IngredientsProcyanidol is one of several interchangeable designations applied to a family of plant polyphenols more formally known as procyanidins or oligomeric proanthocyanidins (OPCs). Synonyms in the scientific and commercial literature include procyanidins, procyanidolic oligomers (PCOs), leucoanthocyanins, condensed tannins, and — historically — pycnogenols, although the latter generic term is no longer used by the scientific community. The term procyanidol appears most commonly in older European pharmaceutical and supplement labeling and corresponds directly to what current nomenclature calls procyanidins or OPCs. For example, Procyanidin C1 is widely recognized under the synonyms cinnamtannin A1, proanthocyanidin C1, epicatechin trimer, and procyanidol C1.
Procyanidins are members of the proanthocyanidin (or condensed tannins) class of flavonoids. They are oligomeric compounds formed from catechin and epicatechin molecules, and they yield cyanidin when depolymerized under oxidative conditions. For practical purposes, proanthocyanidins (including procyanidols) are a group of water-soluble, ethyl-acetate-extractable compounds present in the bark of most trees, and exist mainly as low molecular weight phenolic monomers, dimers, trimers, oligomers, and polymers with reactive hydroxyl groups.
Two major structural sub-types are distinguished by the linkage between their flavan-3-ol units: B-type procyanidins, connected by a single C–C bond at the 4β→8 or 4β→6 position, and A-type procyanidins, which bear an additional ether (C–O–C) bond creating a doubly-linked, more compact ring system. Grape seed and pine bark extracts contain mainly B-type proanthocyanidins and therefore can be readily distinguished from cranberry, which is dominated by A-type proanthocyanidins.
Oligomeric proanthocyanidins (OPCs) strictly refer to dimer and trimer polymerizations of catechins. OPCs are found in most plants and are common in the human diet, with especially high concentrations found in the skin, seeds, and seed coats of purple or red pigmented plants.
Procyanidin is a naturally found polyphenol composed of flavan-3-ol units, epicatechins, and catechins. It is a type of polyphenolic polymer widely distributed in grapes, grains, red wine, nuts, berries, apples, tea, cocoa, and pine bark.
Grapes, particularly their peels and seeds, are the primary commercial source of procyanidins and contribute significantly to global procyanidin production. The reported total proanthocyanidin content in grape seeds reaches up to 35.3 mg/g of seed dry weight, consisting primarily of monomers such as (+)-catechin and (−)-epicatechin, and polymers including dimers, trimers, and larger oligomers. The procyanidin content in grape seeds varies depending on the grape cultivar and the extraction method used; among extraction methods, supercritical CO₂ extraction yields the highest amount of procyanidins, followed by methanol, ethanol, and water extractions.
Procyanidins can be found in many plants, most notably apples, maritime pine bark and that of most other pine species, cinnamon, aronia fruit, cocoa beans, grape seed, grape skin, and red wines of Vitis vinifera; bilberry, cranberry, black currant, green tea, and black tea also contain these flavonoids.
Some of the foods that contain the highest concentration of procyanidin are chocolates, apples, and cocoa powder. A lower concentration of procyanidin can be found in grapes, red wine, kiwis, and pears. Açaí oil, obtained from the fruit of the açaí palm (Euterpe oleracea), is rich in numerous procyanidin oligomers. Apples contain on average per serving about eight times the amount of procyanidin found in wine, with some of the highest amounts found in the Red Delicious and Granny Smith varieties.
Among pine species, a well-known commercial product containing proanthocyanidins is Pycnogenol®, an extract of the maritime pine bark (Pinus pinaster), which is a registered trademark belonging to Horphag Research Ltd. and is a standardized bark extract of the French maritime pine Pinus pinaster, Aiton, subspecies Adantica des Villar. The quality of this extract is specified in the United States Pharmacopeia (USP 28). Other pine species from which proanthocyanidins have been characterized include Pinus radiata and Pinus massoniana.
Procyanidins reach consumers in a variety of standardized and unstandardized preparations:
The Procyanidolic Index (also called the Bates-Smith Assay) has historically been used to measure the OPC content of commercial products. The Procyanidolic Index is a relative value that can measure well over 100. A Procyanidolic Index of 95 was erroneously taken to mean 95% OPC content by some, and this figure began appearing on the labels of finished products; all current methods of analysis suggest that the actual OPC content of these products is much lower than 95%.
The documented use of procyanidin-containing plant materials predates their chemical characterization by centuries. The first historically recorded use of pine bark extracts dates to 1535, when the French explorer Jacques Cartier and his crew escaped death by scurvy by drinking tea made from the bark of a pine tree, indicating that one of the active ingredients in pine bark extracts may share a function with or enhance the function of vitamin C.
