What is Pycnogenol

Pycnogenol is a patented, proprietary powder extract made exclusively from French maritime pine (Pinus pinaster Aiton) bark by Horphag Research (Geneva, Switzerland) ¹, ², ³. Pycnogenol is a standardized extract from the bark of the French maritime pine consists of a concentrate of polyphenols ⁴, ⁵. A pharmacokinetic study with volunteers ingesting Pycnogenol revealed that catechin, caffeic acid, ferulic acid, taxifolin and the metabolite M1 (δ-(3,4-dihydroxy-phenyl)-γ-valerolactone) were detectable in a nanomolar range in plasma ⁶. Moreover, about 65–75 % of the Pycnogenol extract are procyanidins that consist of catechin and epicatechin subunits of varying chain lengths ⁷, besides taxifolin, catechin, and phenol acids ⁸. The active ingredients in maritime pine can also be extracted from other sources, including peanut skin, grape seed, and witch hazel bark. Procyanidin is a powerful antioxidant also found in food such as grapes, berries, pomegranates, red wine and various nuts. Maritime pine bark extract, pycnogenol, is commonly used orally to treat and prevent diabetes, diabetes-related health issues, and problems of the heart and blood vessels among many other uses. Some people use skin creams that contain maritime pine bark extract as “anti-aging” products. Pycnogenol is also applied to the skin to treat foot ulcers in people with diabetes, hemorrhoids, and mouth ulcers caused by chemotherapy. There is limited scientific research to support most of these uses.

French maritime pine bark extract is a complex mixture of polyphenolic compounds ⁹. A catechin metabolite (M1) produced by human intestinal bacteria was found in the plasma samples. Subsequent investigations showed that M1 exerted various anti-inflammatory effects in vitro such as the inhibition of the activity of the matrix metalloproteinases MMP-1, −2 and −9, decrease of the release of MMP-9 from human monocytes or inhibition of the expression of the inducible NO synthase (iNOS) in RAW 264.7 macrophages ¹⁰. In other in vitro experiments using the whole extract a decrease of IL1B mRNA synthesis in RAW 264.7 cells was reported ¹¹ as well as inhibitory effects on the expression of COX-2, IL-8 and iNOS in human chondrocytes and fibroblasts ¹². However, since not all components of the French maritime pine extract are bioavailable and other bioactive molecules such as M1 are generated in vivo, it is not clear whether experiments using the whole extract would be indicative for cellular effects that actually occur in vivo.

Clinical studies indicate that pycnogenol is effective in the treatment of chronic venous insufficiency and retinal micro-hemorrhages ¹³. Pycnogenol protects against oxidative stress in several cell systems by doubling the intracellular synthesis of anti-oxidative enzymes and by acting as a potent scavenger of free radicals. Other anti-oxidant effects involve a role in the regeneration and protection of vitamin C and E. Anti-inflammatory activity has been demonstrated in vitro and in vivo in animals. Protection against UV-radiation-induced erythema was found in a clinical study following oral intake of pycnogenol ¹³. In asthma patients symptom scores and circulating leukotrienes are reduced and lung function is improved ¹³. Immunomodulation has been observed in both animal models as well as in patients with Lupus erythematosus. Pycnogenol antagonizes the vasoconstriction caused by epinephrine and norepinephrine by increasing the activity of endothelial nitric oxide synthase. Dilation of the small blood vessels has been observed in patients with cardiovascular disease, whereas in smokers, pycnogenol prevents smoking-induced platelet aggregation and reduces the concentration of thromboxane ¹³. The ability to inhibit angiotensin-converting enzyme is associated with a mild antihypertensive effect ¹³. Pycnogenol relieves premenstrual symptoms, including abdominal pain and this action may be associated with the spasmolytic action of some phenolic acids ¹³. An improvement in cognitive function has been observed in controlled animal experiments and these findings support anecdotal reports of improvement in ADHD patients taking pycnogenol supplements ¹³.

Chemical identification studies showed that pycnogenol is primarily composed of procyanidins and phenolic acids. Procyanidins are biopolymers of catechin and epicatechin subunits which are recognized as important constituents in human nutrition. Pycnogenol contains a wide variety of procyanidins that range from the monomeric catechin and taxifolin to oligomers with 7 or more flavonoid subunits ¹³. The phenolic acids are derivatives of benzoic and cinnamic acids. The ferulic acid and taxifolin components are rapidly absorbed and excreted as glucuronides or sulphates in men, whereas procyanidins are absorbed slowly and metabolized to valerolactones which are excreted as glucuronides. As all of these constituents of Pycnogenol and its metabolites exhibit anti-inflammatory actions, the progressing appearance of the diverse active substances provides a long-lasting pain relief, so that patients feel less pain, also during the night ¹⁴. Pycnogenol has low acute and chronic toxicity with mild unwanted effects occurring in a small percentage of patients following oral administration.

Pine bark extract vs Pycnogenol

There are many pine bark extracts on the market, from different pine tree species, from different countries and with different levels of efficacy for human health ¹⁵, ¹⁶, ¹⁷, ³. French maritime pine (Pinus pinaster Aiton) bark extract is a complex mixture of bioflavonoids, with oligometric proanthocyanidins as the major constituents. Oligometric proanthocyanidins are dimers or oligomers of catechin, epicatechin, and their gallic acid esters. The major oligometric proanthocyanidins in maritime pine bark are proanthocyanidin B1 (epicatechin-(4β→8)-catechin), catechin, and epicatechin ¹⁸.

Pycnogenol is a patented, proprietary powder extract made exclusively from French maritime pine (Pinus pinaster Aiton) bark by Horphag Research (Geneva, Switzerland) ¹. The French maritime pine (Pinus pinaster Aiton) trees that are used for Pycnogenol grow in Les Landes de Gascogne, along the coast of southwest France ¹⁹. Pycnogenol is a standardized extract from the bark of the French maritime pine consists of a concentrate of polyphenols. A pharmacokinetic study with volunteers ingesting Pycnogenol revealed that catechin, caffeic acid, ferulic acid, taxifolin and the metabolite M1 (δ-(3,4-dihydroxy-phenyl)-γ-valerolactone) were detectable in a nanomolar range in their plasma ⁶. Moreover, about 65–75 % of the Pycnogenol extract are procyanidins that consist of catechin and epicatechin subunits of varying chain lengths ⁷, ²⁰, as well as taxifolin, catechin, and phenolic acids ⁸. The active ingredients in maritime pine can also be extracted from other sources, including peanut skin, grape seed, and witch hazel bark. Procyanidin is a powerful antioxidant also found in food such as grapes, berries, pomegranates, red wine and various nuts.

Figure 1. Pycnogenol mechanisms of action

Abbreviations: TNF-α = tumor necrosis factor alpha; 5-LOX = arachidonate 5-lipoxygenase; COX-2 = cyclooxygenase-2; MMP = matrix metallopeptidases; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells.

[Source ²¹ ]

Pycnogenol health benefits

Clinical research on Pycnogenol started over 40 years ago and various health benefits of Pycnogenol have been observed and investigated ²¹. Due to Pycnogenol’s specific composition, unique specification and standardization processes, the research results obtained from studies with Pycnogenol cannot be extrapolated to other pine bark extracts ²¹. Many of the studies are conducted following a randomized, double-blind and placebo-controlled methodology to assess the efficacy of the extract in comparison to potential placebo effects.

Pycnogenol has been shown to have 4 main effects such as antioxidant effects, anti-inflammatory abilities, beneficial effects on blood circulation and reinforcing activities on the extracellular matrix (Figure 1) ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹ effects on human skin: Clinical and molecular evidence. Skin Pharmacol Physiol. (2016) 29:13–7. 10.1159/000441039)). Mainly through these mechanisms ⁴, Pycnogenol supplementation has been shown in human clinical trials to beneficially affect cardiovascular health, chronic venous insufficiency, cognition, joint health, skin health, eye health, women’s health, respiratory health and allergies, oral health and sports performance ²¹.

Pycnogenol possibly effective for:

• Allergies: Some research shows that taking a standardized extract of maritime pine bark before allergy season begins reduces allergy symptoms in people with birch allergies.
• Asthma: Taking a standardized extract of maritime pine bark daily, along with asthma medications, seems to decrease asthma symptoms and the need for rescue inhalers in children and adults with asthma.
• Athletic performance: Young people (age 20-35 years) seem to be able to exercise on a treadmill for a longer time after taking a standardized extract of maritime pine bark daily for about a month. Also, athletes training for a physical fitness test or a triathalon seem to perform better in the tests and competitions when they take this extract daily for 8 weeks while training compared to only training.
• Circulation problems: Taking a standardized extract of maritime pine bark by mouth seems to reduce leg pain and heaviness, as well as fluid retention, in people with circulation problems. Some people also use horse chestnut seed extract to treat this condition, but using the extract alone appears to be more effective.
• Improving mental function: Research suggests that taking a standardized extract of maritime pine bark by mouth for 3 months improves mental function and memory in both young adults and the elderly.
• Disease of the retina in the eye: Taking a standardized extract of maritime pine bark by mouth for 2 months seems to slow or prevent further worsening of retinal disease caused by diabetes, atherosclerosis, or other diseases. It also seems to improve eyesight..

