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
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 signaling (commonly associated with disease states), pycnogenol suppresses the increase in NO.
This attenuation has also been seen in chondrocytes stimulated with urate.[22]
2.2. Serum
One study evaluated the pharmacokinetics of pine bark extract in 11 healthy volunteers. In response to a single dose of 300 mg of the catechin, caffeic acid, ferrulic acid, and taxifolin as well as 10 unknown compounds were identified in the plasma. Most components of the extract were rapidly absorbed and remained detectable for the duration of the 14 hour monitoring period.[4]
Specificaly, catechin is detected in serum at 60 ng/mL 30 minutes after ingestion, trended upwards to approximately 100 ng/mL (370 nmol/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 through the 14 hour monitoring period.[4] Interestingly, an extract dose of 200 mg for five days (chosen to achieve steady-state concentrations of bioactive compounds) resulted in serum Taxifolin levels below the detectable limit.This suggested that certain clearance mechanisms were upregulated with the longer-term (5 day) taxifolin exposure.[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]
Overall, metabolites in Pycnogenol undergoe relatively fast absorption in the plasma and tend to remain elevated for 14+ hours. There are some distict differences in the pharmacokinetics of individual metabolites, however.
2.3. Cellular Kinetics
The metabolite known as M1 is taken up by immune cells (macrophages and monocytes) as well as endothelial 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] The anti-inflammatory effects of M1 in monocytes/macrophages have been well-characterized, however the potential anti-inflammatory effects of M1 on endothelial cells (cells that line blood vessels) has not been described. Accumulation of pycnogenol-derived M1 in the endothelium could potentially promote cardiovascular health, with possible implications for those with cardiovascular diseases such as atherosclerosis (see below).
Low doses of the pycnogenol-derived metabolite M1 have been shown to accumulate in various types of cells, which may result in a substantial anti-inflammatory effect with extended low-dose exposure. These results were derived in vitro (in cultured cells), however, so more research is needed to determine whether the mechanism is also relevant in humans/ with supplementation.
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 cardiomyopathy that occurred with diabetes as well as failing to improve QT interval (a biomarker of heart function).[25]
3.2. Blood Flow and Vasorelaxation
In persons with Coronary Artery Disease (CAD), 200 mg 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 100 mg Pycnogenol daily for 8 weeks as well in hypertensive persons,[16] and in healthy persons at 2 weeks of 180 mg has been shown to increase acetylcholine-induced blood vessel relaxation.[15]
Oral administration of reasonable doses of pycnogenol reliably increases blood flow in people independent of disease state. These effects may be independent of any change in blood pressure.
3.3. Blood Pressure
A double-blind, placebo controlled cross-over study with hypertensive patients found that oral supplementation with pycnogenol (200 mg/day) reduced systolic blood pressure from hypertensive (140-159 mmHG) to normal levels, although the reduction in diastolic blood pressure wasn't statistically significant.[27]
Although this study was relatively small in sample size (7 men and 4 women participated in the study), other human trials have found that pycnogenol has similar modest blood pressure lowering effects.
