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Antioxidant and Anti-inflammatory Activity

In vitro

Pycnogenol has potent antioxidant activity, which has been reported in several in vitro studies. Studies have shown that Pycnogenol can scavenge both hydroxyl radicals and superoxide anions,26 extend the lifetime and increase the antioxidant function of the ascorbate radical (vitamin C),27 and increase the activity of endogenous antioxidant enzymes, namely superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT).28 Lipids, proteins, and DNA are targets for oxidative damage. Studies have shown that Pycnogenol can prevent oxidative damage to lipids,29-31 proteins, 32,33 and breakage of plasmid DNA.30

Single Pycnogenol components and their metabolites also have antioxidant activity. Catechin inhibits superoxide activity in vitro with effectiveness similar to ascorbic acid.34 Interestingly, a metabolite of catechin that is generated in humans after oral consumption, M1, was found to be significantly more active than catechin or ascorbic acid in superoxide scavenging.34

M1 concentration-dependently inhibits nitrite production and inducible nitric oxide synthase (iNOS) expression in cell culture with a mouse cell line and human monocytes.24

Reactive oxygen species (ROS) not only directly cause cell injury and can initiate a degenerative process, they can also act as signals for other processes, such as proinflammatory pathways involving nuclear factor-kappa B (NF-κB) activation. In vitro, Pycnogenol blocked NF-κB activation in macrophages, which in consequence inhibited expression of the proinflammatory cytokine interleukin (IL)-1.35 Expression of adhesion molecules by endothelial cells is likewise under the control of NF-κB. Adhesion molecules are involved in leukocyte recruitment to inflammatory sites but also contribute to development of vascular disorders. Treatment of endothelial cells with Pycnogenol prior to stimulation with tumor necrosis factor-α (TNF-α) inhibited activation of NF-κB and limited induction of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1).36

ROS are associated with proinflammatory conditions through the stimulation of matrix metalloproteinases (MMPs). MMPs are a family of enzymes that cause lysis of connective tissue proteins. MMP-1 (collagenase 1) and MMP-9 (gelatinase B) are upregulated in arthritis, and they contribute to cartilage degradation in rheumatic diseases. MMP-1 also contributes to the aging effect of UV light on the skin, and MMP-9 also plays a role in asthma. In pulmonary fibrosis, MMP-2 (gelatinase A) also is involved. Pycnogenol had an inhibitory effect on the activity of MMP-1, MMP-9, and MMP-2, and further inhibited their secretion from stimulated human macrophages.37 In addition, the metabolites of catechin, M1 and M2, were significantly more potent for inhibition of MMP-1, MMP-2, and MMP-9 in vitro than the parent molecules in Pycnogenol extract 37

In cell culture of mouse macrophage cell lines, Pycnogenol inhibited expression of the proinflammatory cytokine IL-1. 35

During inflammation, the expression of iNOS leads to excess nitric oxide (NO) production, and Pycnogenol was shown to inhibit this process.38 In vitro experiments showed that Pycnogenol decreased cellular generation of NO via scavenging ROS and NO, inhibition of iNOS activity, and inhibition of iNOS-messenger RNA (mRNA) expression by blocking NF-κB activation in stimulated macrophages. The authors conclude that, based on this experiment, Pycnogenol may be useful during inflammation.38

In adipocyte cell culture, Pycnogenol inhibited lipid accumulation and ROS production via downregulation of adipogenic gene expression and mRNA expression of pro-oxidant enzymes, respectively.39

In a simulation of gouty arthritis in human articular chondrocytes and synovial fibroblasts, Pycnogenol inhibited upregulation of cyclooxygenase-2 (COX-2) and IL-8 and attenuated iNOS gene expression and NO production.40

In human lymphocytes, Pycnogenol reduced chromosome breakage and DNA damage induced by hydrogen peroxide (H2O2).41

Fruit juices enriched with 0.5 g/L Pycnogenol reinforced the antioxidative capacity of the juices, leading to an antiproliferative effect of a colon carcinoma cell line.42

Pycnogenol attenuates the release of proinflammatory cytokines and expression of perilipin-2 (adipose differentiation-related protein [ADRP]) in lipopolysaccharide (LPS)-stimulated mice microglia by inhibition of the NF-κB and activator protein-1 (AP-1) pathway.43


Pycnogenol has anti-inflammatory effects on the skin in vivo. Pycnogenol dose-dependently decreased carrageenan-induced paw edema, a model of inflammation (P < 0.05).44

In a rat model of gouty arthritis, Pycnogenol inhibited acute inflammatory cell infiltration and expression of COX-2 and iNOS in synovial tissue and articular cartilage.40

In mice exposed to ozone, oral Pycnogenol reduced the levels of nitrite and reactive nitrogen species, and the levels of the antioxidants Cu/Zn-SOD (copper-zinc superoxide dismutase), Mn-SOD (manganese superoxide dismutase), GPx, and glutathione reductase (GR) were enhanced.45

In rats with sepsis, intraperitoneal (IP) injection of Pycnogenol significantly decreased DNA damage and increased capacity of DNA repair in lymphocytes, liver, and kidney cells compared with untreated rats. Also in the rats with sepsis, Pycnogenol treatment inhibited TNF-α secretion, and increased total glutathione (GSH) levels (P < 0.05), SOD activity (P < 0.05), and GPx activity (P < 0.05).46

Human (ex vivo)