Insufficient evidence to rate effectiveness for:

• Attention deficit-hyperactivity disorder (ADHD). Taking a standardized extract of maritime pine bark by mouth does not seem to help ADHD symptoms in adults. However, taking it by mouth for one month appears to improve symptoms in children.
• Common cold. Taking a standardized extract of maritime pine bark by mouth twice daily starting at the beginning of a cold seems to reduce the number of days with a cold and the number of lost working days. It also seems to reduce the amount of over-the-counter cold products needed to manage symptoms.
• Clogged arteries (coronary artery disease). There is some evidence that taking a standardized extract of maritime pine bark three times daily for 4 weeks might help improve some complications associated with clogged arteries.
• Blood clots in deep veins (deep vein thrombosis, DVT). There is some evidence that taking a specific combination product containing maritime pine might help to prevent DVT during long-haul plane flights. The product combines a blend of standardized maritime pine bark extract plus nattokinase. Two capsules are taken 2 hours before the flight and then again 6 hours later. Also, taking the standardized maritime pine bark extract before a flight, 6 hours after the flight, and the following day appears to reduce the risk of blood clots forming in the veins during long flights. In addition, taking the extract for one year eems to reduce the risk of post-thrombotic syndrome. This condition can develop in people who already experienced a blood clot.
• Dental plaque. Early research suggests that chewing at least 6 pieces of gum with added extract from maritime pine bark for 14 days reduces bleeding and prevents increased plaque.
• Diabetes. Early evidence suggests that taking a standardized extract of maritime pine bark daily for 3-12 weeks slightly decreases blood sugar in people with diabetes.
• Foot ulcers due to diabetes. Early research suggests that taking maritime pine bark extract by mouth and applying it to the skin helps heal foot ulcers related to diabetes.
• Circulation problems in diabetes. Early research shows that taking standardized maritime pine bark extract three times daily for 4 weeks improves circulation and symptoms in people with diabetes.
• Swelling (edema). Early research suggests that taking standardized extract of maritime pine bark before a flight, 6 hours after the flight, and once the next day reduces ankle swelling.
• Erectile dysfunction (ED). Early research suggests that standardized maritime pine bark extract, used alone or in combination with L-arginine, might improve sexual function in men with ED. It seems to take up to 3 months of treatment for significant improvement.
• Heart failure. Early research suggests that taking a specific combination product containing standardized maritime pine bark and coenzyme Q10 for 12 weeks improves some symptoms of heart failure.
• Hemorrhoids. Early research suggests that taking standardized extract of maritime pine bark by mouth, alone or in combination with a cream containing this same extract, improves quality of life and symptoms of hemorrhoids.
• High cholesterol. A standardized extract of maritime pine bark seems to lower “bad cholesterol” (low-density lipoprotein (LDL) cholesterol) in people with high cholesterol. However, the extract doesn’t seem to improve cholesterol levels in people with other conditions such as high blood pressure, type 2 diabetes, erectile dysfunction, and others.
• High blood pressure. One standardized extract of maritime pine bark (Pycnogenol, Horphag Research) seems to lower systolic blood pressure (the top number in a blood pressure reading) but does not significantly lower diastolic blood pressure (the bottom number). This extract might also help lower blood pressure in some patients already treated with the blood pressure-lowering drug ramipril. However, other maritime pine bark extract (Toyo-FVG, Toyo Bio-Pharma) does not appear to lower blood pressure in obese people with slightly high blood pressure.
• Leg cramps. There is some evidence that taking a standardized extract of maritime pine bark by mouth daily might decrease leg cramps.
• Menopausal symptoms. Early research shows that taking a standardized extract of maritime pine bark by mouth decreases menopausal symptoms, including tiredness, headache, depression and anxiety, and hot flashes.
• Metabolic syndrome. Early research suggests that taking a standardized extract of maritime pine bark by mouth three times dialy for 6 months lowers triglycerides, blood sugar levels, and blood pressure, and increases high-density lipoprotein (“good” or HDL) cholesterol in people with metabolic syndrome.
• Oral mucositis. Applying solution containing a standardized extract of maritime pine bark inside the mouth for one week seems to help heal mouth ulcers in children and adolescents undergoing chemotherapy treatment.
• Osteoarthritis. There is mixed evidence about the effectiveness of maritime pine for osteoarthritis. Taking a standardized extract of maritime pine bark by mouth might reduce overall symptoms, but it does not seem to reduce pain or improve the ability to perform daily tasks.
• Pain in late pregnancy. Early research suggests that taking a standardized extract of maritime pine by mouth daily during the last 3 months of pregnancy reduces lower back pain, hip joint pain, pelvic pain, and pain due to varicose veins or calf cramps.
• Pelvic pain in women. There is early evidence that taking a standardized extract of maritime pine bark by mouth might help reduce pelvic pain in women with endometriosis or severe menstrual cramps.
• Problems with sexual function. Early research suggests that taking a combination product containing a standardized extract of maritime pine bark, L-arginine, L-citrulline, and rose hip extract daily for 8 weeks can help improve sexual function in women.
• Improving symptoms of lupus (SLE). Early research suggests that taking a standardized extract of maritime pine bark by mouth reduces symptoms of SLE in some patients.
• Ringing in the ears (tinnitus). Early research suggests that taking a standardized extract of maritime pine bark by mouth reduces ringing in the ears.
• Stroke prevention.
• Muscle soreness.
• Other conditions.

More evidence is needed to rate pycnogenol for these uses.

Table 1. Summary of randomized, double-blind placebo-controlled human clinical studies on Pycnogenol

