Pycnogenol

Pine Bark Extract; Pycnogenol is investigated for its general health and anti-diabetic properties and its ability to enhance Nitric Oxide, which appears to significantly help erectile dysfunction.

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Pycnogenol is a patented formulation of Pine Bark Extract which is standardized to 65-75% Procyanidin compounds by weight. Procyanidins are chain-like structures consisted of catechins similar to some found in green tea (the Green Tea Catechins that do not have 'gallate' in their names). Pycnogenol is similar to Grape Seed Extract and Cocoa Polyphenols as those are the three most common sources of Procyanidins.

Most of Pycnogenol's benefits appear to be catered towards blood flow (with the common mechanism being related to Nitric Oxide being increased) and towards blood glucose control. The former exerts cardioprotective effects and may help with erectile dysfunction, while the latter appears to be anti-diabetic mostly.

There are many human trials conducted on Pycnogenol, but a good deal of them have industry funding (which, although it does not appear to influence the results, should be noted) and surprisingly the breadth of the studies with Pycnogenol is met with a seeming lack of study replication. The one topic that appears to have been replicated numerous times is the topic of erectile dysfunction, but currently all studies are confounded with the inclusion of L-Arginine so the effects of Pycnogenol per se are still unknown.

It does appear to possess dual anti-oxidant and anti-inflammatory properties, with the latter being confirmed in humans and possibly being subject to a build-up effect over time. The low-dose buildup effect of Pycnogenol as antiinflammatory would make it useful in a multinutrient format, but it may not be the most potent antiinflammatory in isolation. The degree of measured antiinflammatory potential on COX enzymes (targets of Aspirin) are still lower than Aspirin itself.

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Also Known As

Pine Bark Extract, Pine Bark Procyanidins, Procyanidins


Do Not Confuse With

Grape Seed Extract (same molecules, different source)


Stacks Part Of increased usefulness


Caution Notice

Examine.com Medical Disclaimer

Although doses in the range of 40-60mg have been noted to be effective over a prolonged period of time, standard doses of Pycnogenol appear to be in the range of 100-200mg.

Studies have used twice daily dosing (dividing the daily total into two even doses to be taken with breakfast and dinner) as well as once daily dosing with breakfast, both appear effective and no comparative studies have been conducted to see which is better. Although it is usually recommended to be taken with meals out of prudency, this does not appear to be an absolute requirement.


The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Pycnogenol has in your body, and how strong these effects are.
GradeLevel of Evidence
ARobust research conducted with repeated double blind clinical trials
BMultiple studies where at least two are double-blind and placebo controlled
CSingle double blind study or multiple cohort studies
DUncontrolled or observational studies only
Level of Evidence
EffectChange
Magnitude of Effect Size
Scientific ConsensusComments
BBlood Flow

Notable

An improvement in nitric oxide dependent blood flow appears to occur following procyanidin supplementation which has been noted in both unhealthy persons as well as healthy... show

CBlood Pressure

Despite the improvement in blood flow, no significant alterations noted in resting blood pressure

CGeneral Oxidation

Minor

A reduction in general oxidation is noted following prolonged Pycnogenol supplementation

CInflammation

No significant influence on standard inflammatory cytokines

CHeart Rate

No significant alterations in heart rate noted

CC-Reactive Protein

No significant alterations in C-Reactive protein noted

CSymptoms of Menopause

Minor

A decrease in some symptoms of menopause has been noted with Pycnogenol supplementation

CSubjective Well-Being

Minor

An increase in well being and mood has been noted in students undergoing academic testing, which correlated with improved test scores

CCognition

Minor

An improvement in cognitive function has been noted in students during academic testing

CAttention

Minor

An improvement in attention has been noted, possibly secondary to improvements in general cognition, in students during prolonged academic testing

CSkin Elasticity

Minor

An improvement in skin elasticity has been noted with Pycnogenol supplementation

CSkin Quality

Minor

Oral supplementation of standard doses of procyanidins can improve skin quality in elderly women, other demographics not tested

