Grape seed

Grape Seed (Vitis vinifera L.): A Comprehensive Reference

1. Identity and Botanical Description

Botanical name: Vitis vinifera L. (family Vitaceae). The grape seed is the kernel found within the berry of the common grapevine. Commercially, grape seed extract (GSE) is derived from the seeds of Vitis vinifera, the European or common grape, and is occasionally sourced from the American species Vitis labrusca.

Grape seeds are a by-product of the juice and wine industry and represent a rich source of polyphenols. Approximately 60–70% of grape polyphenols are found in the seeds, and the seeds account for approximately 5% of the weight of the whole grape, representing approximately 40–50% of solid waste generated during winemaking.

The term grape seed extract (GSE) refers to a concentrated extract of these seeds, standardized for its polyphenolic content. GSE is one of the world's bestselling dietary supplements. Both fruit- and leaf-derived products are mentioned in many pharmacopeias, including the British and US Pharmacopeias, and are reviewed in agency monographs such as the European Union herbal monograph edited by the Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency (EMA).

Common Forms and Preparations

• Commercial preparations of grape seed polyphenols (GSPS) are marketed in the United States as GSE and are sold as an over-the-counter product in the form of capsules or tablets (100–500 mg), with 95% standardized proanthocyanidins as a dietary supplement.
• Grape seed oil: Its use as an edible oil has been suggested, especially due to its pleasant sensory characteristics. Grape seed oil has beneficial properties for health that are mainly detected by in vitro studies, such as anti-inflammatory, cardioprotective, antimicrobial, and anticancer properties, and may interact with cellular and molecular pathways. These effects have been related to grape seed oil constituents, mainly tocopherol, linolenic acid, resveratrol, quercetin, procyanidins, carotenoids, and phytosterols.
• Phytosome formulations: A preparation called leucoselect phytosome (LP) standardizes smaller grape seed oligomeric procyanidins (OPC) and complexes them with soy phospholipids into phytosomes to improve bioavailability.
• Standardized extracts for clinical use: Named proprietary extracts used in research include Endotélon®, Anthogenol®, Enovita®, and MegaNatural-Gold®, among others, each with defined proanthocyanidin profiles.

2. Traditional and Historical Use

Grapes were domesticated in western Asia prior to 5,000 BC, are depicted in tomb paintings dating to 2,400 BC, and are mentioned in biblical writings. Ancient Egyptians, Romans, and Greeks noted the health benefits of wine drinking, and the cardioprotective effect of regular wine consumption has been observed among Mediterranean populations.

Flavonoids such as flavanols and flavonols, stilbenes such as trans-resveratrol, and phenolic acids such as gallic, vanillic, syringic, and caffeic acids form the basis of the phenolic composition of grapes and their derivatives. Although ancient peoples consumed grapes whole — seeds and all — specific isolation and use of grape seed as a medicinal preparation is largely a modern phenomenon.

The modern scientific study of grape seed polyphenols began in mid-twentieth-century France. A specific grape seed extract containing monomeric and oligomeric flavan-3-ols was created by Jack Masquelier in 1947, becoming a botanical remedy and nutraceutical. In 1947, the French researcher Jack Masquelier extracted a colorless fraction from the red-brown skin of peanuts during his PhD thesis work. He found this fraction to be responsible for the "vitamin P" effect in animals and proposed its major components as oligomers of flavan-3-ol units — specifically (+)-catechin or (−)-epicatechin — now commonly classified as monomeric and oligomeric flavan-3-ols.

Grape seed extract and proanthocyanidins have been marketed in France for decades as treatment for venous and capillary disorders, and the extract is used extensively in Japan as a food additive and antioxidant.

3. Key Constituents and Active Compounds

Proanthocyanidins (OPCs)

Extracts of the seeds are most commonly used as an ingredient in dietary supplements due to their antioxidant potential. Oligomeric proanthocyanidins (OPC), the class of polyphenols primarily shown to be the bioactive constituents, are polymerized (±)-catechin and (±)-epicatechin, often with galloylations.