References	Title	Study details	Main findings
Cardiovascular health and endothelial health
Trebaticky et al. 40	Natural polyphenols improve erectile function and lipid profile in patients suffering from erectile dysfunction	53 male subjects, 120 mg Pycnogenol® per day or placebo for 3 months	Total cholesterol and low density lipoprotein (LDL or bad cholesterol) levels were reduced in subjects taking Pycnogenol®. In diabetes type 2 patients, plasma glucose levels were decreased after Pycnogenol® intake. Erectile function was improved after Pycnogenol® supplementation. Placebo showed no significant effects.
Enseleit et al. 22	Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study	23 subjects, 200 mg Pycnogenol® per day or placebo for 8 weeks	Flow-mediated dilation was significantly improved by 32% in the Pycnogenol® group compared to baseline and by 49% compared to placebo. Lipid peroxidation was decreased by 7% with Pycnogenol®.
Zibadi et al. 35	Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation	48 subjects, 100 mg Pycnogenol® per day or placebo for 3 months	Serum endothelin 1-levels were lowered by 20% after Pycnogenol® intake compared to placebo. low density lipoprotein (LDL or bad cholesterol) cholesterol was reduced by 12% with Pycnogenol® (vs. +3% with placebo). Pycnogenol® was shown to lower glycated hemoglobin by 10% in the Pycnogenol® group, a significant effect compared to placebo. Fasting plasma glucose was lowered by 18.4% in type 2 diabetes subjects, taking Pycnogenol® compared to placebo-controlled subjects.
Nishioka et al. 34	Pycnogenol®, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans	16 subjects, 180 mg Pycnogenol® per day or placebo for 2 weeks	Forearm blood flow in response to acetylcholine significantly increased by up to 41% after Pycnogenol® intake, while placebo had no effect. Forearm blood flow in response to an endothelium independent vasodilator was not influenced by Pycnogenol® intake showing the effect of Pycnogenol® is mediated by the endothelium.
Yang et al. 25	A randomized, double-blind, placebo-controlled trial on the effect of Pycnogenol® on the climacteric syndrome in peri-menopausal women	155 female subjects, 200 mg Pycnogenol® per day or placebo for 6 months	low density lipoprotein (LDL or bad cholesterol)-cholesterol was significantly lowered, and high density lipoprotein (HDL or good cholesterol)-cholesterol was significantly increased after Pycnogenol® intake compared to placebo. Systolic and diastolic blood pressure were significantly reduced after Pycnogenol® supplementation, compared to placebo. All climacteric symptoms improved with Pycnogenol® compared to placebo.
Liu et al. 33	Pycnogenol®, French maritime pine bark extract, improves endothelial function of hypertensive patients	58 subjects, 100 mg Pycnogenol® per day or placebo for 3 months	Endothelin 1-levels were significantly lowered by 16% after Pycnogenol® intake compared to placebo. 6-keto prostaglandin F1a-levels were increased after Pycnogenol®. 57% of the Pycnogenol® subjects and 13% of the placebo subjects could cut their individual anti-hypertensive drug medication by half.
Liu et al. 41	Antidiabetic effect of Pycnogenol® French maritime pine bark extract in patients with diabetes type II	77 subjects, 100 mg Pycnogenol® per day or placebo for 12 weeks	Plasma glucose levels of diabetes type 2 patients decreased significantly with Pycnogenol®, compared to placebo. Glycosylated hemoglobin and vasoconstrictive endothelin-1 in the blood were reduced and vaso-relaxant 6-keto prostaglandin f1 alpha was increased with Pycnogenol® but not in placebo.
uračková et al. 24	Lipid metabolism and erectile function improvement by Pycnogenol®, extract from the bark of Pinus pinaster in patients suffering from erectile dysfunction-a pilot study	21 male subjects, 120 mg Pycnogenol® per day or placebo for 3 months	Total and low density lipoprotein (LDL or bad cholesterol)-cholesterol were significantly reduced while high density lipoprotein (HDL or good cholesterol)-cholesterol was slightly increased after Pycnogenol® intake.
Hosseini et al. 42	A randomized, double-blind, placebo-controlled, prospective, 16-week crossover study to determine the role of Pycnogenol in modifying blood pressure in mildly hypertensive patients.	11 subjects, 200 mg Pycnogenol® per day or placebo for 8 weeks	Systolic blood pressure was significantly lowered after Pycnogenol® supplementation by 5% compared to placebo. In subjects with the highest systolic blood pressure, the reduction was greater (−11% compared to baseline).
Wang et al. 43	The effect of Pycnogenol® on the microcirculation, platelet function and ischemic myocardium in patients with coronary artery diseases	60 subjects, 150 mg Pycnogenol® per day or placebo for 4 weeks	The percentage of patients with improvement of the microcirculation at the fingertips was higher and platelet aggregation of the blood was reduced after Pycnogenol® intake compared to placebo.
Chronic venous insufficiency
Arcangeli 44	Pycnogenol® in chronic venous insufficiency	40 subjects, 300 mg Pycnogenol® per day or placebo for 2 months	Pycnogenol® supplementation reduced symptoms of chronic venous insufficiency.
Petrassi et al. 45	Pycnogenol® in chronic venous insufficiency	20 subjects, 300 mg Pycnogenol® per day or placebo for 2 months	Leg heaviness, swelling and evening edema were relieved in chronic venous insufficiency patients after Pycnogenol® intake, compared to placebo. Venous pressure was significantly decreased with Pycnogenol® not with placebo.
Cognitive function
Weyns et al. 46	Clinical investigation of French maritime pine bark extract on attention-deficit hyperactivity disorder as compared to methylphenidate and placebo: Part 1: efficacy in a randomized trial	88 children, 20 or 40 mg Pycnogenol® /day if < or ≥ 30 kg or 20 or 30 mg methylphenidate hydrochloride /day if < or ≥ 30 kg or placebo for 10 weeks	Hyperactivity and impulsivity were significantly improved with both Pycnogenol® (by 34%) and methylphenidate hydrochloride (by 36%) and deteriorated with placebo, according to teacher’s rating. Inattention (according to teachers) was improved with Pycnogenol® and significantly improved with methylphenidate hydrochloride. The rate of adverse events was statistically significant with methylphenidate hydrochloride (39%) and not with Pycnogenol® (8%) and placebo (9%).
Weyns et al. 47	Clinical investigation of French maritime pine bark extract on attention-deficit hyperactivity disorder as compared to methylphenidate and placebo: Part 2: oxidative stress and immunological modulation	88 children, 20 or 40 mg Pycnogenol® /day if < or ≥ 30 kg or 20 or 30 mg methylphenidate hydrochloride /day if < or ≥ 30 kg or placebo for 10 weeks	methylphenidate hydrochloride intake led to loss of appetite and a significant weight loss. After Pycnogenol® supplementation, children had physiologically appropriate weight gain. The orexigenic peptide, neuropeptide Y was significantly reduced after methylphenidate hydrochloride and insignificantly increased after Pycnogenol® intake.
Donovan et al. 48	A placebo-controlled, pseudo-randomized, crossover trial of botanical agents for gulf war illness: curcumin (Curcuma longa), Boswellia (Boswellia serrata), and French maritime pine bark (Pinus pinaster)	20 subjects, 400 mg Pycnogenol® per day or placebo for 4 weeks	The symptoms of gulf war illness after intake of Pycnogenol® were significantly reduced compared to placebo.
Ryan et al. 26	An examination of the effects of the antioxidant Pycnogenol® on cognitive performance, serum lipid profile, endocrinological and oxidative stress biomarkers in an elderly population	101 subjects, 150 mg Pycnogenol® per day or placebo for 3 months	Spatial working memory and numeric quality of working memory were significantly improved with Pycnogenol® compared with placebo. Lipid peroxidation products (plasma F2 isoprostane) were reduced after Pycnogenol® intake compared to placebo.
Dvorakova et al. 49	Urinary catecholamines in children with attention deficit hyperactivity disorder (attention deficit and hyperactivity disorder (ADHD)): modulation by a polyphenolic extract from pine bark (Pycnogenol®)	61 children, 1 mg Pycnogenol®/kg/day or placebo for 4 weeks	The levels of catecholamines (like adrenaline, noradrenaline and dopamine) in the urine were reduced after Pycnogenol® supplementation.
Chovanova et al. 27	Effect of polyphenolic extract, Pycnogenol®, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder	61 children, 1 mg Pycnogenol®/kg/day or placebo for 4 weeks	The increased levels of 8-oxoG, as a measure of oxidized DNA in attention deficit and hyperactivity disorder (ADHD) children were reduced after Pycnogenol® intake compared to baseline and placebo.
Dvorakova et al. 50	The effect of polyphenolic extract from pine bark, Pycnogenol® on the level of glutathione in children suffering from attention deficit hyperactivity disorder (attention deficit and hyperactivity disorder (ADHD))	61 children, 1 mg Pycnogenol®/kg/day or placebo for 4 weeks	The levels of oxidized glutathione (GSSG) were significantly decreased by 22% after Pycnogenol® intake, while reduced glutathione (GSH) was significantly increased by 26.8%. Placebo had no significant effect on GSSH and GSH.
Trebaticka et al. 51	Treatment of attention deficit and hyperactivity disorder (ADHD) with French maritime pine bark extract, Pycnogenol®	61 children, 1 mg Pycnogenol®/kg/day or placebo for 4 weeks	As rated by parents and teachers, hyperactivity was reduced and attention was increased after Pycnogenol® intake compared to placebo.
Joint health
Belcaro et al. 52	Treatment of osteoarthritis with Pycnogenol®. The SVOS (San Valentino Osteo-arthrosis Study). Evaluation of signs, symptoms, physical performance and vascular aspects	156 subjects, 100 mg Pycnogenol® per day or placebo for 3 months	The joint discomfort scores were reduced after Pycnogenol® intake. Walking distance on a treadmill increased significantly more with Pycnogenol® supplementation compared to placebo.
Cisar et al. 53	Effect of pine bark extract (Pycnogenol®) on symptoms of knee osteoarthritis	100 subjects, 150 mg Pycnogenol® per day or placebo for 3 months	Joint discomfort, stiffness and analgesics consumption were lowered, and physical function increased after Pycnogenol® intake compared to placebo.
Farid et al. 54	Pycnogenol supplementation reduces pain and stiffness and improves physical function in adults with knee osteoarthritis	37 subjects, 150 mg Pycnogenol® per day or placebo for 3 months	Reduced joint discomfort, stiffness and need for nonsteroidal anti-inflammatory drugs (NSAIDs) with Pycnogenol® supplementation compared to placebo.
Skin health
Cai et al. 55	An oral French maritime pine bark extract improves hair density in menopausal women: a randomized, placebo-controlled, double-blind intervention study	76 female subjects, 150 mg Pycnogenol® per day or placebo for 6 months	Hair density of menopausal women was significantly increased after Pycnogenol® supplementation compared to baseline. Scalp water loss was reduced with Pycnogenol® intake compared to placebo. Resting flux of the scalp skin was improved with Pycnogenol® compared to baseline.
Zhao et al. 56	Oral Pycnogenol® intake benefits the skin in urban Chinese outdoor workers: a randomized, placebo-controlled, double-blind, and crossover intervention study	78 subjects, 100 mg Pycnogenol® per day or placebo for 3 months	Skin water loss was decreased while skin elasticity and skin tone regularity increased after Pycnogenol® supplementation, compared to baseline and placebo.
Eye health
Steigerwalt et al. 57	Pycnogenol® improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy	46 subjects, 150 mg Pycnogenol® per day or placebo for 3 months	Retinal edema score and retinal thickness were reduced, and visual acuity was significantly improved after Pycnogenol® intake compared to baseline and placebo.
Spadea and Balestrazzi 58	Treatment of vascular retinopathies with Pycnogenol®	20 subjects, 150 mg Pycnogenol® per day or placebo for 2 months	Vascular permeability of the eyes and retinal vascularization decreased, and visual acuity increased after Pycnogenol® supplementation, compared to placebo.
Women’s health
Kohama and Negami 59	Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women	170 female subjects, 60 mg Pycnogenol® per day or placebo for 3 months	Total menopause symptom score was significantly reduced with Pycnogenol® compared to placebo. Vasomotor symptoms, sleep problems and fatigue were improved with Pycnogenol®. Hormone levels were not changed after Pycnogenol® intake, compared to baseline or placebo.
Suzuki et al. 60	French Maritime Pine Bark Extract significantly lowers requirement of analgesic medication in dysmenorrhea–a multi-center, randomized, double-blind, placebo-controlled study	116 female subjects, 60 mg Pycnogenol® per day or placebo for 2 menstrual cycles	The need for analgesic medication and the number of days on which analgesics were required was significantly reduced with Pycnogenol® supplementation compared to placebo.
Yang et al. 25	A randomized, double-blind, placebo-controlled trial on the effect of Pycnogenol® on the climacteric syndrome in peri-menopausal women	155 female subjects, 200 mg Pycnogenol® per day or placebo for 6 months	Menopause symptoms according to the Women’s health questionnaire were improved after Pycnogenol® intake, significantly more than with placebo. The cholesterol profiles were significantly improved after Pycnogenol® intake compared to placebo. Systolic and diastolic blood pressure were significantly reduced after Pycnogenol® intake.
Respiratory health and allergies
Wilson et al. 61	A randomized, double-blind, placebo-controlled exploratory study to evaluate the potential of Pycnogenol® for improving allergic rhinitis symptoms	39 subjects, 100 mg Pycnogenol® per day or placebo for 5 to 8 weeks	Allergic rhinitis symptoms from pollen allergy, such as nasal and eye symptoms were reduced in subjects, taking Pycnogenol® at least 5 weeks before pollen season. The number of subjects, requiring rescue antihistamines was reduced with Pycnogenol®.
Lau et al. 62	Pycnogenol® as an adjunct in the management of childhood asthma	60 children, 2 mg Pycnogenol® per kg per day or placebo for 3 months	Asthma symptoms and forced expiration volume in 1 second (FEV1) improved after Pycnogenol® intake. Leukotriene levels were significantly reduced in the Pycnogenol® group. The need for albuterol rescue inhalers was reduced with Pycnogenol®.
Hosseini et al. 63	Pycnogenol® in the management of asthma	22 subjects, 2 mg Pycnogenol® per kg per day or placebo for 4 weeks	The forced expiration volume in 1 second (FEV1) was increased after Pycnogenol® intake, compared to baseline and placebo. Subjective asthma symptom rating and the level of plasma leukotrienes reduced after Pycnogenol® intake compared to placebo and baseline.
Oral health
Watanabe et al. 64	Effects of French Pine Bark Extract Chewing Gum on Oral Malodor and Salivary Bacteria	21 subjects, 30 mg Pycnogenol® per day in a gum or placebo gum for 4 weeks	The levels of volatile sulfur compounds in the mouth, the tongue-coating score and hydrogen sulfide-producing bacteria in saliva were reduced with a Pycnogenol® gum compared to a placebo gum.
Sports
Ackermann et al. 65	The effect of an acute antioxidant supplementation compared with placebo on performance and hormonal response during a high-volume resistance training session	15 subjects, 2 ml per kg body weight of a sports drink, containing 4.8 mg Pycnogenol® per 2 ml or placebo drink, single dose, 4 h before training	Muscle contractile performance and accumulated power output during lower limb hypertrophic resistance training was improved after Pycnogenol® supplementation compared to placebo.
Bentley et al. 66	Acute antioxidant supplementation improves endurance performance in trained athletes	9 subjects, 360 mg Pycnogenol® in a drink or placebo drink, single dose 4 h before training	Cycling time before exhaustion was increased by 80 s after Pycnogenol® drink consumption, compared to placebo subjects.
Mach et al. 67	The effect of antioxidant supplementation on fatigue during exercise: potential role for nicotinamide adenine dinucleotide (NADH)	13 subjects, 360 mg Pycnogenol® in a drink or placebo drink, single dose, 3 h before training	The physical work capacity until fatigue during cycling training was increased with Pycnogenol® compared to placebo and baseline. Serum nicotinamide adenine dinucleotide levels were increased significantly with Pycnogenol® compared to placebo.
Pavlovic 68	Improved endurance by use of antioxidants	24 subjects, 200 mg Pycnogenol® per day or placebo for 30 days	Performance time on a treadmill was increased with Pycnogenol® supplementation compared to placebo.

