesis.
- **Antioxidant and Cytoprotection**: Activation of the NRF2/Keap-1 transcriptional pathway upregulates heme oxygenase-1 (HO-1) and superoxide dismutase (SOD), while diosmetin (the aglycone metabolite) raises intracellular glutathione (GSH) and reduces [lipid peroxidation](/ingredients/condition/antioxidant), protecting endothelial and hepatic cells from oxidative damage.
- **Anticancer Potential (Preclinical)**: Diosmin induces cancer cell apoptosis by upregulating p53, p21, p27, FOXO3a, Bax, and caspases-3/9 while downregulating c-Myc, Bcl-2, and matrix metalloproteinases MMP-2/9; it also triggers ROS-mediated S/G2-M cell cycle arrest and [autophagy](/ingredients/condition/longevity) via PI3K/Akt pathway modulation across multiple cancer cell lines in preclinical models.
- **Lymphatic Function and Microcirculation**: Diosmin preferentially accumulates in lymphatic endothelial cells and venous wall tissue, improving lymphatic contractility, reducing capillary hyperpermeability, and decreasing interstitial edema by protecting the glycocalyx and basement membrane integrity.
- **[Hepatoprotect](/ingredients/condition/detox)ion**: Diosmetin and diosmin metabolites protect hepatocytes against oxidative and chemically induced injury by raising GSH levels, inhibiting lipid peroxidation, and modulating inflammatory cytokines, with preclinical models demonstrating attenuation of liver enzyme elevations in toxic injury paradigms.

## Mechanism of Action

Diosmin's primary venotonic mechanism involves inhibition of catechol-O-methyltransferase (COMT) and phosphodiesterase, thereby prolonging the half-life of norepinephrine in venous smooth muscle and elevating intracellular cAMP, which enhances venous contractility and reduces venous capacitance. Its anti-inflammatory effects are mediated through NF-κB pathway suppression, which diminishes transcription of COX-2, iNOS, and [pro-inflammatory cytokine](/ingredients/condition/inflammation)s (TNF-α, IL-1β, IL-6), while phosphodiesterase inhibition simultaneously reduces prostaglandin (PGE2, PGF2α) and thromboxane (TXA2, TXB2) biosynthesis. The NRF2/Keap-1 axis is activated by diosmin to induce phase II antioxidant enzymes including HO-1 and SOD, suppress ROS-driven p38 MAPK signaling, and enhance eNOS-mediated endothelial nitric oxide production, collectively improving [vascular tone](/ingredients/condition/heart-health) and reducing [oxidative stress](/ingredients/condition/antioxidant). In oncological contexts, diosmin acts as an aryl hydrocarbon receptor (AhR) agonist, modulates the PI3K/Akt/mTOR signaling cascade, upregulates pro-apoptotic proteins (Bax, caspase-3/9, p53, FOXO3a), and downregulates anti-apoptotic and invasion-related proteins (Bcl-2, MMP-2/9, c-Myc), establishing its multi-target pharmacology across vascular, inflammatory, and neoplastic conditions.

## Clinical Summary

The most clinically evaluated application of diosmin is in phlebological conditions, where MPFF formulations (diosmin 900 mg + hesperidin 100 mg daily) have been assessed in randomized controlled trials involving patients with chronic venous insufficiency (CVI, CEAP classes C2–C5) and acute hemorrhoidal disease, with consistent findings of reduced leg edema, improved quality-of-life scores, and decreased frequency and duration of hemorrhoidal bleeding episodes versus placebo or active comparators. Effect sizes in venous insufficiency trials are modest-to-moderate, with reductions in ankle circumference (edema) on the order of 20–40% versus baseline and significant improvements in pain and heaviness visual analog scale scores, though heterogeneous outcome measures across trials limit precise meta-analytic pooling. For hemorrhoidal disease, MPFF has demonstrated a roughly 50–65% reduction in bleeding episodes and shortened episode duration in several RCTs, supporting its inclusion in guidelines for adjunctive management of hemorrhoidal symptoms. Outside of phlebology, human clinical trial data are absent or unpublished for diosmin's [anti-inflammatory](/ingredients/condition/inflammation), anticancer, and [hepatoprotective](/ingredients/condition/detox) properties, and confidence in these applications is limited to mechanistic and preclinical data only.