OPCs are typically defined as containing 2–5 degrees of polymerization (DP), while hexamers and larger are typically categorized as tannins (≥6 DP). This differentiation is determined by bioavailability, since dimers to pentamers have been reported to be bioavailable.

Grape seeds contain B-type proanthocyanidins in their galloylated and non-galloylated forms. The flavan-3-ol monomers are singly linked through C4→C6 or C4→C8 bonds.

An additional feature of commercially available GSEs is the presence of free or gallic acid-esterified monomeric catechins (catechin and epicatechin), whose content ranges from 15 to 30%, and depends on both the maturation stage of the grape and the extraction method used.

Other Phenolic Compounds

Grape seed extract from Vitis vinifera (VGSE) is considered a major source of anti-toxic substances such as flavonoids, gallic acids, catechin, epicatechin, and proanthocyanidin. It also contains approximately 35% fiber with 29% extractable components including phenolic compounds and proteins.

Grape Seed Oil Constituents

Other lipophilic constituents largely found in grape seed oil are phytosterols, which may prevent the release of proinflammatory mediators by oxidized low-density lipoprotein-stimulated macrophages during oxidative stress and eicosanoid synthesis.

Polyphenol Content by Tissue

Extractable phenolics in grapes are arranged as follows: about 10% are present in the pulp, 28–35% in the skin, and 60–70% in the seeds. This makes seeds the dominant repository of grape polyphenols by far.

4. Mechanisms of Action

Antioxidant Activity

Grape seed proanthocyanidins (GSPs) have been shown to function as an antioxidant and anti-inflammatory agent with little toxicity in vivo and in vitro. GSPE provided significantly better scavenging activity toward biochemically generated superoxide anion when compared to vitamins C and E.

GSE significantly reduced LPS-induced intracellular reactive oxygen species (ROS) production and mitochondrial superoxide production, and upregulated the expression of antioxidant enzyme genes. GSE also restored the LPS-damaged mitochondrial function by increasing mitochondrial membrane potential.

Anti-inflammatory Mechanisms

GSPs extract has been found to suppress the mRNA expression of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and inflammatory molecule cyclooxygenase-2 (COX-2), while the mRNA level of IL-10 was greatly promoted. Furthermore, GSPs extract inhibited the expression of phosphorylated ERK, JNK, and P38, as well as phosphorylated IKKα/β and NF-κB p65 subunit. GSPs extract showed its anti-inflammatory and immunomodulatory properties by suppressing the activation of MAP kinases and NF-κB signal transduction pathways.

Vascular and Endothelial Mechanisms

Studies on Enovita® grape seed extract investigated in vitro mechanisms including eNOS (endothelial nitric oxide synthase) activation, which has been described for many plant-derived products, in addition to effects on vasoconstrictor factors. Activation of eNOS promotes production of nitric oxide (NO), which mediates vascular smooth muscle relaxation and blood pressure reduction.

Neuroprotective Mechanisms (Preclinical)

In in vitro assays, standardized GSE showed significant GABA-T inhibitory activity, MAO-A and AChE inhibition, and moderate binding affinity to the GABA-A receptor. In neuroprotective assays, GSE provided significant protection to SH-SY5Y neuroblastoma cells against oxidative stress.

Preclinical research has proposed that the grape seed neuroprotective action resulting in blood–brain barrier function protection is mainly through inhibition of MMP-9.

Collagen Stabilization and Capillary Integrity

A well-documented mechanism — established in early OPC research — involves the cross-linking and stabilization of collagen fibers in vessel walls and connective tissue, reducing capillary permeability. This is consistent with the traditional use of Masquelier's OPC extracts in venous and capillary disorders.