Abbreviations: FMD = Flow-mediated dilation; LDL = low density lipoprotein; HDL = high density lipoprotein; CVI = chronic venous insufficiency; MPH = methylphenidate hydrochloride; NPY = neuropeptide Y; 8-oxo-G = 8-oxo-7,8-dihydroguanine; ADHD = attention deficit and hyperactivity disorder; NSAIDs = nonsteroidal anti-inflammatory drugs; FEV₁ = forced expiration volume in 1 second; NAD⁺ = nicotinamide adenine dinucleotide.

[Source ²¹ ]

Anti-inflammatory activity

The constituents of Pycnogenol act in concert, as all of its phenolic compounds are scavengers of free radicals and exhibit a range of anti-inflammatory actions, as documented for ferulic acid, caffeic acid, catechin, and taxifolin ⁶⁹.

The metabolites, formed by ring fission of catechin units by microbiota, possess also remarkable anti-inflammatory activity. The procyanidin metabolite M1 showed in vitro a 100% higher activity than hydrocortisone ⁷⁰. These initial in vitro effects could be proven in ex vivo experiments.

Plasma collected from volunteers subsequent to consumption of Pycnogenol, inhibited the activity of cyclooxygenases 1 and 2, as well as the activation of the inflammation “master switch” nuclear factor kappa B (NFκB) ⁷⁰.

Human pharmacokinetic investigations indicated that the metabolite M1 is enriched in blood cells by active transport mechanisms, so that anti-inflammatory activity of blood is most probably 30 times higher than measured in plasma ⁷¹.

Furthermore, the active metabolite M1, ferulic acid, and caffeic acid are present in the synovial fluid, thus acting directly on the source of inflammation in case of synovitis ⁷².

Protection of articular cartilage

The progression of osteoarthritis is connected with a blockage of synthesis of proteoglycan components and type 2 collagen by inflammatory cytokines and tumor necrosis factor alpha ⁷³. Furthermore, cartilage degrading proteolytic enzymes such as matrix metalloproteinases (MMPs) are liberated as MMP-1, MMP-2, and MMP-13 ⁷⁴. The metabolite M1 formed from the procyanidins of Pycnogenol inhibited the activity of MMP-1, MMP-2, and MMP-9 in vitro and blocked the release of MMP-9 from activated monocytes ⁷⁰. The oral intake of Pycnogenol downregulated the gene expression of various cartilage degradation markers in the patients’ chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant. Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly after three weeks intake of the pine bark extract ⁷⁵. These chondroprotective effects were confirmed in ex vivo experiments. Plasma, taken from human volunteers following intake of Pycnogenol, inhibits the release of NFκB and MMP-9 from activated monocytes. The inhibition of the master switch of inflammation NFκB, acting together with inflammatory cytokines, reduces considerably the inflammatory process connected to osteoarthritis. Analysis of synovial fluid from osteoarthritis patients revealed the presence of ferulic acid, caffeic acid, taxifolin, catechin, and the metabolite M1 in serum, blood cells, and synovial fluid ⁷². The anti-inflammatory substances ferulic acid, caffeic acid, and the active metabolite M1 were enriched in the synovial fluid relative to serum. So, the chondroprotective and anti-inflammatory action take place locally in the synovia.

Pycnogenol acts like a sustained-release formulation by its combination of fast absorbed phenolic compounds and slowly metabolized procyanidins. Its constituent ferulic acid and the metabolite M1 are enriched in synovial fluid and contribute to local anti-inflammatory action.

Pycnogenol as an anti-inflammatory and chondroprotective add-on supplement provided long-lasting positive effects such as enhanced physical mobility and pain relief for patients with mild osteoarthritis. The use of NSAIDs could be significantly reduced, thus diminishing unwanted effects of NSAIDs. Studies involving more patients are needed to confirm the beneficial actions of Pycnogenol on an even broader basis.

The reduced anti-inflammatory activity in osteoarthritis with Pycnogenol is reflected in a decrease of C-reactive protein levels in osteoarthritis patients by 70%, with plasma-free radicals simultaneously scavenged by 30% ⁷⁶.

The cooperation of the diverse anti-inflammatory effects of Pycnogenol in plasma and synovial fluid results in reduction of pain and increased mobility.

Three identically designed clinical trials investigating the role of Pycnogenol in osteoarthritis treatment have been published to date ⁷⁷, ⁷⁸, ⁷⁹.

All studies were randomized, double blind, and placebo controlled. Middle-aged patients (48–54 years) suffering from mild osteoarthritis, stage I or II, verified by X-ray, were treated either with 3 × 50 mg Pycnogenol daily or placebo, added to existing therapy with NSAIDs. Success of the add-on supplementation was objectivated by the Western Ontario McMasters University (WOMAC) questionnaire for osteoarthritis during a period of 3 months. Results are summarized in Table 1. It has to be emphasized that patients were allowed to use their NSAIDs as concomitant medication when needed.

The first, small-scale study (n = 35) showed a clear reduction of scores for pain, functionality, and total WOMAC score, dependent on duration of treatment ⁷⁸. After 3 months, significant differences to placebo were observed, symptoms were reduced by 43%, 35%, 52%, and 49% for pain, stiffness, physical function, and total WOMAC score, respectively.

In the second study, involving 100 patients, the pain score improved significantly with time compared to baseline ⁸⁰. In this study, a considerable placebo effect was observed for pain, daily activity scores, and overall WOMAC scores, and although improvement relative to baseline was highly significant, the difference to placebo did not reach significance level in any case. Only scores for stiffness improved significantly both to baseline and versus placebo after 2 and 3 months, while placebo had no effect.

A total of 156 patients were included in the third study ⁸¹. Symptom scores dropped significantly: pain by 45%, stiffness by 47%, physical function by 43%, and overall WOMAC score by 44%. The decrease under placebo was not significant. A more detailed analysis of the WOMAC scores of the third study revealed a significant reduction of nocturnal pain and pain during troublesome stair climbing, particularly relevant for the quality of life of osteoarthritis patients ⁸¹.

Also, for joint stiffness during the day, only minor changes were observed with placebo, while Pycnogenol improved stiffness remarkably.

An example for an enhanced physical function refers to the onerous rising from sitting: with Pycnogenol the score dropped clearly from initial 3.1 to 0.8, with placebo the score remained nearly unchanged (3.0 to 3.1).

The improvement of osteoarthritis was impressively objectivated by performance of patients on a treadmill. Patients in the Pycnogenol group could increase their walking distance after 3 months from 68 to 198 m, whereas placebo expanded walking distance from 65 m just to 88 m ⁸¹.

These positive effects related to relief from daily pain, stiffness, and physical function had of course a great influence on the well-being of the patients in the Pycnogenol group. As the negative impact of osteoarthritis on daily activities subsided, the emotional status of patients shifted significantly from irritability, frustration, depression, and insomnia to better well-being ⁸¹. The sum of negative emotional scores dropped from 31.4 to 11.5, whereas placebo had a nonsignificant effect (28.4 to 24.1). Thus, quality of life was definitely improved in the Pycnogenol group.

Use of NSAIDs was significantly reduced in all three studies in the Pycnogenol group, in contrast to a slight increase of intake of NSAIDs in the placebo group. A more precise evaluation of NSAID use was performed in the third study ⁸¹.

Intake of Pycnogenol allowed patients to decrease intake of NSAID medication by 58% according to their diaries ⁸¹. Correspondingly, gastrointestinal complications decreased by 63% as well as days spent in hospital (60%). Values under placebo decreased by only 1% (reduction of use of NSAIDs) and 3% (reduction of hospital admissions and gastrointestinal problems).

Together, the three clinical studies demonstrate an improvement of symptoms of mild osteoarthritis under Pycnogenol, despite the reduced intake of NSAIDs. No unwanted effects of Pycnogenol were reported in the three studies. This is in line with the safety profile of Pycnogenol. Unwanted effects such as headache, dizziness, nausea, sleepiness, skin irritation, and gastric troubles were mild with a rate of 1.9% in clinical trials involving 7000 patients ⁸².