Cyclooxygenase-1 (COX-1) and COX-2 are enzymes that produce a cascade of chemical mediators, including prostaglandins, which mediate the inflammatory response. Plasma of 5 healthy participants who had taken 200 mg Pycnogenol for 5 days tended to inhibit COX-1 and COX-2 ex vivo, but not significantly.47 However, a single dose of 300 mg Pycnogenol given to 10 healthy participants produced serum samples showing significant inhibition of COX-1 (P < 0.02) and COX-2 ex-vivo (P < 0.002). According to the authors, this inhibition is consistent with the inhibition of platelet aggregation and the anti-inflammatory effects observed clinically.47

In another ex vivo experiment, plasma samples from 7 healthy participants given 200 mg/day Pycnogenol for 5 days reduced LPS-induced release of MMP-9 from human monocytes by 25% (P < 0.01).37 MMP-9 induction and release are initiated by NF-κB activation. Plasma samples also inhibited NF-κB nuclear translocation by 15.5% (P < 0.05). The correlation between the two was positive (Spearman’s rank correlation coefficient, r = 0.6). These results are consistent with anti-inflammatory effects observed clinically.37

A third ex vivo study evaluated the molecular basis of the anti-inflammatory effect of Pycnogenol supplementation by isolating and activating polymorphonuclear leukocytes (PMNL) from the blood of 6 healthy participants given 150 mg/day Pycnogenol for 5 days. Pycnogenol supplementation inhibited 5-lipoxygenase (5-LOX) gene expression, COX-2 gene expression, and phospholipase A2 (PLA2) activity, and reduced leukotriene production.48 These results further demonstrate the anti-inflammatory properties of Pycnogenol.


The effect of Pycnogenol on plasma antioxidant capacity was tested in 25 healthy participants (10 men and 15 women; mean age, 30 ± 8 years) given 150 mg/day Pycnogenol for 6 weeks, followed by a 4-week washout period.49 Plasma polyphenol levels increased significantly after 3 weeks of supplementation, indicating that Pycnogenol was absorbed (P < 0.05). The antioxidant potential of the plasma, as measured using the oxygen radical absorbance capacity (ORAC) assay, increased by 40% over baseline (P < 0.05), returning to baseline at the end of the washout period. There was no significant change in plasma lipid peroxidation products, as measured using the ferrous oxidation-xylenol orange (FOX) assay, or in ex vivo low-density lipoprotein (LDL) cholesterol oxidation, as measured by an increase in lag phase. The authors conclude that Pycnogenol significantly increased the antioxidant capacity of plasma.49

In a randomized, double-blind, placebo-controlled study, the effect of Pycnogenol on DNA repair associated with oxidative damage was evaluated in 54 elderly people (41 women and 13 men; mean age, 54 years) with knee OA.50 Patients were treated with placebo or 150 mg/day Pycnogenol for 3 months. There was no significant difference between placebo and Pycnogenol treatment on the level of oxidative damage to DNA or DNA repair in the patients’ lymphocytes, as measured by levels of 8-oxo-7,8-dihydroguanine (8-oxoG), a marker of oxidative damage to DNA. This finding is particularly interesting because it demonstrates that Pycnogenol had no effect on oxidative damage to DNA in elderly people, whereas another report found that Pycnogenol was effective in children with ADHD.51 Additional age-related studies are needed to further elucidate this discrepancy.

The anti-inflammatory and antioxidant activities of Pycnogenol were evaluated in patients with elevated C-reactive protein (CRP) and plasma free radicals in a randomized, double-blind, placebo-controlled trial.52 CRP levels are associated with disease progression in OA. Patients (n = 55; mean age, 52 years) with primary OA grade 1 or 2 in 1 or both knees and mild-to-moderate pain not adequately controlled by anti-inflammatory drugs were treated with 100 mg/day oral Pycnogenol or placebo for 3 months. Pycnogenol reduced CRP levels by 71.3%, plasma free radicals by 29.9%, and fibrinogen by 37.1%; the placebo group had minimal changes. There were significant differences in these 3 biomarkers between groups (P < 0.05 for all). The authors conclude that Pycnogenol decreases inflammatory processes in OA.52

Oxidative stress and plasma free radicals are increased during and after exercise. Male triathletes (n = 54) were treated with 150 mg/day Pycnogenol during training for 30 days or served as controls. The Pycnogenol group had a significantly smaller increase of oxidative stress (P < 0.05) and a faster return to normal values compared with the control group. Post triathlon (1 hour after exercise), plasma free radicals were on average 26.7% lower in the Pycnogenol group compared with the control group (P < 0.05). In addition, in normal men and women (n = 147) treated with 100 mg/day Pycnogenol for 8 weeks, the concentration of plasma free radicals significantly decreased compared with the control group following the US Army Physical Fitness Test (P < 0.05).53

Cigarette smoking is associated with elevated free radicals, increased lipid peroxidation, and depleted levels of plasma antioxidants. The antioxidant potential of Pycnogenol was evaluated in otherwise healthy smokers (n = 155) in an open-label, placebo-controlled study. Participants received either placebo or 50 mg/day Pycnogenol for 8 weeks. The Pycnogenol group had a 38% increase from baseline in the biological antioxidant potential, which was significantly higher than the placebo group (P < 0.05). Further, Pycnogenol significantly lowered plasma levels of derivatives of reactive oxygen metabolites (d-ROMs) by 25% compared with baseline, which was significantly lower than the placebo group (P < 0.05).54

The oxidative stress status of patients with asymptomatic metabolic syndrome (n = 130; 45-55 years of age) was assessed in an open-label, controlled study by quantifying d-ROMs. Patients received diet and weight management programs along with 150 mg/day Pycnogenol for 6 months or without Pycnogenol treatment. Plasma free radicals decreased 34.6% in the Pycnogenol group (P < 0.05 vs. baseline) compared with a 13.0% decrease in the control group (P < 0.022 vs. Pycnogenol).55 Reducing the production of ROS is hypothesized to aid in normalization of the metabolic pathways.