Jacques Masquelier of the University of Bordeaux, France, first studied OPCs in depth after reading of explorer Jacques Cartier's 1534 expedition up the St. Lawrence River, in which Cartier's crew — trapped in ice flows and dying of scurvy — survived after Native Americans gave them a tea brewed from the bark and needles of the native pine. Masquelier later postulated that the pine constituents contained vitamin C and flavonoids that aided in the crew's recovery.
Several pine species, including Pinus massoniana Lamb, are native to China, and their bark, needles, pollen, and turpentine have been used in traditional Chinese medicine for the treatment of hemorrhage, rheumatism, arthralgia, inflammation, and cancer.
Grapes — the berries of Vitis vinifera — have been well-known and popularly consumed since ancient times. The nutritional and medicinal values of these fruits have been confirmed by both traditional medicine and a growing number of scientific reports.
The modern scientific era of procyanidin research begins with the mid-20th century. Albert Szent-Györgyi, the 1937 Nobel Prize winner, discovered flavonoids while working on the segregation of vitamin C, terming them "vitamin P." Subsequently, Professor Jacques Masquelier postulated that pine bark exhibited ascorbate-like effects and must contain vitamin C along with flavonoids, which he designated as "pycnogenols." Masquelier improved and patented a technique to extract oligomeric grape seed proanthocyanidins in 1947, and observed that the bioflavonoids derived from grape seeds appeared superior in both concentration and antioxidant effect to those from pine bark.
Human consumption of pine bark dates back thousands of years, and the first commercial pine bark extract was patented in 1948 by Dr. Jacques Masquelier of France.
Procyanidins are not a single compound but a spectrum of structurally related oligomers and polymers. Among polyphenols, procyanidins are oligomeric compounds consisting of (+)-catechin and (−)-epicatechin. The degree of polymerization (DP) — the number of flavan-3-ol units joined — determines much of their biological behavior, absorption, and bioavailability.
In grape seed extracts, the composition has been quantitatively mapped. The extract is composed mainly of catechin and procyanidin oligomers with a total amount of 5,801 mg/100 g, representing 92% of the total individual phenolic content. Among them, the most abundant are catechins (2,047 mg/100 g), followed by procyanidin dimers (1,550 mg/100 g), trimers (1,176 mg/100 g), tetramers (436 mg/100 g), and pentamers (296 mg/100 g).
Grape seeds contain about 5–8% polyphenols depending on variety, including the flavan-3-ol monomers catechin, epicatechin, gallocatechin, epigallocatechin, and epicatechin 3-O-gallate, as well as procyanidin dimers, trimers, and highly polymerized procyanidins.
The well-characterized individual procyanidin molecules include:
Procyanidins (PCs) effectively suppress oxidative stress through repairing DNA damage, preventing lipid peroxidation, and modulating signaling pathways — including the Nrf2, MAPK, and NF-κB pathways — and thereby treat oxidative stress–related diseases such as cardiovascular diseases, neurodegenerative disorders, metabolic diseases, skin disorders, and cancer. The free-radical scavenging capacity of procyanidins arises from their phenolic hydroxyl groups, which donate hydrogen atoms to neutralize reactive oxygen species.
A major proposed mechanism for the cardiovascular effects of procyanidins is stimulation of endothelial nitric oxide (NO) production. It has been proposed that the vasorelaxant properties of procyanidins result from their ability to stimulate the rapid formation of nitric oxide through endothelial nitric oxide synthases (eNOS), leading in turn to increased accumulation of cyclic guanosine monophosphate (cGMP).
More specifically for the trimer procyanidin C1: Treatment of rat aortic endothelial cells with 50 μM procyanidin C1 (4β→8 trimer) resulted in a time- and dose-dependent hyperpolarization, while no effect was observed for (−)-epicatechin (monomer) or procyanidin B2 (dimer). The C1-induced hyperpolarization was inhibited by iberiotoxin, a specific inhibitor of large-conductance Ca²⁺-activated K⁺ channels, as well as by a store-operated Ca²⁺ entry inhibitor. Procyanidin C1 caused a significant increase in NO production from endothelial cells via phosphorylation of both eNOS and Akt.
In vascular tissue studies, procyanidin C1 induced a potent vasorelaxant effect on phenylephrine-constricted endothelium-intact thoracic aortic rings but had no effect on denuded thoracic aortic rings, and caused a significant increase in nitric oxide production in endothelial cells. The endothelium-dependence of this effect indicates a primary role for eNOS activation rather than a direct smooth muscle action.