Table 2. Overview of 3 clinical trials demonstrating efficacy of pycnogenol for arthritis

	Belcaro et al.81	Cisar et al.80	Farid et al.78
	N = 156	N = 100	N = 35
% improvement	100 mg/day	150 mg/day	150 mg/day
Pain	−45%	−40%	−43%
Stiffness	−53%	−40%	−35%
Physical performance	+56%	+22%	+52%
Global score	+50%		+49%

[Source ⁸³ ]

Pycnogenol and ADHD

Attention-deficit and hyperactivity disorder (ADHD) is a complex and multifactorial disorder, influenced by both genetics and the environment. Its exact pathophysiology remains, however, unclear. Dopaminergic dysfunction is involved, but also associations with immune and oxidant-antioxidant imbalances exist ⁸⁴. Various studies demonstrated, for example, increased levels of plasma malondialdehyde (MDA) and exhalant ethane (oxidative stress markers) and decreased activity of antioxidant enzymes such as glutathione peroxidase (GPX) and catalase (CAT) ⁸⁵. ADHD has also been hypothesized to be a hypersensitivity disorder, with a disrupted immune regulation contributing to its cause ⁸⁶; i.e. ADHD has comorbidity with both Th1- and Th2-mediated disorders and several related genes have immune functions ⁸⁶. Ceylan et al. ⁸⁴ observed increased levels of adenosine deaminase, a marker of cellular immunity, and of the oxidative enzymes xanthine oxidase and nitric oxide synthase, and decreased levels of the antioxidant enzymes glutathione-S-transferase and paraoxonase-1. These results indicate the involvement of oxidative changes and cellular immunity in ADHD ⁸⁴.

Methylphenidate, the first-choice medication for ADHD, is a central nervous system stimulant. It increases attentiveness and reduces hyperactivity and impulsivity by inhibition of dopamine reuptake in the striatum, without triggering its release. methylphenidate is prescribed for chronic use to a large proportion of ADHD patients, but is linked to possible publication bias in reported efficacy ⁸⁷. In addition, parents are often disinclined to use methylphenidate due to its negative publicity and its frequent side effects, including serious side effects like arrhythmia, and, subsequently, nonadherence to therapy is high ⁸⁷. A recent review reports adverse effects, like insomnia and decreased appetite, in about 25% of patients using methylphenidate ⁸⁸. Other therapeutic options are therefore warranted, at least for a subgroup of patients ⁸⁷.

In one previous trial on twenty-four adults (24 to 53 years old) with attention-deficit/hyperactivity disorder (ADHD), the effect of Pycnogenol was compared to methylphenidate and placebo. However, neither methylphenidate nor Pycnogenol outperformed placebo, possibly due to the short treatment period of 3 weeks ⁸⁹. Further research is needed to investigate its efficacy, mechanism of action and value, especially compared to methylphenidate treatment. For example, dietary polyphenols and their metabolites exert prebiotic-like effects, stimulating the growth of intestinal microbiota, which play a fundamental role in immunity ⁹⁰. Also the Pycnogenol dosage is based upon this previous clinical trial, using 1 mg/kg body weight ⁹¹.

Pycnogenol effects on human skin

A number of studies provide compelling evidence that oral supplementation with Pycnogenol protects human skin against UV radiation ⁵⁶, ⁵⁵. Accordingly, in a study on 21 fair-skinned volunteers, Saliou et al. ⁹² demonstrated that oral ingestion of 1.10 mg or 1.66 mg/kg body weight/day Pycnogenol is effective in reducing UV-induced erythema. In this study, the UV protective effect of Pycnogenol was found to be dose dependent, to develop after 4-8 weeks of oral intake and to almost double the individual minimal erythema dose which was determined prior to Pycnogenol intake. The strength of this study is the intraindividual comparison of minimal erythema doses before, during and after Pycnogenol intake as well as the observed dose dependency of minimal erythema dose increases. Weaknesses of the study include the lack of a placebo treatment, e.g. in a crossover design or a comparator group. Although the study has been conducted during winter/spring time, the study has not been controlled for the seasonal increase in exogenous antioxidants in the regular diet which is often observed during summer and autumn ⁹³. Also, it should be noted that solar radiation-induced erythema responses mainly result from the formation of DNA photoproducts such as cyclobutane pyrimidine dimers in human skin, which can be reduced by antioxidants only to some extent. In other words, photoprotection by Pycnogenol might be even greater than observed here, if other biological end points, which more strongly depend on UV radiation-induced oxidative damage, would have been studied. Accordingly, oral ingestion of the carotenoid lycopene was previously shown to only moderately reduce solar UV radiation-induced erythema by 37% ⁹⁴, whereas long-wave UVA radiation-induced gene transcription, which strictly depends on the generation of reactive oxygen species in human skin, was almost completely inhibited ⁹⁵. It should also be noted that in vivo animal studies show that oral ingestion by mice significantly reduces the number and growth rate of skin tumors which were induced either by chronic UVB irradiation or by a combination of UVB radiation with topical treatment of skin with the polyaromatic hydrocarbon 7,12-dimethylbenzanthracene ⁹⁶. As UVB- as well as polyaromatic hydrocarbon-mediated skin carcinogeneses both critically involve activation of the aryl hydrocarbon receptor ⁹⁷ and since flavonoids such as catechin and epicatechin, which are a main constituent of Pycnogenol, have been shown to inhibit aryl hydrocarbon receptor activation ⁹⁸, it is tempting to speculate that oral ingestion of Pycnogenol may help to suppress environmentally induced aryl hydrocarbon receptor activation in skin cells.

A recently published randomized double-blind, placebo-controlled study identified Pycnogenol as a natural, safe and effective supplement for women who face hair thinning ⁵⁵. 76 healthy menopausal women between 45 and 60 years were randomly assigned to either take 150 mg Pycnogenol per day or placebo for six months ⁵⁵. Oral intake of Pycnogenol led to a significant increase of hair density of 30%, compared to baseline and of 15% compared to placebo after two months. The effects of Pycnogenol stayed on a highly improved level after six months of supplementation ⁵⁵. In addition, the study showed that Pycnogenol significantly reduced water loss from the skin of subjects’ scalp, compared to the placebo group. This leads to a better regulated scalp skin moisture balance for healthier hair and scalp ⁵⁵. The study also confirmed that Pycnogenol intake positively affects microcirculation in the skin. Using photoplethysmography, Pycnogenol was found to decrease resting flux in the scalp by 21.7% after two, and by 43.5% after six months. In the placebo subjects, the observed decrease was only 5.1 and 20.5%, respectively ⁵⁵. This effect of Pycnogenol leads to a better supply of nutrients and oxygen to hair follicles. In several previously published studies, Pycnogenol was shown to improve circulation in small blood vessels in the body, like the very fine micro vessels in the fingertips or in the retinal capillaries of the eye ⁴³, ⁵⁷. In addition to an improvement of microcirculation, two other mechanisms of action explain Pycnogenol’s efficacy for hair health and beauty. Pycnogenol’s anti-inflammatory and antioxidant activities contribute to protecting hair follicles by capturing free radicals, generated either by stress, sun rays, pollution, or inflammation ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹.

Pine bark extract and photoaged facial skin

In a randomized double-blind, placebo-controlled study, Pycnogenol’s effects on the skin of 78 urban outdoor workers was investigated ⁵⁶. Water loss of the skin during the hot summer season was significantly reduced by 14% with Pycnogenol supplementation for three months and only by 5% with placebo ⁵⁶. Accordingly, skin elasticity was shown to be improved by 13% after Pycnogenol supplementation, compared to an increase of 1% in the placebo group.

During the dry autumn season, Pycnogenol helped achieve a more even skin tone by 7.2% after six weeks and by 13.8% after twelve weeks of Pycnogenol supplementation. These effects were statistically significant versus the placebo control. In the placebo group, subjects experienced a decrease in skin tone regularity because of pollution and sun radiation during the dry season. Skin tone regularity was assessed on the cheeks of the participants by the individual typology angle, which is an objective classification of the skin tone in dermatology and cosmetology.

Several mechanisms behind Pycnogenol’s effects on skin have been researched ³⁸, ³⁹ effects on human skin: Clinical and molecular evidence. Skin Pharmacol Physiol. (2016) 29:13–7. 10.1159/000441039)), ⁹⁹. Clinical investigations of Pycnogenol supplementation for twelve weeks in women aged 55 to 68 years found increased hyaluronic acid synthase mRNA levels by 44% and collagen type 1 mRNA levels by 40% in skin biopsies ³⁸. These mechanisms explain the effects of Pycnogenol on skin hydration and elasticity.

Another study investigated the depigmenting action of Pycnogenol and found a significant reduction of the tyrosinase activity by 66.5%. Tyrosinase is an enzyme that activates the production of melanin, responsible for melasma (a common skin problem caused by brown to gray-brown patches on the face). In addition, Pycnogenol downregulated other pigmentation-related mediators in UV-light treated human melanocytes ⁹⁹. Pycnogenol’s ability to counteract skin hyperpigmentation was clinically validated in another study ³⁹ effects on human skin: Clinical and molecular evidence. Skin Pharmacol Physiol. (2016) 29:13–7. 10.1159/000441039)). In this clinical trial with 20 women, oral supplementation with Pycnogenol was shown to significantly lower UV-induced expression of the pigment synthesizing enzymes TRP1 by 75%, tyrosinase by 51%, MITF by 67% and MART-1 by 67% ³⁹ effects on human skin: Clinical and molecular evidence. Skin Pharmacol Physiol. (2016) 29:13–7. 10.1159/000441039)). These markers are associated with long-lasting pigmentation. From these results, it was concluded that Pycnogenol “contributes to the inhibition of pathways associated with skin hyperpigmentation” ³⁹ effects on human skin: Clinical and molecular evidence. Skin Pharmacol Physiol. (2016) 29:13–7. 10.1159/000441039)), ⁹⁹.