In vitro

Endothelial cells line the inner walls of blood vessels, and endothelial cell damage is an important factor in cardiovascular disease. In an in vitro experiment, Pycnogenol protected cultured endothelial cells from oxidative injury induced by t-butyl hydroperoxide.56 Pycnogenol enhanced clearance of H2O2 and oxygen radicals in endothelial cells treated with hypoxanthine and xanthine oxidase or H2O2. Pycnogenol also increased the activities of the following intracellular antioxidant enzyme systems in endothelial cells: GSH, GPx, GR, SOD, and CAT.57

Pycnogenol protected endothelial cells from GSH depletion caused by co-culture with activated macrophages.58 It also protected endothelial cells from reduction of α-tocopherol levels caused by reactive nitrogen species (e.g., NO or peroxynitrite) generated by activated macrophages or direct administration of peroxynitrite.38

Toll-like receptor 4 (TLR4)-mediated signals stimulate the expression of ADRP, which is involved in atherosclerosis formation. Pycnogenol inhibited TLR4 stimulation of ADRP.59 Also, Pycnogenol suppressed ADRP expression by facilitating mRNA degradation.60

The endothelium-dependent relaxation facilitated by NO is an important component of vascular function. Pycnogenol dose-dependently relaxed constricted rat aorta smooth muscle via stimulation of endothelial NO synthase.61


Intravenous (IV) Pycnogenol administration significantly decreased BP in rats, which was mediated by inhibition of angiotensin-converting enzyme (ACE).62

In a mouse model of heart failure, orally administered Pycnogenol significantly reduced hypertension and cardiac hypertrophy compared with control (P < 0.05 for both). The gene expression pattern and activity of MMP-9 (which is involved in cardiac hypertrophy) were significantly decreased by Pycnogenol (P < 0.001 for both). The authors propose that Pycnogenol may help limit cardiac remodeling (hypertrophy) in patients with heart failure.63

Spontaneously hypertensive rats treated with Pycnogenol had a significant improvement in mesenteric small resistance artery structure and endothelial function, in part due to a normalization of COX-2 and iNOS and reduction of myeloperoxidase activity.64,65

In a mouse model of atherosclerosis, mice were fed a high-cholesterol and high-fat diet. Those treated with oral Pycnogenol had a decreased oxidized LDL-induced lipid accumulation in peritoneal macrophages and decreased size of atherosclerotic lesions compared with untreated controls.66 In addition, Pycnogenol inhibited the LPS-induced upregulation of fatty-acid-binding protein and macrophage scavenger receptor class A through the TLR4 pathway, which supports in vitro reports.66


Pycnogenol-enhanced endothelium-dependent vasodilation was evaluated in a randomized, double-blind, placebo-controlled study with healthy participants.67 Forearm blood flow responses to acetylcholine—an endothelium-dependent vasodilator—and sodium nitroprusside—an endothelium-independent vasodilator—were measured in 16 healthy young men before and after 2 weeks of administration of Pycnogenol (180 mg/day) or placebo. Those taking Pycnogenol had an augmented response to acetylcholine compared with baseline (P < 0.05), while there was no change in the placebo group. There was no difference between groups in response to sodium nitroprusside. Administration of NG-monomethyl-l-arginine (L-NMMA), a NO synthase inhibitor, abolished the Pycnogenol-induced acetylcholine response. The authors suggest that Pycnogenol augments endothelium-dependent vasodilation by increasing NO production. 67

Another randomized, double-blind, placebo-controlled, crossover study was conducted to assess the effect of Pycnogenol on endothelial function.15 Patients (n = 23; aged 49-73 years; mean age, 63 years) with stable coronary artery disease and receiving optimal standard therapy were treated with 200 mg/day Pycnogenol or placebo for 8 weeks. Flow-mediated dilatation (FMD, a test assessing endothelial function) significantly increased with Pycnogenol treatment compared with placebo treatment (P < 0.0001). Concentrations of 15-F2t-isoprostane, an index of lipid peroxidation, significantly decreased after Pycnogenol treatment but not after placebo treatment (P = 0.012). The authors conclude that the improvement in endothelial function was related to the ability of the antioxidant properties of Pycnogenol to increase NO availability.15