CAsthma

Minor

A slight reduction in asthmatic symptoms has been noted with Pycnogenol supplementation

CLDL-C

Minor

May reduce LDL cholesterol for as long as pycnogenol is taken (some evidence to suggest a normalization after supplement cessation)

CLeg Swelling

Notable

Appears to reduce leg swelling secondary to the enhancement of blood flow. While the evidence is not overly robust, it is comparable if not better than the reference supplement... show

CNitric Oxide

Despite one study establishing the blood flow effects are dependent on nitric oxide, there do not appear to be any significant differences in nitric oxide quantities in saliva

CPain

Minor

A reduction in pain secondary to improvements in symptoms of osteoarthritis has been noted, and while notable in this certain instance it is not certain if there are inherenet... show

CSymptoms of Osteoarthritis

Notable

The preliminary evidence at this point in time (promising and independent, but limited) support the usage of pycnogenol in reducing all symptoms of osteoarthritis, reaching... show

CEndothelin-1
CHbA1c
CBlood Glucose
DErections

Minor

May be proerectile in persons with organic erectile dysfunction (due to poor blood flow)

DHDL-C

Minor

May increase HDL cholesterol, but has mixed evidence to support it and may be unreliable

DTriglycerides

No significant alterations on triglycerides

DTotal Cholesterol

Minor

Possible cholesterol lowering effects of small magnitude, but these are not wholly reliable

DChronic Venous Insufficiency

Notable

Appears to reduce symptoms of chronic venous insufficiency, and preliminary evidence suggests a greater potency than the reference supplement of Horse Chestnut

DnF-kB Activity

Minor

A decrease in nF-kB activity has been confirmed in humans given 200mg pycnogenol daily for five days, to the degree of around 15%

DInsulin
DInsulin Secretion

Studies Excluded from Consideration

  • Confounded with other components as a 'anti-oxidant' supplement[1]

Disagree? Join the Pycnogenol Discussion

Table of Contents:


Edit1. Source and Composition

1.1. Sources

Pyncogenol is a source of Procyanidin compounds derived from French Maritime Pine Bark (Pinus pinaster sp. Atlantica), similar to Cocoa Polyphenols and Grape Seed Extract; Procyanidins are chains of two catechin molecules, and vary in effects based on how they are structured.

Pycnogenol is a concentrated mixture of catechin polymers standardized to 65-75% by weight.[2]

1.2. Composition

Pycnogenol tends to contain:

  • Procyanidin compounds (65-75% if weight if standardized) comprised of catechin and epicatechin molecules[2] which include Procyanidin B1,[3] the Procyanidin of Grape Seed Extract
  • Caffeic acid (1.75mcg/mg; 0.2% by weight)[4]
  • Catechin (reference at 1.5%; range of 0.8-2.1%)[2]
  • Ferulic acid (3.25mcg/mg; 0.3% by weight)[4]
  • Taxifolin (14.35mcg/mg; 1.4% by weight)[4]
Per se, Pycnogenol consists of a series of catechin and flavanol chains known as procyanidins and contains a small amount of individual catechins. The actions conducted in the body after oral administration of Pycnogenol are a result of whatever the colon produces after Procyanidins reach the colonic bacteria

Procyanidin metabolite M1 (structurally known as δ-(3,4-dihydroxyphenyl)-γ-valerolactone).[5] This metabolite is found in the urine after consumption of Pycnogenol[6] and Green Tea[7] and appears to be generated by microbial fermantation in the colon. This generation of M1 uses catechins as a substrate, specifically (-)-epicatechin,[8] (+)-catechin,[9] and sometimes from procyanidins themselves (rather than lone catechins).[10][11] M1 itself is a potent anti-inflammatory and anti-oxidant,[12] and despite not being exclusive to Pycnogenol is sometimes seen as the main bioactive ingredient.