Procyanidin-mediated anti-inflammatory molecular mechanisms include the modulation of the arachidonic acid pathway, the inhibition of the gene transcription, protein expression, and enzymatic activity of eicosanoid-generating enzymes, the production and secretion of inflammatory mediators (such as cytokines and nitric oxide), the inhibition of the mitogen-activated protein kinase (MAPK) pathway, and the modulation of the nuclear factor-κB (NF-κB) pathway.
Cell-based studies have detailed these pathways further. Wild grape seed procyanidins significantly reduced NO, PGE₂, and ROS production, and inhibited the expression of proinflammatory mediators such as iNOS and COX-2. They significantly reduced LPS-stimulated expression of TNF-α and IL-1β, prevented nuclear translocation of NF-κB p65 subunit, and inhibited LPS-induced phosphorylation of p38 MAPK — establishing that procyanidins exert anti-inflammatory activity through inhibition of iNOS and COX-2 by regulating NF-κB and p38 MAPK pathways.
Regarding procyanidin A2 specifically: pro-inflammatory cytokines including TNF-α, IL-6, PGE₂, NO, and ROS were suppressed by procyanidin A2 at concentrations of 0–80 μM; mRNA levels of TNF-α and IL-6 were inhibited at 80 μM; and hallmark protein expression of the NF-κB and MAPK pathways was decreased by procyanidin A2 in LPS-stimulated macrophage cells.
Procyanidin-rich fractions from wild grape (Vitis amurensis) seeds strongly induced the reporter activity of the antioxidant response element (ARE) as well as the protein expression of nuclear factor E2-related factor (Nrf2), and also strongly induced the expression of the phase II detoxifying and antioxidant enzymes such as NAD(P)H:quinone oxidoreductase 1 and heme oxygenase 1 in human hepatocarcinoma (HepG2) cells.
Randomized controlled trials have shown that grape seed extract affects platelet aggregation activity and/or blood coagulation activity in humans, and RCTs have additionally shown that grape seed extract increases platelet closure time in humans.
A large portion of orally ingested oligomeric and polymeric procyanidins reaches the colon, where they are subjected to microbial degradation into phenolic acids and valerolactones. The remainder interacts with gut microbiota, resulting in improved microbial diversity, including an increased amount of beneficial gut bacteria such as Akkermansia muciniphila, which ameliorates host metabolic functions, and a lowered ratio of Firmicutes/Bacteroidetes at the phylum level. Procyanidins also have the potential to increase butyrate-producing microbiota and decrease LPS-producing bacteria, contributing to prevention and treatment of metabolic and neurological conditions.
The bioavailability of procyanidins is highly dependent on degree of polymerization. Absorbed intact dimers, trimers, and tetramers undergo limited phase II metabolism in the intestine and liver. Proanthocyanidins with a degree of polymerization over 4 (DP > 4) are not absorbable because of their large molecular size and gut barrier. Depolymerization of proanthocyanidins in the gastrointestinal tract is negligible. The majority of proanthocyanidins reaches the colon intact and is degraded into phenylvalerolactones and phenolic acids by colonic microbiota, and these microbial metabolites may contribute to the health-promoting properties of proanthocyanidins in vivo.
The bioavailability of proanthocyanidins is poor compared to other flavonoids and polyphenols due to their complexity and polymerized structure. In vivo studies suggest proanthocyanidins are not degraded in the stomach and reach the intestine with no relevant alteration. Because no transporters have been found in the small intestine for proanthocyanidins, absorption occurs by passive diffusion through the paracellular pathway. In contrast, polymeric proanthocyanidins (degree of polymerization above four) are not absorbable due to their high molecular weight and polarity, and therefore reach the large intestine unchanged.
Most phenolic compounds in grapes and wine are heavily metabolized by gut flora to produce metabolites that can potentially be well absorbed into the bloodstream by passive diffusion or active transport systems. It is generally accepted that they reach maximum plasma values between five minutes and two hours after administration, depending on the compound.
Importantly, the molecular form of procyanidin reaching the circulation and target tissue matters greatly. Procyanidins are comprised of catechin and epicatechin in monomeric, oligomeric, and polymeric forms; animal results showed that only the monomeric form treatment, rather than oligomers and polymers, resulted in the accumulation of bioactive metabolites in the brain capable of improving cognitive function in a mouse model of Alzheimer's disease.
The strongest body of human clinical evidence for procyanidins concerns cardiovascular parameters, particularly blood pressure regulation and endothelial function.
Meta-analysis evidence: Several clinical trials have shown that grape seed extract can reduce blood pressure, but results are often irreproducible. A meta-analysis sought to systematically evaluate the impact of grape seed extract treatment on systolic and diastolic blood pressure by analyzing available randomized controlled trials; twelve articles involving 16 clinical trials and 810 study subjects were analyzed.