The effect of Pycnogenol on endothelial function was further evaluated in participants with borderline hypertension, hyperglycemia, or hyperlipidemia.71 In this open-label, pilot study, asymptomatic participants with borderline hypertension (n = 32), borderline hyperglycemia (n = 30), or borderline hyperlipidemia (n = 31) received diet and exercise modification plus 150 mg/day Pycnogenol or diet and exercise modification only (control) for 12 weeks. Untreated normal participants (n = 31) served as a second control group. FMD was measured at the level of the brachial artery. In the Pycnogenol-treated participants, FMD increased from a mean 5.3% to 8.2% at 8 weeks and 8.8% at 12 weeks (P < 0.05 vs. baseline for both). No changes in FMD were found in control or normal participants. Skin flux after occlusion was measured at the level of the finger. An increase in flux after occlusion is considered a microcirculatory measure of reactive hyperemia, which is generally decreased in people with endothelial dysfunction. Pycnogenol-treated participants had an increase in flux from a mean 12.4% to 23.3% at 8 weeks (P < 0.05 vs. baseline) and 24.7% at 12 weeks (P < 0.05 vs. baseline). No effects were observed in control or normal participants. No adverse effects (AEs) were observed during the study period. The Pycnogenol-treated group had significantly normalized BP in participants with borderline hypertension (P < 0.05), reduced cholesterol levels in participants with borderline hyperlipidemia (P < 0.05), and improved fasting glucose in participants with borderline hyperglycemia (P < 0.05). The participants treated with both Pycnogenol and diet/exercise modifications had better improvements than those in the control group. A limitation of this study is that statistical analyses were not conducted comparing Pycnogenol with control.68

Cigarette smoking increases the risk for coronary heart disease by increasing BP and increasing the tendency for blood to clot. Pycnogenol reduced the effects of smoking on platelet reactivity in 3 studies.69 In a study of German heavy smokers (smoking ≥ 15 cigarettes per day) (n = 22), 100 mg Pycnogenol was found to be as effective as 500 mg aspirin in completely inhibiting smoking-induced platelet aggregation 2 hours after smoking.69 However, in American heavy smokers (n = 16) treated with 125 mg Pycnogenol or 500 mg aspirin, the smoking-induced platelet aggregation was only partially reduced.69 Pycnogenol had no effect on BP or heart rate. In another group of American heavy smokers (n = 19), Pycnogenol was shown to dose-dependently lower platelet reactivity 2 hours after a single intake of Pycnogenol starting from 25 mg up to 200 mg. The effect on platelets was statistically significant from a single intake of 100 mg (P < 0.01). The benefits from a single dosage of 200 mg Pycnogenol persisted for 6 days.69

The chronic effects of Pycnogenol on platelet aggregation were evaluated in an open-label study with 4 heavy smokers (15 cigarettes per day for ≥ 5 years) and 16 nonsmokers.70 Both groups received 200 mg/day Pycnogenol for 8 weeks. At study end, Pycnogenol taken 3 hours prior to the first cigarette significantly reduced the platelet reactivity index (P < 0.002) to the level of nonsmokers. At baseline, smokers also presented with elevated serum thromboxane levels which, after treatment, were reduced to the levels of nonsmokers.70

The effects of Pycnogenol on microcirculation and platelet function were investigated in patients with coronary artery disease in a double-blind, placebo-controlled study (27 men and 24 women; 45-75 years of age).71 Patients were given 150 mg/day Pycnogenol for 4 weeks, which improved fingernail microcirculation by 53.8%. Myocardial ischemia was improved by 16% in Pycnogenol-treated patients compared with 11% in placebo-treated patients, as judged by electrocardiogram (ECG) (P values not reported). A marker for platelet activation, platelet granulometric membrane protein of 140 Da (GMP-140), increased in the blood of all patients over time, although this increase was significantly less in the Pycnogenol group than in the placebo group (P < 0.01). In addition, ex vivo aggregation of platelets induced by adenosine diphosphate (ADP) was significantly reduced in the treatment group compared with the placebo group (P < 0.05).71

Plasma lipid levels were measured in an open-label study with 25 healthy participants given 150 mg/day Pycnogenol for 6 weeks, followed by a 4-week washout period.49 Compared with baseline measurements, LDL cholesterol decreased significantly by 7% (P < 0.05), an effect that was reversed after the 4-week washout period. High-density lipoprotein (HDL) cholesterol levels increased significantly by 10.4% (P < 0.05); this effect was not reversed after the washout period. There was no significant change in total cholesterol or triglycerides.49

Diabetes and Complications

In vitro

In vitro experiments with α-glucosidase were conducted to determine how Pycnogenol reduces blood sugar in type 2 diabetics.72 α-Glucosidase is an enzyme secreted in the duodenum that mediates hydrolysis of starches to glucose. Inhibition of the enzyme diminishes absorption of glucose and reduces the postprandial blood glucose peaks. The activity of Pycnogenol was compared to acarbose, a prescription α-glucosidase inhibitor. Pycnogenol was found to be a potent inhibitor of α-glucosidase and more potent than acarbose (half maximal inhibitory concentration [IC50]: 5.3 µg/mL and 1 mg/mL, respectively).72

In an in vitro model of diabetic nephropathy, renal tubular cells exposed to high glucose concentrations were protected against apoptosis and morphological changes by Pycnogenol via upregulation of antiapoptotic Bcl-2 protein levels and reduction of proapoptotic Bax protein levels. In addition, Pycnogenol prevented induction of the proinflammatory genes COX-2, iNOS, and NF-κB in the renal tubular cells, and downregulated lipid peroxidation, total reactive species, superoxide, NO, and peroxynitrite.73