Alternatively, M2 (δ-(3-methoxy-4-hydroxyphenyl)-γ-valerolactone) is another bioactive that can be endogenously formed from Procyanidin consumption.[12] Both of these molecules are made from procyanidin chains of catechins, but their structure retains the bond between catechin molecules and the catechin molecule itself is partially metabolized; basic bond hydrolysis of procyanidins would not yeild M1 or M2.

The main ingredient of Pycnogenol does not inherently exist in the supplement, but is formed in vivo in the gut after ingestion of Pycnogenol containing foods or supplements


Edit2. Pharmacology

2.1. Mechanism

Pycnogenol is able to increase Nitric Oxide (NO) levels in serum, in part due to its anti-oxidant properties feasibly reducing conversion of NO to superoxide and prolonging its half-life[13] but also due to direct stimulation of the Nitric Oxide Synthase (NOS) enzyme.[14] In rat aortic rings (removed after death), Pycnogenol induced relaxation in a dose-dependent manner and was inhibited either when the endothelium was removed or when the NOS enzyme was inhibited, and the EC50 for epinephrine and NE-induced contraction were 2.73μg/ml and 3.54ug/mL respectively while maximal attenuations of E/NE-induced contractions reached 93% and 78.3% respectively.[14]

In otherwise young healthy men, 180mg Pycnogenol daily for 2 weeks appears to be associated with an augmentation of an acetylcholine-induced blood vessel relaxation via Nitric Oxide in vivo.[15] Additionally, at least in diabetics it has been found to trend towards an increase in Nitric Oxide levels at rest although it failed to be significant.[16]

Independent of any pro-inflammatory stimuli, Pycnogenol appears to increase endothelium relaxation; this has been noted in otherwise healthy men following 180mg Pycnogenol for 2 weeks, suggesting it is a valid mechanism

In response to inflammatory stimuli, incubating Pycnogenol metabolites (M1) in Macrophages inhibits Nitrite production (used as a biomarker for NO) in a dose-dependent manner with an IC50 value of 1.3ug/mL and suppressed iNOS expression with an IC50 of 3.8ug/mL. with near absolute suppression of NO at 50mcg/mL, although this dose reduced macrophage viability.[5] The potency of M1 in vitro was 20-fold more potent than hydrocortisone, which can partially be explained by direct NO scavenging by M1 (hydrocortisone does not have this ability).[5] The valerolactone structure per se appears to be anti-inflammatory, as benefits have been seen with green tea M4 and M6 to a similar degree of potency (at 20uM; 5mcg/mL).[17] The catechin molecule (chains of which make procyanidins) do not appear to have similar potency even at concentrations of 29-145mcg/mL.[18][19][20]

An attenuation of Nitric Oxide has been noted in rats with overactive Nitric Oxide signalling secondary to the state of Diabetes following standard (10mg/kg) oral dosing of Pycnogenol, suggesting the above mechanisms are biologically relevant.[21]

In response to excessive Nitric Oxide signalling (commonly associated with disease states), Pycnogenol appears to attenuate the increase in NO

This attenuation has also been seen in chondrocytes stimulated with urate.[22]

2.2. Serum

In response to a single dose of 300mg Pycnogenol:

Catechin is detected in serum at 60ng/mL 30 minutes after ingestion, trended upwards to approximately 100ng/mL (370nmol/L) at a Tmax of 4 hours; declining steadily thereafter but still detectable at 14 hours (end of study) although the degree of conjugation varied incredibly from 0% to approximately 100%.[4] These kinetics were mimicked by Caffeic Acid, but the concentrations were lower at all time points; although Caffeic acid was detected in serum as free Caffeic acid it was sometimes conjugated to sulfate or glucuronide groups (average conjugation was 69.4% of caffeic acid).[4][3]

Ferulic acid experienced its Tmax at a time period between 30-60 minutes post ingestion.[4] Ferulic acid is highly conjugated[4] around 60-80%[3] and may take up to 28-34 hours to be fully excreted.[23]

Taxifolin failed to be detected in plasma prior to 2 hours, but was detected with a maximal concentration at 8 hours which remained somewhat constant until 14 hours post ingestion.[4] Interestingly, dosing 200mg for five days results in serum Taxifolin levels below the detectable limit.[4] The authors attempted to see if the anaerobic colonic bacteria Clostridium orbiscindens (able to convert Taxifolin to 3,4-dihydroxyphenylacetic acid or phloroglucin[24]) played a role, but neither metabolite was noted in serum.