Anti-osteoclastogenic Activity

GSPE treatment reduced the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and osteoclast activity and increased differentiation of mature osteoblasts. Receptor activator of NFκB ligand (RANKL) expression in fibroblasts from rheumatoid arthritis patients was abrogated with GSPE treatment. GSPE blocked human peripheral blood mononuclear cell-derived osteoclastogenesis and acted as an antioxidant.

Bioavailability Considerations

The bioavailability of grape seed polyphenol compounds is generally governed by their chemical structures and degree of polymerization (DP). In total, 35 structurally related (epi)catechin metabolites and ring fission metabolites were detected after intake of grape seed proanthocyanidins. Ingestion of grape seed proanthocyanidins resulted in a substantial increase in microbiota-derived 5-carbon side chain ring fission metabolites (5C-RFMs) in plasma. This highlights the important role of the gut microbiota in metabolizing higher-MW proanthocyanidins into absorbable catabolites.

5. Scientific Evidence by Area of Use

5.1 Cardiovascular Health: Blood Pressure

Blood pressure is the area with the most substantial human clinical evidence for GSE.

Meta-analyses: Nine randomized controlled trials (N=390) met inclusion criteria in one meta-analysis. Upon meta-analysis, grape seed extract significantly lowered systolic blood pressure (weighted mean difference −1.54 mm Hg; 95% CI, −2.85 to −0.22; P=0.02) and heart rate (weighted mean difference −1.42 bpm; 95% CI, −2.50 to −0.34; P=0.01).

A 2022 review of 19 studies (1,080 participants) showed that grape seed extract reduced diastolic blood pressure (the lower number in a blood pressure reading) but not systolic blood pressure (the higher number). That meta-analysis also found that GSE supplementation significantly reduced diastolic blood pressure (weighted mean difference: −2.20 mmHg; 95% CI: −3.79 to −0.60) and heart rate (WMD: −1.25 bpm; 95% CI: −2.32 to −0.19), but had no significant effects on flow-mediated dilation.

Individual RCT: In healthy volunteers, supplementation with GSE tablets (300 mg/day for 16 weeks) in a double-blind, placebo-controlled design significantly modulated blood pressure, with a pronounced effect compared to placebo.

Dosage range in studies: In a meta-analysis of 9 trials (N=390), grape seed extract total daily doses ranged from 150 to 2,000 mg and treatment durations ranged from 2 to 24 weeks.

Evidence strength: Multiple meta-analyses of RCTs support modest, statistically significant reductions in blood pressure, particularly diastolic blood pressure. Results of individual studies differed, and the differences may have been related to the dose and duration of grape seed extract supplementation and characteristics of the study participants. The effect magnitude is modest compared to antihypertensive medications, and study populations, dosages, and extract preparations vary considerably.

5.2 Cardiovascular Health: Lipid Profile and C-Reactive Protein

Grape seed extract was associated with significant reductions in heart rate, but no significant effects were found on diastolic blood pressure, lipids, or C-reactive protein in one meta-analysis, and insufficient patient numbers did not allow for full analysis.

In one UC Davis clinical study, the group taking 300 milligrams of grape seed extract also had reduced serum oxidized LDL cholesterol levels; generally, the higher the initial oxidized LDL level, the greater the drop by the end of the study.

Evidence strength: Evidence for meaningful effects on total cholesterol, LDL, HDL, triglycerides, and CRP is inconsistent across trials. Current meta-analyses do not confirm robust lipid-lowering effects. Large, high-quality clinical trials are lacking to recommend GSE use for lipid outcomes.

5.3 Chronic Venous Insufficiency (CVI) and Edema

This is one of the best-supported clinical applications for GSE and OPCs.

There is good evidence that grape seed extract can help treat chronic venous insufficiency and edema. In chronic venous insufficiency, blood pools in the legs, causing pain, swelling, fatigue, and visible veins. A number of high-quality studies have shown that OPCs from grape seed can reduce symptoms.

Randomized controlled trial data: In a study of 92 patients with a mean age of 40 years and venous pathology of an average 7-year duration, patients received 300 mg Endotélon® for 4 weeks. Clinical scoring showed improvement in 75% of patients (versus 41% in the placebo group, P < 0.01). Edema reduction was also apparent.