Pycnogenol’s effect on diabetes was evaluated in a series of in vivo studies that experimentally induced diabetes via streptozotocin. In the first study, rats were treated with 10 mg/kg IP Pycnogenol for 14 days. Pycnogenol significantly reduced blood glucose levels in diabetic rats by 28% (P < 0.05), but not to normal levels.74 In another study, rats received 10, 20, and 50 mg/kg oral Pycnogenol for 6 weeks, and plasma glucose significantly and dose-dependently decreased 4- to 6-fold (P < 0.05).75 Another study used 5 mg/kg oral Pycnogenol for 8 weeks and found no significant reduction in blood sugar.76 Preprandial glycemia was significantly decreased by 10, 20, and 50 mg/kg oral Pycnogenol, and postprandial glycemia was significantly decreased by 10 and 20 mg/kg oral Pycnogenol, compared with nontreated diabetic rats.77

Diabetes can cause liver damage. In a rat model of type 2 diabetes, streptozotocin-induced diabetic rats received IP injection of Pycnogenol (10 mg/kg/day) or no treatment (control) for 4 weeks, and their livers were evaluated at study end. The control group had a significant increase in glycosylated hemoglobin (HbA1c) (P < 0.05) and a significant decrease in hepatic glycogen levels (P < 0.05). Pycnogenol treatment reversed these effects. In addition, Pycnogenol treatment significantly decreased the elevated levels of thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA), and protein carbonyl formation, and restored depleted GSH, glutathione S-transferase (GST), CAT, SOD, GPx, and GR activity (P < 0.05 for all).78 Similar results were found in a study using a type 1 diabetes rat model.79

A study evaluating diabetes-related eye disorders treated normal and streptozotocin-induced diabetic rats with a low-carbohydrate diet plus Pycnogenol (10 mg/kg body weight, IP) for 14 days. The combination treatment reduced the risk of diabetic retinopathy and cataract formation.79

Diabetes can cause high BP. Streptozotocin-induced diabetic rats had an increase in BP, which was dose-dependently reduced by 10, 20, and 50 mg/kg oral Pycnogenol for 6 weeks.75 In the same rat model, diabetes produced thicker left ventriculi wall, weaker myocardial contraction, decreased coronary flow, and prolonged the heart QT interval. Oral Pycnogenol at a dose of 20 mg/kg/day improved the cardiac effects.80

Oral administration of 30 mg/kg/day Pycnogenol for 6 weeks in healthy rats resulted in a significant decrease in blood glucose levels (P < 0.001), BP (P < 0.001), heart rate (P < 0.043), and weight gain (P < 0.002), and a significant increase in antioxidant enzymes (P < 0.001).81

Diabetes can cause diabetic neuropathy, where nerve conduction decreases. In streptozotocin-induced diabetic rats, motor nerve conduction velocity was improved by 10 and 20 mg/kg oral Pycnogenol compared with nontreated diabetic rats.77

Diabetes can also cause diabetic cardiomyopathy and endothelial dysfunction. Pycnogenol corrected diabetic cardiac dysfunction in streptozotocin-induced diabetic rats via direct radical scavenging activity as measured via protein expression of ROS.82 Also, in streptozotocin-induced diabetic rats with cardiac dysfunction, Pycnogenol and metformin (a standard pharmaceutical treatment for diabetes) similarly improved blood glucose levels, vascular reactivity, left ventricular hypertrophy, adenosine monophosphate (AMP)-activated protein kinase (AMPK) expression, glucose transporter type 4 (GLUT4) expression, and calcium/calmodulin-dependent protein kinase II (CaMKII) in the left ventricle of the heart. However, metformin combined with Pycnogenol did not potentiate any of the improvements.83

Diabetes can alter Cu/Zn-SOD (SOD-1) and NO synthase in the brain. Pycnogenol significantly increased the synthesis of SOD-1 and restored neuronal NO synthase levels in the cerebral cortex of streptozotocin-induced diabetic rats.84


The glucose-lowering effect of Pycnogenol was evaluated in an open-label, dose-finding study of 30 patients with type 2 diabetes. Patients received 50, 100, 200, and 300 mg/day Pycnogenol, each for 3 weeks in succession. There were no washout periods between the changes in dose. Pycnogenol dose-dependently and significantly lowered fasting blood glucose (P < 0.05); however, 300 mg was not more effective than 200 mg. HbA1c was significantly decreased by doses of 200 and 300 mg/day (P < 0.05 for both), and endothelin-1 was significantly decreased by doses of 100, 200, and 300 mg/day (P < 0.05 for all). No change of insulin secretion was noted. The following AEs were reported (all were minor and transitory): dizziness (n = 4), headache (n = 2), gastric discomfort (n = 2), and mouth ulcer (n = 1).85


Attention Deficit Hyperactivity Disorder (ADHD)


ADHD may involve a dysregulation of catecholamine (e.g., dopamine, epinephrine, and norepinephrine).86 Urinary catecholamine concentrations were measured in 57 children (47 boys and 10 girls; 6-14 years of age) with ADHD and in 17 healthy children (8 boys and 9 girls; mean age, 11.5 years). Children with ADHD had significantly higher levels of epinephrine and norepinephrine in their urine compared with healthy children (P < 0.001 and P = 0.007, respectively). Concentrations of urinary dopamine were similar in both groups.86 The children with ADHD were then entered into a randomized, double-blind, placebo-controlled study.86 The children were treated with 1 mg/kg body weight Pycnogenol or placebo for 1 month. There was a significant decrease in dopamine levels in the Pycnogenol group compared with baseline (P < 0.05). There were nonsignificant decreases in epinephrine and norepinephrine in the Pycnogenol group compared with baseline. The differences between the Pycnogenol and placebo groups did not reach statistical significance.86

