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. 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 plasma ². Moreover, about 65–75 % of the Pycnogenol extract are procyanidins that consist of catechin and epicatechin subunits of varying chain lengths ³, besides taxifolin, catechin, and phenol acids ⁴. 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 ⁵. 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 ⁶. In other in vitro experiments using the whole extract a decrease of IL1B mRNA synthesis in RAW 264.7 cells was reported ⁷ as well as inhibitory effects on the expression of COX-2, IL-8 and iNOS in human chondrocytes and fibroblasts ⁸. 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 ⁹. 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 ⁹. In asthma patients symptom scores and circulating leukotrienes are reduced and lung function is improved ⁹. 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 ⁹. The ability to inhibit angiotensin-converting enzyme is associated with a mild antihypertensive effect ⁹. Pycnogenol relieves premenstrual symptoms, including abdominal pain and this action may be associated with the spasmolytic action of some phenolic acids ⁹. 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 ⁹.

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 ⁹. 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 ¹⁰. 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

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 ¹¹.

Pycnogenol is a patented, proprietary powder extract made exclusively from French maritime pine (Pinus pinaster Aiton) bark by Horphag Research (Geneva, Switzerland) ¹. 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 plasma ². Moreover, about 65–75 % of the Pycnogenol extract are procyanidins that consist of catechin and epicatechin subunits of varying chain lengths ³, besides taxifolin, catechin, and phenol acids ⁴. 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.

Pycnogenol benefits

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.

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 ¹².

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 ¹³. 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) ¹³.

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 ¹⁴.

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 ¹⁵.

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 ¹⁶. Furthermore, cartilage degrading proteolytic enzymes such as matrix metalloproteinases (MMPs) are liberated as MMP-1, MMP-2, and MMP-13 ¹⁷. 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 ¹³. 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 ¹⁸. 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 ¹⁵. 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% ¹⁹.

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 ²⁰, ²¹, ²².

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 ²¹. 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 ²³. 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 ²⁴. 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 ²⁴.

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 ²⁴.

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 ²⁴. 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 ²⁴.

Intake of Pycnogenol allowed patients to decrease intake of NSAID medication by 58% according to their diaries ²⁴. 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 ²⁵.

Table 1. Overview of 3 clinical trials demonstrating efficacy of pycnogenol for arthritis

	Belcaro et al.24	Cisar et al.23	Farid et al.21
	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 ²⁶]

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 ²⁷. 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) ²⁸. ADHD has also been hypothesized to be a hypersensitivity disorder, with a disrupted immune regulation contributing to its cause ²⁹; i.e. ADHD has comorbidity with both Th1- and Th2-mediated disorders and several related genes have immune functions ²⁹. Ceylan et al. ²⁷ 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 ²⁷.

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 ³⁰. 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 ³⁰. A recent review reports adverse effects, like insomnia and decreased appetite, in about 25% of patients using methylphenidate ³¹. Other therapeutic options are therefore warranted, at least for a subgroup of patients ³⁰.

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 ³². 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 ³³. Also the Pycnogenol dosage is based upon this previous clinical trial, using 1 mg/kg body weight ³⁴.

Pycnogenol effects on human skin

A number of studies provide compelling evidence that oral supplementation with Pycnogenol protects human skin against UV radiation. Accordingly, in a study on 21 fair-skinned volunteers, Saliou et al. ³⁵ 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 ³⁶. 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% ³⁷, 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 ³⁸. 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 ³⁹. As UVB- as well as polyaromatic hydrocarbon-mediated skin carcinogeneses both critically involve activation of the aryl hydrocarbon receptor ⁴⁰ and since flavonoids such as catechin and epicatechin, which are a main constituent of Pycnogenol, have been shown to inhibit aryl hydrocarbon receptor activation ⁴¹, it is tempting to speculate that oral ingestion of Pycnogenol may help to suppress environmentally induced aryl hydrocarbon receptor activation in skin cells.

Pine bark extract and photoaged facial skin

Furumura et al. ⁴² 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. ⁴² 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 ⁴³, 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. ⁴² study, so a less favorable outcome would be expected because of the exponential decline of intrinsic antioxidative potency in the elderly. Furumura et al. ⁴² 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 ⁴⁴.

In the skin, pine bark extract has been found to protect capillary walls ⁴⁵ and to inhibit matrix metalloproteinases ⁴⁶. 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 ⁴⁷. 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 ⁴⁸. 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 ⁴⁹. In fact, oligometric proanthocyanidins from grape seeds have previously been reported to improve melasma to a significant extent ⁵⁰.

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. ⁴² 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 ⁵¹.

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. ⁵² 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 ⁵². 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 ⁵³. 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 ⁵⁴. 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 ⁵⁵. 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 ⁵⁶. 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 ⁵⁷ and ambient air pollution including traffic-related particulate matter ⁵⁸.

Pycnogenol dosage

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 ⁵⁹. Safety trials have demonstrated the absence of mutagenic and teratogenic effects, no perinatal toxicity and no negative effects on fertility ⁶⁰. 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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