Furumura et al. ¹⁰⁰ enrolled 112 healthy women younger than 60 years with age spots, mostly diagnosed as solar lentigines, and multiple symptoms of photodamaged skin, including mottled pigmentation, roughness (including dry flaky skin), wrinkles, and swelling. All women enrolled in this study had mild to moderate facial photodamage graded on the Glogau scale between II and III and Fitzpatrick skin phototypes III to IV. After approval by the institutional ethics committee of Fukuoka University, which adheres to the principles of the Declaration of Helsinki, informed consent was obtained from all participants in the study. None of the subjects took topical/systemic retinoids, health food supplements, oral medications such as hormone replacement therapy, or topical medications, or were pregnant 4 weeks prior to enrolling in this study.

Twenty-four women were enrolled in an open-label, high-dose pine bark extract (Flavangenol®) trial and were treated with 100 mg/day pine bark extract (Flavangenol®) for 12 weeks, while a further 88 women were enrolled in part 1 of a separate low-dose trial and treated with pine bark extract (Flavangenol®) 40 mg/day for a total of 24 weeks in an open-label, randomized, parallel-group comparative fashion. Group 1 participants were asked to take pine bark extract (Flavangenol®) 40 mg/day once daily, and to use a cleanser and sunscreen for 24 weeks throughout part 1 of the study. Group 2 participants were merely placed under observation without taking pine bark extract (Flavangenol®) for the first 12 weeks before starting oral treatment with pine bark extract (Flavangenol®) 40 mg/day once daily for the next 12 weeks, and were instructed to use a cleanser and sunscreen for 24 weeks throughout part 1 of the study.

Furumura et al. ¹⁰⁰ examined the efficacy of pine bark extract in the treatment of photodamaged facial skin, and significant improvement was suggested from multiple dermatological score assessments during this study.

A subject questionnaire concerning subjective facial symptoms demonstrated that a relatively large number of subjects felt that the roughness of their facial skin had improved in the high-dose trial. Although improvement in age spots was only recognized by a relatively small number of subjects in the high-dose trial [100 mg/day pine bark extract (Flavangenol®)], detailed evaluation of digital images revealed that 71% of participants had improvement of their age spots, albeit to a varying extent. In part 1 of the low-dose trial [40 mg/day pine bark extract (Flavangenol®)], there was significant improvement in scores for solar lentigines, mottled pigmentation, skin roughness, and swelling only when subjects were on treatment with pine bark extract. Further, subjects treated with pine bark extract had significantly lower scores for solar lentigines and skin roughness when compared with the untreated patients. Therefore, we consider that both the high-dose and low-dose arms in this study demonstrate a similar trend of improvement in symptoms of photodamaged facial skin. Further significant improvements were seen during the long-term 18-month study (part 2 of the low-dose trial) in almost every photoaging score. This improvement was maintained and enhanced by continuous administration of pine bark extract over a long period. Finally, 72% of the subjects receiving pine bark extract for 12 weeks (group 2) showed improvement versus 87% of those receiving pine bark extract for 24 weeks (group 1). All subjects who completed treatment with pine bark extract for 15–18 months showed improvement in symptoms. In line with the score assessment results, objective biophysical measurements demonstrated a significant gradual decrease in average melanin index during treatment with pine bark extract in both trials.

In an earlier study of treatment of photoaged skin with oral polyphenols ¹⁰¹, a popular polyphenol-rich green tea extract containing (−)-epigallocatechin gallate (EGCG) was used. Although facial photoaging scores improved on treatment with the green tea extract for the first 12 months, there was no significant antiphotoaging effect after 24 months of treatment. In contrast, gradual improvement of photoaging scores even at 18 months was confirmed in their pine bark extract trial. Demographic diversity in subject age and race might account for the different results seen in these two studies. The mean age of the subjects in the previous study was around 12 years older than in Furumura et al. ¹⁰⁰ study, so a less favorable outcome would be expected because of the exponential decline of intrinsic antioxidative potency in the elderly. Furumura et al. ¹⁰⁰ findings in Japanese women might be positively biased by a racial difference, ie, age spots in East Asians often appear as early as in the 20 s and 30 s, while age spots in Caucasians tend to become apparent between the ages of 50 and 60 years ¹⁰².

In the skin, pine bark extract has been found to protect capillary walls ¹⁰³ and to inhibit matrix metalloproteinases ¹⁰⁴. Direct assessment of the antioxidant effects of pine bark extract by electron spin resonance spectroscopy showed that pine bark extract had significant antioxidant effects on the facial skin of ultraviolet B-irradiated hairless mice in vivo ¹⁰⁵. Oligometric proanthocyanidins have also been reported to be effective inhibitors of tyrosinase in skin-derived melanocytes and in the hyperpigmented skin of ultraviolet-irradiated mice and guinea pigs ¹⁰⁶. Oral oligometric proanthocyanidin supplements are expected to have desirable effects on photoaging because they promote tissue elasticity, help heal microinjuries, reduce bruising and swelling by strengthening blood vessels, prevent postinflammatory skin pigmentation, restore dermal collagen, and improve the peripheral circulation ¹⁰⁷. In fact, oligometric proanthocyanidins from grape seeds have previously been reported to improve melasma to a significant extent ¹⁰⁸.

A white complexion is a highly desirable symbol of beauty among Asian women, who believe that it is powerful enough to hide a number of faults. Pine bark extract did not modify facultative skin color in Furumura et al. ¹⁰⁰ trial, suggesting that the skin lightening elicited by pine bark extract is confined to solar lentigines that appear with chronic inflammation, and can persist long after exposure to ultraviolet light. Recent profiling of solar lentigines with cDNA microarrays and immunohistochemical assays revealed a number of upregulated genes for the enzymes that synthesize arachidonic acid, as well as melanogenic and inflammatory genes in those lesions ¹⁰⁹.

Modulation of skin pigmentation by oral ingestion of Pycnogenol

There is now also more and more evidence that Pycnogenol may affect pigmentation of human skin. In 2002, Ni et al. ¹¹⁰ were first to provide evidence that Pycnogenol intake may reduce hyperpigmentation in women with melasma. In this study, a total of 30 Chinese female patients with melasma orally ingested 75 mg Pycnogenol/day for a total of 1 month. The impact of Pycnogenol intake on preexisting melasma was assessed by means of a clinical score, i.e. the melasma area index, which was based on assessing the diameter of the lesional skin area by means of a ruler. In addition, the pigmentary intensity index was determined by means of a color chart. It was found that after the 30-day treatment period both parameters were significantly reduced. Pycnogenol was well tolerated in all patients, and standard blood and urine parameters did not change. The authors concluded that Pycnogenol is therapeutically effective and safe in patients with melasma, and they attributed the observed beneficial effects to the well-known antioxidative properties of Pycnogenol ¹¹⁰. It has to be noted that the design of this study was open, and efficacy parameters were based on subjective assessments. Nevertheless, this study was first to indicate that Pycnogenol intake might be effective to downregulate skin hyperpigmentation. In line with this assumption are in vitro experiments which showed that treatment of cells from the human melanoma cell line B16 with Pycnogenol reduced tyrosinase activity and melanin synthesis in this tumor cell line ¹¹¹. Even more important are results from a recent human in vivo study which provide molecular evidence that the oral intake of Pycnogenol downregulates the expression of genes in human skin which are critically involved in melanin synthesis. The design and part of the results of this clinical trial have previously been published in this journal ¹¹². This study is unique because it is the only one to provide in vivo molecular evidence that Pycnogenol uptake is beneficial for human skin. In this clinical trial, a total of 20 healthy postmenopausal Caucasian women were supplemented with 3 × 25 mg Pycnogenol daily for a total of 12 weeks. It was found that this intervention significantly improved skin elasticity and skin hydration, and that this improvement of skin physiological parameters was associated with a significant upregulation of mRNA steady-state levels for hyaluronic acid synthase-1, an enzyme which is important for hyaluronic acid synthesis in skin, as well as genes involved in collagen de novo synthesis. Further RT-PCR analysis of RNA purified from biopsies obtained in this study additionally revealed a significant effect of intake of Pycnogenol on the transcriptional expression of genes which are critically involved in skin pigmentation ¹¹³. Accordingly, these yet unpublished data, demonstrate that oral Pycnogenol intake was able to significantly inhibit UV radiation-induced upregulation of microphthalmia-associated transcription factor, tyrosinase-related protein 1 and melanoma antigen recognized by T cells, and mRNA expression of tyrosinase was inhibited by trend. These changes provide a molecular basis to explain the previous notion that Pycnogenol intake benefits patients with melasma. The exact mechanism through which Pycnogenol may inhibit the expression of genes involved in skin hyperpigmentation is currently not known. We previously discussed the possibility that Pycnogenol may at least in part function by antagonizing aryl hydrocarbon receptor activation. In this regard it should be noted that aryl hydrocarbon receptor activation in human as well as murine melanocytes has recently been reported to be critically involved in UV radiation-induced skin pigmentation ¹¹⁴. Specifically, aryl hydrocarbon receptor activation was shown to cause upregulation of tyrosinase-related proteins 1 and 2 as well as tyrosinase in primary human melanocytes. In aggregate, these studies indicate that the oral intake of Pycnogenol may be used to reduce skin pigmentation in humans in general and hyperpigmentation caused by melasma in particular. Given the central role of microphthalmia-associated transcription factor in the pathogenesis of skin hyperpigmentation and pigmented skin lesions, this should prompt further controlled clinical trials to assess the effect of oral Pycnogenol intake on pigment spot formation in chronically UV-exposed skin areas.

As discussed above, additional studies being done which take into account very recent evidence that skin damage in general and skin hyperpigmentation/skin aging in particular can also be caused by other environmental factors such as nonionizing radiation in the visible as well as infrared range ¹¹⁵ and ambient air pollution including traffic-related particulate matter ¹¹⁶.

Eye health

Owing to Pycnogenol’s effects on microcirculation, inflammation and oxidation, Pycnogenol was found to have positive effects on eye health ⁵⁸, ⁵⁷. As the retina is the tissue with the highest metabolic rate in the body, it is particularly susceptible to oxidative stress. The eye tissue is particularly exposed to UV light which generates reactive oxygen species in cells. Furthermore, metabolic conditions like diabetes involve a pathological oxidative stress, which can lead to diabetic retinopathy ¹¹⁷.