Catecholamine metabolism may be a source of free radical formation (superoxide radicals and H2O2).51 These free radicals could cause oxidative damage to DNA, lipids, and proteins. Total damage to DNA was measured in 58 children (47 boys and 11 girls; 6-14 years of age) with ADHD and in 56 healthy children (mean age, 11.5 years). Children with ADHD had significantly higher levels of total damage when compared with healthy children (P < 0.001).51 Children with ADHD (50 boys and 11 girls; 6-14 years of age) were then entered into a randomized, double-blind, placebo-controlled study.51 The children were treated with 1 mg/kg Pycnogenol or placebo for 1 month. Levels of 8-oxoG were measured as an indication of oxidative DNA damage. Treatment with Pycnogenol reduced levels of 8-oxoG compared with baseline and placebo controls (P = 0.012 and P = 0.014, respectively). After a 1-month washout period, levels of 8-oxoG returned to baseline.51 The total antioxidant status (TAS) nonsignificantly increased following treatment with Pycnogenol. The decrease in DNA damage and increase in TAS correlated with an improvement in inattention score (P = 0.0045 and P < 0.035, respectively).51

Another study evaluated the effect of Pycnogenol on the levels of oxidative stress in children with ADHD.87 A randomized, double-blind, placebo-controlled study measured the levels of reduced GSH and oxidized glutathione (GSSG) in 43 children (34 boys and 9 girls; 6-14 years of age) with ADHD. The children were treated with 1 mg/kg Pycnogenol or placebo for 1 month. In the Pycnogenol group, GSH increased (P = 0.054), as did the ratio of GSH to GSSG. There was no change in the placebo group.87 The authors conclude that treatment with Pycnogenol tended to normalize catecholamine levels in children with ADHD and resulted in decreased hyperactivity and diminished oxidative stress.



In rats, Pycnogenol increased nerve growth factor in the hippocampus and cortex, areas of the brain important for learning and memory.88 Pycnogenol also improved spatial memory impairment.88 In another study, Pycnogenol attenuated cognitive performance decline in a rat model of oxidative stress-related neurodegeneration (i.e., Alzheimer’s disease).89


There is a relationship between cognition, brain aging, and oxidative stress. A randomized, double-blind, placebo-controlled, matched-pair-design study was conducted to determine whether Pycnogenol could alter biochemical and cognitive measures.90 Elderly participants (n = 101; 60-85 years of age; mean age, 67.8 years) without chronic disease received either 150 mg/day Pycnogenol or placebo for 3 months. Participants were matched between groups based on age, sex, body mass index (BMI), premorbid intelligence quotient (IQ), intake of antioxidants, and intake of micronutrients. At 3 months, the Pycnogenol-treated group compared to the placebo-treated matched group performed significantly better on spatial working memory and quality of working memory (P < 0.05 for both), and had a significant decrease in plasma F2-isoprostane concentrations compared with placebo (P < 0.01), indicating an antioxidant effect.90

Two similarly designed, prospective, pilot, open-label, controlled studies were conducted to evaluate the effect of Pycnogenol on cognitive function, attention, and mental performance. The first study was conducted in healthy professionals with high oxidative stress (as measured by levels of plasma free radicals). Stress can cause mild cognitive impairment. Participants (n = 59; 34 men and 25 women; 35-55 years of age) were treated with 150 mg/day Pycnogenol for 12 weeks or were followed as untreated controls. All participants received a personal plan for sleep, diet, and exercise because improved lifestyle patterns are associated with better professional performance. They were told to avoid caffeine and alcohol before testing. At 12 weeks, the Pycnogenol group had a median 30% decrease in plasma free radicals, which was significantly better than control (P < 0.05). Increased oxidative stress can impair cognitive function. Accordingly, the Pycnogenol group performed significantly better than the control group on measures of attention, mental performance, sustained attention, memory, executive functions, mood, and cognitive function (P < 0.05 for all, except mood, P < 0.01).91 The second such study was conducted in healthy participants with high oxidative stress (as measured by an epidemiological cardiovascular screening program). Participants (n = 77; 55-70 years of age) were treated with 100 mg/day Pycnogenol for 12 months or were followed as untreated controls. All participants received the same recommendations as in the previous study. Cognitive function was evaluated with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), daily tasks, visual analog scales, and the Short Blessed Test. Pycnogenol reduced oxidative stress (plasma free radicals) by 28% at 12 months; in contrast, the control group had no decrease in oxidative stress. Accordingly, at 12 months, the Pycnogenol group had significantly improved cognitive function compared with the control group, with a significant increase in attention, mental performance, sustained attention, memory, executive functions, and mood (P < 0.05 for all). The IQCODE and daily tasks also improved significantly in the Pycnogenol group compared with control (P < 0.05 for both). No AEs were observed.92

Parkinson’s Disease


The effect of Pycnogenol on Parkinson’s disease was evaluated in 2 studies using a mouse model. One study showed that 20 mg/kg body weight IP Pycnogenol pretreatment before inducing the Parkinson’s model significantly protected antioxidant enzyme activity and GSH content; significantly decreased elevated levels of TBARS; and significantly restored the number of dopaminergic D2 receptors and the level of dopamine and its metabolite in the brain striatum.93 The other study showed that mice with Parkinson’s-like disease injected with Pycnogenol had reduced neuroinflammation, neurodegeneration, and behavioral impairments.94