## Nutritional Profile

Diosmin is not a macronutrient or essential micronutrient but a non-essential dietary flavonoid glycoside belonging to the flavone subclass of polyphenols, with the molecular formula C₂₈H₃₂O₁₅ and a molecular weight of 608.54 g/mol. In pharmaceutical formulations, it is provided as a purified or semi-synthetic compound at defined doses (450–1000 mg per tablet/capsule) rather than as a food-matrix constituent, so nutritional concentration data in whole foods are not clinically relevant to supplementation. Bioavailability is approximately 55% from micronized oral formulations and substantially lower from non-micronized preparations due to poor aqueous solubility (log P ~1.86); intestinal bacterial hydrolysis by β-glucosidases converts the parent glycoside to the active aglycone diosmetin, which is further metabolized to glucuronide and sulfate conjugates, with the diosmetin aglycone exhibiting an elimination half-life of 26–43 hours and high affinity for vascular endothelial and lymphatic tissue. Co-administration with dietary fats modestly enhances lymphatic uptake; cyclodextrin complexation or phospholipid binding substantially improves solubility and systemic exposure.

## Dosage & Preparation

- **Micronized Oral Tablet (MPFF, 500 mg)**: Standard adult dose is 2 tablets (1000 mg) daily, or 3 tablets (1500 mg) during acute hemorrhoidal flares for the first four days, then 2 tablets for three days; taken with meals to improve absorption.
- **Micronized Oral Tablet (MPFF, 1000 mg)**: Single daily tablet formulation providing 900 mg diosmin + 100 mg hesperidin; clinical trials support 1–6 months of continuous use for chronic venous insufficiency.
- **Diosmin Alone (Non-MPFF)**: Doses of 450–900 mg twice daily have been used in some formulations; micronization to <2 µm particle size is critical for adequate bioavailability compared to non-micronized preparations.
- **β-Cyclodextrin or HPβCD Complex**: 1:1 molar ratio complexation significantly improves aqueous solubility and oral bioavailability; used in experimental and some commercial formulations to overcome poor water solubility.
- **Phospholipid Complex (Phytosome)**: Diosmin-phospholipid complexes extend the effective half-life of diosmetin (active aglycone) to 26–43 hours and enhance endothelial tissue distribution; administered at equivalent molar doses to standard tablets.
- **Timing**: Administration with food, particularly lipid-containing meals, enhances lymphatic absorption; Tmax for diosmetin metabolite is approximately 18–24 hours post-dose, reflecting intestinal flora-dependent biotransformation.
- **Standardization**: Pharmaceutical-grade MPFF products are standardized to ≥90% diosmin content with defined particle size distribution (D90 <2 µm for micronized forms).

## Safety & Drug Interactions

Diosmin and MPFF formulations demonstrate a well-established tolerability profile at standard therapeutic doses (500–1500 mg/day), with the most commonly reported adverse effects being mild and transient gastrointestinal symptoms including nausea, diarrhea, dyspepsia, and abdominal discomfort occurring in fewer than 3% of patients in clinical trials; no serious hepatotoxic, nephrotoxic, or hematological adverse events have been attributed to standard dose regimens. Drug interaction data are limited but theoretical interactions exist via cytochrome P450 [metabolism](/ingredients/condition/weight-management) (primarily CYP1A2, CYP2C9, and CYP3A4 pathways for diosmetin), suggesting potential for modest interactions with anticoagulants (warfarin), drugs with narrow therapeutic indices metabolized by these enzymes, and anticholinesterase medications given diosmetin's documented AChE inhibition (IC₅₀ 12.24 µM) in vitro. Pregnancy and lactation safety have not been established in adequate human studies; regulatory guidance in most countries recommends avoiding use during the first trimester of pregnancy, and MPFF is listed as Category B/precautionary in several European product monographs, with some European formulations explicitly contraindicating first-trimester use. At suprapharmacological doses used in preclinical cancer research, diosmin has demonstrated genotoxic effects (DNA strand breaks, micronuclei formation) in cancer cell models, though these concentrations substantially exceed clinically achievable human plasma levels and are not considered a safety concern at recommended therapeutic doses.