Pycnogenol showed effects to stop further progression of retinopathy of diabetics by stabilizing and sealing leaky capillaries of the retina, stopping further outflow of blood ⁵⁸, ⁵⁷.

In an randomized double-blind, placebo-controlled study, Pycnogenol was shown to reduce capillary leaking in the eyes ⁵⁸. Using fluorescein angiography as a measurement tool, vascular permeability was found to have decreased by 16 and 23% for left and right eye, respectively, compared to baseline. Retinal vascularization and the presence of macular edema was assessed by ophthalmoscopy, determining the severity of retinal damage. After Pycnogenol supplementation for two months, the ophthalmoscopy score significantly improved by 9% in the left eyes and by 17% in the right eyes compared to baseline, whereas there was no change observed in the placebo group. Furthermore, Pycnogenol® supplementation led to increased visual acuity by 5.7% (left eye) and 7% (right eye). The improvement was statistically significant compared to placebo. Whereas, with placebo treatment, retinopathy continued to progress as the visual acuity was reduced by 3.2% (left) and 7.5% (right), assessed by the Snellen Chart.

Another study showed that Pycnogenol reduced retinal edema and improved visual acuity in early diabetic retinopathy ⁵⁷. The score assessing retinal edema was significantly reduced by 30% in mild edema cases and by 35% in moderate edema cases compared to placebo patients after three months of Pycnogenol supplementation. The retinal thickness, assessed by high resolution ultrasound, significantly decreased by 11% in mild cases and by 25% in moderate cases in Pycnogenol subjects ⁵⁷. The most significant outcome observed in this study was the improvement of the visual acuity by 21% in Pycnogenol patients compared to baseline and placebo patients, which was assessed with the Snellen chart. Furthermore, the retinal blood flow was improved by around 30% after Pycnogenol supplementation.

Pycnogenol’s effects on endothelial function ²² might explain the observed effects on perfusion of the retinal tissue and the resulting restoration of vision loss in diabetic retinopathy patients.

Oral health

A study on oral health, specifically on persistent bad breath (halitosis) was conducted with Pycnogenol ⁶⁴. The 21 healthy participants used either two placebo gums or two gums with 2.5 mg Pycnogenol each, six times daily for 15 min each. After two weeks of Pycnogenol gum usage, the levels of volatile sulfur compounds (hydrogen sulfide, methyl mercaptan and dimethyl sulfide) were significantly reduced compared to baseline and after four weeks, these levels were reduced significantly compared to placebo ⁶⁴. In addition, the Pycnogenol group had a lowered tongue-coating score and significantly reduced hydrogen sulfide-producing bacteria in saliva after four weeks. The mechanism behind these effects has been suggested to be the previously observed bacteriostatic properties of Pycnogenol ¹¹⁸.

Respiratory health and allergies

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and pulmonary hypertension are among the five disease areas with the highest global mortality and morbidity rates ¹¹⁹. With almost 300 million people affected, asthma is one of the most common respiratory diseases worldwide ¹²⁰. Asthma is a chronic inflammatory disease that can be triggered by allergies, by medication such as aspirin or it can arise within the body through yet unclear molecular mechanisms ¹²¹. Recurrent episodes of coughing, shortness of breath, wheezing and chest tightness are typical symptoms for asthma ¹²².

Supplementation with Pycnogenol has been shown to have several beneficial effects on asthma and allergic rhinitis symptoms ⁶³, ⁶², ⁶¹. Especially Pycnogenol’s anti-inflammatory effects are suggested to be responsible for its anti-allergic and anti-asthma efficacy.

In an randomized double-blind, placebo-controlled cross-over study, the effects of Pycnogenol supplementation for four weeks on 22 chronic asthma patients were investigated ⁶³. The patients’ lung function was assessed by analysis of the “forced expiration volume in one second” (FEV1), representing the percentage of lung volume exhaled in a second. In asthmatics, the FEV1 is generally reduced as their breathing is restricted. After Pycnogenol supplementation, the all-adult patients could exhale 70% of their lung volume as compared to 59% at trial start and 63% in response to placebo ⁶³. Additionally, the study participants rated their asthma symptoms regarding severity. Four weeks of Pycnogenol intake led to a reduction of symptom severity by 20%, whereas it was reduced by 4.5% in placebo subjects ⁶³. Furthermore, Pycnogenol® supplementation significantly reduced pro-inflammatory mediators (leukotrienes) in the blood of patients, as compared to both baseline values and placebo.

Most asthmatics develop the disease already during childhood, often before the age of five years. An randomized double-blind, placebo-controlled study investigated the effects of Pycnogenol on 60 children aged six to eighteen years with mild to moderate asthma ⁶². The study showed that the breathing capacity improved significantly already after one month of Pycnogenol supplementation, as assessed by measuring FEV1 ⁶². The severity of asthma symptoms as well as leukotriene levels in the urine decreased drastically after one month of Pycnogenol intake and further decreased significantly throughout the trial period ⁶². The treatment with placebo had no significant effect on leukotriene levels or asthma symptoms. Another interesting outcome of the study is the reduced necessity of using albuterol rescue inhalers as severe asthma attacks appeared less frequently. After one month, eight out of thirty children taking Pycnogenol didn’t require rescue inhalers anymore and eighteen children were completely off the inhaler after the three-month supplementation with Pycnogenol.

In an randomized double-blind, placebo-controlled trial, researchers found that Pycnogenol supplementation improved allergic rhinitis symptoms from birch and other pollen allergy when the supplementation started at least five weeks before the pollen season ⁶¹. Eye symptoms decreased by 35% and nasal symptoms by 20.5% compared to placebo ⁶¹. The number of patients requiring rescue antihistamines was 26% lower in the Pycnogenol group than in the placebo group ⁶¹.

Women’s health

Investigating the efficacy of Pycnogenol on the health of women, two randomized double-blind, placebo-controlled studies on menopausal symptoms ²⁵, ⁵⁹ and one on menstrual discomfort ⁶⁰ have been performed.

An randomized double-blind, placebo-controlled study with 155 peri-menopausal women found the menopause symptoms assessed by the Women’s Health Questionnaire (WHQ) to be significantly improved after six month of Pycnogenol supplementation, as compared to placebo controls ²⁵. The symptoms on the WHQ include somatic (tiredness, headache) and vasomotor problems (hot flashes, sweating), depressed mood, memory and concentration issues, attractiveness, anxiety, sexual behavior (including vaginal dryness), sleep, and menstrual problems. After one month, all symptoms of the Pycnogenol supplemented subjects were significantly improved compared to enrollment and most items significantly compared to placebo ²⁵. In the placebo group, several symptoms also improved significantly compared to baseline after one month; however, after six months, only memory/concentration remained significantly increased compared to baseline. Interestingly, systolic and diastolic blood pressure, as well as LDL-cholesterol levels were found to be significantly reduced after 6 months of Pycnogenol supplementation, compared to placebo ²⁵. The increase of total antioxidant status, measured as Trolox equivalent antioxidant capacity, after Pycnogenol intake was highly significant compared to baseline and placebo. From these results, the authors attributed a positive, protective role to Pycnogenol on the vascular health of peri-menopausal women, which also “clearly reduced the frequency as well as the severity of climacteric symptoms” ²⁵.

Significant efficacy of a low dosage of Pycnogenol (60 mg daily) on menopause symptoms could be shown in an randomized double-blind, placebo-controlled investigation with 170 women ⁵⁹. In this study, the total menopause symptom score of the women was reduced by 17% compared to placebo control after three months ⁵⁹. Vasomotor symptoms (hot flashes), sleep problems and fatigue were significantly improved in the Pycnogenol group compared to placebo ⁵⁹. After 3 months, no significant effects on blood pressure or cholesterol levels were detected but positive trends were observed. In this study, blood plasma levels of different sexual hormones were investigated as well. Interestingly, after Pycnogenol intake, none of the hormone levels showed significant changes compared to baseline or placebo, suggesting non-hormonal mechanisms of Pycnogenol on menopause symptoms ⁵⁹.

The results from these studies demonstrated interesting efficacy of Pycnogenol supplementation in addressing various menopause symptoms. The underlying mechanism has not been investigated fully yet, however, Pycnogenol’s validated effects on blood circulation and endothelial health are good explanations for its beneficial effects on symptoms like hot flashes and sexual behavior ²¹.

An randomized double-blind, placebo-controlled multicenter study from 2008 showed that Pycnogenol supplementation significantly reduced abdominal discomfort in women with menstrual cramps (dysmenorrhea) ⁶⁰. The women took Pycnogenol for two menstrual cycles, during which they needed significantly less analgesic medication than in the registration period of two months before supplementation (−46%) and less than placebo controls (−28%) ⁶⁰. Interestingly, after discontinuing Pycnogenol and placebo intake in the fifth cycle of the study, subjects of the Pycnogenol group reported a continuation of the trend, as their need for analgesics was even more reduced (−50% compared to baseline), while women of the placebo group experienced a rapid return to analgesics ⁶⁰. The number of days on which analgesics were required was significantly reduced with Pycnogenol from 2.1 to 1.3 days and changed less in the placebo group, from 1.9 to 1.7 days.

Inflammatory processes were found to be a key mechanism in menstrual cramps (dysmenorrhea) ¹²³. During menstruation, the tissue lining of the uterine cavity is replaced, leading to wound healing and inflammation. Pycnogenol was shown to have potent anti-inflammatory activities in several studies ²⁸, ²⁹, ³⁰, ³¹.

Sports endurance and performance

In four randomized double-blind, placebo-controlled investigations, Pycnogenol supplementation was shown to enhance sport endurance and performance ⁶⁸, ⁶⁶, ⁶⁵, ⁶⁷.