Traumatic Brain Injury


In a rat model of traumatic brain injury, 100 mg/kg body weight IP Pycnogenol significantly improved levels of protein carbonyls, lipid peroxidation, and protein nitration; significantly reduced the loss of presynaptic and postsynaptic proteins; and significantly reduced the level of proinflammatory cytokines compared to vehicle-treated controls.95 In another rat model of traumatic brain injury, IV injection of 10 mg/kg body weight Pycnogenol 15 minutes after brain injury preserved synaptic function in the hippocampus 7 and 14 days following injury; saline-treated rats did not have preservation of function.96



ROS are thought to damage sperm through lipid peroxidation, resulting in altered sperm plasma membrane integrity and functional impairment. The effect of 200 mg/day Pycnogenol for 90 days was evaluated in subfertile men (n = 19) in an open-label study.97 Subfertility was defined as precapacitation (early sperm structural changes), post capacitation, and/or reduced capacity of the sperm to bind to mannose receptors. Semen samples were analyzed before and after treatment. Compared with baseline, Pycnogenol produced a 38% improvement in sperm morphology and a 19% increase in a mannose-binding assay (P = 0.001 and P < 0.005, respectively). As mannose residues on the oocyte are thought to interact with a sperm surface enzyme prior to fertilization, this result suggests that treatment with Pycnogenol may improve the fertility status of some men. Treatment did not affect sperm count.97

Gynecology/Women’s Health


Oral Pycnogenol for 3 months suppressed bone loss induced by ovariectomy in rats; bone strength and bone density increased. Pycnogenol restored serum osteocalcin and C-terminal telopeptide of type I collagen, thereby decreasing the rate of bone turnover.98

In ovariectomized mice, oral Pycnogenol for 3 months reduced the loss of bone density and prevented trabecular structure deterioration compared with untreated control ovariectomized mice.99


A randomized, blinded, placebo-controlled trial was conducted in healthy perimenopausal women (n = 70; 41-49 years of age) with symptoms of menopause.100 Women received either 100 mg/day Pycnogenol or placebo for 8 weeks. Studies show a correlation between oxidative stress and menopause symptoms. The oxidative stress status of the women was evaluated. At baseline, both treatment groups had elevated oxidative stress, with plasma free radicals exceeding 300 Carratelli units (1 CARR U corresponds to 0.8 mg/L H2O2). After 4 and 8 weeks of treatment, the Pycnogenol group had a significant reduction in plasma free radicals as compared with baseline (P < 0.05 at 4 weeks; P < 0.022 at 8 weeks). This corresponds with Pycnogenol significantly improving the participants’ symptoms of menopause. The authors believe that the improvement in symptoms was related in part to an antioxidant effect of Pycnogenol.100


In vitro

Activation of the proinflammatory and redox-regulated transcription factor NF-κB may play a role in UV-induced erythema. Pycnogenol added to keratinocyte cell culture inhibited UV-induced NF-κB-dependent gene expression in a concentration-dependent manner.101 However, NF-κB DNA-binding activity was not prevented, suggesting that Pycnogenol affects the transactivation capacity of NF-κB. Inhibition of NF-κB-dependent gene expression by Pycnogenol may contribute to its mechanism of protecting human skin against solar UV-simulated light-induced erythema.101

Pycnogenol may be beneficial for patients with inflammatory skin disorders. Human keratinocytes were treated with Pycnogenol or control in cell culture. Pycnogenol downregulated calgranulin A and calgranulin B genes, which are upregulated in patients with psoriasis and other dermatological disorders.102 Also, patients with psoriasis, atopic dermatitis, and lupus erythematosus have upregulation of ICAM-1 expression in keratinocytes. A cell culture experiment revealed that Pycnogenol inhibited interferon-γ (IFN-γ)-induced expression of ICAM-1 and adherence of T-cells to keratinocytes.103

Pycnogenol suppresses melanin biosynthesis via its antioxidative properties. It suppressed superoxide, NO, peroxynitrite, and hydroxyl radical in a melanoma cell culture.104


Pycnogenol dose-dependently and significantly reduced the incidence and severity of skin irritation and histopathological lesions in a rat model of hexavalent chromium-induced dermatotoxicity (P < 0.05 for all). Also, Pycnogenol reduced MDA concentration and increased GST and CAT activities.105

Wound healing was examined in 2 experiments in rats. Pycnogenol at concentrations of 1%, 2%, and 5% shortened the time of wound healing by 1.6 days, 2.8 days, and 3.3 days, respectively (P < 0.05, P < 0.01, and P < 0.01, respectively).106 Pycnogenol gel also dose-dependently reduced scar diameter.106 Pycnogenol at a concentration of 2% decreased MDA and increased SOD in the wound.107


Healthy, nonsmoking postmenopausal women (n = 20; 55-68 years of age) with no history of skin disease were treated with 75 mg/day Pycnogenol for 12 weeks.108 A 4-mm punch biopsy was obtained from the buttock skin for assessment of gene expression. There was a significant 44% increase in mRNA expression of hyaluronic acid synthase-1, the gene involved in hyaluronic acid (a component of cartilage and skin) synthesis, compared with baseline (P < 0.001). Regarding the genes involved in collagen synthesis, there was a nonsignificant 41% increase in COL1A1 gene expression and 29% increase in COL1A2 mRNA expression. The changes in mRNA expression were associated with significant skin biophysical improvements (hydration [P < 0.05], elasticity [P < 0.05], and fatigue [P < 0.01]).108