Two unknown compounds experience a spike in plasma 6 hours after ingestion, and are not detectable at 14 hours suggesting rapid elimination.[4]

Procyanidin metabolite M1 was detected in plasma 6 hours post ingestion, peaking at 10 hours and still detectable in plasma at 14 hours.[4] Repeated daily ingestion of 200mg Pycnogenol for 5 days results in a steady state concentration of approximately 3.01ng/mL for M1, a similar concentration achieved after a single dose;[4] M1 appears to be moderately conjugated by sulfate and glucuronide groups[4] to about 35% of serum concentration;[3] M2 was lower at 26.4% binding.[3]

Various metabolites or compounds in Pycnogenol appear to have varying entry levels into the blood

2.3. Cellular Kinetics

The metabolite known as M1 appears to be taken up into immune cells, where it may accumulate.[5] This is thought to explain how bioactivity is seen in immune cells when the serum concentration (100ng/mL or so) is lower than the required active concentration for immunological effects (10mcg/mL or so), and to explain any possible time-delay loading effects of Pycnogenol.[5]


Edit3. Cardiovascular Health

3.1. Cardiac Tissue

10, 20, or 50mg/kg Pycnogenol given orally to diabetic rats for 6 weeks (a dose able to reduce high blood sugar and high blood pressure) failed to reduce the increase in cardiac tissue size that occurred with diabetes as well as failing to aid the QT interval (biomarker of heart function).[25]

3.2. Blood Flow and Vasorelaxation

In persons with Coronary Artery Disease (CAD), 200mg Pycnogenol daily for 8 weeks in conjunction with standard therapy was associated with an improvement of blood flow by 32% (assessed by FMD) while no change occurred in placebo; these benefits were independent of changes in blood pressure.[26] This has been noted with an oral dose of 100mg Pycnogenol daily for 8 weeks as well in hypertensive persons,[16] and in healthy persons at 2 weeks of 180mg has been shown to increase acetylcholine-induced blood vessel relaxation.[15]

Appears to reliably increase blood flow in people independent of disease state following oral administration of reasonable doses of Pycnogenol; these effects may be independent of an increase or decrease in blood pressure

3.3. Blood Pressure

10, 20, and 50mg/kg oral Pycnogenol to diabteic rats for 6 weeks was unable to normalize systolic/diastolic blood pressure, with 10mg/kg trending to increase blood pressure nonsignificantly.[25]

In spontaneously hypertensive rats, Pycnogenol (10mg/kg) was able to slightly reduce systolic blood pressure but exerted protective effects on the endothelium; deemed mostly independent of changes in blood pressure.[27] These were attributed to its anti-oxidative properties, and were of comparable potency to Melatonin supplementation (10mg/kg).[27] This was later thought to be due specifically to a reduction of myeloperoxidase.[28]

3.4. Platelets and Viscosity

When tested in vitro with a concentration of acetylsalicyclic acid (ASA) that resulted in 25% inhibition of platelet aggregation, pycnogenol (10-100µg/mL) not only had inherent antiplatelet properties mostly via inhibiting ADP-dependent platelet aggregation but augmented the antiplatelet properties of ASA.[29]

May augment the effects of aspirin on reducing blood clotting

3.5. Cholesterol

One intervention in humans noted that 150mg Pycnogenol daily for 6 weeks failed to find alterations in total cholesterol or triglycerides, but a reduction of LDL-C (7%) and an increase of HDL-C (10.4%) was noted at weeks 3 and 6, which was of the same magnitude at both timepoints and returned to baseline 4 weeks after cessation of the supplement.[30] This study noted statistical significance when accounting for all subjects, but only observed benefits in 66% of enrolled subjects.[30] A higher dose (360mg) of Pycnogenol in persons with chronic venous insufficiency also noted a decrease in LDL-C (13%) and total cholesterol (19.7%) but not HDL-C.[31]