Post-surgical edema: One double-blind, placebo-controlled study found that breast cancer patients who took 600 mg of grape seed extract daily after surgery for 6 months had less edema and pain than those who took placebo.

Varicose veins: After 12 weeks, 43 patients in a GSE group and 21 patients in a control group experienced improved venous reflux (P < 0.001), with improvements in symptoms greater in the GSE group. In a separate pilot study using 4D flow MRI, blood flow velocity was significantly increased in participants who underwent GSPE treatment, highlighting the potential of GSPE for CVI treatment.

Evidence strength: Clinical evidence for CVI and edema is among the strongest available for GSE, supported by multiple RCTs and good-quality observational data. GSPE is recommended as Grade C in 2005 and 2008 guidelines for the management of chronic venous diseases of the lower limbs, based on its action of reducing capillary permeability.

5.4 Antioxidant Status in Humans

A study of healthy volunteers found that taking grape seed extract substantially increased blood levels of antioxidants. Antioxidants are substances that destroy free radicals, harmful compounds in the body that damage DNA and even cause cell death. Scientists believe free radicals contribute to aging and the development of a number of health problems, including heart disease and cancer.

Evidence strength: Increases in circulating antioxidant markers following GSE supplementation are consistently reported across human studies. However, whether this translates into clinically meaningful disease prevention in humans remains unproven.

5.5 Cognitive Function and Neuroprotection

A 2021 review indicates that GSE could have a positive effect on cognitive health, suggesting GSE could benefit memory, movement, and executive functions. However, a 2023 trial in older adults with mild cognitive impairments found that GSE did not significantly improve symptoms, and further research is still necessary.

In vitro and animal data suggest mechanisms that could be relevant to neurodegeneration: In vitro assays found that standardized GSE showed significant GABA-T inhibitory activity, MAO-A and AChE inhibition, and moderate binding affinity to the GABA-A receptor. The National Center for Complementary and Integrative Health (NCCIH) is supporting preliminary research on grape seed extract for Alzheimer's disease.

Evidence strength: Predominantly preclinical (in vitro and animal). Human clinical evidence is limited and mixed. No firm conclusions can be drawn about GSE efficacy for cognitive outcomes in humans at this time.

5.6 Cancer — Preclinical and Preliminary Research

In in vitro studies, VGSE treatment significantly reduced viability of MCF-7, Hep-G2, Caco-2, and Huh-7 cancer cell lines after 48-hour treatments. The results reinforce its potential in disease prevention and therapy, especially in relation to cancer.

The National Cancer Institute is supporting preliminary studies on grape seed extract for preventing prostate, lung, and colon cancer.

Evidence strength: Cancer-related findings are almost entirely preclinical (in vitro and animal models). There is currently no adequate human clinical evidence to draw conclusions about GSE's role in cancer prevention or treatment.

5.7 Diabetes and Metabolic Syndrome

Many beneficial properties in cardiovascular, cancer, and neurological diseases as antioxidant, immunomodulatory, antidiabetic, cardio, and neuroprotective agents have long been described for proanthocyanidins.

A UC Davis study was the first human clinical trial to assess the effect of grape seed extract on people with metabolic syndrome, a combination of risk factors that increase the risk for heart disease, including high blood pressure, excess abdominal body weight, high blood cholesterol fats, and high blood sugar. The one-month study involved 24 male and female patients diagnosed with metabolic syndrome, divided into three groups of eight: one group received a placebo, while the second and third groups received 150 mg and 300 mg, respectively, of a new grape seed extract.

In a separate double-blind randomized clinical trial, 50 NAFLD patients were divided into two groups of 25 participants who were treated with 520 mg/day of GSE or placebo for 2 months, with glycemic parameters, lipid profile, blood pressure, and steatohepatitis measured before and after the intervention.