A prospective, open-label, pilot clinical study was conducted in patients (n = 73; 30-45 years of age) with moderate/severe plaque psoriasis. Patients were treated with 150 mg Pycnogenol daily for 12 weeks in addition to standard care or received standard care alone (control). After 12 weeks, both groups had an improvement in the affected body areas; however, the Pycnogenol group had a significantly reduced psoriasis-affected skin area size in all body regions compared with control (P < 0.05). Pycnogenol significantly improved erythema compared with baseline, induration compared with baseline and control, and desquamation compared with baseline and control (P < 0.05 for all). In addition, both groups had an increase in skin water content; however, the Pycnogenol group had significantly greater skin hydration compared to control (P < 0.05). Pycnogenol reduced the need for standard management drugs. The Pycnogenol group, but not control, had significantly reduced oxidative stress at 12 months (P < 0.05 compared with baseline), which plays a role in psoriasis as a possible marker of active inflammation. No AEs were observed.109


In vitro

Pycnogenol dose-dependently reduced histamine release from rat peritoneal mast cells and decreased anti-dinitrophenyl (DNP) immunoglobulin E (IgE)-induced calcium uptake into rat peritoneal mast cells (which is required to perpetuate the allergic reaction).110


Immune system dysfunction was induced in mice via a diet containing only 7.5% of recommended nutrients, and resulted in an abnormal pattern of cytokine secretion, enhanced hepatic lipid peroxidation, low lymphocyte proliferation, and shorter survival time. Oral administration of Pycnogenol restored function of the immune system and prolonged survival time of the mice.111

In a rat model of allergy, oral Pycnogenol significantly inhibited anti-DNP IgE-mediated passive cutaneous anaphylaxis.110 This along with in vitro data110 demonstrate a potential use of Pycnogenol in mast cell-mediated immediate-type allergies.

The effects of Pycnogenol on allergic asthma were evaluated with a mouse model of ovalbumin-induced allergic asthma. Pycnogenol attenuated airway inflammation, decreased mucus hypersecretion, and decreased levels of ILs and IgE in serum and bronchoalveolar lavage fluid.112



Environmental and occupational exposure to chromium compounds can cause nephrotoxicity. Pycnogenol prevented chromium-induced oxidative stress-mediated nephrotoxicity in rats by ameliorating increases in TBARS, MDA, and protein carbonyl, and decreasing levels of GSH and CAT activity.113

Vancomycin treatment can cause nephrotoxicity. Mice were treated with vancomycin, and markers for renal cortical oxidative stress, apoptosis, and autophagy (an intracellular degradation system that delivers cytoplasmic constituents to the lysosome) were induced. Mice receiving Pycnogenol had decreased serum creatinine, blood urea nitrogen (BUN), renal MDA, and immunoexpression of the proapoptotic protein Bax, the autophagic marker protein LC3/B, and iNOS compared with untreated control.114

Oxygen free radicals contribute to ischemia-reperfusion-induced oxidative renal damage. Pycnogenol provided renoprotection in rats with ischemia-reperfusion-induced renal injury by decreasing renal GSH, MDA, and myeloperoxidase.115



Nonalcoholic steatohepatitis is a chronic liver disease. In a rat model of nonalcoholic steatohepatitis, histological liver analysis revealed hepatocytes with macrovesicles of fat and fibrosis. Oral Pycnogenol improved fibrosis and cirrhosis, which would delay the progression of fatty liver to fibrosis. Pycnogenol also significantly reduced liver triglycerides and serum alanine aminotransferase (ALT) levels (P < 0.05 for both) more than control.116

Carbon tetrachloride was given to rats to induce oxidative stress and hepatotoxicity. Accordingly, carbon tetrachloride induced significantly elevated levels of serum aspartate aminotransferase (AST) and ALT, and produced extensive liver injuries; namely, extensive hepatocellular degeneration/necrosis, fatty changes, inflammatory cell infiltration, congestion, and sinusoidal dilatation. In addition, carbon tetrachloride increased MDA concentration and decreased GSH, CAT, SOD, and GST activities in hepatic tissues. When rats were pretreated with oral Pycnogenol, hepatotoxicity and oxidative damage were prevented.117


In vitro

Colon carcinoma cells were exposed to fruit juices enriched with 0.5 g/L Pycnogenol or without Pycnogenol. Cells exposed to Pycnogenol had a greater inhibition of cell growth.42

In a human cell line of oral squamous cell carcinoma, Pycnogenol decreased cell viability and induced apoptosis.118

Pycnogenol selectively induced cell death in a human cell line of fibrosarcoma cells, and caused more apoptosis in the human cell line of fibrosarcoma cells than in the human cell line of fibroblastoma cells. Apoptosis was induced via activation of caspase-3. This indicates that Pycnogenol may have a differential effect on the inhibition of cell growth depending on the cell type.119

Pycnogenol inhibited growth of 3 different human leukemia cell lines via caspase-3 activation, which induced apoptosis.120


Cisplatin, used to treat cancer, is limited by ototoxicity. Rats treated with cisplatin plus Pycnogenol were protected against cisplatin-induced cochlear apoptosis. Pycnogenol alone was not ototoxic. Pycnogenol may have a protective role against cisplatin ototoxicity.121