A further systematic review of 30 eligible RCTs found: pooled results indicated that compared to the control group, consumption of grape products significantly decreased systolic blood pressure (SBP) (WMD = −3.17 mmHg; 95% CI: −5.36, −0.99 mmHg; P = 0.004; I² = 64%). The substantial heterogeneity (I² = 64%) indicates variability across trials, limiting how broadly these average effects can be applied.
Key individual trials: A registry study using standardized grape seed procyanidin extract (Enovita) evaluated two doses in 119 healthy pre- and mildly hypertensive subjects. Two dosages of Enovita were evaluated (150 and 300 mg/day) using blood pressure and heart rate as primary endpoints. After four months of treatment, a statistically significant, dose-dependent improvement in all endpoints was observed in the treatment groups compared to control, with blood pressure normalizing in 93% of the higher-dosage (300 mg) treatment group. These observations suggest that grape seed procyanidin extracts (GSPEs) have beneficial cardiovascular effects that complement current intervention strategies in the hypertension area.
A randomized, double-blind, placebo-controlled study in 30 Japanese adults (6 men and 24 women, aged 40–64) with prehypertension used low-dose (200 mg/day) or high-dose (400 mg/day) GSPE or placebo for 12 weeks. The mean systolic blood pressure in the high-dose group significantly decreased by 13 mmHg after 12 weeks (P = 0.028), although flow-mediated dilation did not change. This study was a randomized, double-blind, placebo-controlled study evaluating various cardiovascular parameters, but a large-scale randomized controlled trial was deemed necessary to verify its findings. The small sample size is a notable limitation.
Overall, there is substantial evidence for procyanidin efficacy against cardiovascular diseases. However, effect sizes in blood pressure studies tend to be modest and results vary with extract standardization, dose, duration, and patient population. Evidence is considered preliminary to moderate in strength at the population level.
Procyanidins have antioxidative properties that may protect against age-related brain oxidative stress, and previous studies indicated that procyanidin-rich foods could improve cognitive function and prevent neurodegenerative diseases.
A community-based randomized, double-blind, placebo-controlled trial specifically tested grape seed procyanidin extract (GSPE) in elderly people with mild cognitive impairment (MCI). This study hypothesized that GSPE would have a favorable effect on cognitive function. Participants aged 60 years or older with MCI were randomly assigned into the GSPE group (n = 35, receiving 320 mg/day) or placebo group (n = 36), receiving capsules for 6 months. Cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA). The evidence from this single trial is preliminary and conclusions require replication in larger samples.
In preclinical settings, procyanidins significantly reduced amyloid-β₄₂ (Aβ₄₂) aggregation and had a dose-dependent ability to disintegrate Aβ₄₂ aggregates; treatment also reduced the Aβ₄₂ load in treated mice compared to untreated LPS-injected mice. Grape seed extract exhibited remarkable cognitive-enhancing activity in animal models, improving spatial memory and preventing memory deficits in the central nervous system. These preclinical findings are intriguing but do not yet translate to established human evidence.
Proanthocyanidins are known to possess antioxidant, antimicrobial, anti-inflammatory, anti-allergic, anti-obesity, and vasodilatory properties. Epidemiological evidence has linked the consumption of proanthocyanidins to a reduced risk of chronic diseases, including certain types of cancer and cardiovascular disease, as well as non-alcoholic fatty liver disease (NAFLD).
Some studies suggest that the consumption of procyanidin-rich foods affects the expression of key genes involved in the regulation of anti-oxidative enzymes and of glucose and lipid metabolism. Animal and in vitro research shows procyanidins can influence adipogenesis and insulin signaling, but robust, large-scale human clinical trials specifically targeting metabolic syndrome outcomes remain limited. Evidence in this area is characterized as preliminary.
Some evidence from human trials addresses bone metabolism in postmenopausal women. A randomized, double-blinded, controlled clinical trial for 12 weeks examined the effects of pine bark extract procyanidin on bone remodeling in postmenopausal osteopenic women. After the 12-week intervention, pine bark extract procyanidin supplementation resulted in a significant increase in bone alkaline phosphatase (BAP) and procollagen type 1 amino-terminal propeptide (P1NP) levels, and a significant decrease in C-terminal telopeptide of type I collagen (CTx1). Compared with the control group, supplementation resulted in a significant increase in P1NP levels (p < 0.05), BAP levels (p < 0.01), and BAP/CTx1 ratio (p < 0.01), and a significant decrease in CTx1 levels (p < 0.01). These findings suggest a favorable impact on bone turnover markers, though longer-term trials measuring bone mineral density outcomes are needed.