Evidence strength: Promising signals from small pilot trials in metabolic syndrome and NAFLD populations, but trials are generally small, short, and heterogeneous. Larger, well-controlled studies are required.

5.8 Wound Healing and Skin

Studies in experimental models suggest that application of grape seed extract to the skin may promote wound healing, but only a very small amount of research has been done on this topic in people, and there isn't enough evidence to conclude whether grape seed extract is helpful for this purpose.

Evidence strength: Insufficient human data to draw conclusions.

5.9 Oral Health / Dental Caries

Although laboratory studies suggest that grape seed extract, used in a mouthrinse, might help to prevent tooth decay, there hasn't been enough research in people to allow its effects to be evaluated.

Evidence strength: Limited to laboratory (in vitro) data. No clinical conclusions can be drawn.

6. Body Systems Associated with Grape Seed Extract

• Cardiovascular system: Blood pressure modulation, capillary integrity, venous tone, endothelial function.
• Venous / lymphatic system: Chronic venous insufficiency, edema, varicose veins.
• Central nervous system: Preliminary neuroprotective and cognitive effects (primarily preclinical).
• Metabolic system: Preliminary associations with glycemic control, lipid metabolism, and metabolic syndrome parameters.
• Gastrointestinal system: Grape polyphenols have previously been shown to improve gut health and attenuate the symptoms of metabolic syndrome; GSE was investigated for its protective effect on bacterial LPS-induced oxidative stress, inflammation, and barrier integrity of human Caco-2 colon cells.
• Immune / musculoskeletal system: GSPE treatment exhibited chondroprotective and antinociceptive properties in rat models of osteoarthritis through antioxidative effect, and showed anti-inflammatory effects in mice with collagen-induced arthritis. These results suggest that GSPE has therapeutic effects against metabolic diseases and autoimmune diseases.
• Oncology (preclinical only): In vitro antiproliferative activity across multiple cancer cell lines.

7. Dosage Forms and Dosages Reported in Studies

In clinical trials, grape seed extract has been studied for effects on various cardiovascular risk markers at oral doses of 150 to 2,000 mg/day; formulations and durations of therapy (range, 2 to 24 weeks) varied.

• A daily dose of 300 mg of grape seed extract was associated with reductions in systolic and diastolic blood pressure of 8 and 5 mmHg after eight weeks in a small, randomized, double-blind, placebo-controlled study.
• A one-month metabolic syndrome study tested 150 mg/day and 300 mg/day against placebo.
• A double-blind, placebo-controlled study in healthy volunteers used 300 mg/day for 16 weeks.
• A chronic venous insufficiency trial used 300 mg (Endotélon®) for 4 weeks in 92 patients.
• A post-surgical edema trial in breast cancer patients used 600 mg/day for 6 months.
• A NAFLD trial used 520 mg/day for 2 months in 50 patients.

Composition of commercial grape seed preparations is highly variable, and this variability complicates direct comparison across trials. Different proprietary extracts (Endotélon®, MegaNatural-Gold®, Enovita®, Anthogenol®) have different proanthocyanidin profiles and standardization levels.

8. Safety Considerations and Drug Interactions

General Tolerability

Grape seed extract is generally well tolerated when taken orally or used topically.

Anticoagulant / Antiplatelet Interactions

A key caution is a potential interaction with anticoagulants and other blood thinners. Memorial Sloan Kettering Cancer Center guidance advises patients to talk with their healthcare provider if they are taking blood thinners such as warfarin, noting that grape seed extract may increase bleeding risk.

It is possibly unsafe if you have a bleeding disorder, are going to have surgery, or take anticoagulants (blood thinners) such as warfarin or aspirin.

Drug Metabolism Interactions

It is important to note that GSE can affect the way certain medications are broken down in the liver. Additionally, GSE may act as an anticoagulant, or blood thinner. It could increase the risk of bleeding if taken with other blood thinners such as warfarin, clopidogrel, or aspirin.