## Scientific Research

The strongest clinical evidence for diosmin exists in the context of chronic venous insufficiency and hemorrhoidal disease, where multiple randomized controlled trials and systematic reviews support the efficacy of MPFF (90% diosmin, 10% hesperidin) at 1000 mg/day, demonstrating reductions in edema volume, symptom severity scores, and hemorrhoidal bleeding episodes compared to placebo; these trials typically enrolled 100–500 participants with follow-up periods of two to six months. Pharmacokinetic studies in healthy volunteers have characterized oral bioavailability at approximately 55%, with Cmax values for diosmetin (the active aglycone metabolite) reported at 417 ± 94.1 ng/dL in a small five-subject study, and composite pharmacokinetic parameters (Cmax 185.4 ± 166.2 ng·mL⁻¹, Tmax 18.7 ± 9.9 h) reflecting the slow, gut flora-dependent conversion of diosmin to diosmetin. Anticancer and [anti-inflammatory](/ingredients/condition/inflammation) data remain largely preclinical, derived from in vitro cell line studies (e.g., IC₅₀ of 45 µg/mL in A431 skin cancer cells) and murine tumor models showing reduced metastatic implantation by up to 79% in B16F10 melanoma, without supporting human trial data. Overall, the evidence base is moderately strong for phlebological indications and preliminary for oncological, [hepatoprotective](/ingredients/condition/detox), and [neuroprotective](/ingredients/condition/cognitive) applications, warranting larger, well-powered RCTs with standardized diosmin formulations and patient-reported outcomes.

## Historical & Cultural Context

Diosmin does not carry a deep history in classical herbal medicine systems such as Ayurveda or Traditional Chinese Medicine, as it was first isolated and chemically characterized in the 20th century rather than being used as a whole-plant remedy. Its pharmaceutical history began in the 1960s when French researchers developed diosmin-based preparations for venous disorders, recognizing that flavonoids from citrus peel possessed venotonic and capillary-protective properties that had been empirically observed in folk use of citrus preparations for leg heaviness and bruising in Mediterranean cultures. The compound gained significant clinical traction in Europe following the development of micronized purified flavonoid fraction (MPFF) technology in the 1980s, which dramatically improved bioavailability and allowed for standardized dosing in registered pharmaceutical products, particularly in France, where MPFF (Daflon®) became a widely prescribed treatment for chronic venous disease and hemorrhoidal disorders. Today, diosmin-containing products are approved as pharmaceutical drugs in numerous European and Asian countries and are marketed as dietary supplements in the United States, representing a paradigm of the transition from empirical citrus folk medicine to evidence-based phlebological pharmacotherapy.

## Synergistic Combinations

Diosmin demonstrates well-documented synergy with hesperidin in the MPFF formulation (9:1 diosmin-to-hesperidin ratio), where hesperidin's complementary inhibition of capillary fragility, anti-exudative effects, and overlapping [NF-κB](/ingredients/condition/inflammation) suppression produce additive-to-synergistic improvements in venous tone and microvascular integrity that exceed the activity of either compound alone in comparative venous pharmacology models. Combining diosmin with vitamin C (ascorbic acid) and bioflavonoids such as rutin or quercetin may further potentiate [antioxidant](/ingredients/condition/antioxidant) capacity through complementary radical scavenging mechanisms and mutual sparing of oxidized intermediates, a rationale employed in several commercial venous health supplement formulations. In the context of bioavailability enhancement, co-formulation with phosphatidylcholine (phytosome technology) or hydroxypropyl-β-cyclodextrin (HPβCD) represents a physicochemical synergy that extends the effective plasma half-life of diosmetin and increases endothelial tissue accumulation, producing superior pharmacodynamic outcomes compared to equivalent doses of standard non-complexed diosmin.

## Frequently Asked Questions

### What is diosmin used for clinically?

Diosmin is most widely used clinically as a venotonic agent for chronic venous insufficiency (CVI), where it reduces leg edema, heaviness, pain, and varicose vein symptoms, and for hemorrhoidal disease, where it shortens acute episodes and reduces bleeding. It is approved as a pharmaceutical drug in numerous European and Asian countries, typically formulated as MPFF (90% diosmin + 10% hesperidin, 1000 mg/day), and is available as a dietary supplement in the United States. Emerging preclinical research also supports anti-inflammatory, antioxidant, hepatoprotective, and anticancer potential, but human clinical evidence outside phlebology remains limited.