The effect of pine bark extract proanthocyanidin for human skin has been documented. In vitro data show procyanidins can reduce oxidative stress induced by UV radiation in human skin cells. Bioactivity assays revealed that procyanidin-rich crude extracts reduced oxidative stress and exhibited anti-inflammatory effects against UVA in human keratinocytes (HaCaT). The evidence base for clinical skin benefits in humans remains preliminary and largely short-term.
Grape seed procyanidin extract (GSE) has been reported to exert antineoplastic properties in preclinical studies. A modified phase I, open-label, dose-escalation clinical study was conducted to evaluate the safety, tolerability, maximum tolerated dose, and potential chemopreventive effects of leucoselect phytosome (a standardized GSE complexed with soy phospholipids to enhance bioavailability) in heavy active and former smokers. Eight subjects aged 46–68 years were enrolled and treated with escalating oral doses of leucoselect phytosome for 3 months; bronchoscopies with bronchoalveolar lavage and bronchial biopsies were performed before and after 3 months of treatment. This represents very early-stage (Phase I) human evidence only; no efficacy conclusions can be drawn.
Preclinical in vitro studies have examined procyanidin effects on cancer cell lines. A polyphenolic fraction of GSE enriched in antioxidant procyanidins was found to significantly inhibit growth and induce G1 cell cycle arrest and apoptosis in DU-145 prostate cancer cells, associated with a reduction of cyclin E and CDKs 2 and 4, as well as phosphorylated ERK1/2, along with an increase in Cip1/p21. These are in vitro findings and do not constitute clinical evidence.
Procyanidins have been studied for effects in the gut lumen, where — owing to their limited upper-gastrointestinal absorption — they reach high luminal concentrations. Grape seed procyanidins are flavan-3-ol oligomers and polymers known for their biological activity in the gut; grape seed extract has been reported to reduce intestinal injury in a rat model of mucositis. Human clinical evidence for gut-specific benefits is limited to preclinical and early-stage studies.
Grape seed extract, which is mainly composed of procyanidins, lowers blood pressure and improves vascular function. The improvement in cardiovascular function with products containing high amounts of procyanidins is consistent with studies on isolated vessels showing that purified procyanidins cause endothelium-dependent vasodilation via NO release.
The following dosages are reported directly from the studies cited; they are not recommendations.
Toxicological data for pine bark extracts are limited, but no serious adverse effects have been reported; pine bark extracts may have potential as nutraceuticals and pharmaceuticals and should be safe for use as food ingredients.
In acute toxicology testing of a procyanidin-rich extract from grape skins and seeds: the LD₅₀ was higher than 5,000 mg/kg, and doses of up to 2,000 mg/kg showed no increase in micronucleated erythrocytes 72 hours after treatment. The bacterial reverse mutation test showed that the extract was weakly mutagenic at the dose of 5 mg/plate, indicating that further studies at lower doses should be conducted to confirm safety.
This is the most clinically significant established interaction area. Randomized controlled trials have shown that grape seed extract affects platelet aggregation activity and/or blood coagulation activity in humans; RCTs have shown that grape seed extract increases platelet closure time in humans.
While grape seed extract is greatly tolerated in modest amounts, there is a possibility that it is hazardous in individuals with bleeding disorders, those undergoing surgery, or in those taking anticoagulant medications such as aspirin and warfarin.
Grape seed procyanidin extract (GSPE) can negatively interact with a number of medications that are metabolized in the liver, specifically by CYP450 3A4 substrates. Other drug interactions include cancer medication regimens, blood pressure medications such as propranolol, and NSAIDs such as ibuprofen and naproxen.
Concomitant consumption of vitamin C with GSPE use may contribute to blood pressure changes, and GSPE may also influence the blood clotting process.
Little is known about whether it is safe to use grape seed extract during pregnancy or while breastfeeding.
According to the U.S. National Center for Complementary and Integrative Health (NCCIH), if a person takes any type of medicine, they should talk with their healthcare provider before using grape seed extract or other herbal products, as some herbs and medicines interact in harmful ways.
Several important caveats apply to the current state of procyanidin research:
Health conditions that Procyanidol may help support.
Procyanidol (also referred to as procyanidin/OPC) is the class of condensed tannin flavonoids found in grape seed and pine bark that has been studied for varicose veins and CVI. As a component class of Pycnogenol and grape seed extracts, procyanidols underlie the clinical evidence of these preparations for CVI, reducing capillary leakage, strengthening vessel walls, and improving venous tone in placebo-controlled trials.
Body systems that Procyanidol may help support.
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