Cancer Drug Interactions

In vitro data suggest that grape seed extract at 10–25 µg/mL significantly enhanced the growth-inhibitory effects of 5-fluorouracil (5-FU) by 26% in Caco-2 cells. Grape seed extract may thus represent a therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting the viability of colon cancer cells. This interaction has not been evaluated in human clinical trials and should not be acted upon clinically without physician guidance.

Liver Safety

Unlike some concentrated botanical extracts that have been associated with liver injury signals, the NIH LiverTox monograph on grape seed addresses its hepatic safety profile.

Pregnancy and Lactation

There is no information on the safety of grape seed extract use during pregnancy or breastfeeding.

Regulatory Status

The extract has received GRAS (generally recognized as safe) certification from the FDA. NCCIH additionally highlights that dietary supplements are not pre-approved like drugs by the U.S. Food and Drug Administration.

Duration of Safety Testing

A series of toxicological studies have been performed to investigate the safety profile of GSEs containing proanthocyanidin. Yamakoshi and colleagues (2002) assessed the safety of GSE in Fischer 344 rats and observed that the no-observed-adverse-effect level in their subchronic toxicity study was 2% of the diet, which correlates to a dietary intake of 1.4 and 1.5 g/kg body weight/day in males and females, respectively.

References

• National Center for Complementary and Integrative Health (NCCIH). Grape Seed Extract: Usefulness and Safety.
• Ras RT, et al. Masquelier's grape seed extract: from basic flavonoid research to a well-characterized food supplement with health benefits. Nutrition Journal. 2017; PMC5248468.
• Khwanchuea P, et al. Multi-Detector Characterization of Grape Seed Extract to Enable in silico Safety Assessment. PMC6102626.
• Shinagawa FB, et al. Grape Seed Oil Compounds: Biological and Chemical Actions for Health. Antioxidants. 2016; PMC4988453.
• Uysal S, et al. Grape seed extract inhibits DNA and protein damage and labile iron, enzyme, and cancer cell activities. PMC9300616.
• Cos P, et al. Grape-seed proanthocyanidins inhibit inflammatory mediator expression via MAPK and NF-κB pathways. PubMed. PMID: 26708200.
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• DARE Review: The effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trials. NCBI Bookshelf NBK85743.
• Foshati S, et al. GSE supplementation on flow-mediated dilation, blood pressure, and heart rate: a systematic review and meta-analysis. Pharmacological Research. 2022;175:105905.
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• Pilot study on the effect of GSPE on inferior vena cava blood flow in CVI patients using 4D flow MRI. PMC9678586.
• Palazzolo E, et al. Grape Seeds Proanthocyanidins: Advanced Technological Preparation and Analytical Characterization. PMC8001487.
• Fraga CG, et al. Grape Seeds Proanthocyanidins: An Overview of In Vivo Bioactivity in Animal Models. PMC6835351.
• Grape-Seed-Derived Procyanidin Attenuates Chemotherapy-Induced Cognitive Impairment by Suppressing MMP-9 Activity. PMC9139059.
• In Vitro Mechanistic Studies of a Standardized Sustainable Grape Seed Extract for Mood-Modulating and Cognition-Enhancing Applications. PMC11510545.
• Bioavailability of red wine and grape seed proanthocyanidins in rats. Food & Function. RSC Publishing. 2020.
• Drugs.com. Grape Seed Uses, Benefits & Dosage. June 2025.
• HerbalGram. Grape Seed Extract Supplementation Reduces Venous Reflux Time in Patients with Varicose Veins. 2026.
• Proanthocyanidin-Rich Grape Seed Extract Reduces Inflammation and Oxidative Stress and Restores Tight Junction Barrier Function in Caco-2 Colon Cells. PubMed PMID: 32492806.
• Grape Seed Extract Dose-Responsively Decreases Disease Severity in a Rat Model of Mucositis; Concomitantly Enhancing Chemotherapeutic Effectiveness in Colon Cancer Cells. PMC3897410.