A larger double-blind, placebo controlled study of 58 patients with hypertension evaluated the ability of pycnogenol (100 mg/ day over 12 weeks) to reduce the required dose of the anti-hypertensive medication nifedipine. The study found that subjects in the pycnogenol group were able to reduce the mean dose of nifedipine required to restore blood pressure levels to normal values. While the placebo group required on average 21.5 mg of nifedipine to remain normotensive, the pycnogenol group required only 15 mg, a reduction of 6.5 mg overall.[16]
The reduced need for medication in the pycnogenol group correlated with significantly decreased endothelin-1 levels (a protein that causes vasoconstriction) as well as increased 6-ketoprostaglandin F1, a metabolite of prostacyclin, a potent vasodilator.[16]
Another study examining the effects of pynogenol on cardiovascular risk factors in patients with type 2 diabetes also found a modest blood-pressure lowering effect. In this double-blind, placebo controlled study 45 patients on ACE inhibitor therapy received either 125 mg pycnogenol or a placebo daily for 12 weeks. Pycnogenol supplementation improved blood pressure in 58.3% of the subjects at the end of the 12 week trial, with a 50% reduction in the required dose of ACE-inhibitors.[28] Most of the effects required two months of supplementation to manifest and were maintained through the end of the 3 month trial. The improvement in blood pressure (as assessed by reduced required dosage of ACE inhibitors to control blood pressure) was associated with decreased endothelin-1 levels. Overall, pycnogenol reduced antihypertensive medication, improved cardiovascular disease factors, and improved markers for diabetic control in this study.[28]
Although pycnogenol has shown promise as a blood pressure lowering agent in some study populations, other studies have reported mixed results. In a double-blind placebo controlled cross-over study of 23 patients with coronary artery disease, 200 mg pycnogenol daily for 8 weeks was not associated with an improvement in blood pressure, although it did improve blood flow via beneficial effects on endothelial function. The improvement in endothelial function was attributed to the ability of pycnogenol to reduce oxidative stress.[26]
Pycnogenol has been shown to have a blood-pressure lowering effect in some patients with hypertension. The results occur through multiple mechanisms, and seem to be dependent on the specific underlying pathology, since mixed results have been reported. Where pycnogenol has been shown to improve blood pressure in hypertensive patients, the effects have been modest. The supplement typically reduces the required dosage of antihypertensive medications with concurrent supplementation, but does not eliminate their need altogether.
Studies on the effects of pycnogenol treatement in animal models for hypertension are similar to the effects noted in humans, in that there are mixed results, likely depending on the underlying pathology of the experimenal model.
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.[29] These were attributed to its anti-oxidative properties, and were of comparable potency to Melatonin supplementation (10mg/kg).[29] This was later thought to be due specifically to a reduction of myeloperoxidase.[30]
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.[31]
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.[32] This study noted statistical significance when accounting for all subjects, but only observed benefits in 66% of enrolled subjects.[32] 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.[33] ]
The above 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)[32] despite previous in vitro evidence suggesting that Pycnogenol could reduce LDL oxidaiton.[34]
Consistent with the aforementioned studies, a double-blind, placebo controlled trial of patients with type 2 diabetes found that pycnogenol at 125 mg/day also reduced LDL levels by on average 12.7 mg/dL. [35]
Pycnogenolhas a consistent LDL cholesterol-lowering effect across several trials with different subjects.
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.[36] 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.[36]
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.[37] 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).[38]
One study in otherwise healthy students consuming Pycnogenol for 8 weeks reported an increase in attention.[39] When another study following a comparative design tested Pycnogenol against Methylphenidate (Ritalin), surprisingly both treatments failed to outperform placebo.[40]
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.[39]
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.[41]
5Inflammation 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),[42] both of which are thought to be mechanisms underlying joint health benefits as NF-kB augments other inflammatory signals[43] and MMP9 facilitates the movement of immune cells across membranes (so they can act locally).[44] Although the correlation between these two reductions was somewhat weak (0.6),[42] NF-kB is also known to regulate MMP9[45][46] and COX-2 enzymes,[47] 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).[48]
PGF2α has also been noted to be reduced by 23% (315ng/mL to 243ng/mL) following an acute dose of 200mg.[48]
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.[49] 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.[50]
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 Rhinitis
Allergic Rhinitis (stuffed nose in response to allergies) may be reduced by Pycnogenol. 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).[51] 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.[51] This may be due to Pycnogenol being able to inhibit IgE secretion from mast cells at high concentrations[52] 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.