The aforementioned study also noted significant improvements in plasma ORAC and polyphenolic content (indicating higher antioxidant status) but did not notice a significant in susceptability of LDL to oxidation (only a trend towards significance)[30] despite previous in vitro evidence suggesting that Pycnogenol could reduce LDL oxidaiton.[32]


Edit4. Neurology

4.1. Cell Survival

One study using SH-SY5Y neuroblastoma cells noted increase cell survival at concentrations of 31.5-250ng/mL to 112-113% baseline.[33] This study also measured ATP concentrations, and noted while St.John's Wort (5mcg/mL) was able to increase ATP to 135+/-9% of control while Pycgenol was ineffective at modifying ATP concentrations.[33]

4.2. Attention

Pycnogenol, at 1mg/kg bodywright taken once daily in 61 children with confirmed ADHD for 4 weeks was associated with improvements in hyperactivity and attention when compared to both placebo and baseline (assessed by CAP rating scale); this effect was transient and the benefit returned to baseline 1 month after cessation of treatment, and assessment by CTRS or Parent assessment barely missed statistical significnace.[34] This was a replication of a previous pilot study showing greater benefits in children, but powered to a lesser degree.[35] Although the mechanism is unknown, one study noted that adrenaline concentrations in urine correlated with degree of symptoms of ADHD and that supplementation Pycnogenol at 1mg/kg bodyweight was able to decrease catecholamines in the urine (dopamine significantly, adrenaline and noradrenaline trended to significance).[36]

One study in otherwise healthy students consuming Pycnogenol for 8 weeks reported an increase in attention.[37] When another study following a comparative design tested Pycnogenol against Methylphenidate (Ritalin), surprisingly both treatments failed to outperform placebo.[38]

Some evidence that standard doses of Pycnogenol can aid in attention, but the degree of efficacy appears to be low and tends to border statistical significance at time

4.3. Cognition

In a study on otherwise healthy students, Pycnogenol for a period of 8 weeks was associated with reduced rate of test failures and increased, memory, executive functions and mood.[37]

4.4. Symptoms of Menopause

One study has reported an average 45.6% reduction in symptoms of menopause (when looking at the six most common ones; hot flushes, night sweats, mood swings, irregular periods, loss of libido and vaginal dryness) associated with 8 weeks of 100mg Pycnogenol supplementation, as assessed by rating questionnaires.[39]


Edit5. Inflammation and Immunology

5.1. Mechanisms

Pycnogenol has been noted to inhibit NF-kB activation following five days of 200mg supplementation (15.5% mean, 6-25% range) paired with a reduction in concentrations of MMP9 (25% baseline inhibition, a variable 4.6-39% inhibition of LPS-stimulated MMP9 secretion),[40] both of which are thought to be mechanisms underlying joint health benefits as NF-kB augments other inflammatory signals[41] and MMP9 facilitates the movement of immune cells across membranes (so they can act locally).[42] Although the correlation between these two reductions was somewhat weak (0.6),[40] NF-kB is also known to regulate MMP9[43][44] and COX-2 enzymes,[45] which are known to be suppressed with single acute dosing of 200mg pycnogenol by 16.5+/-35.3% (COX1 also suppressed by 13.8+/-18.1% but is indepednent of NF-kB).[46]

PGF has also been noted to be reduced by 23% (315ng/mL to 243ng/mL) following an acute dose of 200mg.[46]

Pycnogenol appears to inhibit NF-kB activity, and this has been confirmed in humans following the standard oral supplementation dosages of pycnogenol. It seems comparable or lesser than that of Japanese Knotweed