An randomized double-blind, placebo-controlled crossover study found that the endurance time of a group of recreational athletes was significantly increased after Pycnogenol supplementation ⁶⁸. For the measurements, the subjects performed on a treadmill with individual setting adjusted to 85% of a person’s maximal oxygen consumption. The 20 to 35 years old participants received 200 mg Pycnogenol per day or placebo for 30 days, then switched to the other group for another 30 days ⁶⁸. Endurance was evaluated by measuring the running time in seconds on the treadmill after 30 and after 60 days. The composite performance time of the Pycnogenol groups increased significantly by 23.2% compared to baseline and by 7.1% compared to placebo. The time of placebo subjects was increased by 15% compared to baseline ⁶⁸.

A small randomized double-blind, placebo-controlled study with nine trained 25 to 45 year old cyclists examined the effects of a single dose of a fitness drink with Pycnogenol as the only active ingredient on performance ⁶⁶. The placebo drink consisted of the same ingredients (pineapple pulp, molasses, sodium chloride, flavor, steviol glycosides, sodium benzoate, potassium sorbate), except Pycnogenol. The study protocol included two separate sets of training of five minute cycling at 50% peak power output, eight minute at 70% peak power output and cycling until fatigue at 95% peak power output. The Pycnogenol or placebo drink was consumed four hours before the training. On average, the Pycnogenol supplemented cyclists rode 80 seconds longer until they reached exhaustion compared to subjects, taking a placebo drink ⁶⁶. In addition, considerable evidence was given for positive effects of Pycnogenol intake on performance related variables like the rating of perceived exertion, heart rate and blood lactate concentration at 70% peak power output ⁶⁶.

In a similar randomized double-blind, placebo-controlled study, 15 resistance trained subjects in their twenties took a single dose of the same fitness drink, containing Pycnogenol as the active ingredient ⁶⁵. The participants consumed the placebo or Pycnogenol drink four hours prior to a lower limb hypertrophic resistance training, consisting of six sets of 70% of the individual’s repetition maximum of back squats ⁶⁵. This exercise was repeated at a second visit. The researchers found improved muscle contractile performance after the Pycnogenol drink supplementation during resistance training compared to a placebo drink. Accumulated power output after Pycnogenol intake was significantly higher by 4% compared to placebo controls. Over the course of the six sets, power and velocity during the resistance training sessions was stable after Pycnogenol intake but was reduced significantly with each set in the placebo group ⁶⁵.

Another randomized double-blind, placebo-controlled study with six trained and seven untrained subjects investigated NAD+/NADH levels after continuous progressive exercise and after having taken the fitness drink with Pycnogenol or placebo ⁶⁷. The training setup was comparable to the cycling training in the study of Bentley et al. ⁶⁶. The physical work capacity until fatigue was increased by 17% in the Pycnogenol® group compared to placebo. In addition, serum NAD+ levels were increased significantly with the Pycnogenol drink compared to placebo drink in trained and untrained subjects ⁶⁷.

These results confirm the antioxidant properties of Pycnogenol and its protection against the high post-exercise oxidative stress ²¹.

There are several underlying mechanisms of Pycnogenol to explain these effects. During exercise, heart rate, blood flow and ventilation rapidly accelerate, and to do so, the cardio-pulmonary system adjusts to allow more nutrients, energy and oxygen to muscle tissues and avoid anaerobic build-up of lactic acid ²¹. Sufficient muscle oxygenation is facilitated by relaxed blood vessels and improved blood flow, which warrants aerobic energy generation. This increase in oxygen supply translates into acute oxidative stress due to higher production of free radicals in blood and muscles ¹²⁴. Pycnogenol was shown to have potent antioxidant efficacy and protects lipids, DNA and proteins from oxidation within the body in addition to its ability to increase blood antioxidant capacity ²¹.

Another property of Pycnogenol explaining its effect of increased performance is the improved tissue perfusion by enhancing microcirculation ⁴³ and its effects on endothelial function ³⁷, ³⁶, ³⁵, ³⁴, ³³, ³², ²² contributing to improved blood flow by relaxing blood vessels.

Pycnogenol dosage

Typically, preparations of Pycnogenol are orally ingested in form of capsules or tablets. Pycnogenol can also be added to drinking solutions ¹²⁵. Furthermore, a skin application has been explored ¹²⁶. Daily Pycnogenol oral doses of 30–360 mg have been investigated in clinical studies ¹²⁷.

The following doses have been studied in scientific research:

Adults

By mouth:

• Allergies: 50 mg of a standardized maritime pine bark extract has been used twice daily starting 5 weeks before allergy season.
• Asthma: 1 mg of a standardized maritime pine bark extract per pound of body weight, up to a maximum of 200 mg/day, has been given in two divided doses for one month. Also, 50 mg of the same extract has been used twice daily for 6 months.
• Athletic performance: 100-200 mg a standardized maritime pine bark extract has been used daily for 1-2 months.
• Circulation problems: 45-360 mg of a standardized maritime pine bark extract has been taken daily in up to three divided doses for 3-12 weeks.
• Improving mental function: 150 mg of a standardized maritime pine bark extract has been used daily for 3 months.
• Diseases of the retina in the eye: 50 mg of a standardized maritime pine bark extract has been used three times daily for 2 months.
• Photoaged skin: 40 to 100 mg/day pine bark extract (Flavangenol®) for 12 up to 24 weeks

Children

By mouth:

• Asthma: 1 mg of a standardized maritime pine bark extract per pound of body weight has been taken in two divided doses for 3 months by children and adolescents aged 6-18 years.

Pycnogenol side effects

Pycnogenol is possibly safe when taken by mouth in doses of 50 mg to 450 mg daily for up to one year, and when applied to the skin as a cream for up to 7 days or as a powder for up to 6 weeks. Pycnogenol may can cause dizziness, stomach problems, headache, mouth sores, and bad breath.

Based on data from 70 human clinical studies on 5723 healthy subjects and patients, the overall frequency of adverse side effects due to Pycnogenol is very low (1.8%) and unrelated to dose or duration of use ¹. The majority of adverse effects observed are mild. Gastrointestinal discomfort, the most frequently occurring adverse effect, may be avoided by taking Pycnogenol with or after meals. In children with ADHD, 2 of 41 Pycnogenol-supplemented participants experienced side effects (rise of slowness and moderate gastric discomfort). Pycnogenol did not cause any significant changes in blood pressure or heart rate in four clinical studies (total n = 185). There have been no reports of serious adverse effects since its introduction into the European market around 1970 ¹²⁸. Safety trials have demonstrated the absence of mutagenic and teratogenic effects, no perinatal toxicity and no negative effects on fertility ¹²⁹. Therefore, the use of Pycnogenol in children is considered to be safe ¹.

Special precautions and warnings

Pregnancy and breast-feeding: Early research suggests that a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) is possibly safe when used in late pregnancy. However, until more is known, it should be used cautiously or avoided by women who are pregnant.

There is not enough reliable information about the safety of taking maritime pine products if you are breast-feeding. Stay on the safe side and avoid use.

Children: A standardized extract of maritime pine bark (Pycnogenol, Horphag Research) is possibly safe when taken by mouth, short-term.

“Auto-immune diseases” such as multiple sclerosis (MS), lupus (systemic lupus erythematosus, SLE), rheumatoid arthritis (RA), or other conditions: Maritime pine might cause the immune system to become more active, and this could increase the symptoms of auto-immune diseases. If you have one of these conditions, it’s best to avoid using maritime pine..

Bleeding conditions: In theory, high doses of maritime pine might increase the risk of bleeding in people with bleeding conditions.

Diabetes: In theory, high doses of maritime pine might decrease blood sugar too much in people with diabetes.

Hepatitis: In theory, taking maritime pine might worsen liver function in people with hepatitis.

Surgery: Maritime pine might slow blood clotting and reduce blood sugar. There is some concern that it might cause blood sugar to go too low and increase the chance of bleeding during and after surgery. Stop using maritime pine at least 2 weeks before a scheduled surgery.

Interactions with medications

Moderate

Be cautious with this combination.

Medications for diabetes (Antidiabetes drugs)

Maritime pine might decrease blood sugar levels. Diabetes medications are also used to lower blood sugar. Taking maritime pine along with diabetes medications might cause your blood sugar to be too low. Monitor your blood sugar closely. The dose of your diabetes medication might need to be changed.

Some medications used for diabetes include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), and others. The mechanism of action is unclear.

Medications that decrease the immune system (Immunosuppressants)

Maritime pine seems to increase the immune system. By increasing the immune system, maritime pine might decrease the effectiveness of medications that decrease the immune system.

Some medications that decrease the immune system include azathioprine (Imuran), basiliximab (Simulect), cyclosporine (Neoral, Sandimmune), daclizumab (Zenapax), muromonab-CD3 (OKT3, Orthoclone OKT3), mycophenolate (CellCept), tacrolimus (FK506, Prograf), sirolimus (Rapamune), prednisone (Deltasone, Orasone), corticosteroids (glucocorticoids), and others.

Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs)

Maritime pine might slow blood clotting. Taking maritime pine along with medications that also slow clotting might increase the chances of bruising and bleeding.

Some medications that slow blood clotting include aspirin, clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), warfarin (Coumadin), and others.

Interactions with herbs and supplements

Herbs and supplements that might lower blood sugar

Maritime pine might lower blood glucose levels. Using it with other herbs or supplements that have the same effect might cause blood sugar levels to drop too low. Some herbs and supplements that can lower blood sugar include alpha-lipoic acid, chromium, devil’s claw, fenugreek, garlic, guar gum, horse chestnut, Panax ginseng, psyllium, Siberian ginseng, and others.

Herbs and supplements that might slow blood clotting

Using maritime pine along with herbs that can slow blood clotting could increase the risk of bleeding in some people. These herbs include angelica, clove, danshen, garlic, ginger, ginkgo, Panax ginseng, and others.

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