5.4. Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a gastrointestinal disorder associated with cramping, abdominal pain, bloating and gas which may also present with diarrhea, constipation, or both. The symptoms tend to recur over time in affected individuals and the exact cause of the disease is unknown. Symptoms havce been linked to abnormal communication between the gut/brain that may affect digestion, sensitivity to certain foods, increased stress levels, and inflammation.[53][54]
Some of the common treatments for IBS include antispasmodics, which help to suppress some of the muscle spasms associated with bowel pain.[55][56]
Irritable Bowel Syndrome (IBS) is GI disorder associated with cramping, abdominal pain, bloating and gas. Common treatments include medications that relax intestinal smooth muscle tissue, which helps to relieve muscle spasms that cause cramping and discomfort.
Studies investigating the effects of pycnogenol on menstrual pain and ulterative cholitis indicated that the supplement may have a relaxing effect on smooth muscle tissue,[57][58] which suggested that it may also be useful in treating IBS.
To examine the efficacy of pycnogenol for treating IBS, 77 otherwise healthy subjects were divided into 3 groups in an open-label study design. Group 1 took 10 mg Buscopan, an antispadmodic, as needed. Group 2 took Antispasmina col forte, another antispasmod consisting of 50 mg papaverine hydrochloride+10 mg belladonna extract also when needed. The third group took pycnogenol at a dosage of 150 mg/ day for 3 weeks. Although the number of painful bowel attacks were similar in all groups after 4 weeks, mild pain and abdomen pressure was decreased in all the treatment groups. Improvement of pain symptoms was significantly greater relative to the other treatment groups, however, indicating that pycnogenol may be a useful as a treatment for IBS symptoms.[56]
An open label study suggested that pycnogenol may be a useful treatment for IBS. Although the strength of evidence is limited given that this type of study lacks a blinded approach or placebo-control, the results suggested that pycnogenol efficacy for IBS may be on par with some of the common pharmacological treatments.
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.[59] A suppression of the mRNA levels of fat accumulation genes (CEBP-α, PPAR-γ, aP2) was noted with 100-200mcg/mL.[59] G6PDH mRNA also responded to suppression by pycnogenol, and at 200ug/mL was completely abolished during adipogenesis.[59] Increases of superoxide dismutase as well as glutathione peroxidase were noted at 100-200mcg/mL.[59]
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,[60] and further studies in these same 3T3-L1 adipocytes noted that this was concentration-dependent between 3.75, 37.5, and 375mcg/mL.[61] 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.[61] Propanolol did not block the weaker effects at low concentrations,[61] which may have been mediated via HSL activation (has been noted with procyanidin compounds before).[62]
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.[63] 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.[63]
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.[64]
7Interactions with Oxidation
Mechanistically, Pycnogenol is able to sequester superoxide, hydroxyl, and free oxygen radicals.[65][66][67] It has also been implicated in protective effects against peroxide hydrogen and a reduction of lipid peroxidation in red blood cells[68] and has been implicated in reducing accumulation of oxidatively modified proteins.[69] In vitro studies suggest these general anti-oxidative effects extend to a reduction of lipid peroxidation,[70] and may be additive with CoQ10.[71]
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.[72]
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]
8Interactions 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.[73]
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.[74]
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.[75]
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).[28] 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%[74] and an average reduction in HbA1c from 8.02+/-1.04 to 7.37+/-1.09% (reduction of 0.65%).[74]
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]
9Interactions 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[76] and this was followed up by a larger study of 100mg twice daily alongside corticosteroids showed additive benefits in 55% of subjects.[77]
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.[78] After histological examination of the liver, the increase in cirrhosis and fibrosis seen in control was significantly reduced with pycnogenol.[78] Protective effects have also been noted with rats who were experimentally diabetic, thought to be secondary to anti-oxidative effects.[79]
One study in men with erectile dysfunction noted a lowering of liver enzymes AST and y-GTP, magnitude not disclosed.[75]
Mild hepatoprotective effects
10Interactions 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.[75] 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.[80]
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
11Interactions 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.[81] 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.[81] 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.[81] 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.[75]
Similar results have been found with a supplement called Prelox, which is Pine Bark Extract paired with L-Arginine Asparate;[80][82] 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
12Interactions 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.[83] 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.[83]