5.2. Joint Health

Supplementation of pycnogenol (50mg thrice daily) to persons with knee osteoarthritis was able to reduce symptoms of osteoarthritis when measured at 90 days. The symptom reduction and magnitude noted that pain (43%), stiffness (35%), physical function (52%), and composite WOMAC scores (49%) were all reduced beneficially by 90 days with all but stiffness having lesser benefit on day 60 and no parameter seeing benefit within 30 days.[47] A later study using a smaller dose (100mg once daily) for 90 days noted a 56% reduction in total symptoms as assessed by WOMAC and improved walking distance in a functional treadmill test.[48]

100-150mg of pycnogenol appears to be highly effective for the symptoms of osteoarthritis, but requires up to three months for maximal benefits

5.3. Allergic Rhinitus

Allergic Rhinitus (stuffed nose in response to allergies) may reduce allergic symptoms. One study conducted 5-8 weeks prior to seasonal allergies in a small group of persons with allergies noted that Immunoglobulin E (IgE) increased by 31.9% in placebo yet only 19.4% with Pycnogenol at 50mg and required less rescue medication (anti-histamines to be used when either placebo or Pycnogenol was not effective).[49] This positive study was conducted after a previous study (apparently unpublished by the same authors) that failed to find any difference in allergic symptoms (nose or eyes) or any difference in IgE when Pycnogenol was used at the start of the season.[49] This may be due to Pycnogenol being able to inhibit IgE secretion from mast cells at high concentrations[50] but possible being limited to building up over time (as has been noted in other studies[5], suggesting a build-up effect rather than acute relief.


Edit6. Fat Mass and Obesity

6.1. Mechanisms

Using 3T3-L1 adipocytes (mature fat cell line), Pycnogeol at 100mcg/mL suppressed the H2O2 increase in lipid accumulation into fat cells; this was secondary to antioxidative properties and Pycnogenol was significantly outperformed by 10mM N-AcetylCysteine.[51] A suppression of the mRNA levels of fat accumulation genes (CEBP-α, PPAR-γ, aP2) was noted with 100-200mcg/mL.[51] G6PDH mRNA also responded to suppression by pycnogenol, and at 200ug/mL was completely abolished during adipogenesis.[51] Increases of superoxide dismutase as well as glutathione peroxidase were noted at 100-200mcg/mL.[51]

Possibly anti-obesity effects via preventing an increase in fat accumulation that occurs during oxidant stress

Pycnogenol was previously found to possess direct lipolytic (fat loss) properties,[52] and further studies in these same 3T3-L1 adipocytes noted that this was concentration-dependent between 3.75, 37.5, and 375mcg/mL.[53] Since cAMP was acutely increased and propanolol blocked the effects, this was deemed to be secondary to the B-adrenergic receptor being activated at the higher concentrations.[53] Propanolol did not block the weaker effects at low concentrations,[53] which may have been mediated via HSL activation (has been noted with procyanidin compounds before).[54]

Possibly fat burning effects directly, but no indication of potency (possibly weak, given the concentrations used)

In this same cell line, Pycnogenol increased glucose uptake into fat cells in a dose dependent manner (with 200mcg/mL being as effective as 10nM insulin) via the PI3K/Akt pathway.[55] Oddly though, incubation with Wortmannin (inhibitor of PI3K, able to abolish the effects of insulin on glucose uptake) failed to reduce the effects of Pycnogenol at 300mcg/mL and p38MAPK (which activates GLUT4 vesicles) was actually suppressed by pycnogenol.[55]

May increase glucose uptake into fat cells, which is an anti-diabetic but possibly pro-obesogenic effect

6.2. Interventions

One study using a mouse line (TSOD) genetically prone to type II diabetes and obesity that was fed a Western Diet (to induce type II diabetes and obesity) were given either 3% or 5% Pine Bark Extract in the diet by weight and a slight attenuation of weight gain was noted despite no recorded reduction in food intake.[56]