### What is the recommended diosmin dosage for veins and hemorrhoids?

For chronic venous insufficiency, the standard clinical dose is MPFF 1000 mg once daily (equivalent to 900 mg diosmin + 100 mg hesperidin) taken with meals for one to six months, as established in randomized controlled trials. For acute hemorrhoidal crises, a higher loading dose of MPFF 1500 mg/day (three 500 mg tablets) is recommended for the first four days, then reduced to 1000 mg/day for three days, and followed by 1000 mg/day for maintenance. Micronized formulations with particle size below 2 µm are essential for adequate bioavailability, as non-micronized diosmin has substantially reduced absorption.

### How does diosmin work in the body?

Diosmin is hydrolyzed by intestinal bacterial β-glucosidases to its active aglycone diosmetin, which accumulates in venous and lymphatic endothelial cells where it inhibits COMT and phosphodiesterase, prolonging norepinephrine activity and increasing venous smooth muscle tone. Simultaneously, diosmin suppresses NF-κB signaling to reduce pro-inflammatory cytokines and prostaglandins (PGE2, TXA2), activates the NRF2/Keap-1 antioxidant pathway to upregulate HO-1 and SOD, and enhances eNOS-mediated nitric oxide production, collectively improving microvascular integrity and reducing capillary permeability. These combined venotonic and anti-inflammatory mechanisms explain its efficacy in venous and lymphatic disorders.

### Is diosmin safe, and does it have side effects?

Diosmin at standard therapeutic doses (500–1500 mg/day as MPFF) has a well-established safety profile based on decades of clinical use in Europe, with adverse effects limited primarily to mild, transient gastrointestinal symptoms (nausea, diarrhea, dyspepsia) in fewer than 3% of users and no documented serious organ toxicity. There are no firmly established major drug interactions at clinical doses, though theoretical interactions with CYP1A2/2C9/3A4-metabolized drugs and anticoagulants warrant caution. Diosmin should be used cautiously during pregnancy—most guidelines advise avoiding use in the first trimester—and safety during breastfeeding has not been established.

### What is the difference between diosmin and MPFF (Daflon)?

MPFF (micronized purified flavonoid fraction), marketed as Daflon among other brand names, is a standardized pharmaceutical formulation containing 90% micronized diosmin and 10% micronized hesperidin at a total dose of 500 or 1000 mg per tablet. The combination is intentional—hesperidin provides complementary capillary anti-exudative and anti-fragility effects that synergize with diosmin's venotonic and anti-inflammatory mechanisms, producing superior clinical outcomes to either flavonoid alone. Micronization to particles below 2 µm is the key technological feature that increases the bioavailability of both compounds to approximately 55%, roughly double that of non-micronized diosmin, and most clinical trial evidence supporting venous and hemorrhoidal indications was generated using MPFF specifically.

### Does diosmin absorption improve when taken with food or on an empty stomach?

Diosmin absorption is enhanced when taken with meals, particularly those containing fats, which increases bioavailability of this lipophilic flavonoid. Clinical studies of MPFF formulations typically recommend dosing with breakfast and dinner to optimize absorption and maintain consistent therapeutic plasma levels. Taking diosmin consistently with food helps stabilize digestion and reduces the likelihood of gastrointestinal upset.

### Is diosmin safe to use during pregnancy and breastfeeding?

While diosmin is derived from natural citrus sources, safety data specifically in pregnant and breastfeeding women is limited, and most manufacturers recommend avoiding use during these periods as a precautionary measure. Some clinical guidelines note that MPFF has been studied in pregnant women with hemorrhoids with apparent safety, but individual medical supervision is advised. Pregnant individuals concerned about varicose veins or hemorrhoids should consult their healthcare provider before supplementing with diosmin.

### Can diosmin interact with anticoagulant or antiplatelet medications like warfarin or aspirin?

Diosmin has mild antiplatelet and mild anticoagulant properties, so concurrent use with warfarin, apixaban, or high-dose aspirin should be monitored by a healthcare provider to assess bleeding risk. Most clinical studies suggest diosmin is safe alongside standard anticoagulation when used at recommended dosages, though individual responses vary. Patients on prescription blood thinners should inform their doctor before starting diosmin supplementation to allow for appropriate monitoring.

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