Edit7. Interactions with Oxidation

Mechanistically, Pycnogenol is able to sequester superoxide, hydroxyl, and free oxygen radicals.[57][58][59] It has also been implicated in protective effects against peroxide hydrogen and a reduction of lipid peroxidation in red blood cells[60] and has been implicated in reducing accumulation of oxidatively modified proteins.[61] In vitro studies suggest these general anti-oxidative effects extend to a reduction of lipid peroxidation,[62] and may be additive with CoQ10.[63]

The reduction in protein carbonyl groups has been noted at 44 and 54% at the concentrations ot 5mcg/ml and 10mcg/mL, but failed to exert protective effects against thiol groups; this study also noted that Ginkgo biloba failed to protect against either.[64]

General anti-oxidative properties

200mg Pycnogenol in persons with Coronary Artery Disease is able to reduce levels of 15-F(2t)-Isoprostane (a biomarker of oxidation) by 7% after 8 weeks, suggesting a lowering of oxidation.[26]


Edit8. Interactions with Glucose Metabolism

8.1. Absorption

Pycnogenol appears to be effective in inhibiting alpha-glucosidase (a carbohydrate digestive enzyme) with an IC50 value of approximately 5mcg/mL, which was more effective than Green Tea Catechins and its efficacy was increased when looking at longer procyanidin chains.[65]

8.2. Insulin

A pilot study (open label) noted that supplementation of varying doses of pycnogenol (50-300mg) taken in an increasing dose over the course of 12 weeks was not associated with any alterations in basal insulin nor stimulated insulin secretion rates in type II diabetics, despite a reduction in HbA1c and blood glucose.[66]

8.3. Glycation

One study in men with erectile dysfunction noted a decrease in HbA1c after 8 weeks of 60mg pycnogenol supplementation (confounded with aspartic acid and L-Arginine), but the magnitude of decrease was not disclosed.[67]

A reduction in HbA1c seen in type II diabetics given 150mg pycnogenol for 12 weeks has been noted to reach 0.8%, outperforming placebo which reached only 0.1% and occurring alongside a reduction in blood glucose after eight weeks (maintaining until twelve weeks when the trial ended).[68] This built off a previous open-label study where pycnogenol in doses between 50-300mg (each dose for three weeks, increasing over the course of 12 weeks) noted dose-dependent benefits in reducing blood glucose between 50-200mg with no further benefit at 300mg and being in the range of 11-13%[66] and an average reduction in HbA1c from 8.02+/-1.04 to 7.37+/-1.09% (reduction of 0.65%).[66]

8.4. Type 1 Diabetes

In an animal model of Type 1 diabetes (STZ-induced) who recieved daily injections of 10mg/kg Pycnogenol for 4 weeks after induction of Type 1 Diabetes, Pycnogenol was able to attenuate changes in blood glucose, HbA1c, hepatic glycogen, and insulin in Diabetic rats with no influence on control rats.[21] These were credited to anti-inflammatory actions attenuating the toxin-induced damages to the liver and pancreas, which were confirmed by histoligical examination and reductions in inflammatory cytokines (TNF-a, IL-1b, NO).[21] This reduction of blood glucose in STZ-induced mice has ben seen after oral ingestion in a dose-dependent manner manner for fasting blood glucose from 10-50mg/kg reducing the expected rise in glucose by 13.8-49% (benefit seen with postprandial, but not dose dependent).[25]


Edit9. Interactions with Organ Systems

9.1. Lungs

In asthma patients assigned to 1mg/lb pycnogenol (maximum 200mg dosage) for four weeks in a crossover design, supplementation appears to significantly benefit asthmatic symptoms relative to placebo[69] and this was followed up by a larger study of 100mg twice daily alongside corticosteroids showed additive benefits in 55% of subjects.[70]

9.2. Liver

In a rat model of fatty liver (induced by a methione-choline deficient diet), 10mg/kg bodyweight Pycnogenol over a period of 5 weeks abolished the increase in serum triglycerides while attenuating the increase in liver fat and the expected increase of ALT, indicative of liver damage.[71] After histological examination of the liver, the increase in cirrhosis and fibrosis seen in control was significantly reduced with pycnogenol.[71] Protective effects have also been noted with rats who were experimentally diabetic, thought to be secondary to anti-oxidative effects.[72]

One study in men with erectile dysfunction noted a lowering of liver enzymes AST and y-GTP, magnitude not disclosed.[67]

Mild hepatoprotective effects


Edit10. Interactions with Hormones

10.1. Testosterone

One study in Japanese persons with mild to moderate erectile dysfunction using a combination supplement including Pycnogenol (60mg) noted a trend to increase testosterone that failed to reach statistical significance; this may have been influenced by the inclusion of L-Arginine (690mg) or the racemic mixture of Aspartic Acid (662mg) which contains a D-Aspartic Acid content.[67] Another study noted an increase in testosterone and reached statistical significance, but the increase (19%) was of low magnitude and in a population of 30-50 year olds with erectile dysfunction and baseline levels of testosterone at 15.9+/-2.3nmol/L which is comparatively low in the normal range.[73]

Any interactions with testosterone are weak and currently confounded with inclusion of L-Arginine in studies on sexuality; poor evidence for a testosterone boosting effect from Pycnogenol


Edit11. Interactions with Sexuality

11.1. Erectile Properties

One study has been conducted in men with confirmed organic erectile dysfunction where Pycnogenol at 40mg or 120mg was administered alongside L-Arginine (as 3g Arginyl Aspartate, a dipeptide, at 1.7g total Arginine), with Arginine alone for one month and then adding in Pycnogenol the second month to increase the dose at the third.[74] While only 5% of men (n=40) experienced a normal erection with Arginine, this number was increased to 80% with 40mg Pycnogenol and 92.5% with 120mg after the third month.[74] The self-reported duration of erections as well as the time taken to achieve erection were improved significantly both at the introduction of 40mg Pycnogenol (relative to Arginine) and when the Pycnogenol dose was increased.[74] Pycnogenol was later tested again with L-Argnine and Aspartic Acid (racemic mixture, not D-Aspartic Acid) at 60mg/690mg/552mg daily for 8 weeks in a blinded trial, and this study noted a higher improvement rate associated with the supplement (67% of supplement improved, 36% of placebo) according to scores on the International Index of Erectile Dysfunction (IIEF-5), but the only significant improvements over placebo were penis rigidity during erection and sexual pleasure during intercourse.[67]

Similar results have been found with a supplement called Prelox, which is Pine Bark Extract paired with L-Arginine Asparate;[73][75] most common results are an increased rigidity of the penis during attempted intercourse.

Remarkable results in the first pilot study that were greatly attenuated in effect size once a blinded trial was conducted; Pycnogenol may improve blood circulation and the PSI of erections, but all studies conducted are confounded with L-Arginine


Edit12. Interactions with Aesthetics

12.1. Skin

25mg thrice daily (75mg total) to postmenopausal women over a period of 12 weeks was associated with an increase in skin elasticity secondary to increased production of Hyaluronic Acid, and skin hydration.[76] The improvement in skin elasticity was noted at week 6 and throughout the trial period, whereas the improvement in skin hydration was noted at week 6 and was attenuated at week 12; women who had dry skin at baseline still had improvement, but there was no significant improvement in skin hydration in women without dry skin.[76]

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  3. Kurlbaum M, Högger P. Plasma protein binding of polyphenols from maritime pine bark extract (USP). J Pharm Biomed Anal. (2011)
  4. Grimm T, et al. Single and multiple dose pharmacokinetics of maritime pine bark extract (pycnogenol) after oral administration to healthy volunteers. BMC Clin Pharmacol. (2006)
  5. Uhlenhut K, Högger P. Facilitated cellular uptake and suppression of inducible nitric oxide synthase by a metabolite of maritime pine bark extract (Pycnogenol). Free Radic Biol Med. (2012)
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